ISSN NUMBER: 1938-7172
Issue 6.12

Michael A. Fiedler, PhD, CRNA

Contributing Editors:
Penelope S Benedik, PhD, CRNA, RRT
Mary A Golinski, PhD, CRNA
Gerard Hogan Jr., DNSc, CRNA
Alfred E Lupien, PhD, CRNA, FAAN
Lisa Osborne, PhD, CRNA
Dennis Spence, PhD, CRNA
Cassy Taylor, DNP, DMP, CRNA
Steven R Wooden, DNP, CRNA

Assistant Editor
Jessica Floyd, BS

A Publication of Lifelong Learning, LLC © Copyright 2012

New health information becomes available constantly. While we strive to provide accurate information, factual and typographical errors may occur. The authors, editors, publisher, and Lifelong Learning, LLC is/are not responsible for any errors or omissions in the information presented. We endeavor to provide accurate information helpful in your clinical practice. Remember, though, that there is a lot of information out there and we are only presenting some of it here. Also, the comments of contributors represent their personal views, colored by their knowledge, understanding, experience, and judgment which may differ from yours. Their comments are written without knowing details of the clinical situation in which you may apply the information. In the end, your clinical decisions should be based upon your best judgment for each specific patient situation. We do not accept responsibility for clinical decisions or outcomes.

Table of Contents

Perinatal outcomes associated with obstructive sleep apnea in obese pregnant women

Complications following colonoscopy with anesthesia assistance

Propofol compared with combination propofol or midazolam/fentanyl for endoscopy in a community setting

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

Bupivacaine extended-release liposome injection for prolonged postsurgical analgesia in patients undergoing hemorrhoidectomy: a multicenter, randomized, double-blind, placebo-controlled trial

Single-dose Etomidate is not associated with increased mortality in ICU patients with sepsis: Analysis of a Large Electronic ICU Database



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Obstetric Anesthesia
Perinatal outcomes associated with obstructive sleep apnea in obese pregnant women

Obstet Gynecol 2012;120:1085-92

Louis J, Aukley D, Miladinovic B, Shephard A, Mencin P, Kumar D, Mercer B, Redline S


Purpose The purpose of this study was to compare perinatal outcomes in obese parturients who had obstructive sleep apnea (OSA) with those who did not.


Background OSA is characterized by chronic, frequent, upper airway obstruction, hypoxemia, and hypercarbia during sleep. OSA is associated with multiple cardiovascular, neuropsychologic, and endocrine disorders. It has been estimated that 0.7% to 5% of women of child bearing age may have OSA. Obesity is associated with the development and worsening of OSA. Additionally, obesity is associated with an increased risk of perinatal complications during pregnancy. Some studies suggest OSA during pregnancy contributes to increased rates of gestational diabetes, preeclampsia, and small-for-gestational-age neonates. However, further research is needed to examine the independent effects of OSA on perinatal outcomes in obese parturients.


Methodology This was a prospective, observational study to screen and identify risk factors and outcomes in obese parturients with OSA. Parturients with a body mass index ≥30 kg/m2 (BMI) were enrolled. Exclusion criteria included chronic opioid use or of other drugs that affect the central nervous system, and inability to maintain sleep beyond 2 hours. At 21 weeks gestation, parturients enrolled in the study completed an in-home portable polysomnography exam with the ARES Unicorder 5.2. After completion of this sleep study, an independent, blinded sleep physician scored the studies. The apnea hypopnea index (AHI) was used to determine the severity of OSA.


An AHI < 5 was considered “no OSA,” an AHI ≥ 5 was considered diagnostic of “OSA.” Mild OSA was defined as an AHI of 5-15 per hour, moderate OSA 16-29 per hour, and severe OSA was ≥ 30 per hour. Parturients with OSA were referred for an overnight in-house polysomnography and evaluation by a sleep physician and their obstetrician was notified. Multivariable logistic regression was used to examine the association between OSA and preeclampsia while controlling for age, chronic hypertension history, previous preeclampsia, BMI, and pre-pregnancy diabetes. A P < 0.05 was considered significant.


Result A total of 175 women completed home polysomnography studies and 161completed the research study. The prevalence of OSA was 15%, with 13 having mild OSA (50%), 9 had moderate OSA (35%), and 5 had severe OSA (19%). Parturients with OSA were significantly older (27 years vs. 30 years), had a higher pre-pregnancy BMI (48 kg/m2 vs. 39 kg/m2), and a 25% higher incidence of chronic hypertension (58% vs. 33%) and asthma (50% vs. 23%) (all P <0.05). 


The incidence of cesarean delivery, preeclampsia, wound complications, NICU admission for the neonate, and hyperbilirubinemia in the neonate was higher in parturients with OSA (P < 0.05; Figure 1). Parturients with OSA were 3.6 times more likely to develop preeclampsia (95% CI, 1.1-11.3 [Editor’s Note: this is a broad confidence interval which includes the possibility that there was no increase at all in the rate of preeclampsia in parturients with OSA]). A previous history of preeclampsia and chronic hypertension both were associated with increased rates of preeclampsia in obese parturients in this study.



Figure 1. OSA and Perinatal Complication Rates

Figure 1



Conclusion OSA was an independent risk factor for the development of a number of maternal and neonatal complications. Obese parturients with OSA had higher rates of preeclampsia, perinatal complications, NICU admissions for the neonate, and cesarean delivery. This study highlights the need to identify better ways to screen and treat OSA during pregnancy.



OSA is a significant problem anesthesia providers have to deal with on a daily basis in the operating room. It is estimated that approximately 30% of surgical patients may have OSA; many of which have undiagnosed OSA. Most of the focus has been on the implications of OSA in surgical patients; however, there is emerging evidence highlighting the implications of OSA in the obstetrical population. This study adds to the growing body of evidence on OSA, and highlights the importance of identifying obstetrical patients who may have undiagnosed OSA.


So what do the results of this study tell us? First, the incidence of OSA in this sample of obese parturients was 15%. Additionally, the study provides evidence that OSA in obese parturients increases their risk of preeclampsia and perinatal complications. Even after controlling statistically for pre-existing hypertension, OSA increased the odds of preeclampsia 3.6 times. This is significant to anesthesia providers because preeclampsia, especially when severe, can increase the risk of anesthesia complications and maternal morbidity and mortality. 


What is the take home message of this study?  I think the anesthesia community needs to develop a screening tool for OSA in parturients. The investigators in this study stated this was their primary aim; however they only presented results from their secondary analysis which examined the association between OSA and perinatal complications. I suspect in the next few years we may see a screening tool for OSA in the obstetrical population. In the meantime, I would have a low level of suspicion of an obese parturient having OSA, especially if she reports snoring, frequent obstructions during sleep, witnessed apneas, excessive tiredness during the day, has a neck circumference > 40 cm, and has a history of hypertension. If you suspect a parturient has suspected or known moderate or severe OSA I would have a low threshold for having the patient monitored closely (i.e., with continuous ETCO2) in the early postpartum period after cesarean delivery if neuraxial opioids or intravenous opioids were administered.

Dennis Spence, PhD, CRNA

The views expressed in this article are those of the author and do not reflect official policy or position of the Department of the Navy, the Department of Defense, the Uniformed Services University of the Health Sciences, or the United States Government.

© Copyright 2012 Anesthesia Abstracts · Volume 6 Number 12, December 31, 2012

Patient Safety
Complications following colonoscopy with anesthesia assistance

JAMA Intern Med 2013; March published ahead of print

Cooper GS, Kou TD, Rex DK


Purpose The purpose of this study was to investigate whether or not complications during colonoscopy were more frequent when deep propofol sedation was used vs. limited sedation.


Background Historically, sedation for colonoscopy has been performed with intermittent injection of midazolam and fentanyl. In recent years, propofol has become more commonly used. Propofol is well suited to sedation for colonoscopy because of its rapid onset, fast recovery, and high satisfaction for both patients and endoscopists. But propofol has a narrow margin of safety for loss of airway reflexes and apnea. Because of this, propofol is commonly administered by an anesthesia provider.


Anesthesia providers are administering sedation during colonoscopy more commonly, presumably because propofol is being used. Anesthesia involvement with the sedation of Medicare patients increased from 11% in 2000 to 23% in 2006. Anesthesia involvement with sedation of patients with commercial insurance increased from 14% in 2003 to 36% in 2009. From an economic perspective, the increased involvement of anesthesia has lead to a 20% increase in the cost of colonoscopy. Previous studies have not defined the possible complications associated with propofol use for deep sedation. Obtunded airway reflexes and respiratory depression may result in an increased risk of apnea and aspiration of gastric contents, but the incidence of complications during deep propofol sedation has not been identified.


Methodology This retrospective study used information from the Surveillance, Epidemiology, and End Results (SEER) Medicare database. The SEER project captures data on about 26% of the USA population. Data on Medicare patients 66 years old or older that had colonoscopies between January 2000 and November 2009 were analyzed. The involvement of anesthesia was determined by CPT-4 code (00810). The use of propofol for sedation was assumed if anesthesia was involved. The primary outcome was the occurrence of at least one of the following complications:

  1. aspiration pneumonia
  2. colonic perforation
  3. splenic injury/rupture
  4. splenectomy



Result Data from over 165,000 colonoscopies met inclusion criteria; 130,399 (79%) with no anesthesia involvement and 35,128 (21%) with an anesthesia provider. About 30% of all colonoscopies took place in an ambulatory surgery setting. A majority of the colonoscopies included were performed in the northeast and midwest USA. Only about 36% were performed in the south, southwest, or western USA. An anesthesia provider was more often involved in the case if it was performed in an ambulatory setting. An anesthesia provider was more often involved in the case if it was performed in the northeast (40%). Between the year 2000 and 2009 the presence of an anesthesia provider for sedation became much more common; increasing from 9% of cases in the year 2000 to 35% of cases in 2009.


Overall 30 day mortality was no different whether or not anesthesia was involved. Complications occurred in 0.17% of colonoscopies (284 patients); 0.16% in the no anesthesia group and 0.22% in the anesthesia present group (P<0.001). The majority of complications were aspiration of gastric contents, which occurred in 173 patients overall. Aspiration occurred at a rate of 0.10% in the no anesthesia group vs. 0.14% in the anesthesia present group (P=0.02). All other complications occurred at a similar rate between groups. The following factors were associated with an independent risk of complications during colonoscopy:

  1. more comorbidities (P<0.001)
  2. performed in a hospital vs. ambulatory surgery center (P<0.001)
  3. geographic location northeast or south vs. midwest, southwest, or west (P=0.004)
  4. anesthesia provider present (P<0.001)


The odds ratio (OR) of a complication was 1.46 in the anesthesia present group compared to the no anesthesia group. While the absolute increase in the complication rate was quite low, it amounted to about 518 additional complications a year in the USA alone.


Conclusion The services of an anesthesia provider during colonoscopy were associated with a small increase in absolute risk but a nearly 50% increase in the relative risk of aspiration of gastric contents. This increase in risk was assumed to be due to deeper levels of sedation with propofol. Depth of sedation may be a risk factor for complications during colonoscopy.



While traditionally we have not put much stock in many retrospective studies, we are now beginning to see retrospective studies using large, inclusive databases which collect data completely and systematically. Such studies are a much higher quality retrospective study than when data is harvested from chart reviews.


I selected this article in part because I was talking with two colleagues last week who had both been seeing higher rates of aspiration during their colonoscopies over the last year. We were discussing why that might be and what to do about it. Both of them observed that there was a trend towards “deeper sedation,” or, more accurately, general anesthesia, during colonoscopies. “Sedation” at this depth is primarily due to the endoscopists’ desire that the patient hold still during what would otherwise be painful manipulation of the endoscope far up into the colon (and around several corners). This level of discomfort requires general anesthesia and/or significant analgesia. It is a complete justification for the involvement of an anesthesia provider during colonoscopy. Insurance executives would be wise to endure a colonoscopy to the level of the descending colon with only some Versed before denying claims to pay for anesthesia.


So how did we arrive at a point where the level of sedation during colonoscopy may be contributing to an increased incidence of aspiration of gastric contents? I believe it went like this. Sedation started out light, with patients who could maintain and protect their own airways. As a result, we didn’t worry about patients who would be at risk for aspiration during general anesthesia, patients who we’d put an endotracheal tube in if they were having a general anesthetic. As we began to use propofol, sedation got deeper and deeper over time. We didn’t change our criteria for airway management because we were only administering sedation. We didn’t worry about the transition between sedation and general anesthesia because we were right there to manage the patient and we had all the right monitors just like a “real” anesthetic. At the same time, with the benefit of deeper “sedation,” the endoscopists started pushing on the abdomen to manipulate the endoscope into hard to reach places, and to do so faster. This increased intragastric pressure and increased the risk of regurgitation. If the airway was unprotected and the patient had a general anesthetic they may have aspirated.


If we accept that this risk is real (it is !!!) and that many patients are receiving general anesthesia during at least part of their colonoscopy, what do we do about it? First, our airway assessment must catch up with current practices. Highly experienced CRNAs providing sedation for colonoscopy saw at least brief hypoxia in 13% of propofol sedated patients and airway support was needed in 14% of patients.(1) If the patient’s airway needs to be protected during a general anesthesia then it probably needs the same protection during “deep sedation” for colonoscopy. Second, we all know that it takes very deep sedation to overcome painful stimuli. It may be that the reason we’ve gravitated to “deep propofol sedation” during endoscopy is because the patient really needs some analgesia. With proper analgesia, lighter levels of sedation, levels at which the patient can guard their own airway, may suffice. An infusion of ketamine (little or no respiratory depression) and propofol is used with great success in plastic surgery procedures. Ketamine 1 to 2 mg in every 1 mL (10 mg) propofol seems to work best. And, since the analgesia from 5 mg ketamine is equal to 5 mg morphine or 50 µg fentanyl, it provides profound analgesia. Since our goal is lighter sedation, made possible by including analgesia, while avoiding airway and respiratory depression, the combination of ketamine and propofol seems almost ideal.

Michael A. Fiedler, PhD, CRNA

1) Incidence of Sedation-Related Complications With Propofol Use During Advanced Endoscopic Procedures. Coté GA, Hovis RM,  Ansstas MA, Waldbaum L, Azar RR, Early DS, Edmundowicz SA, Mullady DK, Jonnalagadda SS. Clin Gastroenterol Hepatol 2010;8:137–142

© Copyright 2012 Anesthesia Abstracts · Volume 6 Number 12, December 31, 2012

Propofol compared with combination propofol or midazolam/fentanyl for endoscopy in a community setting

AANA J. 2013;81:31-36

Poulos JE, Kalogerinis PT, Caudle JN


Purpose The purpose of this study was to evaluate the efficiency and patient satisfaction associated with three different sedation procedures: propofol only, propofol / midazolam / fentanyl, or midazolam / fentanyl only.


Background Propofol is generally accepted as producing better sedation for endoscopy than boluses of opioid and benzodiazepine. Propofol allows for faster recovery, higher physician satisfaction, and greater efficiency in the endoscopy suite. Combining fentanyl and midazolam with propofol has been purported to reduce the need for deep sedation, but, despite this, propofol is widely becoming the sole agent used for sedation during endoscopy.


Methodology This retrospective review included 951 patient records for endoscopies performed between 2007 and 2010. Procedures were either esophagogastroduodenoscopy (EGD) or colonoscopy. All procedures were performed in an ambulatory endoscopy center. Three methods of sedation were used:

  1. propofol only - 50 mg bolus with follow up 20 mg boluses throughout procedure (n=330)
  2. propofol / midazolam / fentanyl - 10 mg propofol, 50 µg fentanyl, 2 mg midazolam with follow up propofol 20 mg boluses throughout procedure (n=282)
  3. midazolam / fentanyl only - 2 mg midazolam and 50 µg fentanyl with follow up 1 mg midazolam and 25 µg fentanyl throughout procedure (n=339)


Propofol sedation methods were administered by a CRNA and midazolam / fentanyl sedation was administered by an RN at the direction of the endoscopist. The goal of each sedation technique was to provide analgesia without significant physical signs of discomfort. Sedation was assessed with the Modified Observer’s Assessment of Alertness/Sedation instrument (MOAA/S). Patients also completed a satisfaction survey after the procedure.


Result Of the 951 patient records reviewed, 24% were EGDs and 56% were colonoscopies. The other 20% of cases were both EGD and colonoscopy and these were not included in the analysis. Demographic variables were similar between sedation groups. The level of sedation achieved was similar for EGD cases and colonoscopies.


MOAA/S sedation scores were significantly lower in patients who received propofol only (P<0.05). Likewise, patients who received propofol / midazolam / fentanyl sedation had lower sedation scores than those who received only midazolam / fentanyl (P<0.05). The average level of sedation during propofol only was 0.9. An MOAA/S of “1” signifies that the patient “does not respond to mild prodding/shaking.” In contrast, the average level of sedation in the propofol / midazolam / fentanyl and the midazolam / fentanyl only groups was about “4.” An MOAA/S of “4” signifies that the patient has a “lethargic response to [their] name [spoken] in normal tone.” Thus, the level of sedation was significantly “deeper” in the propofol only group. [Editor’s Note: a lower MOAA/S sedation score is deeper sedation; see note describing the entire scale following the abstract and comment.] No patient required assisted ventilation during sedation.


Patients in the propofol only group who received a 50 mg bolus were ready for the start of the procedure significantly more quickly than patients in the other groups (P <0.05). Depending upon the type of procedure, patients were ready for the start 2 to 3 minutes faster following the 50 mg propofol bolus. Likewise, propofol only patients recovered from sedation significantly more quickly than patients in the other groups (P<0.05) and patients in the propofol / midazolam / fentanyl group recovered more quickly than the midazolam / fentanyl only group (P=0.007). Propofol only patients recovered 9 to 10 minutes faster than midazolam / fentanyl only patients.


Patients in either of the groups that received propofol reported less discomfort during the procedure than those in the midazolam / fentanyl only group when interviewed at discharge (P<0.05). They were also more satisfied with their endoscopy experience and remembered less of what happened during the procedure. However, the differences in satisfaction were very small between groups. Patients from each sedation method rated their overall satisfaction 9.5 or higher on a scale of 1 to 10.


Conclusion The use of propofol only for sedation during EGD or colonoscopy was associated with slightly less time in the procedure room and clinically significantly faster recovery from sedation compared to groups in which midazolam and fentanyl were administered. This, despite the fact that propofol only patients were more “deeply” sedated than patients in the other groups. Patients who received propofol only sedation reported less discomfort and remembered less during the procedure. The faster initiation and recovery times associated with the propofol only group may allow greater efficiency, especially in a busy endoscopy unit. This efficiency may at least partially offset the additional cost of having an anesthesia provider present to sedate the patient.



I feel certain the results of this study are no surprise to anyone who has done much sedation for endoscopies. It points out why propofol is becoming the drug of choice for sedation during endoscopy. 1) Patients are ready for the endoscope to be inserted faster. Two or three minutes faster may not sound like much to the uninitiated, but you and I know how much most physicians don’t like to wait to start their procedure. 2) Patients recover faster. The “system” likes this because patients move through the system faster and it costs less to provide the service. 3) Patients and physicians are highly satisfied and patients tend not to remember anything that would lead to dissatisfaction.


But I’d like to pull out another lesson from this study. Endoscopies would be quite uncomfortable without sedation and/or analgesia. Why were the propofol only patients sedated so much more deeply than the propofol / midazolam / fentanyl group? I believe it was probably because it takes a lot of sedation to overcome painful stimuli. Note that giving only 50 µg fentanyl made it possible to sedate the patient much more lightly and the only real disadvantage was a slower recovery. As we become aware of the aspiration risks associated with deep sedation (see the abstract and comment “Complications following colonoscopy with anesthesia assistance” elsewhere in this issue) we need to think about providing adequate analgesia during sedation for endoscopies so that we don’t need sedation so deep that it boarders on, or is, general anesthesia. It may be that fentanyl can be used to provide this analgesia (without the midazolam) but there will be some additive respiratory depression and, perhaps, slower recovery. My recommendation is to use a combination of propofol and ketamine (1 to 2 mg ketamine per 10 mg propofol). Ketamine is a potent analgesic and amnestic but does not depress respirations like propofol. While we’d usually want to use some midazolam to protect against ketamine induced dysphoria, there are scores of studies in which propofol and ketamine were combined for infusion or TIVA without midazolam and without postop dysphoria. Neither does ketamine slow recovery. Adding ketamine should make lighter sedation possible while achieving the desired results. It will reduce the dose of propofol used and thus increase the margin of safety for respiratory depression. And, lighter sedation should reduce the risk of aspiration as well. Many anesthesia providers are already happily using this sedation technique during endoscopies.

Michael A. Fiedler, PhD, CRNA

MOAA/S sedation scoring:

6 = agitated

5 = responds to name in normal tone

4 = lethargic response to name in normal tone

3 = responds to name called loudly

2 = responds to mild prodding/shaking

1 = does not respond to mild prodding/shaking

0 = does not respond to deep-stimulus “sternal rub”

© Copyright 2012 Anesthesia Abstracts · Volume 6 Number 12, December 31, 2012

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;19:324-29

Blitz JD, Haile M, Kline R, Franco L, Didehvar S, Pachter L, Newman E, Bekker A


Purpose The purpose of this clinical trial was to determine if the combination of palonosetron plus dexamethasone (PAL plus DEX) is more efficacious than palonosetron (PAL) alone for the prevention of postoperative nausea and vomiting (PONV) and postdischarge nausea and vomiting (PDNV) in high risk patients undergoing laparoscopic surgery.


Background Postoperative and postdischarge nausea and vomiting (PONV & PDNV) are common after laparoscopic abdominal and gynecologic surgery. Upwards of 50% to 80% of patients undergoing laparoscopic surgery may experience PONV if they do not receive prophylaxis. PDNV rates in untreated ambulatory surgery patients range from 35%-50%, and may interfere with activities of daily living and delay recovery.


Palonosetron, is a 5-HT3 antagonist (dose: 0.075 mg) approved for the treatment of postoperative nausea and vomiting for up to 24 hours after surgery [Editor’s Note: it is also approved for prevention and treatment of chemotherapy induced nausea and vomiting]. Because of its long duration of action, it may have advantages in the treatment and prevention of PDNV. Previous research studies have found multimodal therapy with traditional 5-HT3 receptor antagonists plus dexamethasone reduced the incidence of PONV in high risk patients; however, the combination of palonosetron plus dexamethasone has not been compared to palonosetron alone for the prevention of PONV and PDNV in high risk patients.


Methodology This was a prospective, randomized, double-blind, clinical trial of patients with 3 or more of the Simplified PONV Risk Scale factors who were undergoing laparoscopic gynecologic or abdominal surgery. Patients were randomized to receive either palonosetron 0.075 mg plus dexamethasone 8 mg or palonosetron alone plus saline placebo prior to induction. A standard anesthetic was used in all patients.


Nausea and vomiting data were collected at 2, 6, 12, 24 and 72 hours after surgery. Nausea was measured on a 4-point likert scale (none, mild, moderate, or severe). Treatment success was defined as the absence of any nausea at the given time interval. Postoperative nausea (PON) time frame was up to 6 hours postoperatively and postdischarge nausea (PDN) from 6-72 hours postoperatively. Early vomiting was defined as any emetic episode up to 6 hours, and late vomiting from 6-72 hours after surgery. A complete response was defined as no vomiting and no rescue medication administration at any time interval.


All patients completed the Quality of Life-Functional Living Index-Emesis (QOL-FLIE) questionnaire at 96 hours after surgery. The study was powered to detect a 20% reduction in the complete response rate (from 60% to 40%). Statistical analysis was appropriate and a P <0.05 was considered significant.


Result There were 118 patients enrolled in the study (100 females/18 males). No significant differences were reported in demographic data or PACU time between the groups. The investigators did not report whether there were differences in anesthetic agents or opioids administered between groups.


The overall incidence of PONV at 0-6 hours was 44% in the palonosetron group vs. 42% in the palonosetron plus dexamethasone group (P > 0.05). The incidence of PDNV from 6-72 hours postop was higher in the palonosetron only group, however the difference was not statistically significant.


No significant differences were found in the incidence of nausea at any time interval (P > 0.05; Figure 1) even though the absolute incidence of nausea was 14% lower in the palonosetron plus dexamethasone group between 6-72 hours. The incidence of severe nausea was higher in the palonosetron only group at all time periods (Figure 2). No differences were found in treatment success (absence of nausea) between the two groups at any time (P > 0.05).


The overall incidence of vomiting was very low and not statistically different at:

  • 0-2 hours (palonosetron 6.8% vs. palonosetron plus dexamethasone 1.7%)
  • 12-72 hours (palonosetron 4.2% vs. palonosetron plus dexamethasone 6.5%)
  • 72 hours (0% both groups)


No difference was found in the complete response rate between the two groups (no vomiting/no rescue medications for 72 hours); palonosetron 60% vs. palonosetron plus dexamethasone 60%. The QOL questionnaire showed only a trend toward greater satisfaction in the nausea domain in the palonosetron plus dexamethasone group, but this was not statistically significant.



Figure 1. Incidence of Nausea

Figure 1



Figure 2. Incidence of Severe Nausea

Figure 2


Conclusion The combination of palonosetron plus dexamethasone did not reduce the incidence of PONV or PDNV when compared to palonosetron alone in patients with 3 or more risk factors for PONV undergoing laparoscopic surgery.



PONV and PDNV are still significant problems in anesthesia. Drug companies are continuing to develop long acting antiemetic agents with the hopes of reducing the incidence of PONV and PDNV. Palonosetron is one of the newer agents to come to the market in recent years and has been efficacious in treating PONV. The investigators found a two-drug multimodal approach (palonosetron plus dexamethasone) was not better than palonosetron alone for completely preventing vomiting or the need for an antiemetic for up to 72 hours. They suggested that the addition of dexamethasone had no advantage when combined with palonosetron for preventing PONV or PDNV.


However, 40% of high-risk patients still experienced some degree of nausea during the 72 hours after surgery. Additionally, 4% of patients in the palonosetron plus dexamethasone and 10% in the palonosetron group experienced severe nausea. This tells me we still have a long way to go in preventing PONV and PDNV. I wonder if adding a third prophylactic antiemetic agent would have made a difference in these high-risk patients?


One issue I had with this study was that the authors glossed over nausea severity. They did not state whether or not the groups differed statistically with regards to nausea severity. However, if you look at figure 2 it appears adding dexamethasone to palonosetron reduced the incidence of severe nausea. I think these results are clinically relevant. This study was funded by the maker of palonosetron, Eisai, Inc, and readers should view the results with this in mind.


Finally, this study was way underpowered and was based on comparing palonosetron plus dexamethasone to dexamethasone alone. Both groups received the long-acting 5-HT3 agent palonosetron, so the effect size, as we saw, was extremely small. Furthermore, the study was probably underpowered to look at all the secondary outcomes. Nonetheless, I think the results highlight the importance of considering the use of long acting antiemetic agents in high risk patients.

Dennis Spence, PhD, CRNA

The views expressed in this article are those of the author and do not reflect official policy or position of the Department of the Navy, the Department of Defense, the Uniformed Services University of the Health Sciences, or the United States Government.

© Copyright 2012 Anesthesia Abstracts · Volume 6 Number 12, December 31, 2012

Bupivacaine extended-release liposome injection for prolonged postsurgical analgesia in patients undergoing hemorrhoidectomy: a multicenter, randomized, double-blind, placebo-controlled trial

Dis Colon Rectum 2011;54:15521559

Gorfine SR, Onel E, Patou G, Krivokapic ZV


Purpose The purpose of this multi-center study was to compare the magnitude and duration of postoperative analgesia after injection of Exparel® vs. placebo in patients undergoing hemorrhoidectomy.


Background Many patients experience moderate to severe pain the first few days after surgery. Multimodal analgesic techniques, including the injection of local anesthetics at the surgical site, are commonly used to reduce postoperative pain; however, the duration of action is limited to, at most, 12 hours. Unfortunately, the worst pain after surgery typically occurs during the first 72 hours. Thus, patients often require opioids and other analgesics which may increase the risk of side effects. Therefore, having a local anesthetic formulation that has a prolonged duration of action for up to 72 hours would be beneficial.


Exparel is an extended-release, multivesicular liposome-based bupivacaine formulation designed to slowly release local anesthetic over an extended period of time (96 hours). This formulation is designed to provide prolonged analgesia after single-dose administration intraoperatively via local infiltration.


Methodology This was a multicenter, randomized, double-blind, placebo-controlled, phase III clinical trial that compared local infiltration with a single 300 mg dose of bupivacaine extended release (Exparel) vs. saline placebo in adults aged 18-86 years undergoing excisional hemorrhoidectomy under general anesthesia in 13 centers in the Republic of Georgia, Poland, and Serbia. Patients were excluded if they were taking any analgesics, antidepressants, or glucocorticoids within 3 days of surgery. Patients were randomized to receive either Exparel 300 mg diluted in 30 mL or placebo (30 mL of normal saline). Both were injected by infiltration technique around the anal sphincter at the end of surgery. Anesthetic technique was standardized in all patients. All patients were admitted to the hospital for 72 hours after surgery and could receive morphine 10 mg intramuscularly every 4 to 6 hours as needed. Patients could receive only pure opioid drugs for breakthrough pain. No topical, intrarectal, or non-opioid analgesics were administered.


Pain was measured with a 0-10 numeric rating scale [NRS] and by recording the total opioid consumption for the first 72 hours after surgery. The cumulative pain score was reflected as the NRS area under the curve for the first 72 hours after drug administration. Statistical analysis and sample size calculations were appropriate. A P < 0.05 was significant.


Result A total of 186 patients completed the study. There were no significant differences in demographics or surgical technique between the two groups. Cumulative pain scores were significantly lower in the Exparel group (142 vs. 203, P < 0.0001). The proportion of patients who did not require opioids between 12 and 72 hours were significantly greater in the Exparel group (P < 0.008). The mean total amount of opioid rescue medication administered was significantly less at every time point in the Exparel group compared to placebo (Figure 1). The median time to first use of opioid rescue medication was significantly longer in the Exparel group (Figure 2). No serious complications occurred in either group.



Figure 1. Cumulative Opioid Rescue Medication Administered

Figure 1

Note. The cumulative amount of opioid rescue medication administered at 12, 24, 36, 48, 60, and 72 hours. Each time frame includes the total amount of opioid administered up to that time point. Overall the placebo group required 7 mg more morphine equivalents than the Exparel® group during the 72 hour study period.





Figure 2. Median Time to First Opioid Rescue Medication Administration

Figure 2



Conclusion A single dose of 300 mg of extended-release liposomal bupivacaine (Exparel) administered by local infiltration after hemorrhoidectomy reduced pain and opioid consumption for 72 hours, and delayed the time to first opioid administration when compared to placebo.



At my facility, some of our plastic surgeons recently started using Exparel. I suspect many of our readers have also started seeing this drug being used as well at their facilities. I think it is an exciting new drug that, when used as part of a multimodal analgesic plan, will help provide extended analgesia for a variety of surgical procedures. Currently, it is only approved for local infiltration, but there are clinical trials being conducted that are examining its use in peripheral and neuraxial techniques. So I expect within the next several years we may see its use increase.


The important thing to remember with Exparel is that administering other local anesthetics, such as lidocaine, together with Exparel will cause an immediate release of bupivacaine. The company recommends waiting at least 20 minutes after injection of lidocaine locally before subsequently injecting Exparel. Additionally, other formulations of bupivacaine should not be administered for 96 hours after Exparel injection. I would also avoid administration of other long acting local anesthetics as well (i.e., ropivacaine). I have not seen any case reports of local anesthetic toxicity with this drug published yet. However, the biggest concern I would have is making sure the patient and other healthcare providers know the patient received this long acting formulation of bupivacaine. The company provides a patient armband to make the patient and other healthcare providers aware that Exparel has been administered. I recommend if you use this drug at your facility you examine what policies you have in place to ensure the safe administration of this drug.

Dennis Spence, PhD, CRNA

Exparel® is FDA approved (since October 2011) for single-dose infiltration into the surgical site to produce postsurgical analgesia. Exparel is a multivesicular liposome-based local anesthetic that utilizes the DepoFoam delivery platform to deliver bupivacaine over an extended period of time. The DepoFoam delivery platform consists of a small amount of free bupivacaine (3%) and microscopic, spherical, lipid-based particles combined in a honeycomb matrix that encapsulates the remaining bupivacaine. Over time there is erosion and/or reorganization of the particles lipid membrane resulting in release of the encapsulated bupivacaine. After injection into soft tissues, there is an immediate local anesthetic effect from the free bupivacaine followed by a delayed release from the liposomes for approximately 96 hours. Systemic plasma levels of bupivacaine following administration of Exparel are not correlated with local efficacy.


Exparel website


The views expressed in this article are those of the author and do not reflect official policy or position of the Department of the Navy, the Department of Defense, the Uniformed Services University of the Health Sciences, or the United States Government.

© Copyright 2012 Anesthesia Abstracts · Volume 6 Number 12, December 31, 2012

Single-dose Etomidate is not associated with increased mortality in ICU patients with sepsis: Analysis of a Large Electronic ICU Database

Crit Care Med. 2013;41:774-783

McPhee L, Badawi O, Gilles F, Lerwick P, Riker, R et al.


Purpose The purpose of this retrospective study was to assess whether or not a single dose of etomidate used for intubation in a large cohort of patients with sepsis was correlated with in-hospital mortality or other clinically important outcomes of care.


Background Etomidate, an hypnotic agent without analgesic properties, is selected frequently to facilitate intubation in the critically ill. Its unique properties minimize untoward hemodynamic effects such as increases in heart rate and decreases in blood pressure. These are typically the reasons why it is selected for use in the high acuity population. As with any drug, it is associated with certain adverse responses. Due to its inhibitory effect on adrenal function (inhibiting the 11-B-hydroxylase enzyme, which converts 11-deoxycortisol to cortisol) which has been reported to last up to 72 hours, much research has been conducted to determine its appropriateness in patients with sepsis or septic shock. The clinical consequences of its adrenal inhibitory effect remain unclear. Two pivotal clinical trials reported higher mortality rates in people diagnosed with sepsis that were intubated with etomidate though a cause and effect relationship has not been established.


Methodology This study was conducted as a retrospective review of an existing dataset (the Philips eICU Research Institute eRI). The dataset contained information taken from the medical records of critically ill adult patients who were hospitalized in an Intensive Care Unit across the United States. Inclusion criteria were as follows:

  1. Adults (>18 years) admitted to the ICU between 2008-2010
  2. Intubated only in the ICU
  3. Comprehensive medication documentation available, including:
    • medical history and physical examination findings
    • demographic profiles
    • other diagnoses (multiple listed when applicable)
    • laboratory data
    • vital signs
  4. Diagnosis of sepsis (see notes)
  5. No evidence of receiving etomidate for a previous intubation


Data was collected from each patient’s clinical ICU flow sheet including the average mean arterial pressure, the lowest systolic blood pressure, and the average heart rate during 24 hours before and after intubation. Vasopressor use was also recorded and defined as the number of days following the intubation that the patient received epinephrine, norepinephrine, phenylephrine, dopamine, dobutamine, and/or vasopressin. The specific medications used for the intubation and whether or not corticoids were used was also recorded.


The primary endpoint for data analysis was in-hospital mortality in septic patients. The variable of interest was not the intubation, but the use of etomidate compared with no etomidate for the intubation. The secondary endpoints used for data analysis were Intensive Care Unit (ICU) mortality, ICU and hospital length-of-stay, days of mechanical ventilation, and days of vasopressor/inotrope use in those with sepsis, severe sepsis and septic shock. The clinical characteristics of those who received etomidate for intubation were compared with those who did not. Records and corresponding data were identified and assessed until the pre-calculated sample size needed for appropriate power was obtained.


Result A total of 2,014 patient records that met inclusion criteria were identified. Of these, 1,102 received etomidate for intubation. Patients who received etomidate were slightly older, had lower pre-intubation blood pressure, and were more likely to have received steroids before intubation (P < 0.05). In the regression model used to assess in-hospital mortality; advanced age (P<0.001), higher APACHE IV score (P < 0.001), African American race (P < 0.05), steroid administration (before or after intubation)(P < 0.001), and the presence of another comorbid diagnoses had a higher risk of death.


The rate of in-hospital mortality was no different between patients who received etomidate for intubation and those who did not (37% vs. 38%, P = 0.77), There was no statistically significant trend between etomidate use and increased mortality. There was no association between etomidate use and any secondary outcome of interest. A separate regression model created to assess in-hospital mortality only in patients with septic shock (N= 650); showed no statistically significant relationship between etomidate use for intubation and in-hospital mortality.


Conclusion In this retrospective cohort study, a single dose of etomidate used for intubation in ICU patients with a diagnosis of sepsis, severe sepsis, or septic shock was not associated with hospital mortality, increased vasopressor or inotrope use, longer duration of mechanical ventilation, or ICU or hospital length-of-stay.



I noted that the researchers did a rigorous job developing the methodology for this study, and analyzing the data knowing a limitation of a retrospective analysis. I very much appreciated the diligence used when defining inclusion criteria; if the patient was NOT intubated in the ICU or a medication interface was absent for example. Those records were not used in the analysis. Retrospective reviews are only as good as the information available. No assumptions were made about missing data and this contributed to the robustness of the study.


Guidelines for the care of septic patients continue to be updated; care is clearly becoming more evidence based. Etomidate does cause cortisol suppression for a short period of time. What is the clinical impact of this fact? This study showed no difference in outcomes when etomidate was used to facilitate intubation in the septic ICU patient. Unless a specific contraindication is noted, I continue to use etomidate in select individuals but I advocate talking with the ICU care team and communicate my plans. Effective communication is a key to safe patient care and our ICU colleagues can provide us with information about patients response to our care.

Mary A Golinski, PhD, CRNA

For this study, septic patients were defined in any one of the following three ways:

  1. Suspected or confirmed infection plus two or more of the following criteria within 24 hours of intubation:  T > 38 C or < 36 C, heart rate > 90 bpm, respiratory rate > 20 breaths per minute or PaCO2 < 32 mm Hg, or WBC > 12,000 or < 4000
  2. A diagnosis of sepsis, severe sepsis, or septic shock within 24 hours after the initiation of mechanical ventilation in the medical record.
  3. ICU admission diagnosis of sepsis

© Copyright 2012 Anesthesia Abstracts · Volume 6 Number 12, December 31, 2012