Postoperative Nausea and Vomiting in Regional Anesthesia

Received from the Department of Anesthesiology, Orthopedic University Clinic Zurich/Balgrist, Zurich, Switzerland.ANESTHESIA has become remarkably safe, and while death and permanent damage have become rare occurrences, other sequelae of anesthesia are gaining more importance. Postoperative nausea and vomiting (PONV) still is the most troublesome adverse event encountered in the recovery room, despite advances in prevention and treatment. 1The incidence of PONV has remained high and has a major negative impact on patient satisfaction about the overall surgical experience. 2Furthermore, the ongoing trend toward ambulatory procedures has increased the focus on PONV as its occurrence may delay discharge 3or cause unanticipated hospital admission. 4General anesthesia has long been considered as causing a greater frequency and severity of PONV than regional anesthetic techniques. Recent studies investigating this time-honored dictum in a controlled manner mostly, but not unanimously, confirmed it. 5–8Accordingly, considerable effort has been invested to examine etiology, define patients at risk, and outline preventive and therapeutic strategies in patients undergoing general anesthesia. Reviews dealing with PONV have discussed almost exclusively general anesthesia and largely ignored regional anesthesia. 9,10This contrasts with the increasing popularity of regional anesthesia. A survey in Europe showed that one third of patients are undergoing regional anesthesia for their operative procedure. 11In France, the proportion of regional anesthesia increased from 15 to 25% of all anesthetics administered from 1980 to 1996. 12The number of local anesthetic and analgesic agents available for regional anesthesia has increased over the last two decades. Since the introduction of intrathecal and epidural morphine in 1979, a multitude of medications, such as synthetic opioids, α2-agonists, and cholinesterase inhibitors, have been introduced in an attempt to enhance the action of local anesthetics. The decision about their usefulness will not only rely on their effects on nerve blockade and pain relief, but also on their influence on side effects such as PONV.This review focuses on PONV in the setting of perioperative regional anesthesia. General aspects of PONV, such as physiology, patient, and perioperative factors involved are discussed. Few studies regarding these issues have been specifically devoted to regional anesthesia. Therefore, much information must be derived from investigations of general anesthesia. Specific regional anesthetic techniques and the influence of adjunctive medications on PONV are also presented. Combined general–regional anesthesia is purposefully excluded, avoiding the many variables introduced by general anesthesia. A final section is devoted to continuous peripheral nerve blocks and their possible impact on PONV.Patients often express fear about PONV when questioned before surgery. Its importance compared with other possible postoperative sequelae varies but is generally high. 13When questioned about issues of concern, 22% of 800 patients gave PONV the highest level of concern, compared with 34% for postoperative pain and 24% for waking up during surgery. 14The investigation of PONV has not proved to be an easy task. Outlines for adequate methodology have been published, 15but several aspects make generalization or comparison of results difficult.There is a wide array of patient, anesthetic, and surgical factors that influence incidence and severity of PONV. 9–10Methods of determining whether a patient suffers PONV vary. Patients may be asked repeatedly about nausea, or only complaints offered spontaneously may be registered. The occurrence of vomiting may be known from patient interrogation or derived from nurses’ notes, which have been shown to underreport emesis events by 50%. 16Some studies distinguish between nausea, retching, and vomiting, whereas others use a single term. The incidence may refer to the number of patients experiencing PONV or the number of events. The severity is either not differentiated or reported in categories (mild–severe), in visual analog scale scores or elaborate nausea scores, or implied by the need for antiemetic medications. Another source of confusion is the observation time. Intraoperative nausea and vomiting and PONV are sometimes not reported separately. The postoperative recording may end with the discharge of the patient from the postanesthetic care unit, the first analgesic administration after a regional anesthetic, or the passing of anywhere between 12 and 72 h after a defined “time zero.”Few studies are specifically designed to investigate PONV associated with regional anesthesia. Usually the main observation is centered on factors describing the block, such as intensity or duration. PONV, if reported at all, is only a secondary endpoint. This implies that the number of patients studied is tailored to the need to show statistical significance regarding the primary endpoint. When such studies report no difference in PONV rates between groups, the risk of a type II error should be kept in mind. 17One way to satisfy the need for high patient numbers is to conduct a multicenter study. But despite using strict protocols, marked variations in the rate of PONV across hospitals were found, which were not explained by the case mix of patients. 16Equally striking are the differences in results among countries reported in multinational investigations. 18Metaanalysis as another means to achieve larger numbers of patients is not only hampered by differences in study designs, but also by the high rate of double-reporting patients, estimated to occur up to 25% in some PONV studies. 19The same problem may also occur in a review article. 20.Several different mechanisms may play a role in causing PONV in patients who receive regional anesthesia. In a retrospective analysis, Crocker and Vandam 21found that hypotension (systolic blood pressure < 80 mmHg), a block higher than the fifth thoracic segment, and the anesthetic mixture (e.g. , addition of vasoconstrictors to the local anesthetic) increased the incidence of nausea and vomiting during spinal anesthesia. The prospective work of Carpenter et al. 22in a similar setting confirmed these findings. It appears that not one single mechanism is responsible for causing PONV. Several mechanisms may be active simultaneously, and the importance of each in a particular case may remain speculative.Nausea and vomiting are not among the cardinal signs and symptoms of toxicity of the currently used local anesthetics when infused systemically, although they may occur in the context of general cerebral toxicity. 23Consequently, they are usually not considered as emetogenic.The addition of other medications to local anesthetics for regional anesthesia has become increasingly popular. When administered intrathecally, hydrophilic substances (e.g. , morphine) tend to remain in the cerebrospinal fluid for prolonged periods of time and can move rostrally by diffusion or bulk movements of cerebrospinal fluid, reaching the area of the chemoreceptive trigger zone. Morphine concentrations in the medulla oblongata reach significant levels within 5–6 h, as evidenced by the onset of trigeminal analgesia. 24This time coincides with the peak time of nausea observed after spinal administration of morphine. 25Lipophilic opioids are taken up quickly into the spinal cord. Nonetheless, about 10% of a dose of fentanyl administered in the lumbal intrathecal space can be recovered in the cervical cerebrospinal fluid as early as 30 min after injection, demonstrating rapid ascension. 26Baricity of the solutions will influence drug kinetics in the cerebrospinal fluid. In fact, hyperbaric neostigmine was shown to cause lower PONV rates than an isobaric formulation, an effect attributed to decreased rostral spread. 27Epidural administration of drugs leads to rapid vascular uptake that provides access to the chemoreceptive trigger zone via the bloodstream. Peak plasma concentrations may be achieved within 5–15 min, 28and systemic concentrations often approach those obtained after a similar intramuscular dose.In the case of peripheral perineural administration, adjuvant drugs are absorbed into the systemic circulation, thereby reaching the chemoreceptive trigger zone. Centripetal intraneural transport of substances like opioids has been documented, 29but this mechanism is considered insignificant in drug distribution. 30Femoral perineural application or intramuscular administration of morphine leads to the same low morphine concentrations in cerebrospinal fluid. 31Hypotension is a common occurrence during neuraxial anesthesia. Low blood pressure may lead to brain stem ischemia, which is thought to activate the circulatory, respiratory, and vomiting centers grouped together in the medulla. 32Consequently, supplemental oxygen can relieve nausea in such circumstances. 33Other investigators have speculated that hypotension rather leads to gut ischemia and the release of emetogenic substances (e.g. , serotonin) from the intestines. 34These different hypotheses linking hypotension and PONV still need to be clarified and the mechanism linking hypotension to nausea and vomiting defined. 32,35Strategies avoiding hypotension were shown to be effective in reducing emesis. 36,37Many of these investigations were limited to patients undergoing cesarean section, and most used ephedrine as a pressor agent, which is suspected to possess antiemetic activity unrelated to its hemodynamic action. 38Neuraxial anesthesia also changes the function of the gastrointestinal tract. 39Sympathetic blockade by local anesthetics creates unopposed vagal action, resulting in gastrointestinal hyperactivity. The efficacy of vagolytic agents to relieve nausea during spinal anesthesia has been taken as evidence of the importance of this mechanism. 33Considerable effort has been invested to identify patients at increased risk of PONV. These studies often involve the use of elaborate statistics, and they vary in patient characteristics as well as surgical and anesthetic case mix. 16,22,40,41Unfortunately, because most do not analyze a regional anesthesia group separately, there is little information available on the influence of specific patient risk factors on PONV in the context of regional anesthesia.Younger age was shown to be a risk factor for PONV in the studies by Apfel et al. , 40Sinclair et al. , 41and Cohen et al. 16No significant correlation, however, was found by Larsson et al. 42or Koivuranta et al. 43Quinn et al. 44reported results of 3,850 inpatients and analyzed separately the 606 patients undergoing regional anesthesia. Younger age was significantly associated with nausea or vomiting in both general and regional anesthesia groups. Standl et al. 8interviewed 217 patients 4 days after spinal anesthesia for lower extremity orthopedic surgery. Patients younger than 20 yr complained most often of PONV (20%), while only 4% of patients between 40 and 60 yr of age did so. For patients older than 60 yr, the risk increased again to 9%. This increase at older age was also observed by Kalso 45in 50 cases of spinal anesthesia for orthopedic surgery, but older patients had more complex surgeries and more hypotensive episodes.In conclusion, the role of age remains unclear in view of these results in general as well as mixed and regional anesthetic groups. It might be safe to speculate, therefore, that any influence of age on PONV that exists in regional anesthesia patients may be limited, but the impact of the wake state—stress—needs to be clarified. Finally, awake patients would be more likely to respond to certain medications (e.g. , opioids) with nausea and vomiting.There is more consistency regarding the influence of gender. Female patients were found to be at significantly higher risk of PONV in the studies of Apfel et al. , 40Cohen et al. , 16Sinclair et al. , 41Larsson et al. , 42and Koivuranta et al. 43The latter also specified this relation for their regional anesthetic group, where they found PONV rates of 48% for females and 26% for males. The same results were found by Quinn et al. 44In the regional anesthesia group, they reported postoperative nausea in 28% of women and 14% of men, and vomiting in 17% and 7%, respectively. 44A relation of nausea and vomiting to the menstrual cycle was pointed out in an investigation of 68 women with epidural anesthesia for lower extremity surgery, with the peak incidence during days 25 to the end of cycle. 46These studies indicate that female gender is a significant risk factor for PONV in patients receiving general and regional anesthesia, while the influence of the menstrual cycle needs further study.Other factors, such as previous history of PONV or motion sickness, smoker–nonsmoker status, or obesity have not been sufficiently investigated in patients undergoing regional anesthesia.To summarize, patient factors linked to increased risks of PONV in patient undergoing general anesthesia need to be further clarified those undergoing in regional anesthesia.The role of premedication in regional anesthesia remains largely uninvestigated, and there is no information that any difference exists as compared with general anesthesia. Therefore, no conclusion can be drawn from the various premedication given, with the exception that opioids remain a risk.In addition to premedication, many patients receive intraoperative sedation to supplement regional anesthesia, to improve patient acceptability and comfort, and to reduce stress and anxiety. A wide variation exists in the frequency of use of sedation and the agents administered. 47While clonidine is considered not to influence the incidence of PONV, 48methohexital, 49γ-hydroxybutyrate, 50or etomidate 51have shown to cause significantly more nausea and vomiting compared with midazolam or propofol sedation, respectively. From these data, it is evident that the decision to administer adjunctive sedation must be followed by a careful evaluation of what agents to use, as the consequences of PONV might well be significant. The sedatives most often given to supplement regional anesthesia are midazolam and propofol. Both drugs may have a positive impact on PONV. Midazolam has been shown to be as effective as droperidol in preventing PONV after strabismus surgery in outpatient children. 52The same group found similar results after tonsillectomy in children. 53Propofol has been claimed to possess antiemetic effects at sedative doses, 54but these results were not confirmed by Lacroix et al. 55However, it is accepted that propofol should be part of the intraoperative management in a patient with PONV. 56The mechanism of action of any antiemetic effect of propofol has not been elucidated, but Cechetto et al. 57recently showed that propofol decreases the concentration of both serotonin and 5-hydroxyindoleacetic acid within the central nervous system of the fourth ventricle at the level of the area postrema. Although the positive effects of either midazolam or propofol on PONV has not been specifically studied in the context of regional anesthesia, these two drugs appear most appropriate to supplement a central or peripheral block. Propofol has the advantage of having better pharmacokinetic properties, 58making its titration easier than midazolam or other sedatives. 59Another factor that has been implicated in negative postoperative outcome is dehydration. The administration of extra fluid is standard practice, especially in neuraxial techniques, and the amount is usually titrated to blood pressure. Correspondingly, Carpenter et al. 22found no correlation between intraoperative amount of fluid administration and intraoperative nausea as long as no hypotension occurred during spinal anesthesia. Fluid administration for the purpose of blood pressure stabilization is rarely an issue in peripheral nerve blocks, but data regarding the impact of different regimens of hydration regimens on PONV are not available.The possible influence of postoperative pain management on PONV remains incompletely understood. While there is no doubt that opioid administration can provoke nausea, opioid analgesia relieved PONV in 80% of patients who experienced both pain and PONV concomitantly in the study by Andersen et al. 60Some investigators used analgesic regimens with nonopioid adjunctive medications. Opioid consumption was thereby reduced, but PONV rates did 61,62or did not 63,64diminish. Opioid reduction was 65,66or was not 67,68followed by reduced PONV rates during use of regional techniques. Opioid-free intraoperative and postoperative regimens are rare, but could provide insight into the complex issue of pain, pain medication, and PONV. Callesen et al. 69compared three groups of patients undergoing hysterectomy receiving either opioid-free epidural–spinal anesthesia, general anesthesia with continuous epidural bupivacaine, or continuous epidural bupivacaine and morphine, respectively. Despite poorer pain control, patients in the opioid-free group experienced significantly less PONV in the postoperative period. Similar findings were published by Wajima et al. 70In a series of investigations in patients undergoing arm surgery with brachial plexus anesthesia continued postoperatively by catheter infusion, the investigators observed that complete omission of opioids led to the lowest incidence of PONV despite more frequent need for nonopioid rescue pain medication, while the route of administration of opioids (systemically or by brachial plexus catheter) did not matter. Such findings would, contrary to the conclusions of Andersen et al. , 60lend support to the statement that it is opioid-based pain management rather than pain itself that provokes PONV. In this context, the application of continuous regional anesthesia and the subsequent opioid-sparing effect is most likely beneficial in reducing the incidence of PONV.The impact of other factors such as movement on PONV and oral intake have not yet been investigated in patients undergoing regional anesthesia.To summarize, operative and postoperative factors that have been identified as risk factors for PONV after general anesthesia have not been thoroughly investigated in the context of regional anesthesia and cannot be automatically extrapolated from one technique to the other. Further studies are warranted to specify the impact of these factors on PONV in the context of regional anesthesia.It is clear that PONV is a complex, multifactorial problem. To design and complete a study with sufficient size, controlling for all factors influencing PONV, represents a monumental task. Furthermore, the published studies differ in design in a way that makes comparison often difficult or impossible. 71Heterogeneity is a recognized weakness of systematic reviews and metaanalysis and may therefore weaken the impact of the results, particularly when dealing with regional anesthesia and PONV, since the latter has rarely been a primary endpoint.The reported incidence of PONV associated with spinal anesthesia varies widely. 22,72,73Carpenter et al. 22studied 952 patients undergoing all of found an intraoperative rate of nausea of and vomiting of 7%, but it must be that of their patients anesthesia. prospective studies reported postoperative and vomiting in nausea and vomiting in patients after spinal anesthesia. rates of have been in patients younger than high rates have been repeatedly observed in the context of major orthopedic , surgery and cesarean would indicate that the of local anesthetic used for intrathecal not influence PONV. investigations found no difference when local but the number of patients involved was usually the patients receiving in the study by Carpenter et al. significantly more nausea and vomiting than those given other local anesthetics despite similar of The investigators could not this A more study by et al. to for ambulatory surgery confirmed this as the incidence of PONV did not differ between groups. It therefore appears that the used is of little the dose of drug not to influence the occurrence of PONV, as long as hypotension is et al. bupivacaine in of or 20 to 60 patients undergoing of the with no difference in nausea between groups, while hypotension was with et al. no case of nausea or vomiting in 30 patients given either 25 or 30 bupivacaine, resulting in a block of and when blood pressure was with there was no difference in sequelae 60 80 of influence of the of the solutions has not been investigated in the context of PONV, but one has to that hyperbaric solutions usually have a greater addition of to local anesthetics more nausea and vomiting in the patients studied by Carpenter et al. occurred despite no difference in the rate of This would the of a retrospective from in which Crocker and Vandam associated intraoperative emesis with the use of but the investigators attributed the effect to a higher level of block. the use of and in significantly more PONV in 60 patients undergoing procedures when compared with did not differ between groups, but patients administered more investigations various solutions with or in different have found higher PONV rates in patients receiving no data indicate that may be a significant factor in PONV. The mechanism of the action in the of hemodynamic or block differences remains but systemic has been linked to increased serotonin release well as to effects on the chemoreceptive trigger zone by morphine a increase in vomiting in when dealing with patients undergoing surgery, the less Several studies investigated the efficacy and side effects of intrathecal morphine. Kalso over h, a but not significant difference in nausea or vomiting after or morphine to bupivacaine for orthopedic surgery 50 et al. PONV rates of 60 50 after and morphine, used in surgery. In a study patients for hysterectomy with spinal anesthesia, patients receiving morphine had significantly more sequelae than those administered between and et al. a investigation patients undergoing major orthopedic surgery of the lower bupivacaine to bupivacaine with morphine. was no significant difference between groups with to or consumption of These data at in more surgery where effective postoperative pain is intrathecal morphine is not associated with higher PONV rates than opioid-based systemic especially if a dose of less than is in surgical procedures has not been well but about significantly higher PONV incidence after intrathecal morphine for of the compared with a should early studies the for morphine to pain secondary to nausea and vomiting rates although morphine were usually high reduced dose of also significantly more nausea and vomiting than a epidural when were studied by et al. a investigation in however, et al. a with or morphine and found no difference in nausea or morphine was to local anesthetics to provide spinal anesthesia for cesarean section, an increase of nausea or vomiting was observed postoperatively but not is in with an investigation the peak incidence of nausea and vomiting between 4 and h after of surgery when intrathecal morphine was administered. the PONV rates were higher after larger or of morphine were administered compared with et al. a trend toward lower sequelae with of and morphine in a study A metaanalysis confirmed a increase in PONV when morphine is synthetic opioids, fentanyl and but analgesia than morphine when The administration of intrathecal fentanyl to by et al. not provoke of intrathecal fentanyl with opioid-free solutions in patients undergoing lower extremity procedures no difference in PONV incidence among groups. Several studies showed rather low rates of vomiting in the perioperative in patients receiving intrathecal fentanyl patients, although the were et al. a spinal anesthetic to patients of undergoing various surgical procedures and continued a mixture via the intrathecal route for days and of their patients complained of nausea or This contrasts with the PONV rate reported by et al. h of intrathecal fentanyl infusion, but almost all of their patients intramuscular studies the use of intrathecal fentanyl for of While et al. not a single occurrence of nausea and vomiting in administered up to 25 et al. up to in women and that this side effect was in all groups, for any to be studies in patients undergoing cesarean section have also shown that intrathecal fentanyl led to no greater frequency of nausea or vomiting than when local anesthetics were confirmed by investigators found lower rates of nausea or vomiting during surgery when using intrathecal 20 to bupivacaine proved more effective than 4 given after spinal beneficial effect of fentanyl was to of pain during intrathecal of has led to sequelae in study in patients for found no increase in PONV at the highest dose of 20 but the that patients administered lower significantly more propofol because of analgesia might have the comparison of to in a similar setting no increase in nausea or vomiting in patients receiving the comparison of fentanyl in patients after surgery a similar incidence of PONV. has popularity for intrathecal use in the of investigations different from to overall low for nausea and vomiting with no dose published study in women reported significantly higher rates of both nausea and vomiting, however, when a dose of was compared with the group for nausea and 15 for but most nausea was as compared with no difference in PONV was found with information has been published regarding use during cesarean et al. or with bupivacaine and found significantly less intraoperative vomiting compared with the was no difference compared with the group that fentanyl intrathecally, results of an report by et al. local anesthetic as well as opioid can therefore be administered or in with local anesthetics to provide operative spinal anesthesia. studies have shown no difference in vomiting or PONV when was compared with local