Sergio D. Bergese

Consensus Guidelines for the Management of Postoperative Nausea and Vomiting

The present guidelines are the most recent data on postoperative nausea and vomiting (PONV) and an update on the 2 previous sets of guidelines published in 2003 and 2007. These guidelines were compiled by a multidisciplinary international panel of individuals with interest and expertise in PONV under the auspices of the Society for Ambulatory Anesthesia. The panel members critically and systematically evaluated the current medical literature on PONV to provide an evidence-based reference tool for the management of adults and children who are undergoing surgery and are at increased risk for PONV. These guidelines identify patients at risk for PONV in adults and children; recommend approaches for reducing baseline risks for PONV; identify the most effective antiemetic single therapy and combination therapy regimens for PONV prophylaxis, including nonpharmacologic approaches; recommend strategies for treatment of PONV when it occurs; provide an algorithm for the management of individuals at increased risk for PONV as well as steps to ensure PONV prevention and treatment are implemented in the clinical setting.

Monitored anesthesia care with dexmedetomidine: A prospective, randomized, double-blind, multicenter trial

BACKGROUND: Dexmedetomidine (DEX) is increasingly being used as a sedative for monitored anesthesia care (MAC) because of its analgesic properties, “cooperative sedation,” and lack of respiratory depression. In this randomized, multicenter, double-blind, Phase III Food and Drug Administration study, we evaluated the safety and efficacy of two doses of DEX for sedation of patients undergoing a broad range of surgical or diagnostic procedures requiring MAC. METHODS: Three hundred twenty-six patients were randomized 2:2:1 to DEX 0.5 &mgr;g/kg, DEX 1 &mgr;g/kg, or saline placebo initial loading dose, followed by a maintenance infusion of 0.2–1.0 &mgr;g · kg−1 · h−1 of DEX (or equivalent volume of saline) titrated to a targeted level of sedation (≤4 on the Observers Assessment of Alertness/Sedation Scale [OAA/S]). Study drug was started at least 15 min before placement of regional or local anesthetic block. Midazolam was given for OAA/S >4 and fentanyl for pain. The primary end-point was the percentage of patients not requiring rescue midazolam. RESULTS: Significantly fewer patients in the 0.5- and 1-&mgr;g/kg DEX groups required supplemental midazolam compared with placebo (59.7% [80/134], 45.7% [59/129] vs 96.8% [61/63], respectively; P < 0.001) and at lower doses to achieve an OAA/S ≤4 before and during surgery compared with the saline group (1.4 and 0.9 mg vs 4.1 mg, respectively; P < 0.001, each group compared with placebo). Both DEX groups required significantly less fentanyl (84.8 and 83.6 &mgr;g vs 144.4 &mgr;g, respectively; P < 0.001, for both DEX groups versus placebo) for all surgical subtypes. Anesthesiologists indicated significantly increased ease of achieving and maintaining targeted sedation in both DEX groups compared with placebo with midazolam (P < 0.001). Patient satisfaction was significantly higher with DEX (P ≤ 0.009, both groups versus placebo). Common adverse events with DEX were protocol-defined bradycardia and hypotension that were predominately mild to moderate in severity. The incidence of clinically significant respiratory depression (defined as a respiratory rate of <8 or an oxygen saturation of <90%) was lower in DEX-treated patients (P = 0.018, for both groups versus placebo). CONCLUSIONS: DEX is an effective baseline sedative for patients undergoing MAC for a broad range of surgical procedures providing better patient satisfaction, less opioid requirements, and less respiratory depression than placebo rescued with midazolam and fentanyl.

The efficacy and safety of DepoFoam bupivacaine in patients undergoing bilateral, cosmetic, submuscular augmentation mammaplasty: a randomized, double-blind, active-control study.

BACKGROUND Breast augmentation can result in significant postsurgical pain. OBJECTIVES The authors evaluate the extent and duration of analgesia achieved with extended-release DepoFoam bupivacaine (Pacira Pharmaceuticals, Inc., Parsippany, New Jersey) in patients undergoing bilateral, cosmetic, submuscular augmentation mammaplasty under general anesthesia. METHODS In this randomized, multicenter, double-blind study, patients received a single dose of DepoFoam bupivacaine 600 mg or bupivacaine HCl 200 mg divided into the implant pockets at the conclusion of surgery. The primary efficacy measure was cumulative pain score with activity through 72 hours postoperatively. Secondary efficacy measures included pain intensity with activity and at rest, postsurgical consumption of rescue opioids, and integrated rank analysis combining pain scores at rest with the amount of opioid used. RESULTS One hundred thirty-six patients were randomized and treated (DepoFoam bupivacaine, n = 66; bupivacaine HCl, n = 70). Reflecting the underpowered nature of the study, the mean cumulative pain score (numeric rating scale with activity through 72 hours) was 441.5 with DepoFoam bupivacaine versus 468.2 with bupivacaine HCl (P = .3999). Total amounts of opioid consumed were significantly lower in the DepoFoam bupivacaine group through 24 hours (P = .0211) and through 48 hours (P = .0459). The prespecified integrated rank analysis showed statistically-significant differences at multiple time points up to and including 60 hours; results on most other efficacy measures trended in favor of DepoFoam bupivacaine. No serious adverse events were reported, and no patients discontinued the study due to adverse events. CONCLUSIONS DepoFoam bupivacaine trended toward benefit versus bupivacaine HCl on most efficacy measures. Due to early termination, the study was underpowered to achieve statistical significance.

Efficacy profile of liposome bupivacaine, a novel formulation of bupivacaine for postsurgical analgesia

Background Liposome bupivacaine is a novel formulation of the local anesthetic bupivacaine, designed to provide prolonged postsurgical analgesia. This analysis examined pooled efficacy data as reflected in cumulative pain scores from 10 randomized, double-blind liposome bupivacaine clinical studies in which the study drug was administered via local wound infiltration. Methods A total of 823 patients were exposed to liposome bupivacaine in 10 local wound infiltration studies at doses ranging from 66 mg to 532 mg in five surgical settings; 446 patients received bupivacaine HCl (dose: 75–200 mg) and 190 received placebo. Efficacy measures were assessed through 72 hours after surgery. Results Overall, 45% of patients were male and 19% were ≥65 years of age. In the analysis of cumulative pain intensity scores through 72 hours, liposome bupivacaine was associated with lower pain scores than the comparator in 16 of 19 treatment arms assessed, achieving statistically significant differences compared with bupivacaine HCl (P < 0.05) in five of 17 treatment arms. These results were supported by results of other efficacy measures, including time to first use of opioid rescue medication, proportion of patients avoiding opioid rescue medication, total postsurgical consumption of opioid rescue medication, and patient/care provider satisfaction with postoperative analgesia. Local infiltration of liposome bupivacaine resulted in significant systemic plasma levels of bupivacaine, which could persist for 96 hours; systemic plasma levels of bupivacaine following administration of liposome bupivacaine were not correlated with local efficacy. Liposome bupivacaine and bupivacaine HCl were generally well tolerated. Conclusion Based on this integrated analysis of multiple efficacy measures, liposome bupivacaine appears to be a potentially useful therapeutic option for prolonged reduction of postsurgical pain in soft tissue and orthopedic surgeries.

Prevention of murine cardiac allograft rejection with gallium nitrate : Comparison with anti-CD4 monoclonal antibody

Gallium nitrate (GN) was evaluated for its ability to interfere with a cute rejection of DBA/2-->C57BL/6 heterotopic cardiac allografts, in comparison with the depleting anti-CD4 mAb, GK1.5. The administration of GN for 30 days (s.c. 30 mg/kg elemental gallium on days 0 and 3, 10 mg/kg every third day) resulted in >60-day graft survival in 78% (25 of 32) of the graft recipients, whereas 2 perioperative injections of anti-CD4 monoclonal antibody (mAb) resulted in >60-day graft survival in 58% (24 of 41) of the graft recipients. Serum gallium levels peaked at about 2000 ng/ml after 2-3 weeks of treatment and decreased to about 300 ng/ml by day 60, a level that was maintained for at least 30 more days. During the early posttransplant period, 25% of GN-treated grafts, but not anti-CD4 mAb-treated grafts, exhibited an unusual, transient reduction in graft impulse strength, suggesting a transient rejection response. Macroscopically, the long-surviving (>60 days) grafts from either treatment group exhibited none of the features of rejecting allografts. Histologically, they exhibited minor edema and rare epicardial inflammation but no tissue necrosis. However, there were vascular changes in allografts from GN-treated mice, including altered endothelial morphology, associated with moderate intimal hyperplasia and mild perivascular leukocytic infiltration. Allografts from anti-CD4 mAb-treated mice exhibited prominent neointimal hyperplasia associated with endothelial morphologic changes and prominent vascular and perivascular leukocytic infiltration. In general, both GN and anti-CD4 mAb promoted long-term allograft survival, but these allografts displayed the histopathologic signs of ongoing inflammation and chronic allograft rejection.

Intraoperative use of remifentanil and opioid induced hyperalgesia/acute opioid tolerance: systematic review

Introduction: The use of opioids has been increasing in operating room and intensive care unit to provide perioperative analgesia as well as stable hemodynamics. However, many authors have suggested that the use of opioids is associated with the expression of acute opioid tolerance (AOT) and opioid-induced hyperalgesia (OIH) in experimental studies and clinical observations in dose and/or time dependent exposure even when used within the clinically accepted doses. Recently, remifentanil has been used for pain management during anesthesia as well as in the intensive care units because of its rapid onset and offset. Objectives: Search of the available literature to assess remifentanil AOT and OIH based on available published data. Methods: We reviewed articles analyzing remifentanil AOT and OIH, and focused our literature search on evidence based information. Experimental and clinical studies were identified using electronic searches of Medline (PubMed, Ovid, Springer, and Elsevier, ClinicalKey). Results: Our results showed that the development of remifentanil AOT and OIH is a clinically significant phenomenon requiring further research. Discussions and Conclusions: AOT – defined as an increase in the required opioid dose to maintain adequate analgesia, and OIH – defined as decreased pain threshold after chronic opioid treatment, should be suspected with any unexplained pain report unassociated with the disease progression. The clinical significance of these findings was evaluated taking into account multiple methodological issues including the dose and duration of opioids administration, the different infusion mode, the co-administrated anesthetic drug’s effect, method assessing pain sensitivity, and the repetitive and potentially tissue damaging nature of the stimuli used to determine the threshold during opioid infusion. Future studies need to investigate the contribution of remifentanil induced hyperalgesia to chronic pain and the role of pharmacological modulation to reverse this process.

Apoptosis in murine cardiac grafts

Apoptosis, or the induction of programmed cell death, is a mechanism commonly used by cytotoxic T cells to cause target cell lysis. We evaluated the frequency and distribution of apoptotic cells in DBA/2-->DBA/2 heterotopic cardiac isografts, acutely rejecting DBA/2-->C57BL/6 cardiac allografts, and accepted, 60 day DBA/2-->C57BL/6 allografts from mice treated with anti-CD4 Mab (GK1.5) or gallium nitrate (GN). Apoptosis was identified in histologic sections via TUNEL analysis of nuclear DNA fragmentation. We observed the following. (1) Cardiac isografts display no detectable TUNEL+ cells. (2) Rejecting cardiac allografts display rare (<1% of nucleated cells/field), diffuse TUNEL+ cells, peaking on day 3 and declining to 50% of peak by the day of rejection (approximately day 10), and TUNEL+ cells were localized to regions of cellular infiltrate rather than myocyte regions. (3) Accepted cardiac allografts display relatively high numbers of TUNEL+ cells localized in and around the large cardiac arteries (about 20% of nucleated cells/periarterial field). These arteries often showed evidence of transplant vascular sclerosis characteristic of chronic allograft rejection. While a few TUNEL+ cells were found in the arterial tissue, most were observed in the periarterial cellular infiltrate. Similar frequencies and distributions of TUNEL+ cells were observed in grafts that were accepted due to treatment with the anti-CD4 mAb GK 1.5 or gallium nitrate. In general, apoptosis did not correlate with graft failure or parenchymal cell damage, suggesting that cytotoxic T cell-mediated destruction of graft tissues is rare in cardiac allografts. While apoptosis does not appear to be indicative of acute rejection, the characteristic periarterial clustering of apoptosis in accepted grafts may be indicative of immunoregulatory processes that maintain graft acceptance or repair processes that promote chronic vascular remodeling.

A phase IIIb, randomized, double-blind, placebo-controlled, multicenter study evaluating the safety and efficacy of dexmedetomidine for sedation during awake fiberoptic intubation

GABA-mediated sedatives have respiratory depressant properties that may be detrimental in patients with difficult airways. In this randomized, double-blind, multicenter, Phase IIIb Food and Drug Administration study, safety and efficacy of dexmedetomidine compared with placebo were evaluated as the primary sedative for awake fiberoptic intubation (AFOI). Patients were randomized to receive dexmedetomidine or saline. Patients were sedated with dexmedetomidine or rescue midazolam to achieve targeted sedation (Ramsay Sedation Scale ≥ 2) before topicalization and throughout AFOI. Primary efficacy endpoint was percentage of patients requiring rescue midazolam; secondary efficacy endpoints were total dose of rescue midazolam, percentage requiring additional rescue nonmidazolam medications, anesthesiologists assessment of ease of subject care, and patient recall and satisfaction 24 hours postoperatively. Less rescue midazolam was required to maintain Ramsay Sedation Scale ≥2 (47.3% vs. 86.0%, P < 0.001), and supplemental midazolam dose was lower (1.07 ± 1.5 mg vs. 2.85 ± 3.0 mg, P < 0.001) with dexmedetomidine compared with placebo. More Mallampati Class IV patients treated with dexmedetomidine were successfully intubated without midazolam than with placebo (66.7% vs. 8.3%, P = 0.009). Dexmedetomidine decreased blood pressure and heart rate compared with placebo patients sedated with midazolam. Patients and anesthesiologists showed favorable satisfaction responses in both groups. Adverse events and patient recall were similar in both groups. Dexmedetomidine is effective as the primary sedative in patients undergoing AFOI. Some patients may require small supplemental doses of midazolam, in addition to dexmedetomidine, to achieve sufficient sedation for AFOI. Dexmedetomidine provides another AFOI option for sedation of patients with difficult airways.

Prolonged murine cardiac allograft acceptance: characteristics of persistent active alloimmunity after treatment with gallium nitrate versus anti-CD4 monoclonal antibody.

We have treated DBA/2-->C57BL/6 murine cardiac allograft recipients with anti-CD4 monoclonal antibody or with gallium nitrate to promote long-term (>60 days) allograft survival. Within this period, all grafts developed histologic evidence of ongoing vascular and parenchymal tissue remodeling, including interstitial fibrosis and neointimal hyperplasia, which are characteristic of chronic allograft rejection. To evaluate residual alloimmunity associated with the pharmacologic avoidance of acute graft rejection and the development of chronic tissue remodeling, we subjected these graft recipients to a battery of histologic and immunologic tests. Similar test results were obtained for graft recipients treated with either of the two immunosuppressive agents. All long-surviving allografts displayed histologic evidence of ongoing microvascular endothelial activation and interstitial leukocytic infiltration. Reverse transcriptase-polymerase chain reaction analyses demonstrated intragraft expression of mRNAs for interleukin (IL)-1, IL-2, IL-4, IL-6, tumor necrosis factor, interferon-gamma, and transforming growth factor-beta. All recipients had limiting dilution analysis-detectable, graft-reactive cytolytic T lymphocytes and helper T lymphocytes in their spleens and grafts, and all produced high titers of graft-reactive alloantibodies. In general, these observations indicate that (1) a similar immune status is achieved in long-surviving allografts and their recipients when either anti-CD4 monoclonal antibody or gallium nitrate was used for antirejection therapy, (2) this immune status is characterized by continuous, long-term inflammatory and immune processes that are qualitatively similar to those observed during acute allograft rejection, and (3) no specific immune responses developed selectively in long-term graft recipients to account for the avoidance of acute graft rejection or the development of chronic tissue remodeling in the graft.

Perioperative Aspirin and Clonidine and Risk of Acute Kidney Injury A Randomized Clinical Trial

IMPORTANCE Acute kidney injury, a common complication of surgery, is associated with poor outcomes and high health care costs. Some studies suggest aspirin or clonidine administered during the perioperative period reduces the risk of acute kidney injury; however, these effects are uncertain and each intervention has the potential for harm. OBJECTIVE To determine whether aspirin compared with placebo, and clonidine compared with placebo, alters the risk of perioperative acute kidney injury. DESIGN, SETTING, AND PARTICIPANTS A 2 × 2 factorial randomized, blinded, clinical trial of 6905 patients undergoing noncardiac surgery from 88 centers in 22 countries with consecutive patients enrolled between January 2011 and December 2013. INTERVENTIONS Patients were assigned to take aspirin (200 mg) or placebo 2 to 4 hours before surgery and then aspirin (100 mg) or placebo daily up to 30 days after surgery, and were assigned to take oral clonidine (0.2 mg) or placebo 2 to 4 hours before surgery, and then a transdermal clonidine patch (which provided clonidine at 0.2 mg/d) or placebo patch that remained until 72 hours after surgery. MAIN OUTCOMES AND MEASURES Acute kidney injury was primarily defined as an increase in serum creatinine concentration from the preoperative concentration by either an increase of 0.3 mg/dL or greater (≥26.5 μmol/L) within 48 hours of surgery or an increase of 50% or greater within 7 days of surgery. RESULTS Aspirin (n = 3443) vs placebo (n = 3462) did not alter the risk of acute kidney injury (13.4% vs 12.3%, respectively; adjusted relative risk, 1.10; 95% CI, 0.96-1.25). Clonidine (n = 3453) vs placebo (n = 3452) did not alter the risk of acute kidney injury (13.0% vs 12.7%, respectively; adjusted relative risk, 1.03; 95% CI, 0.90-1.18). Aspirin increased the risk of major bleeding. In a post hoc analysis, major bleeding was associated with a greater risk of subsequent acute kidney injury (23.3% when bleeding was present vs 12.3% when bleeding was absent; adjusted hazard ratio, 2.20; 95% CI, 1.72-2.83). Similarly, clonidine increased the risk of clinically important hypotension. In a post hoc analysis, clinically important hypotension was associated with a greater risk of subsequent acute kidney injury (14.3% when hypotension was present vs 11.8% when hypotension was absent; adjusted hazard ratio, 1.34; 95% CI, 1.14-1.58). CONCLUSIONS AND RELEVANCE Among patients undergoing major noncardiac surgery, neither aspirin nor clonidine administered perioperatively reduced the risk of acute kidney injury. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01082874.