Randomized, Double-Blind, Placebo-Controlled Study of Intravenous Amisulpride as Treatment of Established Postoperative Nausea and Vomiting in Patients Who Have Had No Prior Prophylaxis.

BACKGROUND: Postoperative nausea and vomiting (PONV) occurs commonly in surgical patients despite widespread prophylactic antiemetic use. Rescue options are currently limited. 5HT3 antagonists are most frequently used for prophylaxis, but if they fail, additional doses are not effective as rescue medication. Intravenous (IV) amisulpride, a well-studied D2/D3 antagonist, has been shown in trials to prevent PONV. This study was designed to determine if amisulpride could be used to treat established PONV in patients at low-to-moderate risk of PONV who had not received any prior prophylaxis. METHODS: Men and women aged over 18 years were permitted to enroll if they were to undergo general inhalational anesthesia, expected to last at least 1 hour, for an outpatient or inpatient surgical procedure. Patients who then suffered PONV were randomized equally to 1 of 3 single-dose IV regimens: placebo or 5 or 10 mg amisulpride. The primary end point was complete response, defined as no emesis in the period 30 minutes to 24 hours after study drug treatment and no use of rescue medication in the entire 24-hour period. RESULTS: One thousand nine hundred eighty-eight patients were enrolled preoperatively, of whom 560 were randomized to a treatment arm. Complete response occurred in 39 of 181 patients (21.5%) in the placebo group compared to 60 of 191 patients (31.4%; P = .016) and 59 of 188 patients (31.4%; P = .016) in the amisulpride 5 and 10 mg groups, respectively. The adverse event profile of amisulpride at either dose was similar to placebo. CONCLUSIONS: IV amisulpride at 5 and 10 mg was safe and efficacious in the treatment of established PONV in surgical patients undergoing general anesthesia with no prior PONV prophylaxis.

Fibrinolytic Shutdown Is Associated With Intraoperative Thrombosis and Hemorrhage During Visceral Transplant.

Background and Objective. End-stage liver disease is characterized by a precarious imbalance of hemostasis. Detrimental consequences of hypofibrinolysis, also known as fibrinolytic shutdown, have been recently demonstrated, and its significance in visceral (ie, an allograft that contains the intestine) transplant remains unknown. Design and Setting. To fill this gap, following institutional review board approval, this retrospective study included 49 adult recipients of visceral allografts (14 "visceral allograft without the liver" and 35 "multivisceral" with the liver) transplanted between 2010 and 2018 in a single university hospital, and for whom pre-incisional thromboelastography was available. Based on percent clot lysis 30 minutes after maximal amplitude, patients were stratified into 3 fibrinolysis phenotypes: fibrinolytic shutdown, physiologic fibrinolysis, and hyperfibrinolysis. Results. Fibrinolytic shutdown occurred in 57% of patients, with higher incidence in recipients of multivisceral transplant (69%) compared with visceral allograft without liver (29%) allografts (P = .04). Fibrinolytic shutdown was associated with an increase in both intraoperative thrombosis and hemorrhage. Intraoperative thrombosis (18%) occurred only with multivisceral transplant, and accounted for 36% of in-hospital mortality. A clinically meaningful reduction in incidence of intraoperative thrombosis was noted in recipients who received intravenous heparin thromboprophylaxis. Logistic regression identified pretransplant platelet count as a risk factor for fibrinolytic shutdown (odds ratio = 0.992, 95% confidence interval = [0.984-0.998]; χ2 = 7.8, P = .005). Conclusions. This study highlights fibrinolytic shutdown as a dominant and clinically important feature of the hemostatic imbalance in recipients undergoing visceral transplantation.

Thrombotic and hemorrhagic complications during visceral transplantation: risk factors, and association with intraoperative disseminated intravascular coagulation-like thromboelastographic qualities: a single-center retrospective study.

This study describes the risk of thrombotic and hemorrhagic complications, both intraoperatively, and up to 1 month following visceral transplantation. Data from 48 adult visceral transplants performed between 2010 and 2017 were retrospectively studied [32 multivisceral (MVTx); 10 isolated intestine; six modified-MVTx]. Intraoperatively, intracardiac thrombosis (ICT)/pulmonary embolism (PE) occurred in 25%, 0% and 0% of MVTx, isolated intestine and modified MVTx, respectively, and was associated with 50% (4/8) mortality. Preoperative portal vein thrombosis (PVT) was a significant risk factor for ICT/PE (P = 0.0073). Thromboelastography resembling disseminated intravascular coagulation (DIC) (r time <4 mm combined with fibrinolysis or flat-line) was statistically associated with occurrence of ICT/PE (P < 0.0001). Compared to subgroup without ICT/PE, occurrence of ICT/PE was associated with an increased demand for all blood product components both overall, and each surgical stage. Hyperfibrinolysis (56%) was identified as cause of bleeding in MVTx. Incidence of postoperative thrombotic event at 1 month was 25%, 30% and 17% for MVTx, isolated intestine and modified MVTx, respectively. Incidence of postoperative bleeding complications at 1 month was 11%, 20% and 17% for MVTx, isolated intestine and modified MVTx. In conclusion, MVTx recipients with preoperative PVT are at an increased risk of developing intraoperative life-threatening ICT/PE events associated with DIC-like coagulopathy.

Acute Hypoglycemia Induces Painful Neuropathy and the Treatment of Coenzyme Q10.

Diabetic neuropathic pain is reduced with tight glycemic control. However, strict control increases the risk of hypoglycemic episodes, which are themselves linked to painful neuropathy. This study explored the effects of hypoglycemia-related painful neuropathy. Pretreatment with coenzyme Q10 (CoQ10) was performed to explore the preventive effect of CoQ10 on hypoglycemia-related acute neuropathic pain. Two strains of mice were used and 1 unit/kg of insulin was given to induce hypoglycemia. Mechanical sensitivity of hindpaw withdrawal thresholds was measured using von Frey filaments. Blood glucose levels were clamped at normal levels by joint insulin and glucose injection to test whether insulin itself induced hypersensitivity. Results suggest that the increased mechanical sensitivity after insulin injection is related to decreased blood glucose levels. When blood glucose levels remained at a normal level by the linked administration of insulin and glucose, mice demonstrated no significant change in mechanical sensitivity. Pretreatment with CoQ10 prevented neuropathic pain and the expression of the stress factor c-Fos. These results support the concept that pain in the diabetic scenario can be the result of hypoglycemia and not insulin itself. Additionally, pretreatment with CoQ10 may be a potent preventive method for the development of neuropathic pain.

Catechol-o-methyltransferase polymorphisms predict opioid consumption in postoperative pain.

BACKGROUND: Previous studies have associated the catechol-O-methyltransferase (COMT) enzyme rs4680 polymorphism with opioid consumption in the treatment of chronic cancer pain. In this study, we evaluated the association between COMT rs4680 and rs4818 polymorphisms and opioid consumption in the acute postoperative period after a nephrectomy. METHODS: Opioid consumption and pain scores were evaluated in 152 patients for 48 hours after nephrectomy. The genotype of each patient was determined using polymerase chain reaction on DNA extracted from blood samples. The association between rs4680 and rs4818 genotypes and opioid consumption was evaluated using general linear model regression analysis. All P values and confidence intervals were Bonferroni corrected for the 3 comparisons among genotypes. RESULTS: In the 24-hour period after surgery (COMT rs4680), patients homozygous for the variant Val/Val consumed 36% (95% confidence interval, 31%-41%) more opioids than patients homozygous for the Met/Met group (P = 0.009). No statistically significant differences among the 3 genotype groups were noted for pain scores or emesis medication use in the first 24 hours after surgery. There was a statistically significant increase in emesis medication use in patients possessing the CC genotype of rs4818 when compared to patients carrying the GG genotypes (P = 0.035). In the 6- to 48-hour postsurgery period, there was significantly higher opioid consumption in the high-activity homozygotes Val/Val than in the homozygous Met/Met group for COMT rs4680 (0-6 h: P = 0.005; 0-12 h: P = 0.015; 0-24 h: P = 0.015; and 0-48 h: P = 0.023). Patients in the homozygous GG group COMT rs4818 single nucleotide polymorphism showed statistically significant differences in opioid consumption in the first 6 hours after nephrectomy compared with heterozygous CG patients (P = 0.02). CONCLUSIONS: The genetic variant of the COMT rs4680 single nucleotide polymorphism is associated with variability in opioid consumption in postoperative nephrectomy patients. The COMT rs4818 polymorphism may prove useful in predicting emesis medication use postoperatively.

Single-nucleotide polymorphism C3435T in the ABCB1 gene is associated with opioid consumption in postoperative pain.

BACKGROUND: ABCB1 is a major determinant of opioid bioavailability; however, no previous studies have provided positive evidence of an association between single-nucleotide polymorphisms (SNPs) of ABCB1 and opioid usage in acute pain management. The aim of this study was to test the association between the functional SNP C3435T in ABCB1 and opioid consumption in postoperative pain in patients undergoing a nephrectomy. Additionally, we explored the association between C3435T and opioid side effect. METHODS: C3435T was genotyped in 152 patients undergoing a nephrectomy. Opioid consumption and pain scores were evaluated as well. The effect of genotype on opioid consumption was modeled using a general linear mixed model. RESULT: Based on a mixed linear model, the ABCB1 three genotypes showed a statistically significant effect on opioid consumption (F = 4.20, P = 0.017). There was a statistically significant difference in opioid consumption among the ABCB1 three genotypes in the 0-6 hours (P = 0.031, 95% confidence interval [CI] CC 14.7-24.8 mg and TT 5.2-14.6 mg) and 6-12 hours (P = 0.009, 95% CI CC 5.6-13.8 mg and TT 1.2 mg-5.1 mg) postoperative period. There were no significant statistical differences in opioid consumption among the ABCB1 three genotypes in the 12-24 hours (P = 0.302) and 24-48 hours (P = 0.763) postoperative period. The TT genotype had significantly lower levels of cumulative opioid consumption compared with the CC genotype in first 24 hours after surgery (P = 0.029). No statistically significant differences among the three genotype groups were noted for postoperative pain scores or emesis medication use in the first 24 hours after surgery. CONCLUSION: Our results demonstrate an association between the ABCB1 polymorphism (C3435T) and interindividual variations in opioid consumption in the acute postoperative period after nephrectomy. The ABCB1 polymorphism may serve as an important factor to guide acute pain therapy in postoperative patients.

Diabetic neuropathic pain development in type 2 diabetic mouse model and the prophylactic and therapeutic effects of coenzyme Q10.

UNLABELLED: The early onset of type 2 diabetes mellitus (DM), driven by increasing obesity, is associated with peripheral neuropathy. Here, we characterize diabetic neuropathic pain in New Zealand obese diabetic mice (NZO/HILtJ) as a polygenic model of obesity with type 2 diabetes and investigate the role of coenzyme Q10 (CoQ10) in the prevention and treatment of diabetic neuropathic pain. Since the overexpression of mitogen-activated protein kinase (MAPK), nuclear factor-κB proteins (NF-Kb), toll-like receptor 4 (TLR4) and downstream cytokines (such as CCL2, CXCL10) are considered important factors contributing to the development of neuropathic pain, the expression of these factors and the inhibitory effects of CoQ10 were evaluated. NZO/HILtJ mice spontaneously developed type 2 DM and increased body mass with diabetic neuropathic pain. CoQ10 treatment decreased pain hypersensitivity and long-term supplementation prevented the development of diabetic neuropathic pain but did not attenuate diabetes. Spinal cord, blood serum, liver tissue, and dorsal root ganglia (DRG) from diabetic mice demonstrated increased lipid peroxidation, which was decreased by CoQ10 treatment. The percentage of positive neurons of p65 (the activated marker of NF-KB) and MAPK in DRG were significantly higher in DM mice compared to controls. However, CoQ10 treatment significantly decreased p65 and MAPK positive neurons in the DRG of DM mice. RT-PCR demonstrated that elevated levels of mRNA of CCL2, CXCL10 or TLR4 in the spinal cord of DM mice decreased significantly when DM mice were treated with CoQ10. CONCLUSION: This model may be useful in understanding the mechanisms of neuropathic pain in type 2 DM induced neuropathic pain and may facilitate preclinical testing of therapies. CoQ10 may decrease oxidative stress in the central and peripheral nervous system by acting as an anti-oxidant and free-radical scavenger. These results suggest that CoQ10 might be a reasonable preventative strategy for long-term use and using CoQ10 treatment may be a safe and effective long-term approach in the treatment of diabetic neuropathy.

Prophylactic and antinociceptive effects of coenzyme Q10 on diabetic neuropathic pain in a mouse model of type 1 diabetes.

BACKGROUND: Oxidative stress is a key factor implicated in the development of diabetic neuropathy. This study evaluates the prophylactic and antinociceptive effects of the antioxidant coenzyme Q10 (CoQ10) on diabetes-induced neuropathic pain in a diabetic mouse model. METHODS: Total 56 mice with type 1 diabetes induced by streptozotocin were used, 20 normal mice were used as control. Mechanical and thermal nociceptive behavioral assays were applied to evaluate diabetic neuropathic pain. Tissue lipid peroxidation, immunohistochemistry, reverse transcription, and polymerase chain reaction were used to evaluate the molecular mechanisms of CoQ10. Data are presented as mean ± SEM. RESULTS: CoQ10 administration was associated with reduced loss of body weight compared with nontreated diabetic mice, without affecting blood glucose levels. Low dose and long-term administration of CoQ10 prevented the development of neuropathic pain. Treatment with CoQ10 produced a significant dose-dependent inhibition of mechanical allodynia and thermal hyperalgesia in diabetic mice. Dorsal root ganglia, sciatic nerve, and spinal cord tissues from diabetic mice demonstrated increased lipid peroxidation that was reduced by CoQ10 treatment. CoQ10 administration was also noted to reduce the proinflammatory factors in the peripheral and central nervous system. CONCLUSIONS: The results of this study support the hypothesis that hyperglycemia induced neuronal oxidative damage and reactive inflammation may be pathogenic in diabetic neuropathic pain. CoQ10 may be protective by inhibiting oxidative stress and reducing inflammation by down-regulating proinflammatory factors. These results suggest that CoQ10 administration may represent a low-risk, high-reward strategy for preventing or treating diabetic neuropathy.

A comparison of different types of hazardous material respirators available to anesthesiologists.

OBJECTIVE: Despite anesthesiology personnel involvement in initial treatment of patients exposed to potentially lethal agents, less than 40 percent of US anesthesiology training programs conduct training to manage these patients.(1) No previous studies have evaluated performance of anesthesiologists wearing protective gear. The authors compared the performance of anesthesiologists intubating a high-fidelity mannequin while wearing either a powered air-purifying respirator (PAPR) or a negative pressure respirator (NPR). METHODS: Twenty participants practiced intubations on a high-fidelity simulator until comfortable. Each subject performed 10 repetitions, initially without any gear, then while wearing a protective suit, gloves, and respirator. The order of gear use was randomized and all subjects used both devices. Time for task completion were recorded, and at the end of the trial, subjects were asked to rate their comfort with the equipment. RESULTS: After controlling for other variables, overall statistically slower total performance times were observed with use of the PAPR when compared to the control arm and use of the NPR (p 5 0.01 and p < 0.007, respectively). Of the total 90 intubations, only one proved to be esophageal and initially undetected. CONCLUSIONS: The use of an NPR or PAPR does not preclude an anesthesiologist from successfully intubating, but practice is necessary. The slightly better performance with the NPR is weighed against the improved comfort of the PAPR and the fact that PAPR users could wear eyeglasses. Neither type of gear allowed the users to auscultate the lung fields to confirm correct endotracheal tube placement.

CYP2D6 poor metabolizer genotype and smoking predict severe postoperative pain in female patients on arrival to the recovery room.

UNLABELLED: Recent studies have shown that CYP2D6 acts at critical steps for endogenous morphine biosynthesis. The present study assessed the contribution of CYP2D6 genetic polymorphisms, smoking, and other factors on acute severe postoperative pain (linear analog pain scores ≥8). METHODS: Two hundred thirty-six female patients were found to have adequate information in a previously developed female surgical patient database to be included in this current analysis. Multiple logistic regression analysis was used to assess the predictors for acute severe postoperative pain. DNA had been previously extracted from blood samples in all patients and was genotyped by the Amplichip to determine the specific CYP2D6 genotypes. RESULTS: It was noted that the incidence of acute severe postoperative pain (linear analog pain scores ≥8) was more frequent in patients with the CYP2D6 poor metabolizer (PM) genotype, 71%, compared with 28% in intermediate metabolizers (IMs), 26% in extensive metabolizers (EMs), and 27% in ultrarapid metabolizers (UMs). The overall association between metabolizer groups and severe postoperative pain was significant (P=0.023). PMs were significantly more likely to suffer from severe postoperative pain than IMs, EMs, and UMs (P=0.007, 0.002, and 0.050, respectively). There were no significant differences among IMs, EMs, and UMs. Additionally, it was noted that there was an increased frequency of acute severe postoperative pain in smokers vs nonsmokers (P=0.014). CONCLUSION: This study demonstrated that female patients possessing the PM genotype of CYP2D6 and patients who smoke had a higher incidence of acute severe postoperative pain.

Polymorphism in the interleukin-1 receptor antagonist gene is associated with serum interleukin-1 receptor antagonist concentrations and postoperative opioid consumption.

BACKGROUND: The interleukin-1 receptor antagonist (IL-1Ra) is the principal determinant of IL-1ß bioactivity within the IL-1 gene cluster, regulating IL-1α and IL-1ß release. This study was designed to determine whether polymorphisms of the IL-1Ra gene (IL1RN) produce clinically measurable differences in serum IL-1Ra concentrations and opioid consumption in the postoperative period. METHODS: Opioid consumption and pain scores were evaluated in 96 patients undergoing a nephrectomy. DNA was extracted from all patients, and the genotypes of IL1RN were determined by polymerase chain reaction amplification of the variable number of tandem repeats of 86 base pairs in intron 2 of IL1RN. The concentrations of serum IL-1Ra concentrations at baseline and at 24 h postoperatively in 58 subjects were measured. RESULTS: Differences in opioid consumption among the three genotype groups (IL1RN*1 homozygotes and *2 and *3 carriers) were statistically significant in the first and second 12-h postoperative periods (P = 0.010). The IL1RN*2 carrier group consumed 43% (95% CI, 38-48%) less opioids in the first 24 h after surgery than the IL1RN*1 homozygote group (P = 0.003). Differences in the serum IL-1Ra concentration among the three genotype groups were statistically significant at 24 h postoperatively (P = 0.003), with IL1RN*2 carriers having the highest serum IL-1Ra concentrations. CONCLUSIONS: The variable number of tandem repeats in intron 2 of IL1RN may contribute to interindividual variations in opioid consumption in the first 24 h after surgery. Patients homozygous for the IL1RN*1 allele have lower concentrations of IL-1Ra and require higher doses of opioids postoperatively than patients carrying at least one IL1RN*2 allele.

Radiostethoscopes: an innovative solution for auscultation while wearing protective gear.

OBJECTIVE: To demonstrate a radiostethoscope that could be modified and successfully used while wearing protective gear to solve the problem of auscultation in a hazardous material or infectious disease setting. DESIGN: This study was a randomized, prospective, and blinded investigation. SETTING: The study was conducted at the University of Miami-Jackson Memorial Hospital Center for Patient Safety. PARTICIPANTS: Two blinded anesthesiologists using a radiostethoscope performed a total of 100 assessments (50 each) to evaluate endotracheal tube position on a human patient simulator (HPS). INTERVENTIONS: Each lung of the HPS was ventilated separately using a double lumen tube. Four ventilation patterns (ie, right lung ventilation only; left lung ventilation only; ventilation of both lungs; and an esophageal intubation or no breath sounds) were simulated. The ventilation pattern was determined randomly and participants were blinded. An Ambu-Bag was used for ventilation. An assistant moved the radiostethoscope to the right and left lung fields and then to the abdomen of the HPS while ventilating. Subjects had to identify the ventilation pattern after listening to all three locations. A third member of the research team collected responses. Each subject, who wore both types of respirator (positive and negative), performed a total of 25 trials. Participants later compared the two types of respirators and their ability to auscultate for breath sounds. RESULTS: Subjects were able to verify the correct ventilation pattern in all attempts (100 percent). CONCLUSIONS: Radiostethoscopes appear to provide a viable solution for the problem of patient auscultation while wearing protective gear.

Double-blind comparison of granisetron, promethazine, or a combination of both for the prevention of postoperative nausea and vomiting in females undergoing outpatient laparoscopies.

PURPOSE: Postoperative nausea and vomiting (PONV) and postdischarge nausea and vomiting (PDNV) are common problems after surgery. Prophylactic combination antiemetic therapy is recommended for patients at high risk for developing PONV and PDNV. Granisetron, a serotonin antagonist, is an effective antiemetic that is devoid of sedative side effect. Although promethazine is effective, commonly used doses are associated with sedation. This study investigates the combination of low doses of granisetron and promethazine for the prevention of PONV. METHODS: Women undergoing ambulatory gynecological laparoscopy were enrolled. A standard general anesthetic regimen was prescribed. Fifteen minutes before the expected end of surgery, the patients were randomly assigned to receive granisetron 0.1 mg iv, promethazine 6.25 mg iv, or a combination of the two drugs. Prophylaxis with oral promethazine 12.5 mg, granisetron 1 mg, or both was started in the respective groups 12 hr after the end of surgery and continued every 12 hr until postoperative day 3 (a total of five oral doses). The following outcomes were recorded: total response rate (defined as no vomiting, no more than mild nausea, and no use of rescue antiemetic); incidence of nausea, vomiting, and use of rescue antiemetics; severity of nausea; patient activity level; and patient satisfaction with PONV management. RESULTS: Patients in the combination group had a higher total response rate at 6, 24, 48, and 72 hr after surgery compared with those who received promethazine alone (at 24 hr, Combination 69.6%, Promethazine 36.2%, Granisetron 53.3%; P = 0.0079). The maximum nausea scores were also lower in the combination group at 6, 24, 48, and 72 hr (Combination 1.7 +/- 2.2, Promethazine 4.0 +/- 3.6, Granisetron 3.1 +/- 3.2 at 24 hr; P < 0.05). There was no difference in the sedation scores, incidence of drowsiness, patient activity level, and satisfaction with PONV management. CONCLUSIONS: Low-dose granisetron and promethazine combination was more effective in reducing PONV and PDNV than promethazine monotherapy. The combination also reduced the severity of nausea.

The effect of needle bevel position on pain for subcutaneous lidocaine injection.

It is a common practice for medical practitioners to use subcutaneous infiltration of lidocaine to alleviate the pain of intravenous cannulation or line insertion. Although previous studies have assessed several factors affecting the pain associated with local anesthetic infiltration, there is a paucity of data on the effects of needle bevel position. In this prospective, randomized, controlled trial, we compared the effect of two different needle bevel positions (bevel up versus bevel down) and the pain associated with the subcutaneous injection of 1% lidocaine in 50 adult volunteers. Significantly higher pain scores were observed when the needle was placed bevel down compared with bevel up (P = .02). No significant differences in pain scores were noted between the groups for age and gender.

The impact of CYP2D6 genetic polymorphisms on postoperative morphine consumption.

BACKGROUND: Endogenous morphine-like compounds have been identified in humans and are released in response to stress. Human monocytes and granulocytes express the micro opiate receptor, micro3, which is morphine selective but opiate peptide insensitive. Recent studies have shown that CYP2D6 acts at critical steps for endogenous morphine biosynthesis. We theorized that ultrarapid (UM) CYP2D6 metabolizers may have an enhancement of their endogenous pain modulating mechanisms. METHODS: After institutional review board approval, a previously developed surgical patient database was evaluated for information concerning CYP2D6 genotypes and morphine consumption. One hundred forty-two patients were found to have adequate information to be included in this current analysis. The study group was divided, based on morphine consumption, into two subgroups: low morphine consumers (LMC) (< or =10 mg/4 h, N = 80) and high morphine consumers (HMC) (>10 mg/4 h, N = 62). DNA was extracted from blood in all patients and was genotyped by the Amplichip (Roche, Pleasanton, CA) to determine the specific CYP2D6 genotypes. RESULTS: CYP2D6 UM were found to occur more frequently in the LMC group than in the HMC group (8/80 vs 0/62, P = 0.0091). No significant differences were noted for the poor, intermediate, or extensive metabolizers. CONCLUSIONS: Our current results suggest that CYP2D6 UM appear to require less morphine in the acute postoperative period compared with other CYP2D6 metabolizer groups. One possible mechanism for this observation is that CYP2D6 UM may have higher efficiency in synthesizing endogenous morphine compared with other metabolizers, thus increasing endogenous pain modulation and reducing the need for exogenous morphine.