Keith A. Candiotti

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.

Reversal of profound neuromuscular block by sugammadex administered three minutes after rocuronium: a comparison with spontaneous recovery from succinylcholine.

Background:Rocuronium in intubation doses provides similar intubation conditions as succinylcholine, but has a longer duration of action. This study compared time to sugammadex reversal of profound rocuronium-induced neuromuscular block with time to spontaneous recovery from succinylcholine. Methods:One hundred and fifteen adult American Society of Anesthesiologists Class I-II surgical patients were randomized to this multicenter, safety-assessor–blinded, parallel group, active-controlled, Phase IIIa trial. Anesthesia was induced and maintained with propofol and an opioid. Neuromuscular transmission was blocked and tracheal intubation facilitated with 1.2 mg/kg rocuronium or 1 mg/kg succinylcholine. Sugammadex (16 mg/kg) was administered 3 min after rocuronium administration. Neuromuscular function was monitored by acceleromyography. The primary efficacy endpoint was the time from the start of relaxant administration to recovery of the first train-of-four twitch (T1) to 10%. Results:One hundred and ten patients received study treatment. Mean times to recovery of T1 to 10% and T1 to 90% were significantly faster in the rocuronium-sugammadex group (4.4 and 6.2 min, respectively), as compared with the succinylcholine group (7.1 and 10.9 min, respectively; all P < 0.001). Timed from sugammadex administration, the mean time to recovery of T1 to 10%, T1 to 90%, and the train-of-four (T4/T1) ratio to 0.9 was 1.2, 2.9, and 2.2 min, respectively. Reoccurrence of the block was not observed. There were no serious adverse events related to study treatments. Conclusion:Reversal of profound high-dose rocuronium-induced neuromuscular block (1.2 mg/kg) with 16 mg/kg sugammadex was significantly faster than spontaneous recovery from 1 mg/kg succinylcholine.

Prehospital Intubations and Mortality: A Level 1 Trauma Center Perspective

BACKGROUND: Ryder Trauma Center is a Level 1 trauma center with approximately 3800 emergency admissions per year. In this study, we sought to determine the incidence of failed prehospital intubations (PHI), its correlation with hospital mortality, and possible risk factors associated with PHI. METHODS: A prospective observational study was conducted evaluating trauma patients who had emergency prehospital airway management and were admitted during the period between August 2003 and June 2006. The PHI was considered a failure if the initial assessment determined improper placement of the endotracheal tube or if alternative airway management devices were used as a rescue measure after intubation was attempted. RESULTS: One-thousand-three-hundred-twenty patients had emergency airway interventions performed by an anesthesiologist upon arrival at the trauma center. Of those, 203 had been initially intubated in the field by emergency medical services personnel, with 74 of 203 (36%) surviving to discharge. When evaluating the success of the intubation, 63 of 203 (31%) met the criteria for failed PHI, all of them requiring intubation, with only 18 of 63 (29%) surviving to discharge. These patients had rescue airway management provided either via Combitube® (n = 28), Laryngeal Mask Airway® (n = 6), or a cricothyroidotomy (n = 4). An additional 25 of 63 patients (12%) had unrecognized esophageal intubations discovered upon the initial airway assessment performed on arrival. We found no difference in mortality between those patients who were properly intubated and those who were not. Several other variables, including age, gender, weight, mechanism of injury, presence of facial injuries, and emergency medical services were not correlated with an increased incidence of failed intubations. CONCLUSION: This prospective study showed a 31% incidence of failed PHI in a large metropolitan trauma center. We found no difference in mortality between patients who were properly intubated and those who were not, supporting the use of bag-valve-mask as an adequate method of airway management for critically ill trauma patients in whom intubation cannot be achieved promptly in the prehospital 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.

A randomized, double-blind comparison of the NK1 antagonist, aprepitant, versus ondansetron for the prevention of postoperative nausea and vomiting

BACKGROUND: Antiemetics currently in use are not totally effective. Neurokinin-1 receptor antagonists are a new class of antiemetic that have shown promise for chemotherapy-induced nausea and vomiting. This is the first study evaluating the efficacy and tolerability of the neurokinin-1 receptor antagonist, aprepitant, for the prevention of postoperative nausea and vomiting. METHODS: In this multicenter, double-blind trial, we randomly assigned 805 patients receiving general anesthesia for open abdominal surgery to a preoperative dose of aprepitant 40 mg orally, aprepitant 125 mg orally, or ondansetron 4 mg IV. Vomiting, nausea, and use of rescue therapy were assessed over 48 h after surgery. Treatments were compared using logistic regression. RESULTS: Incidence rates for the primary end point (complete response [no vomiting and no use of rescue] over 0–24 h after surgery, tested for superiority of aprepitant) were not different across groups (45% with aprepitant 40 mg, 43% with aprepitant 125 mg, and 42% with ondansetron). The incidence of no vomiting (0–24 h) was higher with aprepitant 40 mg (90%) and aprepitant 125 mg (95%) versus ondansetron (74%) (P < 0.001 for both comparisons), although between-treatment use of rescue and nausea control was not different. Both aprepitant doses also had higher incidences of no vomiting over 0–48 h (P < 0.001). No statistically significant differences were seen among the side effect profiles of the treatments. CONCLUSIONS: Aprepitant was superior to ondansetron for prevention of vomiting in the first 24 and 48 h, but no significant differences were observed between aprepitant and ondansetron for nausea control, use of rescue, or complete response.

The impact of pharmacogenomics on postoperative nausea and vomiting: Do CYP2D6 allele copy number and polymorphisms affect the success or failure of ondansetron prophylaxis?

Background:Some patients treated with ondansetron for postoperative nausea and vomiting do not respond to therapy. One possible mechanism for this failure is ultrarapid drug metabolism via the cytochrome P-450 system, specifically the enzyme 2D6 (CYP2D6). Ultrarapid metabolism is seen in patients with multiple functional copies (≥ 3) of the CYP2D6 allele. This study was designed to determine whether patients who were given prophylactic ondansetron and had multiple CYP2D6 alleles had an increased rate of postoperative nausea and vomiting. Methods:Two hundred fifty female patients undergoing standardized general anesthesia were given 4 mg ondansetron 30 min before extubation. Patients were observed for symptoms of nausea and vomiting. DNA was extracted from blood in all patients and was analyzed by using a gene-specific probe to determine the CYP2D6 gene copy number and genotyped by polymerase chain reaction amplification with a custom oligonucleotide microarray to determine the specific CYP2D6 genotypes. Results:Eighty-eight patients experienced nausea, and 37 of those patients also had vomiting. In patients with one, two, or three CYP2D6 copies, the incidences of vomiting were 3 in 33 (27%), 27 in 198 (14%), and 7 in 23 (30%), respectively. The incidence of vomiting in subjects with three CYP2D6 copies was significantly different from those with two copies, but not from those with one copy. When analyzed by genotype, the incidences of vomiting in poor, intermediate, extensive, and ultrarapid metabolizers were 1 in 12 (8%), 5 in 30 (17%), 26 in 176 (15%), and 5 in 11 (45%), respectively (P < 0.01 vs. all other groups). There were no differences between groups in the incidence of nausea based on CYP2D6 copy number or genotype. Conclusions:Patients with three copies of the CYP2D6 gene, a genotype consistent with ultrarapid metabolism, or both have an increased incidence of ondansetron failure for the prevention of postoperative vomiting but not nausea.

Transgenic Inhibition of Glial NF-kappa B Reduces Pain Behavior and Inflammation after Peripheral Nerve Injury

&NA; The transcription factor nuclear factor kappa B (NF‐&kgr;B) is a key regulator of inflammatory processes in reactive glial cells. We utilized a transgenic mouse model (GFAP‐I&kgr;B&agr;‐dn) where the classical NF‐&kgr;B pathway is inactivated by overexpression of a dominant negative (dn) form of the inhibitor of kappa B (I&kgr;B&agr;) in glial fibrillary acidic protein (GFAP)‐expressing cells, which include astrocytes, Schwann cells, and satellite cells of the dorsal root ganglion (DRG) and sought to determine whether glial NF‐&kgr;B inhibition leads to a reduction in pain behavior and inflammation following chronic constriction injury (CCI) of the sciatic nerve. As expected, following CCI nuclear translocation, and hence activation, of NF‐&kgr;B was detected only in the sciatic nerve of wild type (WT) mice, and not in GFAP‐I&kgr;B&agr;‐dn mice, while upregulation of GFAP was observed in the sciatic nerve and DRGs of both WT and GFAP‐I&kgr;B&agr;‐dn mice, indicative of glial activation. Following CCI, mechanical and thermal hyperalgesia were reduced in GFAP‐I&kgr;B&agr;‐dn mice compared to those in WT, as well as gene and protein expression of CCL2, CCR2 and CXCL10 in the sciatic nerve. Additionally, gene expression of TNF, CCL2, and CCR2 was reduced in the DRGs of transgenic mice compared to those of WT after CCI. We can therefore conclude that transgenic inhibition of NF‐&kgr;B in GFAP‐expressing glial cells attenuated pain and inflammation after peripheral nerve injury. These findings suggest that targeting the inflammatory response in Schwann cells and satellite cells may be important in treating neuropathic pain.

A Randomized, Double-Blind Study to Evaluate the Efficacy and Safety of Three Different Doses of Palonosetron Versus Placebo for Preventing Postoperative Nausea and Vomiting

BACKGROUND: In this randomized, double-blind study we assessed the efficacy and safety of three different doses of the 5-HT3 receptor antagonist palonosetron, compared with placebo, on the incidence and severity of postoperative nausea and vomiting (PONV) for 72 h postsurgery. METHODS: Five hundred seventy-four patients undergoing either outpatient abdominal or gynecological laparoscopic surgery were stratified according to gender, history of PONV or motion sickness, and nonsmoking status. Patients with ≥2 PONV risk factors were eligible and randomized to receive one of three doses of IV palonosetron (0.025 mg, 0.050 mg, or 0.075 mg) or placebo immediately prior to induction of anesthesia. Co-primary efficacy end-points included complete response (CR: no emetic episodes and no rescue medication) during the 0 to 24 h and 24 to 72 h postoperative time intervals. RESULTS: A dose-response trend in the proportion of patients with a CR was observed with increasing doses of palonosetron in the first 24 hrs. CR rates for placebo and palonosetron 0.075 mg were 26% and 43%, respectively, for the 0 to 24 h postoperative interval (P = 0.004), and 41% and 49%, respectively, for the 24 to 72 h interval (P = 0.188). Compared with placebo, palonosetron 0.075 mg was associated with a significant downward shift toward less intense nausea (P = 0.042) and with significant reduction in the impact of PONV on patient functioning (P = 0.004) during the 0 to 24 h interval. CONCLUSIONS: A single 0.075-mg IV dose of palonosetron significantly increased the CR rate (no emetic episodes and no rescue medication) from 0 to 24 h, decreased nausea severity and patients experienced significantly less interference in their postoperative function due to PONV.

The impact of current antiemetic practices on patient outcomes: a prospective study on high-risk patients.

BACKGROUND: In this prospective, multicenter, observational study, we evaluated the incidence and time course of postoperative nausea and vomiting (PONV), assessed prophylactic and rescue antiemetic use in high-risk patients, and determined population-based effectiveness of antiemetics, including the impact of American Society of Anesthesiologists (ASA) and American Society of Perianesthesia Nurses (ASPAN) guideline compliance. METHODS: Eligible patients undergoing elective laparoscopic or major plastic surgery possessed two or more of the following Apfel PONV risk factors: female gender, history of PONV or motion sickness, and nonsmoking status. Antiemetic use, emetic episodes, severity of nausea, and functional interference due to PONV were documented during the first 72 h after surgery. Complete response (CR) was defined as no emesis or rescue medication use, and complete control was defined as CR and no moderate-severe nausea. The effect of compliance (versus noncompliance) with ASA and ASPAN guidelines on PONV outcomes was also analyzed. RESULTS: The proportion of patients experiencing postoperative emesis ranged from 18% to 40% depending on the number of antiemetics administered. The rate of rescue medication (45%) was similar to the reported incidences of moderate-to-severe nausea (47%) and functional interference due to emetic symptoms (44%). The administration of three or more antiemetics produced better patient outcomes overall compared to <1 prophylactic antiemetic. CR rates were <70% despite adherence to current organizational PONV management guidelines (ASA: 69%; ASPAN: 63%). The complete control rates were 10% lower than CR rates over the 3 day study period. CONCLUSIONS: Administration of three or more prophylactic antiemetics had the most positive impact on emetic outcomes over 72 hrs in patients at risk of developing PONV. Although compliance with organizational PONV management guidelines improved patient outcomes, postoperative emetic symptoms and interference with patient functioning still occurred in more than 30% of these high-risk patients.

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.