The risk of developing postoperative nausea and vomiting (PONV) is at least 30% in general surgery patients1 and is up to 80% in high-risk surgical patients.2 In the approximately 80 million outpatient and inpatient surgeries performed in the United States each year,3,4 PONV is a leading cause of unexpected admission to the hospital after outpatient surgery, contributing to unanticipated admission in 0.1% to 0.2%.5–8 Preventing PONV is reported to be economically beneficial.9 From the patient’s perspective, vomiting can be a worse experience than postoperative pain.10 Patients at the highest PONV risk include patients of female gender, nonsmokers, and those with a history of PONV or motion sickness.11,12
Previous investigations into the impact of IV fluid and dextrose administration on the incidence of PONV and the use of antiemetic medications have reported variable results. Some investigators have reported that IV fluid or dextrose administration in the perianesthetic period is associated with decreased PONV frequency or severity.12–16 Adequate hydration may contribute to prophylaxis and treatment of PONV17 and allow earlier discharge from recovery after elective surgery while decreasing overall health care cost and improving patient satisfaction. Additionally, an oral carbohydrate load before surgery was associated with less PONV, perhaps by decreasing postoperative catabolism and insulin resistance.18 However, there may be an optimal dose of dextrose to obtain this favorable outcome because larger amounts of supplementary IV dextrose do not prevent PONV after outpatient surgery and may increase PONV.19
We hypothesized that individual differences in blood glucose response, perhaps related to the timing of administration, may contribute to the inconsistent impact of IV dextrose on PONV. It is possible that glucose administration during emergence from anesthesia could impact the incidence of PONV. We sought to determine the relationship of IV dextrose administered in small amounts during emergence from anesthesia to PONV.
This prospective, double-blind randomized placebo-controlled trial was approved by the IRB of Loma Linda University and registered with ClinicalTrials.gov (NCT01123837). Written informed consent was obtained from ASA physical status I and II female patients, 18 to 65 years of age, scheduled for outpatient gynecologic, urologic, or breast surgery at Loma Linda University Medical Center. A history of PONV risk factors was recorded. Patients were excluded for severe hypertension, coagulopathy, significant hepatic or renal disease, diabetes mellitus, abnormal blood glucose on the morning of surgery, or withdrawal of consent. Patients were excluded from analysis for severe intraoperative hypotension requiring large volume intravascular fluid treatment or protocol violations including nitrous oxide administration.20
After consenting, patients were assigned by hospital pharmacists using a computerized randomization function to lactated Ringer’s solution (group P) or 5% dextrose in lactated Ringer’s solution (group D). The study fluid was delivered in opaque bags labeled “study fluid,” and infusion controlled by infusion pumps at 125 mL/h IV for 2 hours (250 mL) beginning with the start of surgical closure. This volume was chosen to provide small glucose supplements, and blood glucose increases after infusion. The anesthesia providers, surgeons, perioperative nurses, postanesthesia care unit (PACU) nurses, patients, and investigators were blinded to group assignment throughout.
Subjects received general anesthesia using propofol (2–2.5 mg/kg) for induction and sevoflurane in oxygen and air for maintenance. Anesthesia depth was maintained at moderate general anesthesia based on processed electroencephalogram (Patient State Index between 30 and 50; SEDLine©; Masimo, Irvine, CA). Intraoperative IV maintenance fluid was standardized at 3 mL/kg/h with additional IV crystalloid given as needed at the discretion of the anesthesia provider if arterial blood pressure decreased >20% from baseline. Prophylactic administration of 1 antiemetic medication was reported to decrease PONV from nearly 60% to approximately 35% with only small additional decreases in PONV from prophylactic administration of 2 or more antiemetics in a subset of patients who received volatile anesthetics in air.1 Thus to decrease the possibility that treatment effects of study fluid administration could be masked, no prophylactic antiemetics were given. We anticipated that 3 risk factors for PONV21 would be present in our patients (female, nonsmoker, postoperative opioids), with approximately 60% PONV risk.22 The increased PONV risk resulting from withholding antiemetic prophylaxis was discussed thoroughly with patients during informed consent, as was the usual antiemetic prophylaxis given. Patients were encouraged to seriously consider their risk for PONV and their desire to limit that risk by antiemetic prophylaxis. Additionally, patients were informed they could request prophylactic antiemetic treatment or withdraw consent at any time before anesthesia induction, with subsequent exclusion from the study but no negative impact on their perioperative care.
Blood glucose was measured using a point-of-care device (ACCU-CHEK©, Roche Pharmaceuticals, Basel, Switzerland) at presurgical preparation area baseline (using blood in the needle used for IV catheter placement), intraoperatively immediately before study fluid infusion (finger stick sample), and immediately after study fluid infusion by PACU nurses (finger stick sample).
The PACU nurses assessed and documented PONV using a Verbal Descriptive Scale,23 which correlates to visual analog nausea scores, with an objective measure of severity:
- 0 = no PONV: patient reports no nausea and has had no emesis episodes;
- 1 = mild PONV: patient reports nausea but declines antiemetic treatment;
- 2 = moderate PONV: patient reports nausea and accepts antiemetic treatment; and
- 3 = severe PONV: nausea with any emesis episode (retching or vomiting).
The score was obtained at 0, 30, 60, 90, and 120 minutes after PACU arrival; thus 5 scores were recorded during PACU stay. A 24-hour PONV assessment that elicited any nausea and emesis episode since PACU discharge was obtained by a blinded investigator by telephone or in person at the patient’s bedside. Initial antiemetic treatment was 4 mg IV ondansetron, with additional treatment at the discretion of the anesthesiologist caring for the patient. PONV severity was further assessed by comparing the number of antiemetic doses and drug classes given. Intraoperative and PACU pain medications and doses were recorded and converted to fentanyl equivalents (µg/kg/h) as few patients received opioids other than fentanyl for these scheduled outpatient procedures.
Sample size was calculated using the incidence of PONV within 2 hours after anesthesia (yes or no) assuming a 60% prevalence of PONV associated with the expected number of PONV risk factors. A sample size of 160 was needed to detect an absolute 20% decrease in PONV, with power of 0.8 and P = 0.05 considered significant.
The primary outcome measure was the intergroup difference in PONV incidence within 2 hours after surgery, expressed as mean and 95% confidence interval (CI) of the intergroup difference. Secondary outcome measures were intergroup differences of patient and perioperative characteristics; the occurrence and severity of PONV including emesis episodes and PONV scores, the number of doses and classes of antiemetic drugs needed to control PONV, and the incidence of delayed PONV (onset after 2 hours). Further secondary analysis was done to compare intraoperative and patient characteristics, including changes in blood glucose after study fluid infusion, in patients with or without PONV. Statistical analysis was performed using computerized software (JMP 10.0.0, SAS Institute, Cary, NC; Prism 6.0b, GraphPad Software, La Jolla, CA) with P < 0.05 considered significant. Continuous data were analyzed for normal distribution by the Shapiro–Wilk test with P < 0.05 indicating data was not normally distributed. Normally distributed data were analyzed using the t test. Data that were not normally distributed were analyzed using the Wilcoxon test, and differences between medians analyzed using the Hodges–Lehmann method as data were symmetrically distributed. Results of continuous data are shown as mean, 95% CI for normally distributed data and median, 95% CI if not normally distributed. Ordinal data were compared using Pearson χ2 or Fisher exact test when bivariate. The association between the sum of severity scores and the number of antiemetic medication doses given within 2 hours of anesthesia was assessed by Kendall τ and LOWESS (locally weighted scatterplot smoothing) regression. Intergroup differences in proportions were compared using the adjusted Wald test and expressed as mean and 95% CI of the intergroup difference.
We enrolled 202 patients between June 7 and December 29, 2010, of whom 18 did not receive the allocated intervention. As shown in Figure 1, this included 8 given prophylactic antiemetics before anesthesia and 5 who withdrew consent. The remaining 184 patients received the allocated intervention, of whom 22 were excluded from analysis, including 17 given nitrous oxide (group D n = 4; group P n = 13). Data from 162 patients with normal baseline blood glucose were analyzed. There were no significant intergroup differences in demographics, history of PONV or tobacco use, perioperative characteristics, or unplanned admission (Table 1).
PONV occurred during the first 2 hours after anesthesia in 81 of 162 (50%) patients, equally in group D (52.9%) and group P (46.7%; P = 0.53; difference, 6.2%; 95% CI, −9.2% to 21.6%). Emesis episodes within 2 hours after anesthesia occurred in 9 patients: 4 group D (4.6%) and 5 group P (6.7%; P = 0.73; difference, −2.1%; 95% CI, −9.3% to 5.1%).
There were no significant intergroup differences in time of onset of PONV, duration of PONV, or the number of antiemetic doses or drug classes given to control PONV (Table 2). PONV severity scores were not normally distributed but the data were symmetrical (Fig. 2), and analysis showed no significant intergroup differences in severity at any time the score was obtained (Table 1). The sum of PONV severity scores was associated with the number of antiemetic medication doses given within 2 hours of PACU arrival (Kendall τ = 0.88; 95% CI, 0.84–0.92; Fig. 3). More than 1 dose of antiemetic medication was used to treat PONV in 48 of 81 (59.3%) patients who developed PONV (intergroup difference, 5.5%; 95% CI, −13.5% to 14.6%), and >1 antiemetic drug class in 42 of 81 (51.9%; intergroup difference, 1.1%; 95% CI, −12.4% to 14.6%). Ten patients had unplanned admission (6.2%; intergroup difference, 1.6%; 95% CI, −5.8% to 8.9%). Six patients were admitted for pain control, and 1 was admitted for each of PONV, oxygen desaturation, dizziness, and ureteral obstruction. PONV was present >2 hours after PACU arrival in 9 group D (10.3%) patients and 13 group P (17.3%; P = 0.33) patients, including 4 patients (group D n = 1; group P n = 3) in whom the first episode of PONV was >2 hours after PACU arrival. In total, 47 group D (54.0%) patients and 38 group P (50.7%) patients experienced nausea or an emesis episode at some point during the 24 hours after surgery (intergroup difference, 3.4%; 95% CI, −12.1% to 18.8%). As expected, infusion of dextrose was associated with a larger increase in blood glucose after study fluid infusion (Table 3).
Secondary analysis of PONV regardless of study group revealed similarly increased PONV risk scores in those who had PONV within 2 hours after anesthesia compared with those who did not. PONV was neither correlated to demographic characteristics nor to history of PONV or smoking. Further comparisons of patients with and without PONV are shown in Table 4. Of interest, only 3 of 15 patients (20%) in whom surgery was <1 hour experienced PONV within 2 hours after anesthesia, compared with 45% when surgery duration was 1 to 2 hours and 57% when surgery duration was >2 hours. Eight of 81 patients who had PONV within 2 hours after anesthesia had unplanned admission, but only 1 admission was for PONV.
Fifty percent of patients experienced PONV during the 2 hours after surgery, somewhat less than predicted based on the average number of PONV risk factors present. Patients who received the small amount of IV glucose had higher blood glucose after study fluid infusion and larger increases in blood glucose between baseline and the end of the study fluid infusion, despite normal baseline blood glucose. Dextrose administration during emergence was not associated with any difference in either the time of onset or severity of PONV. The need for >1 dose or >1 drug class of antiemetic treatment was not affected by study fluid administration. Delayed onset (>120 minutes after anesthesia) PONV and emesis episodes were found equally in groups D and P. Thus, IV dextrose as administered was not associated with a difference exceeding 20% in the incidence of PONV or in the severity of PONV within 2 hours of anesthesia.
Our results are in contrast to those reported in 62 women undergoing outpatient gynecologic surgery.16 In that study, administration of IV dextrose in balanced salt solution after surgery was associated with similar nausea scores but fewer doses of antiemetic rescue administration compared with administration of plain balanced salt solution. Despite administration of antiemetic prophylaxis 30 minutes before surgery end to all their subjects, nausea occurred in 54.8% of their subjects (62.5% of control), similar to what we found without antiemetic prophylaxis. The amount and rate of IV dextrose administration was greater than our patients received, and no comparison was made between baseline and postinfusion blood glucose measurements. In a study of 120 ASA physical status I female patients who did not receive antiemetic prophylaxis,19 fewer patients developed PONV than we found: 29% in dextrose and 22% in control group patients. Those patients had shorter surgery (mean, 23 minutes) compared with ours (mean, 174 minutes) and received a larger amount of dextrose. While this makes direct comparison difficult, the PONV incidence they reported was similar to that found in our patients in whom surgery duration was ≤60 minutes. Furthermore, because intraoperative blood glucose levels were not reported, it is not possible to determine whether blood glucose changes were related to PONV in their patients.
The finding of larger blood glucose increases after study fluid administration in patients who developed PONV within 2 hours after anesthesia (Fig. 4) was interesting. This difference was found in the time corresponding to surgical closure, emergence and early PACU stay, not during the majority of surgical manipulation. Although more blood glucose samples would likely be necessary to establish this, the timing of blood glucose increase we found may indicate a stress response during emergence and early recovery. Blood glucose increases in response to surgical stress have been reported in both diabetic and nondiabetic patients to whom IV dextrose infusion was given during surgery in hopes of treating fasting hypoglycemia.24 While it is not clear whether blood glucose increases directly contributed to PONV, blood glucose increases may reduce gastric emptying and increase the sensation of gastric fullness, which could perpetuate a sensation of nausea.25 These relationships could be the focus of future study.
There are several limitations to our study. More P group patients were excluded from analysis for nitrous oxide administration protocol violation, but analysis including patients who received nitrous oxide did not alter results for the primary outcome of PONV difference between groups D and P or for the secondary outcome measures of PONV severity. Similarly, more group P patients were excluded for other protocol violations, but analysis including those patients did not alter results for the primary outcome or for secondary measures. Our sample size would need to be much larger (>2000 patients) to show statistical significance for the difference in PONV we found. Surgery type was not identical between groups. However, results of analysis in each subgroup of patients by surgery type for the primary outcome of PONV difference between groups D and P were the same as for all patients. Recovery room stay was not longer in patients with PONV, which may reflect nursing protocols rather than readiness for discharge, which we did not assess. We did not find more PONV in patients with a history of PONV, in contrast to the previously reported importance of patient history of PONV as a predictive factor.21 This may reflect the increased PONV risk from 3 PONV risk factors on average, potentially limiting the predictive power of additional risk factors.26 We found an apparent effect of increasing surgery length because patients who experienced PONV had longer surgery. Furthermore, PONV was less common in patients whose surgery was <1 hour duration compared with longer surgery. However, this study was not designed to investigate the combined interactions of surgery type and duration on analgesic requirements and PONV, which could be of interest for future investigations. It is unlikely that the lack of difference between groups was related to the type of fluid given, because the use of IV crystalloid or colloid was reported to have no impact on PONV.27
We sought to investigate the relationship of dextrose infusion during anesthesia emergence to PONV and did not find a positive or negative impact of dextrose as administered. Dextrose administration during emergence from and early recovery after anesthesia was not associated with differences in the frequency of PONV exceeding 20% or in the severity of PONV. The relationship of PONV to the optimal dose and timing of dextrose administration remains unclear and may warrant further study.
Name: Parul Patel, MD.
Contribution: This author was involved in study design, conduct of the study, data collection, data analysis, and manuscript preparation.
Attestation: Parul Patel, MD, approved the final manuscript and attests to the integrity of the original data and the analysis reported in this manuscript.
Name: Minhthy N. Meineke, MD.
Contribution: This author was involved in conduct of the study, data collection, data analysis, and manuscript preparation.
Attestation: Minhthy N. Meineke, MD, approved the final manuscript and attests to the integrity of the original data and the analysis reported in this manuscript.
Name: Thomas Rasmussen, MD.
Contribution: This author was involved in conduct of the study, data collection, and manuscript preparation.
Attestation: Thomas Rasmussen, MD, approved the final manuscript.
Name: Donald L. Anderson, MD.
Contribution: This author was involved in conduct of the study, data collection, and manuscript preparation.
Attestation: Donald L. Anderson, MD, approved the final manuscript.
Name: Jennifer Brown, MSN, CRNA.
Contribution: This author was involved in data collection and manuscript preparation.
Attestation: Jennifer Brown, CRNA, approved the final manuscript.
Name: Sam Siddighi, MD, MS.
Contribution: This author was involved in conduct of the study and manuscript preparation.
Attestation: Sam Siddighi, MD, MS, approved the final manuscript.
Name: Richard L. Applegate II, MD.
Contribution: This author was involved in study design, conduct of the study, data collection, data analysis, and manuscript preparation.
Attestation: Richard L. Applegate II, MD, approved the final manuscript, attests to the integrity of the original data and the analysis reported in this manuscript, and is the archival author.
This manuscript was handled by: Peter S. A. Glass, MB, ChB.
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