ISSN NUMBER: 1938-7172
Issue 5.10

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
Lisa Osborne, PhD, CRNA
Dennis Spence, PhD, CRNA
Cassy Taylor, DNP, DMP, CRNA
Steven R Wooden, DNP, CRNA

Guest Editor:
Jason M. McGuire, PhD, CRNA

Assistant Editor
Jessica Floyd, BS

A Publication of Lifelong Learning, LLC © Copyright 2011

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

Prevention of intraoperative awareness in a high-risk surgical population

Cognitive and functional predictors and sequelae of postoperative delirium in elderly patients undergoing elective joint arthroplasty

Prior epidural lidocaine alters the pharmacokinetics and drug effects of extended-release epidural morphine (DepoDur®) after cesarean delivery

A cost-benefit analysis of the ENIGMA trial

Ultrasound imaging facilitates spinal anesthesia in adults with difficult surface anatomic landmarks

Respiratory resistance during anaesthesia with isoflurane, sevoflurane, and desflurane: A randomized controlled trial


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Equipment & Technology
Prevention of intraoperative awareness in a high-risk surgical population

N Engl J Med 2011;365:591-600

Avidan MS, Jacobson E, Glick D, Burnside BA, Zhang L, Villafranca A, Karl L, Kamal S, Torres B, O’Connor M, Evers AS, Gradwohl S, Lin N, Palanca BJ, Mashour GA, BAG-RECALL Research Group


Purpose The purpose of this study was to determine if a bispectral index (BIS) protocol was better than an end-tidal anesthetic-agent concentration protocol at decreasing the incidence of intraoperative awareness in high risk surgical patients.


Background Unintended intraoperative awareness is defined as the experience of explicit recall of sensory perceptions during surgery. These sensory perceptions can include hearing voices, feeling pain, and not being able to move. It is estimated that up to 70% of patients who experience intraoperative awareness may develop post-traumatic stress disorder. In high risk patients the incidence of awareness is as high as 1% (e.g., cardiac surgery, history of awareness, anticipated or history of difficult airway, ASA status 4). The Joint Commission for Accreditation of Healthcare Organizations (JCAHO) Sentinel Event Alert estimates that between 20,000 and 40,000 cases of intraoperative awareness occur every year. Some cases of awareness may result from inadequate dosing of anesthetic agents, and thus could be preventable.


Inhaled anesthetic agents are most commonly administered during general anesthesia. Maintaining a minimum alveolar concentration (MAC) greater than 0.7 during surgery is reported to decrease the incidence of awareness. Additionally, some use depth of anesthesia monitors in an effort to detect light anesthesia which may result in intraoperative awareness. BIS index values range from 0 to 100, with 40 to 60 purported to be the target range for preventing intraoperative awareness. The JCAHO alert states that the use of BIS technology to guide anesthetic administration may reduce the incidence of awareness. (Editor’s note: there is no credible evidence to support this claim; and much evidence to dispute it.)


Previous large trials have found conflicting results when a BIS protocol was compared to a standard anesthetic protocol in high risk patients. The B-Aware trial found a BIS protocol decreased intraoperative awareness by an absolute 0.74 percentage point; however, the B-Unaware trial showed that compared to an end-tidal anesthetic-agent concentration protocol which maintained the MAC between 0.7 and 1.3, a BIS protocol did not decrease the incidence of awareness. Therefore, this multi-center, international trial sought to determine if a BIS protocol was superior to an end-tidal anesthetic-agent concentration protocol at decreasing awareness in patients at high risk for awareness.


Methodology This was a prospective, randomized, evaluator-blinded, multi-center trial (University of Chicago, Washington University in St Louis, and University of Manitoba, Canada). A total of 6,041 patients at high risk for intraoperative awareness were randomized to either a BIS protocol or end-tidal anesthetic-agent concentration protocol. Patients at high risk were defined as those with at least one risk factor for intraoperative awareness (see note at end of abstract and comment).


In the BIS protocol the volatile anesthetic was titrated to maintain a BIS value between 40 and 60. In the end-tidal anesthetic-agent concentration protocol the volatile anesthetic concentration during maintenance was kept between 0.7 and 1.3 MAC. Anesthesia providers in the end-tidal anesthetic-agent concentration group were blinded to BIS values; however anesthesia providers were aware of the end-tidal anesthetic-agent concentration. Audible alarms were set to indicate if the BIS exceeded 60 or fell below 40. In the end-tidal anesthetic-agent concentration group audible alarms were set to indicate when the end-tidal anesthetic-agent concentration exceeded 1.3 MAC or fell below 0.7 MAC. A sign was posted to remind providers to check the BIS or end-tidal anesthetic-agent concentration when the alarm sounded. The protocols were not designed to prescribe or restrict the use of anesthetic agents, but rather to increase anesthesia provider vigilance.


Intraoperative awareness was assessed using a modified Brice questionnaire within 72 hours and at 30 days after surgery. Patients who reported recall between “going to sleep” and “waking up” were evaluated with a structured questionnaire. Three experts, blinded to group assignment, graded the awareness as definitive awareness, possible awareness, or no awareness using the Michigan Awareness Classification Instrument. The investigators hypothesized that the BIS protocol would be superior to the end-tidal anesthetic-agent concentration protocol in decreasing intraoperative awareness. Power analysis determined that 6,000 patients would be needed to detect a clinically significant reduction in definitive awareness by 0.4%. Statistical analysis was appropriate. A P < 0.05 was significant.


Result Out of 49,000 patients screened over a 25-month period, 5,809 were included in the trial. Of these patients, 5,713 completed at least one postoperative interview. A total of 5,413 patients completed both interviews (93.2%). No significant differences were found in demographics, risk factors for awareness, or preexisting medical conditions between the two groups. The average age was 65 years, 57.5% were male, and 83.5% were Caucasian. The patients enrolled had a high incidence of serious or life threatening systemic disease, with 50% being ASA physical status 3 and 34% being ASA 4. No significant differences were found in the amount of sedatives, hypnotics, neuromuscular blockers, or opioids administered between the groups. Median age-adjusted MAC values were 0.9 in both groups. Median BIS values in both groups were 41 (interquartile range 38 to 45).


There were 27 cases of possible or definite recall out of 5,713 patients (overall incidence 0.47%; 95% CI, 0.32% to 0.68%). Of these cases, 9 patients had definite intraoperative awareness (0.16%), and 18 had possible awareness (0.32%). Overall, the incidence of awareness was less than predicted. 


There were 7 cases of definite awareness in the BIS group and 2 cases in the end-tidal anesthetic-agent concentration group (0.24% vs. 0.07%; P = NS). There were 19 patients in the BIS group and 8 in the end-tidal anesthetic-agent concentration group, who had definite or possible awareness (0.66% vs. 0.28%; P = NS). Of those who experienced definite or possible awareness, 8 in the BIS group and 1 in the end-tidal anesthetic-agent concentration group described the awareness as distressing (0.28% vs. 0.04%; P = NS). A majority of the cases of awareness in the BIS group were tactile perceptions such as perception of surgical manipulation or the endotracheal tube, whereas in the end-tidal anesthetic-agent concentration group patients experienced auditory perceptions (Figure 1). In 41% of the cases of definitive or possible awareness the BIS values were less than 60 and/or end-tidal anesthetic-agent concentration values greater than 0.7 age-adjusted MAC. A majority of the cases of intraoperative awareness occurred during cardiothoracic surgery (Figure 2).



Figure 1. Incidence of Definite and Possible Awareness Events 

Figure 1

Note. ETAC = end-tidal anesthetic concentration.
Class 1 indicates isolated auditory perceptions, class 2 tactile perceptions, class 3 pain, class 4 paralysis, and class 5 pain and paralysis. A D indicates that there is associated distress (e.g., reports of fear, anxiety, suffocation, sense of doom, or sense of impending death).




Figure 2. Incidence of Intraoperative Awareness by Surgical Procedure

Figure 2

Note. ETAC = end-tidal anesthetic concentration.



Conclusion The BIS protocol was not superior to the end-tidal anesthetic-agent concentration protocol in decreasing the incidence of awareness. Implementation of an end-tidal anesthetic-agent concentration protocol which includes a brief, structured educational program, measurement of exhaled anesthetic agents, routine setting of audible alarms for end-tidal anesthetic-agent concentration values, and checklists to maintain anesthesia provider vigilance could be implemented in high risk patients to prevent intraoperative awareness.




EDITOR’S NOTE: Consciousness monitoring, either to determine depth of anesthesia or in an attempt to prevent recall, is a controversial topic so we decided to include two comments with this abstract. One favorable to consciousness monitoring and one critical of it.



Intraoperative awareness is one of those rare, but highly publicized complications of anesthesia. In this study of high risk patients, the investigators wanted to see if keeping the BIS values between 40 and 60 was better at reducing the incidence of intraoperative awareness than keeping the volatile anesthetic between 0.7 and 1.3 MAC. Both groups had audible alarms that sounded when the levels were too high or too low. What they found was opposite of what they expected; the incidence of awareness was lower when an end-tidal anesthetic-agent concentration protocol was used. It is important to point out that the difference was not statistically significant.


So, how do these results inform out clinical practice? It is important to point out that the patients were all at high risk for intraoperative awareness. The patients were older and sicker, and thus the results may not apply to other surgical populations or patients that are at low risk for intraoperative recall. As you can see, cardiothoracic surgery was associated with the highest incidence of intraoperative awareness. This is not surprising given these cardiac surgery patients tend to be older and sicker and may not tolerate high concentrations of volatile anesthetics.


What is reassuring is that most of the cases of awareness were not distressing to the patients. Most of the patients heard voices or felt non-painful stimuli. Unfortunately, in 41% of the cases of intraoperative awareness, the level of anesthesia was adequate (BIS < 60 and end-tidal anesthetic-agent concentration > 0.7). This tells us that neither protocol can completely prevent intraoperative awareness. There are several possible explanations. There is probably some variability between patients in terms of their level of consciousness or awareness at a given depth of anesthesia. It may be that there are underlying genetic differences which make some patients more resistant to general anesthesia and more susceptible to awareness.


So what can we take home from this study? Should we stop using a BIS monitor because it is no better than a standard end-tidal anesthetic-agent concentration protocol? My answer is no, I think the BIS should be kept in our tool box as one additional monitor which we can use to gauge how “deep” the patient at a given end-tidal anesthetic concentration. What I take home from this study is that it might be a good idea to set audible alarms for both the BIS monitor and end-tidal anesthetic-agent concentration when the BIS drops below 40 or exceeds 60, or when the end-tidal anesthetic-agent concentration drops below 0.7 or exceeds 1.3. It is still essential to look at the big picture and view these values in the context of what else is going on in the case for a given patient. I think having alarms on these monitors would be especially helpful for students because it can help remind them to monitor the BIS and end-tidal anesthetic-agent concentration values when they are doing their scans of the patient and monitors.


Dennis Spence, PhD, CRNA


This study confirms the result of many studies before it, yet, as a group, anesthesia providers have not uniformly accepted the evidence that consciousness monitors don’t monitor consciousness or help us prevent recall. The evidence that the BIS monitors depth of anesthesia or to assist in avoiding recall is weak to non-existent and the evidence that it does neither is plentiful. This is the second large scale study in the New England Journal of Medicine to indicate that so called consciousness monitors neither monitor consciousness nor help us prevent recall. Historically we have been so experience based that I think anecdotal clinical experiences tempt us to believe that consciousness monitors work as advertised despite a superabundance of carefully controlled empiric evidence to the contrary.  Here is a quick list of some of the evidence attesting to the inability of the BIS to monitor consciousness:

  • There are numerous case reports of patients being “awake” and experiencing recall with BIS numbers between 40 and 60 (both adults and children)
  • BIS doesn’t count the contribution of opioids to depth of anesthesia
  • BIS doesn’t count the contribution of nitrous oxide to depth of anesthesia
  • BIS Value depends on drug used; same depth, different drug, different BIS number
  • BIS values change with changes in patient position (head up, Trendelenburg)
  • Paralysis without anesthesia shown to produce BIS values below 40
  • The BIS goes up as ketamine causes unconsciousness

Even if consciousness monitoring did "work" some of the time, it is certainly unreliable and thus more likely to be a distraction than a helpful tool. We already have numerous valid monitors vying for our constant attention. Consciousness monitoring is also costly compared to pursuing the same goals (adequate depth, amnesia) with other methods. In fact, in a best case scenario using the BIS in an attempt to prevent recall in high risk patients (similar to this study), the BIS was associated with a reduction in the incidence of recall by only 0.1 percentage point. To achieve this required using the BIS on almost 2,500 patients and cost $2,200 for every patient in whom it may have helped to prevent recall. (I say “may” because the confidence interval was a 17% to 98% overall reduction in recall, so wide that it is highly questionable whether using the BIS was actually associated with any real reduction in the incidence of awareness.) It is a miracle the accountants haven’t killed it already.

Consciousness monitors may give a qualitatively true picture of changes in consciousness occasionally when everything goes right. I suspect that is why some of my colleagues have had experiences that convince them they work. But even if this is the case, consciousness monitors are unquestionably at least unreliable. Would you use a blood pressure machine that only gave you true readings occasionally? I want a consciousness monitor that works as much as the next anesthetist. That would be great. But right now, we simply don’t have one; no matter how much we want to believe.


Michael A. Fiedler, PhD, CRNA


NOTES: Risk factors for intraoperative awareness included: preoperative long-term use of anticonvulsant agents, opiates, benzodiazepines, or cocaine; a cardiac ejection fraction less than 40%; a history of awareness; a history of difficult intubation or anticipated difficult intubation; ASA physical status class 4; aortic stenosis; end-stage lung disease; marginal exercise tolerance not resulting from musculoskeletal dysfunction; pulmonary hypertension; planned open-heart surgery; and daily alcohol consumption.


Anesth Analg 2005;101:169

Anesth Analg 2005;100:1363 

Can J Anesth 2004;51:472 

Anesthesiology 2007;106:472

Br J Anaesth 2004;92:167

Br J Anaesth 2003;91:329

Anesth Analg 2004;99:1723

Anesth Analg 2009;109:1843

Anesth Analg 2003;97:488

Lancet 2004;363:1757


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 2011 Anesthesia Abstracts · Volume 5 Number 10, October 31, 2011

Geriatric Anesthesia
Cognitive and functional predictors and sequelae of postoperative delirium in elderly patients undergoing elective joint arthroplasty

Anesth Analg 2011;112:1086-93

Jankowski CJ, Trenerry MR, Cook DJ, Buenvenida SL, Stevens SR, Schroeder DR, Warner DO


Purpose The purpose of this study was to determine if the level of preoperative neurocognition and functional status predicted postoperative delirium in a sample of elderly patients without clinically apparent cognitive impairment who underwent joint arthroplasty. In addition, the purpose was to determine if cognitive or functional decline was present 3 months after surgery in those individuals that experienced postoperative delirium.


Background Postoperative delirium is one of the most common postoperative complications among the elderly and is a major contributor to their morbidity and mortality. In fact, acute delirium that occurs in the hospital setting has been associated with a later decrease in cognitive function among elderly patients. Previous research has identified that highly sensitive neurocognitive tests are able to detect subtle changes in cognitive function in elderly patients who otherwise display no obvious signs of cognitive decline.1,2 Specifically, postoperative delirium and its association with cognitive decline and loss of functional status among elderly who appear cognitively normal has never been studied in the context of elective surgery.


Methodology This was a prospective, descriptive study of 418 patients ≥65 years of age who were scheduled for elective knee or hip arthroplasty. Since the primary aim was to assess whether the scores on neurocognitive tests predicted later postoperative delirium, individuals that scored ≤23 on the Mini-Mental State Examination (indicating some cognitive impairment) were excluded from the study. Other preoperative cognitive measures included: 1) The American National Adult Reading Test, a measure of verbal intelligence; 2) The Auditory Verbal Learning Test (AVLT), a measure of memory and verbal learning; 3) The Controlled Word Association Test (COWAT), a measure of verbal fluency; and 4) The Stroop Color Word Test (SCWT), a measure of executive functioning. The participant’s functional status was measured preoperatively with 1) the Center for Epidemiological Studies Depression Scale, 2) the CAGE questionnaire, and 3) the Specific Activity Scale.


Postoperative dysfunction was assessed using the Confusion Assessment Method (CAM). Participants were assessed using the CAM twice-a-day, starting with the first postoperative day and ending on the fourth. Those scoring positive on the CAM, indicating delirium, were paired with a case-control (participant with similar demographics and Mini-Mental State Examination score that did not have delirium) and both participants returned 3 months postoperatively for repeated cognitive and functional tests. Power analysis and statistical analysis (multiple logistic regression) were appropriate. A P value of < 0.05 was considered significant.


Result Forty-two participants developed postoperative delirium, resulting in a 10% incidence in this sample. The independent predictors for postoperative delirium were:

  • greater age (P=0.017)
  • decreased ability to perform activities of daily living (P<0.001)
  • impaired verbal memory (P=0.002)
  • history of psychiatric illness (P=0.014).

There was no association between postoperative delirium and neurocognitive function (P=0.66). Hospital stay was lengthened from 5 to 6 days in participants who developed postoperative delirium (P<0.001). Furthermore, postoperative complications were greater among those participants who experienced postoperative delirium when compared to those who did not (28.6% vs 6.9%, P<0.001).


Conclusion While controlling for all potential cognitive and functional predictors described in this report; age, activities of daily living, memory, and a history of psychiatric illness were independent predictors of postoperative delirium among the elderly population following elective joint arthroplasty. However, postoperative delirium was not associated with neurological or functional decline 3 months after surgery.



Numerous studies have been conducted over the past several decades that focused on how one might predict delirium that occurs in the hospital setting. Postoperative delirium is only one type of delirium and is defined by the context in which it occurs: changes in consciousness and attention following surgery. Episodes of delirium have been linked to future decline in neurocognitive function, although this study failed to make that association. Knowing the predictors for postoperative delirium may aid in the clinicians ability to preoperatively identify those patients that are at high risk.


This study suggested that age, memory, the extent to which the patient can perform activities of daily living, and a history of psychological disorders are all predictive of postoperative delirium. These findings are interesting, but how can we apply them in a clinically useful way?


Neurocognitive tests are lengthy and can be expensive. Age is too broad a predictor for the anesthesia practitioner to be clinically useful in the elderly population. Identifying a history of a psychiatric illness is again, too broad to be useful because this study did not individually separate psychological conditions: is it depression, anxiety, bipolar disorder, or the myriad of other conditions that affect your population? This study failed to make this distinction.


A functional status questionnaire, such as the Specific Activity Scale used in this study, could be used preoperatively in order to identify those individuals that are at high risk for developing POD. It is quick, taking less than two minutes to complete, easy to use, and is free of charge. Unfortunately, the author did not describe the predictive cut-off point for a decrease in activities of daily living using this instrument.


Clinicians like you and I need suggested ways in which to employ these types of instruments in order to take advantage of their predictive power. Although I believe use of the Specific Activity Scale would be helpful in predicting postoperative delirium in this population, I am unable to recommend its use without a delineated cut-off point. The findings of this clinical research study are profound, but the discussion makes it difficult for the practitioner to use the information to improve practice. For now all we can say is that older patients with impaired ability to carry out normal activities of daily living, impaired verbal memory, or a history of some psychiatric illnesses are, in general, more likely to experience postoperative delirium following a general anesthetic. And that’s a little more than we knew before this study.

Jason M. McGuire, PhD, CRNA

  1. Greene NH, Attix DK, Weldon BC, Smith PJ, McDonagh DL, Monk TG. Measures of executive function and depression identify patients at risk for postoperative delirium. Anesthesiology. 2009;110(4):788-95.
  2. Smith PJ, Attix DK, Weldon BC, Greene NH, Monk TG. Executive function and depression as independent risk factors for postoperative delirium. Anesthesiology. 2009;110(4):781-87.

NOTE: If you are interested in learning more about the Specific Activity Scale and how it may be useful to your practice, I encourage you read the author’s publication on the instrument for more information:

Goldman L, Hashimoto B, Cook EF, Loscalzo A. Comparative reproducibility and validity of systems for assessing cardiovascular functional class: advantages of a new specific activity scale. Circulation. 1981;64:1227-34.

© Copyright 2011 Anesthesia Abstracts · Volume 5 Number 10, October 31, 2011

Prior epidural lidocaine alters the pharmacokinetics and drug effects of extended-release epidural morphine (DepoDur®) after cesarean delivery

Anesth Analg 2011;113:251-8

Ralls LA, Drover DR, Clavijo CF, Carvalho B


Purpose The purpose of this study was to compare the effects of a 20-35 mL bolus of 2% lidocaine through an epidural catheter on the pharmacokinetics of extended-release epidural morphine (Depodur®) in women undergoing cesarean delivery. Effects on postoperative analgesia and side effects were also examined.


Background Cesarean delivery is associated with moderate to severe pain. Recent research suggests that extended-release epidural morphine, a multivesicular liposomal preparation, can provide up to 48 hours of postoperative analgesia. However, some studies suggested that if DepoDur is administered within 3-15 minutes after a 3 mL epidural test dose consisting of 1.5% lidocaine with epinephrine 1:200,000, increased peak serum concentrations of morphine may result. No studies have examined the effect of a large bolus of 2% lidocaine with 1:200,000 epinephrine and sodium bicarbonate (1 mEq per 10 mL) on extended-release epidural morphine in women undergoing cesarean delivery. This is important because this latter solution is the most common local anesthetic used to top-up an existing epidural catheter for a cesarean delivery.


Methodology This was a randomized controlled trial of 30 ASA I or II women aged 18-40 years old with a singleton pregnancy undergoing cesarean delivery with neuraxial anesthesia. Patients were excluded if they were morbidly obese, had significant comorbidities, experienced inadvertent dural puncture, required conversion to general anesthesia, had a history of chronic pain or opioid use, or required emergency cesarean delivery. All patients were randomized to a Combined Spinal Epidural Group (Group CSE) or Epidural Group (Group E). All patients received 8 mg extended-release epidural morphine 1 hour after Continuous Spinal Epidural placement (CSE Group) or epidural bolus (Epidural Group). Group CSE underwent elective cesarean delivery. They received 12 mg hyperbaric 0.75% bupivacaine with 20 mcg fentanyl and no epidural test dose. Patients in Group E underwent elective or nonelective cesarean delivery during labor. They received an epidural “C-section dose” of 2% lidocaine with 1:200,000 epinephrine with sodium bicarbonate (1 mEq per 10 mL) in 5-mL increments to achieve a T-6 level. [Editor’s note: investigators did not report if patients in Group E had a continuous solution of local anesthetic infusing through the epidural catheters prior to nonelective cesarean delivery.] Patients in Group E also received 100 mcg fentanyl through the epidural catheter. The maximum lidocaine volume was 35 mL in Group E. If patients in Group CSE experienced intraoperative pain, and required additional lidocaine bolus, they were excluded from the analysis.


Blood samples to analyze morphine concentrations were collected at 0, 5, 10, 15, and 30 minutes and 1, 4, 8, 12, 24, 36, 48 and 72 hours after extended-release epidural morphine administration. Pharmacokinetic parameters included maximal observed morphine concentration (Cmax), time to Cmax (Tmax), and area under the concentration curve until the last observed plasma concentration (AUC 0-last). Pain at rest and sitting was evaluated at 1, 4, 8, 24, 36, 48 and 72 hours after study drug administration. Time to first request of supplemental pain medications was recorded. Patient satisfaction, adverse events, side effects, sedation scores, and respiratory parameters were also measured. Statistical analysis was appropriate.


Result No significant differences were found between the groups, with the exception of age. Patients in Group CSE averaged 4 years older. The maximal observed concentration, Cmax, was significantly higher in Group E (P = 0.038; Figure 1). The time to maximal observed concentration, Tmax, was approximately 3 hours longer in Group E (P = 0.318; Figure 2). However, there was no significant difference in the AUC0-last between the groups (Group CSE: 37 ± 20.2 vs. Group E: 39.9 ± 12.8; P = NS).



Figure 1. Maximal Morphine Concentration

Figure 1




Figure 2. Time to Maximal Morphine Concentration

Figure 2



Mean pain scores over the 72 hours study period were low in both groups; < 2.5 at rest and <4 while sitting (0-10 scale). Patients in Group E had significantly lower pain scores at rest at 4, 8, and 24 hours; and significantly lower pain scores when sitting at 8 hours (P < 0.05). Patients in Group E used 14 mg less morphine compared to Group CSE, though this was not statistically significant (20 ± 19 vs. 34 ± 26, P = 0.09). Patients in Group E required significantly less oxycodone within the first 24 hours after surgery compared to Group CSE (9 ± 11 vs. 22 ± 15, P = 0.01). Time to first analgesic request was longer in Group E, though this difference was not significant (24.5 ± 27 hrs vs. 16.3 ± 29 hrs, P = NS). The incidence of nausea was 53% in Group E and 36% in Group CSE (P = NS). The incidence of vomiting was significantly higher in Group E compared to Group CSE (67% vs. 14%, P = 0.01). Pruritus severity was significantly higher at 4 hours in Group E (P < 0.05). Satisfaction scores were high and similar between the two groups (P = NS).


No serious adverse events occurred in any patient. There was a significantly higher incidence of hypotension (> 25% reduction in baseline) during the study period in Group E (40% vs. 7%, P = 0.04). No patient experienced significant bradypnea (respiratory rate < 8/min). However, patients in Group E had a higher incidence of needing supplemental oxygen (40% vs. 0%, P = 0.02). In Group E 33% (n = 5) of patients experienced mild desaturations (< 93%), between 7 and 24 hours after extended-release epidural morphine administration. No patient experienced significant somnolence or sedation.


Conclusion A 20-35 mL bolus dose of epidural lidocaine administered 1 hour before administration of 8 mg of extended-release epidural morphine resulted in significantly higher maximum morphine concentrations. These results suggest that extended-release epidural morphine should be avoided, doses significantly reduced, or extended-release epidural morphine given more than 60 minutes after a large volume lidocaine 2% bolus for cesarean delivery. If extended-release epidural morphine is used, it should be administered into the epidural space using a CSE technique with no concomitant administration of epidural lidocaine.



DepoDur® is a long acting (up to 48 hours) extended-release morphine liposome injection designed specifically for epidural administration. It has an onset of approximately 3 hours. It should not be administered intravenously, intramuscularly, or intrathecally. According to the manufacturer, patients should be monitored for respiratory depression for a minimum of 48 hours. Monitoring adequacy of ventilation, oxygenation, and level of consciousness should occur hourly for the first 12 hours, followed by every 2 hours for the next 12 hours, then every 4 hours for the next 24 hours. The manufacturer recommends a 10 mg dose for cesarean delivery. No epidural local anesthetic with the exception of a 3 mL test dose or analgesic dose of 0.25% bupivacaine (maximum 20 mL) should be administered before or after DepoDur® administration. No other medications should be injected through the epidural catheter for at least 48 hours.


These results suggest that a large bolus of a typical lidocaine solution used for epidural anesthesia for cesarean delivery results in higher and later maximum morphine concentrations when compared to extended-release epidural morphine administered alone. These pharmacokinetic differences explain the lower pain scores and opioid requirements, higher side effect rates, and oxygen requirements in the epidural group. It is important to point out that some patients experienced late oxygen desaturations; > 23 hours after extended-release epidural morphine administration. This is an important safety concern, and points to the importance of close monitoring of patients receiving extended-release epidural morphine after a large lidocaine bolus (and after manufacturers recommended dosing). If providers choose to use extended-release epidural morphine for analgesia after cesarean delivery I would recommend avoiding it in patients who were morbidly obese or had a history of obstructive sleep apnea.


One limitation of this study is that investigators did not state whether or not the patients in Group E received any local anesthetic through their existing epidurals. If so, this could have influenced their results. Additionally, they did not have a large enough sample size to see a difference in some of their secondary outcomes (i.e., opioid consumption).


I have never used extended-release epidural morphine, nor have I been at any facility that routinely uses it. Results of this study make me want to avoid it in patients undergoing cesarean delivery under epidural anesthesia. I think our current preservative free morphine in combination with NSAIDs around the clock provides effective analgesia for a majority of patients after cesarean delivery. Extended-release epidural morphine use may increase anesthesia providers’ workload because they need to follow the patients for a minimum of 48 hours as opposed to the routine 24 hours after epidural or intrathecal morphine.

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 2011 Anesthesia Abstracts · Volume 5 Number 10, October 31, 2011

A cost-benefit analysis of the ENIGMA trial

Anesthesiology 2011;115:265-72

Graham AM, Myles PS, Leslie K, Chan MTV, Paech MJ, Peyton P, El Dawlatly AA


Purpose The purpose of this study was to compare inpatient costs for ENIGMA trial patients administered a nitrous oxide free anesthetic and those whose anesthetic included nitrous oxide (N2O free: volatile + 80% oxygen; N2O anesthetic: volatile + 70% N2O).


Background The ENIGMA trial was a prospective, randomized, multination trial of 2,050 patients randomized to receive a N2O-free or N2O anesthetic. Patients enrolled in the study were scheduled for surgery expected to exceed 2 hours in duration and require at least a 3 day admission. The ENIGMA trial found that an N2O-free anesthetic resulted in reduced postoperative complications. The investigators found an N2O-free anesthetic resulted in 13% lower incidence of severe nausea or vomiting, 2.3% lower incidence of wound infection, 6% lower incidence of fever, 1.5% lower incidence of pneumonia, and a 5.5% lower incidence of atelectasis. No differences were found in the incidence of myocardial infarction, thromboembolism, need for blood transfusion, stroke, awareness, or death within 30 days.


A criticism of the ENIGMA trial was that it did not conduct a cost analysis to determine if elimination of N2O reduced overall costs. This study sought to address that concern by conducting a cost analysis of ENIGMA trial data.


Methodology In the original ENIGMA trial 2,050 patients were enrolled to receive an N2O or N2O-free anesthetic. Patients were excluded if they were less than 18 years old, presented for surgery < 2 hours in duration or less than a 3 day admission, were undergoing cardiac surgery or one-lung ventilation, or if the anesthesia provider considered nitrous oxide contraindicated. In the trial, severe postoperative nausea and vomiting (PONV) was defined as two or more episodes of emesis at least 6 hours apart or three or more doses of antiemetic medication. Wound infection was defined as purulent discharge with or without positive cultures. Pneumonia was defined as radiological evidence with > 38ºC temperature and WBC > 12,000/mL, or a positive culture.


Direct health-care costs per patient were estimated for anesthesia maintenance, hospitalization, and medications. Additional visits or other health-care provider costs were not included, nor were costs due to patient lost work days. Table 1 lists the drug and median complication costs used for estimates based on review of the literature. Statistical analysis was appropriate. A P < 0.05 was significant.




Table 1. Cost Estimates

Bulk gas supplies


Oxygen and air





$1.40 per vial


$12.60 per vial

Inhalation agent (per MAC hour)








Prophylactic antiemetic therapy 

(dexamethasone and ondansetron)


PACU stay




Wound infection




ICU stay

$2,110 per day


Result In the ENIGMA trial there were no significant differences in demographics or perioperative characteristics. The mean age of the sample was approximately 56 years old, with over 50% being men. Surgical duration was just over 3 hours and 25% were ASA 3 or 4. Approximately 46% of all surgeries were general or colorectal surgery. Immediate postoperative ICU admission was required in 13% of patients. Median duration of hospital stay was 7 days in both groups. Patients in the N2O group were more likely to be discharged on any given day from the ICU (hazard ratio: 1.35, P = 0.02). PONV, wound infection, and pneumonia rates were significantly higher in the N2O group (P <0.05).


No differences were found in costs for anesthetic drugs. Total estimated costs were $2,366 higher in the N2O group compared to the N2O -free group (P = 0.002). Complication costs resulted from a higher incidence of severe PONV, wound infection, and pneumonia in the N2O group (P = 0.006; Figure 1). Higher bed day costs include PACU, ICU, and hospital bed costs (P = 0.005).



Figure 1. Estimated Costs per Patient in ENIGMA Trial

Figure 1


Conclusion This cost-benefit analysis suggests that the use of N2O resulted in significantly higher costs in patients undergoing major surgery. The increased costs were due to increased rates of complications in patients who received N2O. There is no strong argument to continue using nitrous oxide simply because it is a cheap drug.



Over the last several years the routine use of nitrous oxide has become less and less common. The reason for this is probably due to its association with higher rates of PONV, introduction of short acting inhalation and intravenous anesthetic agents, and possibly complications associated with its use as outlined in the original ENIGMA trial1. Many of the adverse effects of nitrous oxide are due to its irreversible inhibition of vitamin B12, which inhibits methionine synthase, folate metabolism, and DNA synthesis. Some evidence suggests it may delay wound healing and may increase the risk of cardiovascular events due to its association with increased homocysteine levels.


When I originally read the ENIGMA trial I was a little skeptical of the results. However, after reading this study, I am more convinced that use of high concentrations of nitrous oxide are associated with increased costs secondary to a higher incidence of PONV, wound infection, and pneumonia rates in patients undergoing major surgery. It is not known if these same complications or costs would be seen in patients undergoing lower risk surgeries or lower nitrous oxide concentrations. Given what I now know, I think I may avoid the use of high concentrations of nitrous oxide. In this day of rising health care costs, I think it is important that anesthesia providers find ways to reduce costs which are based on the best evidence.

Dennis Spence, PhD, CRNA

1. Myles PS, Leslie K, Chan MT, Forbes A, Paech MJ, Peyton P, Silbert BS, Pascoe E, ENIGMA Trial Group: Avoidance of nitrous oxide for patients undergoing major surgery: A randomized controlled trial. Anesthesiology 2007; 107:221–31.

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 2011 Anesthesia Abstracts · Volume 5 Number 10, October 31, 2011

Regional Anesthesia
Ultrasound imaging facilitates spinal anesthesia in adults with difficult surface anatomic landmarks

Anesthesiology 2011;115: 94-101

Chin KJ, Perlas A, Chan V, Brown-Shreves D, Koshkin A, Vaishnav V


Purpose The purpose of this study was to determine if the use of preprocedural ultrasound facilitated placement of spinal anesthesia in adults with presumed difficult surface anatomy.


Background Factors that improve the successful placement of spinal anesthetics include the ability to identify the midline and palpate an interspace. Poor surface anatomy, obesity, scoliosis, and degenerative changes may increase the technical difficulty with placement of spinal anesthetics. Recent reports suggest that the use of preprocedural ultrasonography may help facilitate placement of neuraxial anesthetics. One study found that preprocedural ultrasound scanning resulted in an 84% first attempt success rate in adults undergoing spinal anesthesia for surgical procedures.


Methodology This prospective, randomized, controlled trial included 160 adults undergoing elective lower limb joint surgery. Only patients with difficult surface anatomy were enrolled. The definition of difficult surface anatomy included: (1) poorly palpable or impalpable spinous processes and a BMI > 35 kg/m2, (2) moderate to severe lumbar scoliosis on clinical exam, or (3) previous lumbar spinal surgery. Patients were randomized to a palpation group (PALP) or ultrasound group (US).


The ultrasound scan and spinal anesthesia were performed by the same provider with at least 5 years of experience and performance of at least 30 preprocedural ultrasound scans for neuraxial anesthesia. The spinal anesthetic procedure was standardized. Each patient received 15 mg of 0.5% isobaric bupivacaine with 100 mcg morphine. A successful spinal anesthetic was defined as complete motor block and a sensory dermatome level of T-7 or higher 30 minutes after injection. Preprocedural ultrasound scanning was completed using a 2-5 MHz curved array probe. The scanning technique was standardized and included a longitudinal paramedian and transverse scan (Figures 1 and 2). The midline was identified, the depth estimated with the built in calipers, and skin marks made to mark the ideal insertion point.



Figure 1. Example of Preprocedural Ultrasound Scanning

Figure 1



Figure 2. Example of Transverse Ultrasound Image

Figure 2

Note. Example ultrasound scan of the L3-4 interspace. LF-D = ligamentum flavum-dura unit.



The primary outcome was the rate of successful dural puncture on the first attempt. An attempt was defined as advancement of the needle preceded by complete removal of the spinal needle or introducer. Needle redirection was defined as any change in needle insertion trajectory in which the needle or introducer was not removed. A needle pass was defined as either a needle insertion or redirection attempt. Secondary outcomes included:

  1. number of needle insertion attempts
  2. number of needle passes
  3. time taken to establish landmarks
  4. time taken to perform spinal anesthesia
  5. total procedure time
  6. block associated pain using 0-10 scale
  7. patient satisfaction with block procedure

Sample size calculations and statistical analysis were appropriate. A P <0.05 was considered significant.


Result The study was stopped after 120 subjects were enrolled when an unplanned interim analysis revealed results favoring the US group (Table 1). Baseline demographics were similar between the two groups, with the average age being approximately 62 years old. BMI was 38.5 ± 8.8 kg/m2 in the US group and 41.2 ± 5.9 kg/m2 in the PALP group (P = 0.051). First attempt success rate was 65% in the US group and 32% in the PALP group (P <0.001). Time to establish landmarks and total procedure duration was significantly longer in the US group (P <0.001; Table 1).There was a trend towards more patients in the PALP group having difficult or impossible landmarks (US group: n = 37 vs. PALP group: n = 50; P = 0.054). However, there was a higher rate of scoliosis in the ultrasound group (15% vs. 3%). Approximately 12.5% had a history of previous spinal surgery in both groups.


Given the baseline differences in BMI and landmark palpation difficulty between the two groups, a post hoc analysis was completed. For patients with a BMI > 35 kg/m2 , those in the US group had a 59% first attempt success rate as compared to 30% in the PALP group (P = 0.004). For those with difficult or impossible landmarks, the first attempt success rate was 57% in the US group and 30% in the PALP group (P = 0.012). In the post hoc analysis no difference was noted in the time taken to perform spinal anesthesia. However, in the overall analysis it took approximately 2 minutes longer to place the spinal anesthetic in the PALP group (P = 0.038). No differences were noted in block associated pain or patient satisfaction.




Table 1. Primary and Secondary Outcomes


US Group

(n = 60)

PALP Group

(n = 60)

P value

1st attempt success rate




1st needle pass success rate




Within 5 needle passes




Within 10 needle passes




Total number of needle passes

6 [1-10]

13 [5-21]


Time taken to establish landmarks (min)

6.7 ± 3.1

0.6 ± 0.5


Time taken to place spinal (min)

5 ± 4.9

7.3 ± 7.6


Total procedure time (min)

12.2 ± 6

7.9 ± 7.7


Note. Data are presented as % or median [interquartile range].



Conclusion Preprocedural ultrasonography facilitated spinal anesthetic placement in surgical patients undergoing lower extremity surgery with difficult anatomic landmarks. Anesthesia providers should consider acquiring this skill given the increasing number of aging patients requiring lower extremity orthopedic surgery.



There is a growing body of evidence supporting the use of preprocedural ultrasonography to facilitate placement of labor epidurals in obstetric patients1 (see Anesthesia Abstracts July 2009, volume 3, number 7). This is the second study demonstrating efficacy of preprocedural ultrasonography to facilitate placement of spinal anesthetics in nonobstetrical patients.2 Together, the evidence suggests that preprocedural ultrasonography may facilitate placement of neuraxial anesthetics in obstetrical and surgical patients, especially in those with presumed difficult landmarks or history of difficult placement.


I believe that a majority of patients do not require preprocedural ultrasonography to assist in placement of spinals or epidurals. However, in my clinical experience and review of the literature, I believe that this is an important skill to learn because it may assist in patients in whom it is difficult or impossible to palpate an interspace, or in those with a history of scoliosis or low back surgery. Readers are directed to several excellent review articles on how to perform the procedure.3,4 It is important to take time to practice the procedure because there is a learning curve.5 Additionally, preprocedural ultrasonography is a useful tool for demonstrating to students the lumbar anatomy and estimated depth to the epidural space.


It is important to point out that currently ultrasonography is not routinely used “real-time” to place neuraxial anesthetics like what is done with peripheral nerve blocks. Additionally, it does take 3-10 minutes to complete a longitudinal and transverse scan, and to make skin marks. However, in my experience one can save time in the neuraxial anesthetic placement because the number of attempts is decreased. While I have no evidence to support it, clinically I have seen patients report less pain at the insertion site when preprocedural ultrasonography is used because fewer skin punctures are required. Just like it is important to know how and when to use a fiberoptic to perform an awake intubation, I believe in coming years it will be equally important for anesthesia providers to gain ultrasonography skills to facilitate line, peripheral nerve block, and neuraxial block placement.

Dennis Spence, PhD, CRNA

  1. Schnabel A, Schuster F, Ermert T, Eberhart LH, Metterlein T, Kranke P. Ultrasound guidance for neuraxial analgesia and anesthesia in obstetrics: a quantitative systematic review. Ultraschall Med 2010. 10.1055/s-0029-1245724. 
  2. Chin KJ, Perlas A, Singh M, Arzola C, Prasad A, Chan V, Brull R. An ultrasound-assisted approach facilitates spinal anesthesia for total joint arthroplasty. Can J Anaesth 2009;56: 643-50.
  3. Grau T, Leipold RW, Conradi R, Martin E, Motsch J. Ultrasound imaging facilitates localization of the epidural space during combined spinal and epidural anesthesia. Reg Anesth Pain Med. 2001;26:64-67. 
  4. Carvalho JC. Ultrasound-guided epidural anesthesia video tutorial. Accessed June 8, 2011. 
  5. Margarido CB, Arzola C, Balki M, Carvalho JC. Anesthesiologists' learning curves for ultrasound assessment of the lumbar spine. Can J Anaesth. 2010;57:120-126.

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 2011 Anesthesia Abstracts · Volume 5 Number 10, October 31, 2011

Respiration & Ventilation
Respiratory resistance during anaesthesia with isoflurane, sevoflurane, and desflurane: A randomized controlled trial

Br J Anaesth 2011;107:454–61

Nyktari V, Papaioannou1 A, Volakakis N, Lappa A, Margaritsanaki P, & Askitopoulou H


Purpose The aim of this study was to measure the effects of 1 and 1.5 MAC desflurane on respiratory system resistance (Rrs) and and the component parts of that resistance. The study also compared Rrs during desflurane anesthesia with the effects of sevoflurane and isoflurane on Rrs during the first 30 minutes of anesthetic administration.


Background Desflurane has been characterized as an airway irritant that should be used with great caution or even avoided in patients with reactive airway disease. Two previous studies have demonstrated that 1) 1 MAC of desflurane has no effect on Rrs in healthy subjects but increases Rrs in smokers1 and 2) 2 MAC of desflurane significantly increases Rrs.2 However, this previous research studied these effects for only 5 or 10 minutes, respectively, a substantially shorter duration than the typical anesthetic.


Methodology Fifty-nine healthy adult patients without known lung disease or history of bronchodilator use were randomized to receive desflurane (D), sevoflurane (S), or isoflurane (I) during general endotracheal anesthesia for non-thoracic, non-abdominal surgery. There were no differences in patient characteristics between the D, S, or I groups. Anesthesia induction drugs were standardized (remifentanil, propofol, cisatracurium) and all patients were intubated with an uncut 7.5 mm ID endotracheal tube. Patients were maintained with propofol TIVA prior to the introduction of the study agent for baseline Rrs measurements and remained paralyzed throughout the measurement periods.


Patients were ventilated with tidal volume 7 mL/kg ideal body weight, rate 10 bpm, PEEP 5 cm H2O, inspiratory pause 50% of inspiratory time, and total flow 5 lpm. The long inspiratory pause was required to allow adequate time to measure the inspiratory plateau pressure; necessary to determine respiratory system resistance and that of its components.


Measurements of flow and pressure were obtained by averaging the values of 5 consecutive breaths every 5 minutes up to 30 minutes after achieving steady-state at 1 MAC of agent. Measures were repeated after agent termination as the end-tidal concentrations dropped to 0.5 MAC and zero. After 10 minutes of propofol TIVA, baseline measurements were repeated followed by the same sequence of measurement during steady-state concentrations of 1.5 MAC of agent. See notes following this abstract and comment for a discussion of the airway resistance calculations.


Result Administering 1 MAC of desflurane, sevoflurane or isoflurane had no effect on respiratory resistance. At 1.5 MAC, desflurane increased all 3 types of respiratory resistance while no differences in resistance occurred with sevoflurane or isoflurane. The Rmin of desflurane at 1.5 MAC declined slowly over time and dissipated rapidly as agent concentration was reduced to 0.5 MAC and zero.


Conclusion One MAC of desflurane, sevoflurane, or isoflurane did not cause an increase in total respiratory resistance or its components. Sustained increases in respiratory resistance occurred during the administration of 1.5 MAC of desflurane but not during 1.5 MAC of sevoflurane or isoflurane. The increased Rmin of desflurane was likely due to the increased density of desflurane rather than direct effects of bronchoconstriction.



This and previous studies were performed in healthy patients without airway disease and demonstrate that at high concentrations, desflurane has detrimental effects on respiratory resistance. However, I have safely administered 1 MAC of desflurane to patients with a history of reactive airways and I have observed bronchospasm with 1 MAC of desflurane in patients with NO history of airway disease. Some patients have subclinical reactive airway disease with no overt wheezing or chronic cough of “unknown etiology.” Close attention to patient responses during desflurane administration allows for a rapid diagnosis and easy reversal of the problem (switch to another agent). I feel comfortable administering low doses of desflurane when its low blood:gas solubility coefficient is desired. What is the likelihood that I will administer 1.5 MAC of desflurane – 9% desflurane? Extremely low.

Penelope S Benedik, PhD, CRNA, RRT

  1. Anaesthesia 2003;58:745–748.
  2. Anesthesiology 2000;93:404–8.

NOTES: Respiratory resistance calculations included Rrs ([Pmax – Pplat]/flow), 

minimal resistance (Rmin), and effective resistance (DRrs).


Rrs ([Pmax – Pplat]/flow) represents the difference between peak inspiratory pressure and plateau pressure divided by the flow rate (units are cm H2O/L/sec).

Rmin is one component of Rrs and reflects the airflow dependent change in airflow resistance as a result of airway and endotracheal tube diameters. Rmin represents airway effects.

DRrs is the second component of Rrs and represents both the viscoelastic elements of the lung and chest wall and ventilation inhomogeneity—it is the “slow decay” in pressure during the plateau phase that occurs between the first point of zero flow and the end-inspiratory pressure. DRrs represents tissue effects.

© Copyright 2011 Anesthesia Abstracts · Volume 5 Number 10, October 31, 2011