IJCP’s
Volume 21, October-December 2013
Trial Puts Sedative Dosing to the Test Effort to Minimize Hemodynamic AnomaliesSmokers’ from Dexmedetomidine Lung Function Likely Mediated by Heavy Metals
SAMBA’s Registry Yields Initial Findings on Surgery Outcomes
For ICU Patients, Quiet (If Not Quite Silence) is Golden
Post-op Cognitive Changes Tied to Brain Anatomy
Researchers Discuss Steroid Controversies in Sepsis Treatment More...
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Contents 1.
Trial Puts Sedative Dosing to the Test Effort to Minimize Hemodynamic Anomalies from Dexmedetomidine.................... 6
2.
SAMBA’s Registry Yields Initial Findings on Surgery Outcomes.... 8
3.
For ICU Patients, Quiet (If Not Quite Silence) is Golden............. 10
4.
Post-op Cognitive Changes Tied to Brain Anatomy.................... 12
5.
Researchers Discuss Steroid Controversies in Sepsis Treatment... 14
6.
Senate Passes Bill to Address Drug Shortages............................ 16
7.
Too Many Tacks Associated with Postoperative Hernia Pain ....... 18
8.
New Agent Rapidly Reverses Rocuronium, Vecuronium Block..... 21
9.
Seeking Prognostic Cues During Lumbar Injections.................... 26
10. Eight Principles for Safer Opioid Prescribing: An Interview with Lynn Webster, MD................................................................... 28 11. Experts: SCS Underused in Failed Back Surgery Syndrome......... 31 12. Analgesics After Low-Risk Surgery Linked to Long-Term Use....... 33 13. Opioid Use for Abdominal Pain Sees Recent Spike.................... 34
EDITORIAL ●● A comparison between four different infragluteal probe and needle alignment approaches concluded that the LA-IP approach resulted in a rapid onset of sciatic nerve blockade (SNB) and was associated with the best satisfaction for postoperative analgesia as compared to LA-OP, SA-IP, and SA-OP approaches for patients undergoing foot and ankle surgery. The four approaches compared were: SI patients received SNB using short-axis (SA) view of the SN and in-plane (IP) placement of block needle (SA-IP approach); LI patients received SNB using long-axis (LA) view of the SN and IP needle placement (LA-IP approach); SO patients received the block using SA view of the SN and out-of-plane (OP) needle placement (SA-OP approach); LO patients received SNB using LA view of the SN and OP needle placement (LA-OP).1 ●● In a retrospective study, intraoperative blood loss during spinal surgery was decreased in patients who received remifentanil as an opioid adjuvant vs fentanyl (125 ± 67 mL vs. 165 ± 82 mL, P = 0.035) possibly because of significantly lower intraoperative BP. The authors recommend a larger-scale prospective randomized controlled trial to confirm these results and to test whether remifentanil can decrease intraoperative blood loss during other surgical procedures.2 ●● Prophylactic variable rate phenylephrine infusion and rescue phenylephrine bolus dosing is more effective than relying on rescue phenylephrine bolus dosing with respect to limiting clinician workload and maternal symptoms during spinal anesthesia for cesarean delivery.3 ●● Surgical patients with a history of intraoperative awareness with explicit recall (AWR) are five times more likely to experience AWR than similar patients without a history of AWR. Anesthetic management did not differ between the study groups, but there was a significant effect of a history of AWR on the end-tidal anesthetic concentration versus bispectral index relationship. Modifying perioperative care and postoperative evaluation of patients with a history of AWR should be considered.4
References
1. Tammam TF. Ultrasound-guided sciatic nerve block: a comparison between four different infragluteal probe and needle alignment approaches. J Anesth 2013 Dec 6. [Epub ahead of print]. 2. Kawano H, Manabe S, Matsumoto T, et al. Comparison of intraoperative blood loss during spinal surgery using either remifentanil or fentanyl as an adjuvant to general anesthesia. BMC Anesthesiol 2013;13(1):46. 3. Siddik-Sayyid SM, Taha SK, Kanazi GE, et al. A randomized controlled trial of variable rate phenylephrine infusion with rescue phenylephrine boluses versus rescue boluses alone on physician interventions during spinal anesthesia for elective cesarean delivery. Anesth Analg 2013 Dec 2. [Epub ahead of print] 4. Aranake A, Gradwohl S, Ben-Abdallah A, et al. Increased risk of intraoperative awareness in patients with a history of awareness. Anesthesiology 2013 Oct 9. [Epub ahead of print].
Source: UpToDate.com Dr KK Aggarwal
Padma Shri and Dr BC Roy National Awardee Sr. Physician and Cardiologist, Moolchand Medcity, New Delhi President, Heart Care Foundation of India Group Editor-in-Chief, IJCP Group and eMedinewS National Vice President Elect, IMA Member, Ethics Committee, MCI Chairman, Ethics Committee, Delhi Medical Council Director, IMA AKN Sinha Institute (08-09) Hony. Finance Secretary, IMA (07-08) Chairman, IMA AMS (06-07) President, Delhi Medical Association (05-06) emedinews@gmail.com http://twitter.com/DrKKAggarwal Krishan Kumar Aggarwal (Facebook)
IJCP’s ANESTHESIOLOGY NEWS, Volume 21, October-December 2013
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CLINICAL ANESTHESIOLOGY
Trial Puts Sedative Dosing to the Test Effort to Minimize Hemodynamic Anomalies from Dexmedetomidine T
o bolus or not to bolus? When it comes to dexmedetomidine, the answer has proved elusive. But a multicenter team of Canadian researchers has found that although hemodynamic abnormalities occur in 40% to 60% of postsurgical patients receiving dexmedetomidine in the intensive care unit, the incidence of such events is lower with a slower—or no—loading dose of the drug. “The dosing recommendation for dexmedetomidine is to give it as a bolus over 10 or 20 minutes,” said C. David Mazer, MD, professor of anesthesia at the University of Toronto, Ontario, who helped lead the study. “One of the problems with giving it as a bolus is its potential hemodynamic effects, so some practitioners just start it as an infusion. And although there is good documentation about the hemodynamic effects related to the bolus, there’s nothing in the literature about the hemodynamic effects with just the infusion.” As Dr. Mazer and his colleagues reported at the 2012 annual meeting of the Canadian Anesthesiologists’ Society (abstract 1328069), 301 patients were enrolled in the open-label, non-randomized trial. Patients with bradycardia, hypotension or heart block (Mobitz 2 or 3) were excluded from the study, which was supported by Hospira.
The investigators allocated patients to one of three loading-dose regimens: no dose (n = 156), slow dose (1 mcg/kg over 20 minutes; n = 82) and fast dose (1 mcg/kg over 10 minutes; n = 63). In each group, the bolus was followed by an infusion of 0.2 to 0.7 mcg/kg per hour for two to 24 hours.
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The primary outcome was the incidence of clinically meaningful hemodynamic abnormalities within the first two hours of receiving the sedative. Anomalies were defined as slow heart rate (<50 beats per minute [bpm] requiring intervention or <40 bpm), low systolic blood pressure (<80 mm Hg), an increase in systolic blood pressure of more than 20% above baseline, the initiation of a pacemaker or the use of a vasoactive agent. Secondary outcomes included other adverse events, as well as use of sedatives and analgesics. All three regimens were associated with hemodynamic abnormalities, Dr. Mazer told Anesthesiology News. “The lowest rate of abnormalities was in patients who received no bolus, which is not surprising based on the characteristics of the drug.” Nearly 43% of patients who did not receive a loading dose experienced hemodynamic abnormalities, compared with 49% of those in the slow loading-dose group and 61.7% of those in the fast loading-dose group (P = 0.015 vs. no loading dose). The higher incidence of hemodynamic abnormalities in the group that received a rapid loading dose was accompanied by the increased use of vasoactive agents in this group: 8.5% versus 25% among patients who did not receive a loading dose (P = 0.003). Furthermore, the time to first occurrence of hemodynamic abnormalities was significantly shorter in the bolus groups than the non-bolus group (P = 0.013).
IJCP’s ANESTHESIOLOGY NEWS, Volume 21, October-December 2013
The most common adverse events in all groups were procedural pain (26.8%-37.8%), nausea (22.2%-30.5%), hypotension (15.9%-23.1%), pain (12.2%-14.3%) and hypertension (10.9%-14.6%). Yet as Dr. Mazer explained, the clinical scenario plays a critical role in determining which loading regimen of dexmedetomidine an anesthesiologist may choose. “If the patient needs rapid achievement of therapeutic levels without using any other agent, then I think a bolus may be the way to go,” he said. “In some patients, I might actually give the whole loading dose over a 10-minute period. In those who have pre-existing hemodynamic abnormalities, I might reduce the bolus or eliminate it.” G. Burkhard professor and anesthesia at the in Seattle, said surprised by the
Mackensen, MD, PhD, chief of cardiothoracic University of Washington, he was not particularly results given the dosing
regimens the researchers used in the study. “I certainly found the treatment allocation very interesting, because it was left to the individual anesthesiologist,” Dr. Mackensen said. “If anything, the effect size may be underestimated given the way treatment was allocated.” Dr. Mackensen said he typically does not administer boluses of dexmedetomidine before starting an infusion. “I use smaller boluses in the operating room, but that’s without starting an infusion,” he said. “I keep a stick of the drug in my pocket, and use it at the time of weaning and extubation to smooth things out for the patient. I have pretty good results with giving small boluses in these instances, although admittedly I’m not starting an infusion there, and it’s a different indication.”
IJCP’s ANESTHESIOLOGY NEWS, Volume 21, October-December 2013
—Michael Vlessides
7
CLINICAL ANESTHESIOLOGY
SAMBA’s Registry Yields Initial Findings on Surgery Outcomes
T
he typical ambulatory surgical procedure runs 38 minutes, not including the 14 minutes between the time the patient enters the operating room and the first incision, according to preliminary findings from a new registry from the Society of Ambulatory Anesthesia (SAMBA). Nearly all of the patients who required antibiotic prophylaxis received it within one hour before the incision: 92%, according to the study. Patients spent an average of 45 minutes in the postanesthesia recovery unit before being discharged; however, the average
time to discharge for patients who received spinal anesthetics was twice as long. The overall incidence of postoperative nausea and vomiting (PONV) for which antiemetic rescue was required was 4%. Those findings are the first to emerge from SAMBA’s clinical outcomes registry (SCOR), created in 2010 to identify nationwide trends and promote quality in anesthesia care for patients undergoing ambulatory procedures. Its developers hope to use the data they gather to create benchmarks for best practice for such surgeries, which are becoming an increasing part of the anesthesia workload.
Samba Clinical Outcomes Registry Patient Database Form
Basic Info Preop
Surgery start (24h : mm)
Intraop
Surgery end (24h : mm)
PACU
OR out (24h : mm)
Adverse Events
Follow-up Contact
Gold: current section Silver: completed section Aqua: incomplete section
8
OR in (24h : mm)
Anesthesia*
General
Sedation
Neither
Temperature Management Active warming in OR
Y
N
Patient temp at end of case (xx x centigrade)
IJCP’s ANESTHESIOLOGY NEWS, Volume 21, October-December 2013
In addition to standard patient information, the registry is a repository for data specific to ambulatory events such as anesthetic technique, adverse events, physical status, pain control and PONV.
focuses specifically on outcomes within the area of ambulatory care. The AQI and SAMBA are collaborating to ensure uniformity of data collection and to facilitate the sharing of appropriate information.
The SAMBA registry has been populated with data from members ranging from large academic medical centers to small private practices. Approximately a dozen centers entered more 20,000 individual case files into SCOR’s online system, providing sufficient data to identify initial trends. The majority of data (80%) were provided by freestanding and hospital ambulatory surgical centers (ASCs), whereas office-based and hospital out-treatment departments comprised the remaining 20%.
The registry is web-based, so all a practice needs is a computer and an Internet connection. Several ways to input the information exist; paper records can be transcribed into the system or input directly online by computer, smartphone or electronic pen-based records. Users can download their own data at any time and save it to a spreadsheet and also can compare them to national trends when they receive a quarterly report of aggregated data that has been de-identified to comply with federal privacy requirements.
“We’re in the growth phase at the moment,” explained Lucy Everett, MD, chief of pediatric anesthesia at Massachusetts General Hospital, in Boston, who is helping to build the registry. “We hope to have 100,000 cases by this time next year.” Further analysis showed that patients undergoing tonsillectomy or adenoidectomy were more prone to emesis, with 11.1% experiencing postdischarge vomiting and 15.6%, postdischarge nausea. Postoperative pain was somewhat more common, with 14% of patients saying their pain was not “always well controlled,” according to the researchers. ASCs, both single and multispecialty, have become more prevalent in the United States over the past few decades. According to SAMBA, the percentage of surgical procedures performed in an ambulatory setting in the United States rose from 19% in 1996 to 65% in 2007. Although a national anesthesia outcomes database already exists—the Anesthesia Quality Institute (AQI)—the SCOR registry
“A lot of ASCs have no automated system, so this registry can serve them but for those who do, they don’t want to have to input information twice so SAMBA is working to enable linkages with other systems to avoid duplication,” Dr. Everett said. The SCOR registry is primarily a member benefit, but nonmembers can pay a sliding fee to participate. Mark Saxen, DDS, PhD, president-elect of The American Society of Dentist Anesthesiologists, said that participation in SAMBA and SCOR is a natural fit for its members: “We follow the same essential clinical guidelines and recognize the importance of tracking outcomes for office-based anesthesia practice. Dentist anesthesiologists welcome the opportunity to participate in a registry that examines our results with the same assessment tools that are used to evaluate the broader community of all anesthesia providers.”
IJCP’s ANESTHESIOLOGY NEWS, Volume 21, October-December 2013
—Maureen Sullivan
9
CLINICAL ANESTHESIOLOGY
For ICU Patients, Quiet (If Not Quite Silence) is Golden
M
anaging intensive care patients in quiet, private rooms with ready access to natural light can reduce their risk for postoperative delirium by nearly 50%, Canadian researchers have found. The findings, reported at the 2012 annual meeting of the Canadian Anesthesiologists’ Society (abstract 1343666), confirm the suspicions of many clinicians that the intensive care unit environment may play a role in the development of delirium. “For years, people have talked about how delirium can be influenced by the way we do things in the hospital, which is typically designed for the convenience of staff and not necessarily the patient,” said Hilary Grocott, MD, professor of anesthesia and surgery at the University of Manitoba, who led the study. “It’s only now that people are thinking about designing hospitals and ICUs around some of the factors that we know affect patients.” Dr. Grocott’s institution recently renovated its intensive care rooms to incorporate certain features known to be appealing to patients, he said—creating a natural experiment. “We went from what we call an open design—no physical barriers between the different beds, no outside windows, small, loud space—to a unit that had all private rooms, wall-to-wall windows along one side and very little noise. Then we looked at the incidence of delirium before and after we moved, where the only thing that changed was the environment.”
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The chart review comprised 286 patients who had undergone cardiac surgery at the institution between May 1 and June 15, 2010, or May 1 and June 15, 2011. Other than the change in environment, the groups were comparable, including age, operative risk or the medications they had been taking. Delirium assessments were performed every 12 hours until postoperative day 7. The analysis found that 44 patients (15.4%) had at least one episode of delirium during their time in the hospital. In people aged 65 years and older, the more patient-friendly ICU was associated with a significant reduction in postoperative delirium (12.9% vs. 24.7%; P = 0.048), a difference Dr. Grocott called “meaningful.”
IJCP’s ANESTHESIOLOGY NEWS, Volume 21, October-December 2013
Increasing age also was an independent risk factor for the occurrence of delirium (odds ratio [OR], 1.55 per 10 years of age; 95% confidence interval [CI], 1.11-2.17; P = 0.0105). On the other hand, extubating patients in the operating room was associated with a reduction in the incidence of delirium (OR, 0.24; 95% CI, 0.10-0.59; P = 0.0009). Dr. Grocott recognized that most anesthesiologists do not have the luxury of a state-of-the-art ICU. But there are ways older facilities can mimic newer hospitals to produce similar benefits, he said. “We think right now that it’s the natural light, the quiet environment and the privacy that reduced delirium, but the missing link here may be improved patient sleep–wake cycles,” Dr. Grocott explained. “If that’s the case, then there probably are things that anesthesiologists can do pharmacologically to induce that more natural pattern.” These measures include minimizing sedatives or incorporating agents such as clonidine or dexmedetomidine, which have been shown to improve sleep–wake cycles. “It’s arguably a bit speculative because we don’t know for sure if it is the sleep–wake cycle,” Dr. Grocott added. “But certainly all those parameters that we adjusted by moving to a new ICU would be consistent with improving sleep–wake cycles.”
Charles S. Brudney, MBBCh, associate professor of anesthesiology and medicine at Duke University Medical Center in Durham, N.C., noted that the study supports existing research showing that the ICU environment affects patients’ sleep and delirium and the risk for developing post-traumatic stress disorder. “Some people have shown that if you improve the environment and make the nighttime seem more like nighttime, patients seem to have better outcomes and less delirium,” Dr. Brudney said. “I think the quality of sleep also needs to be looked at,” he continued. “You could argue—as a lot of people do—that because these patients are sedated, it doesn’t matter if it’s night or day. But our goal is to sedate our patients less, so you’ve got to change the environment or they are not going to get particularly restful sleep.” Changing the culture of an institution is not necessarily easy, however, particularly when health care personnel have jobs to do regardless of the time of day—or night. “I’ve historically tried to change my unit,” Dr. Brudney said. “I’ve banned food from the main nursing area in front of the patients and asked nurses to take their breaks in the back coffee room. But they still have all the lights on, take x-rays throughout the night, draw labs throughout the night and it’s all disruptive for the patient. No wonder they don’t get restful sleep.”
IJCP’s ANESTHESIOLOGY NEWS, Volume 21, October-December 2013
—Michael Vlessides
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CLINICAL ANESTHESIOLOGY
Post-op Cognitive Changes Tied to Brain Anatomy
T
he cognitive decline that sometimes follows heart surgery may be associated with changes in brain anatomy and function, according to findings presented at the 2012 annual meeting of the Society for Cardiovascular Anesthesiologists (Anesth Analg 2012;114[suppl]:1-94). Reviewing data collected from 11 patients who underwent cardiac surgery, Joseph Mathew, MD, chief of cardiothoracic anesthesiology at Duke Medical Center, in Durham, N.C., and his colleagues found that the patients exhibited edema in their white matter and less brain activity six weeks following the procedure. These changes were not seen in nine control patients with coronary artery disease who did not undergo surgery. These findings help confirm that cognitive changes do, indeed, occur after surgery, Dr. Mathew told Anesthesiology News. “Obviously, there is some disruption as a consequence of surgery, which is not seen in control patients,” he said. “There is something occurring during surgery that is resulting in an increase in cerebral edema and in how different areas of the brain are connected. Now, we can start to try to understand why it’s occurring, which will lead to ways to control it.” His hypothesis is that some of the changes may be due to air emboli, which could be remedied by trying to eliminate any trapped air before separating the patient from bypass. Although cognitive impairment typically is associated with cardiac surgery, researchers
12
have reported the same phenomenon following other types of surgery, said Gregory Crosby, MD, associate professor of anaesthesia at Harvard Medical School and Brigham and Women’s Hospital, both in Boston, who was not involved in the study. The cognitive changes—usually in memory and attention—are not always permanent, Dr. Mathew said. “Typically, 50% of patients recover by one year” after surgery. To investigate more fully the cognitive changes that happen after cardiac surgery, Dr. Mathew and his team administered five
IJCP’s ANESTHESIOLOGY NEWS, Volume 21, October-December 2013
cognitive tests at baseline and six weeks later to patients who underwent cardiac surgery and similar nonsurgical patients. At both points, they also measured the integrity of participants’ white matter and brain function using functional magnetic resonance imaging. The researchers found that patients who underwent surgery were more likely to exhibit cerebral edema six weeks later, largely in the prefrontal cortex. The swelling also was associated with cognitive decline (correlation coefficient, 0.74). Moreover, the white matter changes in surgical patients were accompanied by a significant decrease in brain activity, both relative to their baselines and to controls (P < 0.01). A unique aspect of the study, Dr. Crosby said, is that most previous reports have relied on neuropsychological testing to assess cognitive impairment after surgery, whereas Dr. Mathew and his team focused on structural and functional changes in the
brain. “These researchers are moving in the right direction—using sophisticated brain imaging technology to look at a common problem in an interesting way,” he said. However, the study was relatively small and the patients were relatively young (mean age, 63.9 years), he added, so it is premature to make any changes in practice based on these results. Furthermore, he said, it is unclear if the brain changes in these patients were specific to cardiac surgery, or whether the same patients undergoing colon resection, for example, would have had these changes on neuroimaging. “This study does not prove these changes are unique to cardiac surgery,” Dr. Crosby added.
Dr. Mathew and his colleagues are continuing to enroll patients in the study to determine if the same changes occur in a larger population of subjects.
IJCP’s ANESTHESIOLOGY NEWS, Volume 21, October-December 2013
—Alison McCook
13
WEB EXCLUSIVES
Researchers Discuss Steroid Controversies in Sepsis Treatment
I
f there was a treatment that was inexpensive, relatively safe, doubled the rate of extubations in patients with acute respiratory distress syndrome (ARDS) and did not increase mortality, how many doctors would use it? Gianfranco Umberto Meduri, MD, professor of medicine at the Memphis VA Medical Center in Memphis, Tenn., posed this question to the audience at the recent Society of Critical Care Medicine (SCCM) annual meeting. He was referring to using corticosteroids in septic shock and ARDS, and many in the audience raised their hands. Speaking at a session on ongoing sepsis controversies, Dr. Meduri said the evidence for using corticosteroids in patients with septic shock is strong for improvements in patient-centered outcomes and weak for mortality reduction. The biologic rationale for the treatment is solid: Systemic inflammation is the hallmark of sepsis and corticosteroids modulate the immune response to sepsis through genomic and non-genomic effects. In almost half of patients with septic shock, cytokines suppress cortisol production or access to tissues, inducing corticosteroid insufficiency. Research has shown that unfavorable outcomes in sepsis and ARDS are related to the degree of inflammatory response at the onset and during the course of the disease (Chest 1995;107:1062-1073). Furthermore, findings from large datasets indicate that systemic inflammation extends beyond clinical resolution of acute illness and has
14
a significant negative affect on long-term outcome (Am J Respir Crit Care Med 2008;177:1242-1247). For this reason, Dr. Meduri said, corticosteroid treatment should be directed at achieving biological and not clinical resolution and followed by slow tapering (six to nine days) to avoid rebound inflammation. Among the evidence Dr. Meduri discussed arguing for the use of steroids in ARDS patients was a 2009 review that concluded that prolonged low- to moderate-dose glucocorticoid therapy promotes the down-regulation of inflammatory cytokine transcription at the cellular level (Chest 2009;136:16311643). This review incorporated eight controlled studies (five randomized) in patients with ARDS (most sepsis-induced) that consistently reported a significant reduction in markers of systemic inflammation, pulmonary and extrapulmonary organ dysfunction scores, mechanical ventilationfree days (weighted mean difference, 6.58 days; 95% confidence interval [CI], 2.93-10.23; P < 0.001) and intensive care unit (ICU)-free days (weighted mean difference, 7.02 days; 95% CI, 3.20-10.85; P < 0.001). This is a sizable response not observed with any other investigated intervention in ARDS, said Dr. Meduri. In the aggregate (n = 628), the eight studies found a substantial reduction in mortality for all patients (relative risk [RR], 0.75; 95% CI, 0.63-0.89; P < 0.001) and for those treated before day 14 (RR, 0.71; 95% CI, 0.59-0.85; P < 0.001).
IJCP’s ANESTHESIOLOGY NEWS, Volume 21, October-December 2013
More Recent Evidence Also Encouraging
The most recent data comes from a study in early ARDS patients that found that administration of methylprednisolone was associated with improvement in important biomarkers of inflammation and coagulation and clinical outcomes compared with placebo (Crit Care Med 2012;40:495-501).
Turning to septic shock, he pointed out that a meta-analysis of 12 trials investigating prolonged low-dose corticosteroids reported a significant reduction in 28-day mortality (37.5% vs. 44%; P = 0.02), organ dysfunction and duration of ICU stay (JAMA 2009;301:2362-2375). The CORTICUS (Corticosteroid Therapy of Septic Shock) study, however, showed no mortality benefit, despite reduction in duration of vasopressor use (N Engl J Med 2008;358:111-124). This randomized Phase III study carried weight because it was a large randomized study of 500—mostly surgical—patients comparing hydrocortisone or placebo every six hours for five days followed by a six-day taper. In a 2010 review, several sepsis experts concluded that despite the disappointment of the CORTICUS trial, the evidence suggests a modest to high probability (80%-98%) of efficacy for low-dose steroids with respect to both mortality and shock reversal (Crit Care 2010;14:R134). A new analysis of the CORTICUS dataset found reductions in organ dysfunction scores for hydrocortisone-treated patients from day 0 to day 7 compared with placebo-treated patients (P = 0.0027) (Intensive Care Med 2011;37:17651772). This was driven by an improvement in cardiovascular organ dysfunction/failure (P = 0.0005) and in liver failure (P < 0.0001) in the hydrocortisone-treated patients. At the SCCM meeting, researchers from the University of Manitoba presented a retrospective, multicenter propensity-matched cohort study, in which half of the 3,676 patients were treated with low-dose corticosteroid therapy within 48 hours of documented septic shock and half were not (abstract 389). The investigators did not identify any significant differences in 30-day mortality among the three lowest APACHE II quartiles. In the highest quartile,
the use of low-dose corticosteroids was associated with a significantly lower 30-day mortality (50% vs. 55.8%; HR, 0.81; 95% CI 0.68-0.97). According to Dr. Meduri, there is strong evidence that prolonged glucocorticoid therapy down-regulates systemic inflammation and is consistently associated with large and significant improvements in patientcentered outcomes. Moderate to strong evidence exists that the use of prolonged glucocorticoids is not associated with increased risk for nosocomial infections and is associated with a reduction in post-traumatic stress disorder. There is weak evidence, he said, that prolonged use of glucocorticoid therapy is associated with decreased mortality. “The risk–benefit ratio supports the use of prolonged treatment [with steroids] with slow tapering in unresponsive pressor-dependent shock, early severe ARDS and unresolving ARDS. There is a large and significant improvement in patient outcomes,” Dr. Meduri said, noting large and significant reductions in vasopressor duration, multisystem organ failure, and duration of ICU stay. “The risk of treatment is limited to hyperglycemia that is decreased with infusion and neuromuscular weakness that is decreased by avoiding neuromuscular paralysis,” Judith Jacobi, PharmD, critical care pharmacist at Indiana University Health Methodist Hospital, in Indianapolis, who attended Dr. Meduri’s presentation at SCCM, said she uses corticosteroids in her patients with shock. “We have known for a long time that when you give steroids to someone in shock, they resolve their shock more quickly. The CORTICUS trial concluded there is no impact of steroid replacement on mortality [in septic shock patients],” she said. “I suspect that the apparent conflict has led to differing practice patterns.” She said she does not use steroids in her ARDS patients. “That needs to be confirmed in a large-scale, multicenter clinical trial.”
IJCP’s ANESTHESIOLOGY NEWS, Volume 21, October-December 2013
—Drs. Meduri and Jacobi
have no relevant disclosures
—Kate O’Rourke
15
WEB EXCLUSIVES
Senate Passes Bill to Address Drug Shortages
O
n June 26, in a 92-4 vote, the Senate approved reauthorizing the Prescription Drug User Fee Act, in a bill that includes provisions addressing the nation’s rampant drug shortages. Known as the Food and Drug Administration Safety and Innovation Act (s. 3187), the bill already had been passed by the House and now goes to President Obama for signature. Joseph M. Hill, director of federal legislative affairs at the American Society of Health-System Pharmacists (ASHP), said that the President is expected to sign the bill. To address drug shortages, the legislation requires drug manufacturers to notify the FDA at least six months in advance of a product discontinuation or interruption, or as soon as possible. In the event of noncompliance, the FDA will send a letter to the manufacturer and require a response within 30 days that explains the noncompliance. In addition, the bill calls for a task force to establish a strategic plan to deal with shortages, and permits health systems to repackage drugs and transfer them to other hospitals within the system. The FDA and Drug Enforcement Administration are required to collaborate and, if necessary, adjust quotas related to shortages of controlled substances. The bill’s establishment of user fees for generic drugs and biosimilars “will help FDA to approve generic products faster; this will speed up approval times and get products to market quicker,” Mr. Hill said in an email.
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A coalition of organizations was active in the effort to produce the legislation. The Institute for Safe Medication Practices (ISMP) is part of that coalition; other core members include the American Society of Health-System Pharmacists, the American Hospital Association, the American Society of Clinical Oncology and the American Society of Anesthesiologists, according to Allen J. Vaida, PharmD, FASHP, executive vice president of ISMP, in Horsham, Pa. “We’re pleased the legislation finally came through, although it’s taken a long time,” said Dr. Vaida, who noted that the coalition has been working on the issue since 2010. “A lot of our suggestions have gotten incorporated into the legislation.” Speaking of ASHP’s position on the bill, Mr. Hill said, “We are very much in support of it.” Commenting on the legislation, Erin R. Fox, PharmD, FASHP, director of the Drug Information Service at the University of Utah Hospitals & Clinics and adjunct associate professor in the Department of Pharmacotherapy at the University of Utah College of Pharmacy, in Salt Lake City, said, “It’s a great start and I think it will help.” Referring to the FDA’s record of success with voluntary early notification, Dr. Fox said, “If notified early enough, [the] FDA can try to prevent shortages. Once a shortage starts, there’s not always much FDA can do.” Dr. Fox noted that the number of new shortages beginning in 2012 is about half the number that occurred during the same time
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period in 2011. Calling this an “encouraging” sign, she said, “I believe we are seeing the results of [the FDA’s] efforts in the rate of new shortages.” Drs. Fox and Vaida both stressed that other changes besides this legislation would be needed to improve the shortage problem. Dr. Fox said manufacturing is a major issue: “Manufacturers need to step up quality and adhere to good manufacturing practices.” Dr. Vaida said redundancy in the supply chain is needed, such as requiring that several different manufacturing facilities be approved
to produce a drug if a company is the sole supplier. In the meantime, Dr. Fox said her hospital faces continuing shortages of drugs such as leucovorin, naloxone, lorazepam, fentanyl, sufentanil, etomidate and midazolam. To deal with shortages, she said, “We rotate the stock frequently, try to centralize stock and draw up doses in the clean room.” She also uses alternative agents, such as levoleucovorin instead of leucovorin. “We’re getting by with time and effort and lots of concern for potential errors.”
IJCP’s ANESTHESIOLOGY NEWS, Volume 21, October-December 2013
—George Ochoa
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WEB EXCLUSIVES
Too Many Tacks Associated with Postoperative Hernia Pain Caution Advised Against Liberal Use of Tacks, Regardless of Type
F
ixing hernia meshes with more than 10 tacks, even if they are absorbable, doubles the risk for early postoperative pain while having no benefit on reducing rates of recurrence, suggests a review published in the Annals of Surgery. Moreover, surgeons are more likely to use tacks liberally when using the absorbable variety, the study showed (2011;254:709-715). “Absorbable tacks take months to degrade, and in the short-term, these tacks are just as liable to induce postoperative pain as their permanent counterparts,” wrote Igor Belyansky, MD, a fellow in laparoscopic surgery at Carolinas Medical Center, in Charlotte, N.C., and colleagues in their report. Dr. Belyansky and colleagues used the International Hernia Mesh Registry (IHMR) to compare postoperative quality of life in patients undergoing laparoscopic totally extraperitoneal (TEP), transabdominal preperitoneal (TAPP) or modified Lichtenstein (ML) hernia repairs. The IHMR is a prospectively collected, multicenter database with more than 30 participating sites in the United States, Europe and Canada. “Patients are allowed to enter their own quality-of-life data and this is the first study to directly compare quality-oflife outcomes of TEP, TAPP and open repair in such a manner,” Dr. Belyansky said. Investigators studied almost 2,000 patients who underwent inguinal hernia repairs completed between 2007 and 2010.
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The distribution of unilateral procedures was TEP (n = 217), TAPP (n = 331) and open repair (n = 953), with bilateral repairs in 413 patients. Analysis showed that one month after surgery, patients in whom absorbable tacks were used experienced higher rates of postoperative pain than those in whom nonabsorbable tacks were used (25.7% vs. 11.5%; P = 0.015). However, further investigations found that absorbable tacks were, on average, applied in greater quantities than nonabsorbable tacks (P = 0.001). When using absorbable tacks, surgeons placed more than 10 tacks in 33% of cases compared with 2.7% of cases with permanent tacks. When controlling for the number of tacks, no difference was observed in pain levels during early or long-term follow-up between absorbable and permanent tacks. That suggests it is the number of tacks used, and not the materials used in the absorbable tacks, that account for the higher rates of postoperative pain. There was no difference in recurrence rates when more tacks were used or with the application of absorbable or permanent tacks, the study showed. Investigators encouraged surgeons to use the same degree of caution with absorbable tacks as they would with permanent ones. Absorbable tacks do carry certain advantages, including the reduction of adhesion-related complications, but it’s their
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overuse that is problematic, said Todd Heniford, MD, principal investigator in the study and chief of gastrointestinal and minimally invasive surgery at Carolinas Medical Center. Some surgeons now use surgical glues alone for mesh fixation in order to reduce postoperative discomfort, said Dr. Heniford. This helps mitigate pain in the early postoperative phase, although their unpublished data now demonstrate that these patients complain of significantly more discomfort in prolonged follow-up than tack patients. “With further investigation, we have found that with at least a year follow-up, nearly three times as many patients whose mesh was fixated with glue believe that their hernia has recurred because of increased symptoms and quality-of-life limitations,” Dr. Heniford said. The finding needs to be validated with randomized studies, said Robert J. Fitzgibbons, MD, professor of surgery at Creighton University School of Medicine, in Omaha, Neb. “It’s interesting that surgeons use absorbable tacks more liberally and I’m sure I’m guilty of that myself,” he said. However, the investigators used a database to which surgeons can voluntarily submit data, which may skew the results. “Before I really trust the conclusions or make any practice changes, I’d want to see a randomized trial,” Dr. Fitzgibbons said. The investigators note that the study was carried out among regional and national hernia specialists. Of any group studies, patients undergoing TAPP repair had the highest frequency of symptoms after one month, as measured by the Carolinas Comfort Scale (CCS). More than 16% of first-time unilateral TAPP repair patients and 40.7% of recurrent unilateral repair patients had CCS scores greater than 1. Similar scores were reported by 8.9% of first-time and 21.4% of recurrent TEP repair
patients and 16.5% and 20% of unilateral and current ML repair patients. Subgroup analysis showed more tacks were used in patients who underwent TAPP repairs. In all, 18.2% of TAPP patients had more than 10 tacks compared with only 2.3% of TEP repairs. Tacks are not generally used for an ML repair: Only 0.2% of these patients received any tacks. When controlling for number of tacks, no difference in symptoms was observed between TEP and TAPP methods. Some surgeons may choose to use tacks more often for TAPP repairs because of the need to close the peritoneum, said the authors. “Excess tacks cause patients early postoperative discomfort and diminish some of the central benefits of the laparoscopic approach. We hope this body of work will encourage hernia surgeons to reassess their current practice of peritoneal closure when performing a TAPP repair,” Dr. Belyansky said. Alternative methods for mesh fixation exist, including sutures, fibrin glue and no fixation as mesh is placed in the preperitoneal space. One surgeon expressed concern about the simplified pain score used in the analysis. “Your abstract suggests causality with the use of tacks; you cannot, of course infer that from your data set,” said Dion Morton, MD, professor of surgery, University of Birmingham, United Kingdom. Previous studies have shown that tacks in inappropriate locations or in excess can contribute to pain following laparoscopic hernia repair. Absorbable tacks were developed in hopes that the dissolution of the tack would reduce incidence of long-term pain and adhesions. The study also showed that repair of recurrent hernia was a strong predictor of postoperative pain. “The difference in quality-of-life outcomes may be secondary to
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19
extensive tissue trauma caused by dissection of reoperative, scarred area,â&#x20AC;? the authors concluded.
There was little difference in recurrence between the three operative methods. Recurrence rates ranged from 0.5% to 1.4%.
Bilateral inguinal hernia repairs also were associated with higher pain levels during the early postoperative period when compared with unilateral repairs. Here, too, use of more than 10 tacks on each side was associated with higher frequency of symptomatic patients in the first month.
The authors are currently investigating predictors of chronic pain after undergoing an inguinal hernia repair. After the key factors contributing to chronic pain are identified, they plan to develop an algorithmic model that can be used in the preoperative setting.
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â&#x20AC;&#x201D;Christina Frangou
IJCPâ&#x20AC;&#x2122;s ANESTHESIOLOGY NEWS, Volume 21, October-December 2013
PHARMACOLOGY
New Agent Rapidly Reverses Rocuronium, Vecuronium Block Agent that Selectively Binds Two Neuromuscular Blockers Is Currently in Phase II Trials
T
he results of four ongoing Phase II trials indicate that a new selective relaxant binding agent, a γ-cyclodextrin (GC) compound, has the potential to radically change the way neuromuscular blockade is administered and reversed. Depending on the dose of the GC compound, moderate and deep neuromuscular blockade in patients receiving either rocuronium or vecuronium was reversed rapidly and safely, often in less than two minutes.
“Sugammadex [the GC derivative, also known as Org 25969; Organon Inc.] is revolutionary, especially when you look at its implications in a difficult airway, for example,” commented Scott B. Groudine, MD, Professor of Anesthesiology and Critical Care Medicine and Director of Research at Albany Medical College in Albany, N.Y. “Basically, it’s like putting an eraser on your pencil.” “We have an antidote for opioids, we have an antidote for midazolam, and now we have an antidote for rocuronium,” he added. “This way, if you give rocuronium erroneously, you can give Sugammadex, bind the rocuronium and render it inactive within a couple of minutes.” Although there are other agents available for reversal of neuromuscular blockade, all have certain limitations. Anticholinesterases and cholinergic drugs can have significant side effects, and are typically only used once patients have demonstrated some recovery of activity at the neuromuscular junction.
Cyclodextrins may form inclusion complexes with several types of molecules. The GC derivative, on the other hand, acts as a selective relaxant binding agent specifically designed to encapsulate rocuronium; most of this complex is then excreted renally. Rather than antagonize a neuromuscular blockade, the GC compound reduces the concentration of blocking agent at the neuromuscular junction, which promotes rapid reversal from neuromuscular block.
Dose-Response Relationship Study Four trials were presented at the 2005 annual meeting of the American Society of Anesthesiologists. In the first one (Abstract A1117), a team of Dutch researchers explored the dose-response relationship between the
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GC compound and 1.2 mg/kg rocuronium in ASA I-II patients. Forty-six ASA I-II patients (23 males, 23 females) participated in the multicenter, randomized, double-blind, parallel, dose-finding Phase II trial.
Each patient underwent a standardized anesthesia protocol comprising propofol, remifentanil, oxygen and air; rocuronium 1.2 mg/kg was administered for intubation. Neuromuscular function was monitored using train-of-four (TOF) nerve stimulation and acceleromyography (TOF-Watch SX). Five minutes after rocuronium administration, participants received placebo or a GC dose of 2, 4, 8, 12 or 16 mg/kg. The primary efficacy variable, as in all studies reported here, was the time from GC injection to recovery of TOF ratio >0.9. The investigators also assessed clinical signs that could indicate recurarization. Safety assessments were performed on postoperative days 0, 1 and 7. It was found that the four patients receiving placebo attained a 0.9 TOF ratio in 122:05 ± 18:05 minutes (mean). By comparison, those receiving 2 mg/kg (n = 5) and 4 mg/kg (n = 5) doses of GC reached this milestone in 56:30 ± 5:22 minutes and 15:47 ± 17:45 minutes, respectively. Patients receiving the higher doses of GC (8, 12 and 16 mg/ kg) achieved much faster reversal times: 2:45 ± 0:33 minutes, 1:23 ± 0:19 minutes and 1:55 ± 2:13 minutes, respectively. “In the 16 mg/kg group, the time to recovery was somewhat slower than in the 12 mg/kg group because one patient had a very slow recovery compared with the rest of the group,” commented principal investigator Hans de Boer, MD, Staff Anesthesiologist at the University Medical Centre Nijmegen, in Nijmegen, the Netherlands. “The fastest recovery we observed in this dose group was 41 seconds, and the outlier was six minutes and 45 seconds.” Three serious adverse events were reported (all, QTc prolongations), none of which was considered to be related to GC. “In addition, two patients had what might be drug-related adverse events,” he added. One patient experienced diarrhea, and the other light 22
anesthesia/movement during surgery. Signs of recurarization were not observed. Dr. de Boer’s co-investigators were Marco Marcus, MD, Peter Schouten, MD, Marten Heeringa, PhD, and Jacques Driessen, PhD.
Efficacy Study A second trial (Abstract A1119) examined the efficacy of GC in reversing moderate rocuronium- and vecuronium-induced neuromuscular block (defined as the reappearance of T2 by the TOF watch) in 79 ASA I and II patients aged 19 to 84 years. Of the participants, 39 received 0.6 mg/kg rocuronium; the remainder received 0.1 mg/kg vecuronium. Rocuronium patients were randomly allocated to receive placebo or a GC dose of 0.5, 1, 2, 3 or 4 mg/kg. Vecuronium patients received placebo or a GC dose of 0.5, 1, 2, 4 or 8 mg/kg. The researchers at Onze-Lieve-Vrouw Hospital in Aalst, Belgium—Koen Suy, MD, Karl Morias, MD, Pol Hans, MD, Marten Heeringa, PhD, and Ignace Demeyer, MD— found a dose-response relationship between the GC dose and recovery time for both rocuronium and vecuronium (Table 1). “A curve was then calculated,” commented Dr. Suy, Attending Anesthesiologist at the institution. “The slope and plateau for vecuronium and rocuronium start between 1 mg/kg and 2 mg/kg for moderate neuromuscular block.” Only one rocuronium patient experienced an adverse event, which was a moderate incident of tachycardia. Three vecuronium patients experienced adverse events, including moderate abdominal discomfort, mild erythema and delayed recovery from anesthesia. “The side effects we saw were mild to moderate in intensity,” Dr. Suy told Anesthesiology News, “and they needed no treatment at all. Their relationship to Sugammadex is questionable, because we also see many of them when Sugammadex is not used.”
IJCP’s ANESTHESIOLOGY NEWS, Volume 21, October-December 2013
Dose-Response Study of Reversal of High-Dose Rocuronium A third trial (Abstract A1129) evaluated the dose-response relationship of the GC compound for reversal of deep neuromuscular blockade after high-dose rocuronium (1.2 mg/kg), in 87 ASA I-III patients aged 18 to 82 years. Each participant in the international, multicenter, Phase II trial received 1.2 mg/kg rocuronium for intubation, followed by the study drug or placebo either three minutes (n = 58) or 15 minutes (n = 29) later. GC was administered in doses of 2, 4, 8, 12 and 16 mg/kg. The researchers—Christopher Rex, MD, Karin Khuenl-Brady, MD, Andreas Sielenkaemper, MD, Casper C. Kjaer, MD, and Friedrich K. Puehringer, MD—found that administering GC 15 minutes after rocuronium administration appeared to result in a superior recovery profile (Table 2). As Dr. Rex explained, the outlier in the 16-mg/kg group was largely the result of the study design. Patients had to attain a TOF
ratio > 0.9 in three consecutive measurements to be considered recovered. One subject in this group had a TOF of 0.89 immediately, but stayed between 0.87 and 0.89. He reached 0.9 five minutes later. Fifteen adverse events were reported, all of which occurred in patients receiving the study drug three minutes after rocuronium: anesthetic complications (including wake-up reactions due to light anesthesia [n = 5]), nausea (n = 2), vomiting (n = 2), hypertension (n = 2), QTc prolongation (n = 1), vertigo (n = 1), dizziness (n = 1) and hypotension (n = 1). No recurarization was observed.
A Case Study The fourth presentation (Abstract A1130) was a case study of a 54-year-old woman (61 kg) enrolled in an ongoing Phase II trial in the United States. The woman, who presented for a urinary stent procedure, underwent uneventful induction of general anesthesia and paralysis with rocuronium (1.2 mg/kg); surgery lasted 55 minutes. A propofol-based I.V. technique was used for maintenance of general anesthesia.
Table 1. Dose-Response of g-Cyclodextrin Compound or Placebo Versus Rocuronium and Vecuronium Recovery Times Rocuronium Reversal, min:sec
Vecuronium Reversal, min:sec
31:48 ± 21:00
Placebo
48:45 ± 27:53
0.5 mg/kg
3:4 ± 1:02
0.5 mg/kg
7:43 ± 2:34
1.0 mg/kg
2:19 ± 0:35
1.0 mg/kg
2:30 ± 0:49
2.0 mg/kg
1:43 ± 0:36
2.0 mg/kg
2:15 ± 0:48
3.0 mg/kg
1:53 ± 1:10
4.0 mg/kg
1:31 ± 0:32
4.0 mg/kg
1:07 ± 0:18
8.0 mg/kg
1:24 ± 0:28
Placebo
Table 2. Recovery Profile of g-Cyclodextrin or Placebo with Rocuronium at 3 and 15 Minutes Rocuronium, 3 Min Later, min:sec
Rocuronium, 15 Min Later, min:sec
Placebo
122:59 ± 28:28
139:37 ± 79:53
2.0 mg/kg
65:40 ± 24:35
42:12 ± 29:20
4.0 mg/kg
13:47 ± 7:38
5:58 ± 2:28
8.0 mg/kg
3:14 ± 0:59
2:20 ± 0:18
12.0 mg/kg
2:05 ± 0:51
1:46 ± 1:11
16.0 mg/kg
1:19 ± 0:25
4:44 ± 6:41*
* Include one outlier. The median time to reversal was 1:56.
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240 220
Time (min) after rocuronium
200
3 min 15 min
180 Recovery time (min)
160 140 120 100 80 60 40 20 0
0
2.0
4.0
8.0
12.0
16.0
Dose (mg/kg)
Figure. Dose-response curve of g-cyclodextrin administered 3 and 15 min after rocuronium 1.2 mg/kg.
At the conclusion of surgery, the subject was deeply paralyzed, with no TOF response and a post-tetanic count of 1. GC was administered at 11:38:12, at a dose between 0.5 and 8 mg/kg (the exact dose was blinded to investigators). One minute after administration of GC, the TOF ratio was 68%. The ratio reached 93% at two minutes and stayed above 90% until the patient was extubated. This reversal was confirmed clinically when the patient demonstrated return to full muscular strength with prolonged headlift, no diplopia and a strong bite test (inability to remove a tongue depressor from between the patient’s clenched teeth). No evidence of recurarization was seen as long as 400 minutes after GC administration. “The response is so profound that you put the drug in an I.V., you walk around the foot to the computer screen where the TOF watch was being recorded, and you already have four twitches back,” principal investigator Dr. Groudine told Anesthesiology News. “Then, within another minute, the train-of-four ratio could be greater than 90.
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We had one patient that had full recovery in 55 seconds.” Although he acknowledged that the potential for side effects always exists, Dr. Groudine noted that he had witnessed nothing serious in the ongoing trial. “We had one person who got a little bradycardic, but we’re not ready to say whether it was drugor surgical-related,” he said. “The biggest thing I’ve found is that you go from no muscle tone to full muscle tone in two minutes, which is a radical change in physiology,” he added. “The first time I gave what appeared to be a large dose, the patient almost got off the table before I got to the head of the table. He was sitting up, ready to extubate himself. And this is a person who had no response to a train of four a minute before. It doesn’t even cross your mind that somebody who has a 0 train of four is going to arm-wrestle you to extubate themselves a minute later. “But this is what’s happening with this drug. And I think it’s very exciting, a new era in anesthetic care.”
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Dr. Groudine’s co-investigators were Roy Soto, MD, Melissa Ehlers, MD, Kevin Roberts, MD, and Khallid El-Mohtar, MD.
the Chief of Anesthesiology and Medical Director of Perioperative Services at Virginia Mason Medical Center in Seattle.
Barbara W. Brandom, MD, who co-moderated one of the sessions in which the research was presented, found GC very promising, but also acknowledged the need for more research during these early stages of the agent’s development. “I think there’s more work to be done in terms of reversing repeated doses of neuromuscular blocker,” said the Professor of Anesthesiology at the University of Pittsburgh Medical Center. “For instance, if a patient got rocuronium or vecuronium for several days in the ICU, should Sugammadex be used, and if so, what dose would be appropriate? Similarly, will greater doses of Sugammadex be necessary in the presence of antibiotics or magnesium, which might potentiate neuromuscular block?”
“Succinylcholine is currently used by many for fast onset, but more importantly [for] the ability to have rapid wear-off to allow the ‘safe harbor’ of restoration of spontaneous ventilation should the anethesiologist encounter a difficult intubation. Sugammadex could allow use of a steroid nondepolarizing drug for intubation and then rapid antagonism should that clinical need arise. It could eliminate the need for the use of neostigmine for reversal. This drug is associated with an increase in postoperative nausea and vomiting.”
Nevertheless, the drug has significant potential to mitigate the problem of residual block, she continued. “Residual block is very common but often unrecognized by anesthesiologists, putting our patients at some level of risk. If sugammadex can be given at any level of neuromuscular block, and the patient is guaranteed complete recovery, then it’s a great advance.” Dr. Brandom did not consider Sugammadex to be the first line of defense against unexpected different intubations, however. “I wouldn’t consider Sugammadex the great solution to a difficult intubation, because really the solution to difficult intubation is clinical judgment before anesthesia is induced. I wouldn’t want to imply that rocuronium or vecuronium should be used for difficult intubations.” Co-moderator Stephen M. Rupp, MD, also saw the potential for the GC compound to change anesthetic practice. “Sugammadex might eliminate the use of succinylcholine entirely from anesthetic practice,” commented
“Sugammadex might also allow a different approach to the titration of muscle relaxant during surgery,” Dr. Rupp added. “Currently, practitioners are keenly aware of the need to have some spontaneous thumb twitch recovery prior to antagonism of neuromuscular blockade. This target may affect the quality of surgical relaxation and creates tension between the immediate objectives of the surgeon and the broader objectives of the anesthesiologist (who wants to provide adequate relaxation but allow a reversible block at the end of the case). With Sugammadex, a much deeper level of relaxation might be able to be provided with the relaxant right up to the end of the case. This potentially could improve surgical conditions, yet allow fast and reliable recovery at the end.” Yet, despite these potential benefits, Dr. Rupp was quick to point out that the GC compound does not have a proven safety record, warranting caution in its use, especially at higher doses. All four studies were supported through grants from NV Organon, in Oss, the Netherlands.
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—Michael Vlessides
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PAIN MEDICINE
Seeking Prognostic Cues During Lumbar Injections
I
nterlaminar lumbar epidural steroid injections (LESI) are a proven method for providing short-term relief of low back and unilateral radicular pain. But predicting how patients will respond to such treatments has not been so straightforward. But a study by a Chicago research team has found that ipsilateral pressure paresthesias occurring during LESI correlates with pain relief, and can be used as a prognostic factor when a parasagittal approach to the epidural space is used. “Lumbar epidural steroid injections are among the most commonly performed interventional pain procedures in the country,” said Nebojsa Nick Knezevic, MD, PhD, director of anesthesiology research at Advocate Illinois Masonic Medical Center. “In this study we tested ... the parasagittal approach—which means we’re going 1 cm laterally from the midline, depending on the side where the pain is.” The investigators hypothesized that a pressure paresthesia occurring in the same distribution of the radicular pain would give prognostic information regarding the efficacy of the LESI. The investigators enrolled 100 adult patients, all of whom received LESI by either the midline (n = 50) or parasagittal approach (n = 50), both under fluoroscopic guidance. Patients confirmed whether or not they experienced a pressure paresthesia, and if so, whether it was in the distribution of “usual and customary pain.” Patients also graded
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pressure paresthesias (0 = no paresthesia; 1 = mild; 2 = moderate; 3 = severe), both ipsilaterally and contralaterally. As Dr. Knezevic reported at the 2012 annual meeting of the American Society of Anesthesiologists (abstract 202), most parasagittal patients felt pressure paresthesias as “usual and customary pain” (39 of 50). In contrast, 23 patients undergoing the midline approach gave the same response (P = 0.002). With respect to severity, 32 parasagittal patients felt moderate or severe paresthesia on the ipsilateral side as their radicular pain compared with 19 midline patients. By comparison, only five patients in the parasagittal group felt pressure paresthesia on the contralateral side and 18 in the midline group. Average pain score before injection was 5.1 ± 2.4 at rest and 7.2 ± 2.2 during movement in the midline group, and 4.9 ± 2.5 at rest and 7.6 ± 1.9 during movement in the parasagittal group. Both LESI approaches clinically and statistically significantly reduced unilateral lumbosacral radiculopathic pain compared with the basal level (both at rest and during movement), according to the researchers. The investigators found a statistically significant negative correlation between ipsilateral pressure paresthesia and both types of pain score in parasagittal patients, and with only pain at rest in midline patients.
IJCP’s ANESTHESIOLOGY NEWS, Volume 21, October-December 2013
“The correlation between pain relief and pressure paresthesia was indirect when the paresthesia was on the ipsilateral side and direct when identified on the contralateral side,” Dr. Knezevic explained. “This means that a more severe pressure paresthesia ipsilaterally and a less severe paresthesia contralaterally is related to better pain relief.” As a result, he added, the findings “could be utilized to optimize our therapeutic success in patients who get these injections for radiculopathic pain.”
The association between pressure paresthesia and pain relief did not surprise David Provenzano, MD. “To me it indicates that directing the medicine toward the area of nerve compromise is important,” said Dr. Provenzano, executive director of the Institute for Pain Diagnostics and Care at Ohio Valley General Hospital, in Pittsburgh. “That’s one of the reasons why some practitioners advocate for the use of transforaminal steroid injections. The downside of the midline interlaminar approach is the medicine may never get where you want it to go.”
IJCP’s ANESTHESIOLOGY NEWS, Volume 21, October-December 2013
—Michael Vlessides
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PAIN MEDICINE
Eight Principles for Safer Opioid Prescribing: An Interview with Lynn Webster, MD L
ynn R. Webster, MD, became president of the American Academy of Pain Medicine (AAPM) on April 19, at the AAPM annual meeting in Fort Lauderdale, Fla. At that time, he announced three ambitious goals for the academy for the coming year: ●● Educating physicians and patients about safer prescribing and use of pain medications, when they are appropriate to be used at all; ●● Improving the health care delivery system so that comprehensive treatment is available to patients with chronic pain; and ●● Investigating new treatments that are more effective and safer than current options. Dr. Webster has agreed to participate in three interviews with our sister publication, Pain Medicine News, to address each of the goals. The first interview, which describes eight principles for safer opioid prescribing (box), addresses the first goal.
Pain Medicine News: I don’t recall the AAPM president ever announcing an agenda like you have. Why did you do this and why these goals? Dr. Webster: AAPM has advocated for all of these ideas at various times in the past. What’s different about now is that the Academy has committed itself to pursuing these three goals in a comprehensive manner. We must play a leadership role in making a difference for our patients and society.
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PMN: What led the AAPM to target these three goals? Dr. Webster: These three goals are consistent with the mission and vision of the Academy and will help us focus on activities that can make a difference within one year. They are specific, practical and achievable this year.
PMN: How did you become interested in addressing prescription drug overdoses? Dr. Webster: Like others who practice in the field, I became concerned about reported upswings in prescription drug overdose deaths. I felt strongly that physicians needed to assume the leadership role in addressing this issue and began researching the root causes of overdose death. I learned that one of the major contributing factors was a lack of knowledge and information that, if corrected, might prevent unintentional overdoses. In 2006, I started a nonprofit foundation with the purpose of funding research and educational programs to prevent overdoses from opioids. The eight principles for safer opioid prescribing are an extension of the past seven years of that effort.
PMN: What are these eight principles for safer opioid prescribing, and how were they chosen? Dr. Webster: The principles are what AAPM considers highly specific “best practices” that physicians should consider to reduce the risk for unintentional deaths if an opioid is
IJCP’s ANESTHESIOLOGY NEWS, Volume 21, October-December 2013
prescribed. The principles were created by analyzing the scientific literature on overdose deaths. For example, because opioids are the sole agents in only one-third of poisoning deaths, physicians must be aware of the other medications a patient is using before prescribing opioids. Similarly, reports show that patients with mental health disorders are at greater risk for problems with opioids, including overdose. This makes a mental health assessment an important part of the evaluation before prescribing opioids.
PMN: Why is this a primary goal for the AAPM? Doesnâ&#x20AC;&#x2122;t treating pain entail more than prescribing opioids? Dr. Webster: Absolutely. The AAPM advocates an interdisciplinary approach to treating pain using multiple treatment options, including complementary and alternative therapies. Opioid therapy is only one available treatment, and opioids are not appropriate for all people. Safer opioid prescribing is one of our primary goals because opioids are associated with significant harm, and the prominence of the issue obscures patient access and the need for better treatments. If we can eliminate or significantly reduce the harm from opioids, we can focus on other research and innovations to help people in pain.
PMN: Why these eight principles? Could there be other equally important steps to addressing the problem? Dr. Webster: These principles are actions physicians and clinicians can implement themselves to have an immediate effect and should prevent many deaths. Some could argue for more or different principles but, we, as pain physicians, think these principles will make a difference immediately. Bottom line, our first objective must be to prevent deaths in patients prescribed opioids for pain.
PMN: Should the FDA require the educational programs of the Risk Evaluation and Mitigation Strategies (REMS) for extended-release and long-acting opioids to include the eight principles?
Dr. Webster: We believe that the FDA and those who are committed to preventing deaths will consider principles such as these for their programs. Although no one has a lock on knowledge or can guarantee outcomes, these principles are compelling to us and could reduce deaths.
PMN: How are you planning to make physicians aware of these principles? Dr. Webster: The Academy is developing a plan to promote the principles to all AAPM members and ask that they promote them in their communities. Iâ&#x20AC;&#x2122;m going to take this on as a personal initiative as well. AAPM state representatives will be asked to promote them in their state pain organizations, and I will make myself available to organizations interested in learning more about them. We are looking for opportunities to make the principles part of electronic medical record systems and part of quality improvement projects within large medical clinics or group practices.
PMN: How can educators partner these principles?
regulators and with AAPM on
Dr. Webster: The eight principles could be included in educational programs, added to websites, printed and distributed to medical clinics and be placed in mailers by payers. The AAPM would like to partner with other organizations on live presentations and web-based educational modules to make the material easily available and REMS-compliant.
PMN: What realistic effect do you think these eight principles can have, clinically and societally? Dr. Webster: When a similar program was administered in Utah, overdose deaths decreased by 30%. We believe that it is realistic to expect a similar decline in unintentional overdose deaths on a national level within three years if all of the principles were practiced by a majority of prescribers in the country.
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In addition to serving as AAPM president, Dr. Webster is medical director of CRI Lifetree Research, Salt Lake City, Utah.
Eight Prescribing Principles For Providers ●● Assess patients for risk of nonmedical use or medical misuse before starting opioid therapy and manage accordingly. ●● Watch for and treat comorbid mental disease when it occurs. ●● Conventional conversion tables may cause harm when rotating (switching) from one opioid to another. ●● Avoid combining benzodiazepines with opioids, especially during sleep hours. ●● Use methadone as a secondary or tertiary agent, starting with a low dose and titrating very slowly. ●● Assess for sleep apnea in patients on high daily doses of methadone or other opioids and in patients with a predisposition. ●● Tell patients on long-term opioid therapy to reduce opioid dose during upper respiratory infections or asthmatic episodes. ●● Avoid using long-acting opioid formulations for acute, postoperative or trauma-related pain.
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IJCP’s ANESTHESIOLOGY NEWS, Volume 21, October-December 2013
PAIN MEDICINE
Experts: SCS Underused in Failed Back Surgery Syndrome
R
esearchers specializing in spinal cord stimulation (SCS) are struggling to understand why this modality is used much less than reoperation for failed back surgery syndrome (FBSS), believing SCS is more effective and far less invasive in patients with FBSS. Previous studies have shown that FBSS affects as much as 5% to 40% of those treated with lumbosacral spine surgery. “Many spine surgeons still view SCS as a salvage operation rather than a superior alternative in select patients,” said Nandan Lad, MD, PhD, assistant professor of neurosurgery, Duke University School of Medicine, in Durham, N.C., whose team presented results of a study on SCS for FBSS at the 2012 annual meeting of the North American Neuromodulation Society. “Additional studies are needed to increase awareness and use of SCS for the treatment of chronic pain syndromes such as FBSS.” Researchers from Duke University, the University of Louisville in Kentucky and Cedars-Sinai Medical Center in Los Angeles analyzed patient records from 2000 to 2009. Only 2.4% (394) of the 16,455 FBSS patients underwent SCS implantation. The mean patient age in the two groups was 54 years. Comorbidities were more common in the lumbar surgery patients, as reflected in their higher average Charlson Index scores (P = 0.0003). A significantly higher percentage of Medicaid patients underwent SCS implantation than reoperation (19% vs. 7.5%).
The complication rate during the procedure-related hospitalization was significantly lower in the SCS group—5% versus 11.7%—as were complication rates at 30 and 90 days postoperatively (6.65% vs. 14.35%, and 6.51% vs. 14.42%, respectively; P < 0.0001 for all). The investigators also conducted a parallel comparison of the outcomes of 222 patients who were matched on the basis of sex and age: 111 who underwent SCS and 111 who had repeat surgery. They found that the average length of stay for the index hospitalization also was considerably shorter in the SCS patients, at four versus two days in the unmatched population, and three versus two days in the matched cohorts (P < 0.0001 for both). This resulted in markedly lower index hospitalization charges in SCS patients, both in the matched and unmatched populations compared with their reoperation counterparts. However, none of the other types of charges—such as those for outpatient emergency room care or medication—was significantly lower than in the reoperation patients, whether in the matched or unmatched populations. Ashwini Sharan, MD, professor of neurosurgery at Thomas Jefferson University Hospital, in Philadelphia, called the studies “incredibly important work” because “spinal neurosurgeons and orthopedic surgeons just are not aware of SCS’s benefits.” However, he noted, the data cannot address which patients benefit from repeat spinal
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surgery. “You can’t assume that SCS should always be the next approach [just] because it has fewer complications,” said Dr. Sharan, who was not involved in the investigation. “In addition, it would have been nice to know
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which physicians were performing SCS versus the spinal surgery—how often is there bias in the practice of a physician, who does both but opts for surgery far more often?” —Rosemary Frei
IJCP’s ANESTHESIOLOGY NEWS, Volume 21, October-December 2013
IN BRIEF
Analgesics After Low-Risk Surgery Linked to Long-Term Use
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rescription of opioids or nonsteroidal anti-inflammatory drugs (NSAIDs) to older adults after low-risk surgery is associated with long-term use of the analgesics, according to a study in Archives of Internal Medicine (2012;172:425-430). The article is “a good reminder that initiation of short-term opioid therapy may lead to their longer-term use,” wrote Mitchell H. Katz, MD, in an accompanying editor’s note (2012;172:430). Analyzing population-based data in Ontario, Canada, the retrospective cohort study investigated opioid-naive individuals aged 66 years and older who underwent short-stay, low-pain surgical procedures (N = 391,139). Of these patients, 27,636 (7.1%) were issued a prescription for an opioid within seven days of hospital discharge. A total of 30,145 patients (7.7%) were prescribed opioids one year after surgery. Of patients prescribed an opioid within seven days of surgery, 2,857 (10.3%) were long-term opioid users a year later. After multivariate adjustment, patients who received an opioid prescription within seven days of surgery were approximately 44% more likely to become long-term opioid users than those who received no prescription (adjusted
odds ratio [OR], 1.44; 95% confidence interval [CI], 1.39-1.50). Although the primary analysis concerned opioids, a secondary focus involved NSAID use. Of 383,780 patients, 1,169 (0.3%) were prescribed NSAIDs within seven days of discharge and 30,080 (7.8%) were prescribed NSAIDs one year later. Of those prescribed NSAIDs early, 285 (24.4%) continued to receive NSAIDs a year later. Patients receiving an early NSAID prescription were 3.7 times more likely to become long-term NSAID users than those who were not early NSAID users (adjusted OR, 3.74; 95% CI, 3.27-4.28). The surgeries studied occurred from April 1, 1997, to Dec. 31, 2008. The procedures included cataract surgery, laparoscopic cholecystectomy, transurethral resection of the prostate and varicose vein stripping surgery. “Concerted patient safety efforts must continue to focus on providing an opportunity for patients to heal from operations free of short-term pain while minimizing the risks for long-term adverse events,” the authors wrote.
IJCP’s ANESTHESIOLOGY NEWS, Volume 21, October-December 2013
—George Ochoa
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IN BRIEF
Opioid Use for Abdominal Pain Sees Recent Spike F
rom 1997 to 2008, opioid prescriptions for chronic abdominal pain more than doubled in the United States, according to a new study in Clinical Gastroenterology and Hepatology (2011;9:1078-1085). In the study, the investigators estimated the national prescribing trends and factors associated with prescribing opioids for chronic abdominal pain. They identified visits to outpatient clinics for this disorder using reason-for-visit codes from the National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey from 1997 to 2008. Data were weighted to produce national estimates of opioid prescriptions over time.
The researchers found that the number of outpatient visits for chronic abdominal pain consistently decreased over time from 14.8 million visits in 1997 to 1999 to 12.2 million visits in 2006 through 2008 (P = 0.04). However, the adjusted prevalence of visits when an opioid was prescribed increased from 5.9% in 1997 through 1999 to 12.2% in 2006 through 2008 (P = 0.03). Opioid prescriptions were most common among patients aged 25 to 40 years (odds ratio [OR], 4.6) and less
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common among uninsured (OR, 0.1) and black (OR, 0.3) patients. The investigators noted that this increase in opioid prescriptions has been problematic, in part because no study has shown opioids to be effective for treating chronic abdominal pain. When used over long periods of time, opioids may worsen other gastrointestinal symptoms, such as constipation, nausea and vomiting. The growing use of opioids to treat “persistent abdominal pain highlights the growing challenges clinicians face trying to manage chronic illness without the time, infrastructure and incentives needed to take the integrated approach that experts suggest,” said lead study author Spencer D. Dorn, MD, MPH, assistant professor of medicine at the University of North Carolina at Chapel Hill, in a statement. The researchers speculated that the growth in opioid use likely has been driven by a tendency to generalize recommendations for the use of opioids in treating pain, campaigns to recognize pain as the “fifth vital sign” and marketing efforts. The researchers concluded that future studies could help illuminate the reasons for and consequences of this trend. —AN Staff
IJCP’s ANESTHESIOLOGY NEWS, Volume 21, October-December 2013