An exploratory study of factors associated with long-term, high-dose opioid prescription in cancer patients in Japan based on a medical claims database.

PURPOSE: As the cancer survivors increase, patients using long-term and high-dose opioids are also increasing. Therefore, the promotion of appropriate use is important. This study investigated the actual status of opioid prescriptions in Japan and identified factors associated with long-term, high-dose prescription. METHODS: We conducted a case-control study using a hospital-based administrative claims database. Patients with a diagnosis of cancer and prescriptions of opioids were included. Patients who received continuous opioid for less than 183 days were defined as the "control," and patients who received continuous opioid at higher dose levels (≥ 120 mg/day of oral morphine equivalent) for 183 days or more were defined as the "case." The case was subdivided into two groups: those with the duration of less than 730 days (case I) and 730 days or more (case II). After describing factors possibly associated with long-term, high-dose opioid prescription, ordinal logistic regression analysis was conducted. RESULTS: We included 19,176 patients; of these, 13,517 were in the control, 111 were in the case I, and 682 were in the case II. The analysis showed that distant metastasis, back pain, dose of opioids, non-opioid analgesics, prescription, and chemotherapy during the opioid prescriptions were significantly associated with long-term, high-dose opioid prescription. CONCLUSION: Four percent of the study population were prescribed long-term, high-dose opioids, and several comorbidities and concomitant medications were identified as associated factors. Opioids might be also prescribed for non-cancer chronic pain. It is necessary to properly distinguish the type of pain and to use opioids safely and appropriately.

Effects of the addition of dexamethasone on postoperative analgesia after anterior cruciate ligament reconstruction surgery under quadruple nerve blocks.

BACKGROUND: Anterior cruciate ligament (ACL) reconstruction is an invasive surgical procedure for the knee. Quadruple nerve blocks including continuous femoral nerve block and single-injection sciatic, obturator, and lateral femoral cutaneous nerve blocks can provide effective intraoperative anesthesia and analgesia in the early postoperative period. However, severe pain often appears after the effect of single-injection nerve blocks resolves and that is why we conducted two studies. The first study was to determine whether dexamethasone administered along with local anesthetic for sciatic nerve block could prolong the duration of analgesia in patients given quadruple nerve blocks, including continuous femoral nerve block, for ACL reconstruction using a hamstring tendon autograft. The second study was designed to evaluate any difference in effects from dexamethasone administered perineurally versus intravenously. METHODS: Patients undergoing unilateral arthroscopic ACL reconstruction using a hamstring tendon autograft were enrolled into two studies. The first study was prospectively conducted to see if dexamethasone 4 mg could prolong the duration of analgesia when administered perineurally to the subgluteal sciatic nerve with 0.5% ropivacaine. In the second study, we retrospectively evaluated the effects of intravenous dexamethasone 4 mg as compared with those of perineural dexamethasone to the sciatic nerve block and effects with no dexamethasone. RESULTS: In the first study, perineural dexamethasone prolonged the duration of analgesia by 9.5 h (median duration: 22.5 and 13.0 h with and without perineural dexamethasone, respectively, P = 0.011). In the second study, the duration of analgesia was similarly prolonged for intravenous and perineural dexamethasone compared with no dexamethasone. CONCLUSION: Perineural dexamethasone administered along with local anesthetic for single sciatic nerve block prolonged the duration of analgesia of quadruple nerve blocks for ACL reconstruction, however the effects were not different from those of intravenous dexamethasone. TRIAL REGISTRATION: The protocols of both studies were approved by the Institutional Review Board of Shimane University Hospital, Japan (study number 2821 and 3390 for study 1 and study 2, respectively). Study 1 was registered in University Hospital Medical Information Network Clinical Trials Registry ( UMIN000028930 ). Study 2, which was a retrospective study, was not registered.

Incidence and effects of postoperative migration of interscalene catheter tips placed using ultrasound-guided anterior and posterior approaches.

BACKGROUND: Continuous interscalene brachial plexus block (CISB) provides analgesia after shoulder surgery. However, even a catheter securely fixed at the insertion site may be susceptible to migration, precluding the block from working consistently. We examined to see if catheter tip migration would occur with no catheter-at-skin change after anterior and posterior approaches to CISB in patients undergoing shoulder surgery, and compared the incidence rate and pain scores between approaches and between catheters with and without tip migration, respectively. METHODS: Patients were randomly assigned to receive CISB using either anterior or posterior approach. Catheter tip was observed using a cross-sectional view. The rates of catheter tip migration with no catheter-at-skin change at 24 h after the two approaches were calculated and compared, and pain scores were compared between catheters with and without tip migration after each approach. RESULTS: Fifty-four patients were analyzed. Catheter tip migration occurred at 24 h at a similar rate after both approaches (anterior approach 40.7% versus posterior approach 33.3%, p = 0.78). Worst pain score was significantly higher for 24 h in patients whose catheter tip had migrated as compared with those whose catheter had not migrated after anterior (median [IQR] 53 [42-73] versus 18 [0-50], p = 0.003) and posterior approaches (median [IQR] 63 [57-81] versus 29 [3-47], p < 0.0001). CONCLUSION: In patients undergoing shoulder surgery, an interscalene catheter tip can migrate after both anterior and posterior approaches at a similar rate, even if the catheter insertion length is not changed. The tip migration does decrease the analgesic effect of CISB.

Positive End-expiratory Pressure and Distribution of Ventilation in Pneumoperitoneum Combined with Steep Trendelenburg Position.

BACKGROUND: Pneumoperitoneum and a steep Trendelenburg position during robot-assisted laparoscopic prostatectomy have been demonstrated to promote a cranial shift of the diaphragm and the formation of atelectasis in the dorsal parts of the lungs. However, neither an impact of higher positive end-expiratory pressure (PEEP) on preserving the ventilation in the dorsal region nor its physiologic effects have been fully examined. The authors hypothesized that PEEP of 15 cm H2O during robot-assisted laparoscopic prostatectomy might maintain ventilation in the dorsal parts and thus improve lung mechanics. METHODS: In this randomized controlled study, 48 patients undergoing robot-assisted laparoscopic prostatectomy were included in the analysis. Patients were assigned to the conventional PEEP (5 cm H2O) group or the high PEEP (15 cm H2O) group. Regional ventilation was monitored using electrical impedance tomography before and after the establishment of pneumoperitoneum and 20° Trendelenburg position during the surgery. The primary endpoint was the regional ventilation in the dorsal parts of the lungs while the secondary endpoints were lung mechanics and postoperative lung function. RESULTS: Compared to that in the conventional PEEP group, the fraction of regional ventilation in the most dorsal region was significantly higher in the high PEEP group during pneumoperitoneum and Trendelenburg position (mean values at 20 min after taking Trendelenburg position: conventional PEEP, 5.5 ± 3.9%; high PEEP, 9.9 ± 4.7%; difference, -4.5%; 95% CI, -7.4 to -1.6%; P = 0.004). Concurrently, lower driving pressure (conventional PEEP, 14.9 ± 2.5 cm H2O; high PEEP, 11.5 ± 2.8 cm H2O; P < 0.001), higher lung dynamic compliance, and better oxygenation were demonstrated in the high PEEP group. Postoperative lung function did not differ between the groups. CONCLUSIONS: Application of a PEEP of 15 cm H2O resulted in more homogeneous ventilation and favorable physiologic effects during robot-assisted laparoscopic prostatectomy but did not improve postoperative lung function.

Continuous basal infusion versus programmed intermittent bolus for quadratus lumborum block after laparoscopic colorectal surgery: a randomized-controlled, double-blind study.

BACKGROUND: Quadratus lumborum block (QLB) has recently attracted attention as a part of multimodal analgesia after abdominal surgery. It has been shown that programmed intermittent boluses of local anesthetic can produce better analgesia and wider sensory blockade compared with continuous basal infusion with some peripheral nerve blocks. The present study was conducted to see if this theory holds true for QLB in patients undergoing laparoscopic colorectal surgery. METHODS: Fifty patients undergoing laparoscopic colorectal surgery were divided into 2 groups to receive continuous basal infusion (group C) or programmed intermittent boluses (group PIB) of local anesthetic. After surgery, patients received the posterior approach to QLB and a catheter was introduced bilaterally. Patients in group C received a continuous infusion of 0.15% levobupivacaine at 3 ml/h, and those in group PIB received a bolus of 12 ml every 4 h. All patients received intravenous patient-controlled analgesia using fentanyl. Measurements were taken for cumulative fentanyl consumption, pain scores, cutaneous sensory blockade, analgesic requirements, and adverse events for 46 h. RESULTS: The primary outcome of cumulative fentanyl consumption at 22 h showed no significant difference between the groups [group C: 11.9 (11.2-15.5) µg/kg (median (interquartile range)) and group PIB: 12.3 (11.6-15.3), p = 0.473]. Pain scores, demands for rescue analgesics, and spread of cutaneous sensory blockade were similar for the two groups. CONCLUSION: Programmed intermittent boluses of local anesthetic for continuous QLB did not produce better analgesia or wider sensory blockade compared with continuous basal infusion in patients undergoing laparoscopic colorectal surgery.

Continuous quadratus lumborum block and femoral nerve block for total hip arthroplasty: a randomized study.

BACKGROUND: Continuous femoral nerve block (FNB) has been effectively used after total hip arthroplasty (THA). Recently the anterior approach to quadratus lumborum block (QLB) has been shown to produce postoperative pain relief after THA. Continuous QLB would benefit from a catheter insertion site that is farther away from the surgical site compared with continuous FNB. In this randomized controlled study, we compared analgesic effects of the two techniques in patients undergoing THA. METHODS: Thirty patients undergoing THA were randomly allocated into two groups receiving continuous QLB and FNB. Under ultrasound guidance, QLB and FNB were conducted before general anesthesia using 0.25% levobupivacaine 30 ml and 0.5% levobupivacaine 15 ml, respectively, and a catheter was introduced. Postoperatively, all patients received continuous infusion of 0.125% levobupivacaine at 4 ml/h. Postoperative measurements included visual analog scale (VAS) pain scores at rest and on movement, postoperative analgesic demands, cutaneous sensory blockade and adverse events for 48 h. RESULTS: Six patients were excluded and 24 patients (13 and 11 patients in QLB group and FNB, respectively) were analyzed. VAS scores on movement at 6 h [median (IQR): 67 (41-80) and 38 (22-41) in QLB and FNB groups, respectively, p = 0.008] and 24 h [60 (40-80) and 39 (28-64) in QLB and FNB groups, respectively, p = 0.018] were lower with FNB than with QLB. QLB did not produce consistent cutaneous sensory blockade. CONCLUSIONS: Analgesic effects of continuous QLB were inferior to those of continuous FNB in patients undergoing THA under the current study condition.

Cold atmospheric-pressure nitrogen plasma induces the production of reactive nitrogen species and cell death by increasing intracellular calcium in HEK293T cells.

Cold atmospheric-pressure plasma (CAP) has been emerging as a promising tool for cancer therapy in recent times. In this study, we used a CAP device with nitrogen gas (N2CAP) and investigated the effect of the N2CAP on the viability of cultured cells. Moreover, we investigated whether N2CAP-produced hydrogen peroxide (H2O2) in the medium is involved in N2CAP-induced cell death. Here, we found that the N2CAP irradiation inhibited cell proliferation in the human embryonic kidney cell line HEK293T and that the N2CAP induced cell death in an irradiation time- and distance-dependent manner. Furthermore, the N2CAP and H2O2 increased intracellular calcium levels and induced caspase-3/7 activation in HEK293T cells. The N2CAP irradiation induced a time-dependent production of H2O2 and nitrite/nitrate in PBS or culture medium. However, the amount of H2O2 in the solution after N2CAP irradiation was too low to induce cell death. Interestingly, carboxy-PTIO, a nitric oxide scavenger, or BAPTA-AM, a cell-permeable calcium chelator, inhibited N2CAP-induced morphological change and cell death. These results suggest that the production of reactive nitrogen species and the increase in intracellular calcium were involved in the N2CAP-induced cell death.

A double-blind, randomized comparative study to investigate the morphine to hydromorphone conversion ratio in Japanese cancer patients.

OBJECTIVE: To confirm the morphine to hydromorphone conversion ratio for hydromorphone (DS-7113b) immediate-release tablets in cancer patients who achieved pain control with oral morphine. METHODS: This was a multicenter, active-controlled, randomized, double-blind, parallel-group, comparative study (July 2013 to December 2014) at 39 Japanese sites. Seventy-one patients (aged >20 years) who had achieved pain control with morphine 60 mg/day and 90 mg/day were randomly allocated 1:1 to hydromorphone immediate-release tablets at a dose converted at a hydromorphone:morphine ratio of 1:5 or 1:8, respectively, and treated for up to 5 days. The efficacy was evaluated as the pain control ratio. RESULTS: The pain control ratio in the full analysis set was 83.3% (25/30) in the conversion ratio 1:5 group and 95.0% (38/40) in the conversion ratio 1:8 group, and both groups demonstrated highly successful pain control. The incidence of adverse events was 46.7% (14/30) in the conversion ratio 1:5 group and 58.5% (24/41) in the 1:8 group; the difference was not clinically relevant. Frequently observed adverse events (incidence ≥5%) were nausea, vomiting, diarrhea, somnolence and dyspnea. CONCLUSIONS: A high pain control ratio was maintained by a switch at either conversion ratio, and no notable difference was observed in the incidence of adverse events. A switch from morphine to hydromorphone is effective at a dose converted at ratios of 1:5 and 1:8.

A randomized, double-blind, non-inferiority study of hydromorphone hydrochloride immediate-release tablets versus oxycodone hydrochloride immediate-release powder for cancer pain: efficacy and safety in Japanese cancer patients.

BACKGROUND: Hydromorphone is a standard opioid analgesic for cancer pain that, prior to this study, was not approved in Japan, where options for opioid switching are limited. We aimed to investigate the efficacy and safety of hydromorphone (DS-7113b) immediate-release tablets in opioid-naïve cancer patients with moderate to severe cancer pain. METHODS: Multicenter, active-controlled, randomized, double-blind, parallel-group, non-inferiority study of 183 cancer patients over 20 years of age at 50 clinical sites in Japan. Hydromorphone tablets or oxycodone hydrochloride powder was orally administered four times daily for 5 days. The initial doses of hydromorphone and oxycodone hydrochloride were 4 mg/day and 10 mg/day, respectively, and adjusted as necessary. Efficacy was evaluated as the intergroup difference (95% confidence interval [CI]) of the least squares mean by analysis of covariance, using the baseline visual analog scale (VAS) as a covariate for change in VAS score at treatment completion/discontinuation in the full analysis set. RESULTS: Non-inferiority of hydromorphone versus oxycodone was confirmed, with an intergroup difference (95% CI) in the least squares mean of -3.4 mm (-9.8 to 3.1 mm) for change in VAS scores, which was below the upper limit of the 95% CI at 10 mm, the non-inferiority limit determined during study planning. Adverse events occurred in 83.0% (73/88) of patients in the hydromorphone group and 77.4% (65/84) in the oxycodone group. The most frequently observed adverse events were somnolence, constipation, vomiting and nausea. CONCLUSIONS: The efficacy and safety of hydromorphone tablets are equivalent to those of oxycodone immediate-release powder.

Prophylactic Pentazocine Reduces the Incidence of Pruritus After Cesarean Delivery Under Spinal Anesthesia With Opioids: A Prospective Randomized Clinical Trial.

BACKGROUND: The incidence of pruritus after cesarean delivery under spinal anesthesia with opioids is high, ranging from 50% to 100%. Pruritus is difficult to prevent; however, pentazocine has been shown to be an effective treatment. Despite this, the prophylactic effect of pentazocine on pruritus has not been defined. This randomized double-blind trial aimed to evaluate the effect of intraoperative IV pentazocine on the incidence of opioid-induced pruritus within the first 24 hours after administration of neuraxial opioids. METHODS: We obtained institutional review board approval and written informed consent from the 122 patients (American Society of Anesthesiologists [ASA] physical status II; aged 20-40 years) scheduled for elective cesarean delivery who were included in this study. Spinal anesthesia was performed with 10 mg of 0.5% hyperbaric bupivacaine, 10 µg of fentanyl, and 100 µg of morphine. After delivery of the baby and placenta, the parturient women were randomized to intravenously receive 15 mg (1 mL) of pentazocine or 1 mL of saline. All women received postoperative analgesia with the epidural infusion of 0.15% levobupivacaine. The presence of pruritus within the first 24 hours after intrathecal administration of opioids was recorded, and severity of itch, numerical rating scale (NRS) for pain, and adverse effects were also recorded at the time of the arrival on the ward, as well as 3, 6, 12, and 24 hours after the intrathecal administration of opioids. RESULTS: A total of 119 women completed the study. IV pentazocine reduced the overall incidence of pruritus within the first 24 hours compared to IV saline, with an estimated relative risk of 69% (95% confidence interval [CI], 52%, 90%; P = .007). IV pentazocine also reduced the severity of pruritus. The incidence of nausea and vomiting was not significantly different. There were no significant differences in postoperative NRS scores. CONCLUSIONS: A single 15-mg dose of IV pentazocine after delivery can reduce both the incidence and severity of pruritus in women who have received subarachnoid opioids during cesarean delivery.

Monitored anesthesia care based on ultrasound-guided subcostal transversus abdominis plane block for continuous ambulatory peritoneal dialysis catheter surgery: case series.

Planning safe perioperative management for patients undergoing continuous ambulatory peritoneal dialysis (CAPD) catheter surgery (insertion and extraction of the catheter) is often difficult because many of these patients not only have renal insufficiency but also have co-existing disorders, such as heart diseases. As increased indications for perioperative anticoagulation therapy have limited the choice of anesthesia, selecting an appropriate anesthetic method, particularly for patients with poor systemic conditions, is becoming more challenging. We report seven cases of CAPD catheter surgery successfully managed by monitored anesthesia care using subcostal transversus abdominis plane (TAP) block with additional local anesthetic infiltration and analgesics. Despite co-existing cardiac disease and/or coagulation disorders, all patients were safely managed without any other major anesthetic methods. Subcostal TAP block is a useful anesthetic option for CAPD catheter surgery, particularly for patients with poor systemic conditions and/or in whom neuraxial blocks are contraindicated.

[Treatment of intrathecal fentanyl-induced itch with pentazocine: a case report].

Pentazocine has activities both of kappa-opioid receptor agonist and weak micro-opioid receptor antagonist. Recent study has suggested that kappa-opioid receptor agonists have antipruritic effects. We experienced a case of pentazocine inhibiting itch evoked by intrathecal fentanyl in a patient with idiopathic pulmonary fibrosis (IPF). A 50-year-old woman with IPF was diagnosed with fallopian tube abscess and which necessitated emergency surgery. We mainly performed regional anesthetic management to prevent acute exacerbation of IPF by tracheal intubation under general anesthesia. About 30 minutes after intrathecal administration of a combination of bupivacaine and fentanyl, she began to complain of itch. Although propofol was given intravenously, pruritus still recurred. Following that, when pentazocine was administered intravenously, pruritus disappeared immediately and then never recurred. Therefore, it is suggested that pentazocine can be useful in reducing pruritus on intrathecal opioid-induced itch. Future studies are necessary to evaluate the efficacy of pentazocine for the treatment and prevention of opioid-induced itch.

[Recipient of living kidney transplantation during which heparin-induced thrombocytopenia (HIT) was suspected: a case report].

A 67-year-old woman with a diabetic renal failure was scheduled for a living kidney transplantation. Heparin was first used during hemodialysis 5 days before operation. Thrombocytopenia was found immediately after induction of general anesthesia, and the diagnosis of HIT was wade based on clinical symptom and 4 T's scoring. The surgery was continued because of the progress of donor surgery. Argatoroban was administered based on APTT measurement as an anticoagulation therapy during and after the operation. Although deep vein thrombosis was found 13 days after the operation, the transplanted kidney was established successfully. It is necessary to take a great caution in HIT development after heparin use.

[A case report: perioperative management of adenotonsillectomy in a morbidly obese patient with severe obstructive sleep apnea syndrome].

A male patient in his thirties was scheduled to undergo adenotonsillectomy due to dyspnea from bilateral tonsillar hypertrophy. He was morbidly obese (body mass index 56 kg x m(-2)) with severe obstructive sleep apnea syndrome (OSAS), and thus was evaluated with extreme risk for difficult ventilation and intubation. We planned awake intubation via video-assisted laryngoscopy and fiberoptic bronchoscopy under dexmedetomidine sedation, and the intubation was successfully performed. After adenotonsillectomy, upper airway obstruction due to hemorrhage and oropharyngeal swelling can be life-threatening requiring emergent airway management. Thus for postoperative airway management, due to the possibility of "cannot intubate, cannot ventilate" (CICV) and presumed difficult tracheotomy, we scheduled to perform tracheotomy during adenotonsillectomy, right after anesthetic induction and awake intubation. On postoperative day 1, he started walking with no need of sedative drugs. On day 4, after confirmation of minimal oropharyngeal swelling, tracheal cannulae was removed, and no further complications were observed in his postoperative course. We conclude that careful preoperative evaluation of the airway, retention of spontaneous breathing via awake intubation, and preventive tracheotomy for postoperative airway management are important points in perioperative management of a morbidly obese patient with severe obstructive sleep apnea syndrome.

Effect of tranexamic acid on blood loss reduction in patients undergoing orthognathic surgery under hypotensive anesthesia: a single-center, retrospective, observational study.

Objectives: Orthognathic surgery is a surgical procedure performed by intraoral approach with established and safe techniques; however, excessive blood loss has been reported in rare cases. In response, investigative efforts to identify methods to reduce the amount of blood loss have been made. Among such methods, the administration of tranexamic acid was reported to reduce the amount of intraoperative blood loss. However, few studies to date have reported the effect of tranexamic acid in orthognathic surgery under hypotensive anesthesia. The present study aimed to investigate the effect of the administration of tranexamic acid on intraoperative blood loss in patients undergoing bimaxillary (maxillary and mandibular) orthognathic surgery under hypotensive anesthesia. Patients andMethods: A total of 156 patients (mean age, 27.0±10.8 years) who underwent bimaxillary orthognathic surgery under hypotensive anesthesia performed by the same surgeon between June 2013 and February 2022 were included in this study. The following data were collected from the medical records of each patient: background factors (age, sex, and body mass index), use of tranexamic acid, surgical procedures, previous medical history, duration of surgery, American Society of Anesthesiology physical status findings before surgery, intraoperative blood loss as a primary outcome, in-out balance, and blood test results. Descriptive statistics were calculated for statistical analysis, and a t -test and the chi-squared test were used for between-group comparisons. Group comparisons were performed after 1:1 propensity score matching to adjust for confounding factors. Statistical significance was set at P<0.05. Results: Comparison between the groups based on the use of tranexamic acid revealed a significant difference in operation time. Propensity score matching analysis revealed that intraoperative blood loss was significantly lower in the tranexamic acid group. Conclusion: The administration of tranexamic acid was effective in reducing intraoperative blood loss in patients undergoing bimaxillary orthognathic surgery under hypotensive anesthesia.

[The importance of preanesthetic evaluation: malignant tumors discovered on preoperative chest radiography, in patients scheduled for operation of benign tumors].

Preanesthetic evaluation is essential for the perioperative period. We report 2 preoperative patients with benign disease, whose preoperative chest radiography revealed intrathoracic malignant tumors. Case 1: A woman in her eighties with vascular necrosis of the femoral head was scheduled for bipolar hip arthroplasty under general anesthesia. On preanesthetic evaluation, widened mediastinum was detected on preoperative chest radiography. Instead of the scheduled operation, she underwent thoracoscopic surgery under general and epidural anesthesia. She was diagnosed with malignant thymoma. Case 2: A woman in her thirties with bilateral oviduct obstruction was scheduled for laparoscopic surgery. On preanesthetic evaluation, right middle lung lesion was detected. She underwent thoracoscopic biopsy under general and epidural anesthesia, and was diagnosed with malignant lymphoma. The result of preanesthetic chest radiography is reported to change the perioperative treatment only in 0.1%; our cases indicate the importance of preanesthetic evaluation of chest radiography in detecting possible underlying disease in the preoperative patient.

Whole lung lavage decreases physiological dead space in patients with pulmonary alveolar proteinosis: two case reports.

BACKGROUND: Pulmonary alveolar proteinosis (PAP) is a rare disease characterized by progressive accumulation of the alveolar surfactant. Whole lung lavage (WLL) using a high volume of warmed saline remains the standard therapy. However, no established bedside monitoring tool can evaluate the physiological effect of WLL in the perioperative period. Indirect calorimetry, which is generally used to measure resting energy expenditure, can detect carbon dioxide (CO2) production and mixed-expired partial pressure of CO2 breath by breath. In this physiological study, we calculated CO2 elimination per breath (VTCO2,br) and Enghoff's dead space using indirect calorimetry and measured the extravascular lung water index to reveal the effect of WLL. CASE PRESENTATION: We measured VTCO2,br, Enghoff's dead space, and the extravascular lung water and cardiac indices before and after WLL to assess the reduction in shunt by washing out the surfactant. A total of four WLLs were performed in two PAP patients. The first case involved an Asian 62-year-old man who presented with a 3-month history of dyspnea on exertion. The second case involved an Asian 48-year-old woman with no symptoms. VTCO2,br increased, and the Enghoff's dead space decreased at 12 h following WLL. An increase in the extravascular lung water was detected immediately following WLL, leading to a transient increase in Enghoff's dead space. CONCLUSION: WLL can increase efficient alveolar ventilation by washing out the accumulated surfactant. However, the lavage fluid may be absorbed into the lung tissues immediately after WLL and result in an increase in the extravascular lung water.

Steady-State Pharmacokinetics of Intravenous Hydromorphone in Japanese Patients With Renal Impairment and Cancer Pain.

Background: The opioid analgesic hydromorphone has a low renal excretion ratio; however, exposure after oral administration is several times higher in those with moderate or severe renal impairment. Objectives: We evaluated the impact of renal impairment on the steady-state pharmacokinetics of intravenously administered hydromorphone in patients with cancer being treated for pain. Design: This was an open-label, prospective, parallel-comparison, interventional clinical pharmacology study. Setting/Subjects: This study was conducted at one hospital in Japan. Using creatinine clearance (CLcr) values, patients were grouped according to kidney function: CLcr ≥90 mL/min (normal), 60-<90 mL/min (mild impairment), 30-<60 mL/min (moderate impairment), or <30 mL/min (severe impairment). Measurements: Hydromorphone was administered by constant infusion to patients at the same constant dose rate as at the time of enrollment. Hydromorphone and its glucuronide metabolite concentrations in plasma and urine were measured by liquid chromatography-mass spectrometry. Pharmacokinetic parameters at steady state were assessed using noncompartmental analysis. Results: Thirty-two patients were enrolled (normal, n = 3; mild, n = 10; moderate, n = 15; and severe, n = 4). Adjusted geometric mean ratios for hydromorphone steady-state clearance (CLss) for patients with impaired versus normal renal function were 0.69 (90% confidence interval [CI], 0.41-1.14), 0.52 (90% CI, 0.31-0.84), and 0.55 (90% CI, 0.30-1.02) for mild, moderate, or severe impairment, respectively. Exposures to the metabolite hydromorphone-3-glucuronide generally increased with renal impairment. No adverse event was reported. Conclusion: Hydromorphone CLss in patients with impaired renal function (moderate and severe) was decreased ∼50% of that of normal renal function.

Gabapentin augments the antihyperalgesic effects of diclofenac sodium through spinal action in a rat postoperative pain model.

BACKGROUND: Gabapentin and nonsteroidal antiinflammatory drugs (NSAIDs) attenuate postoperative pain and neuropathic pain in humans. The combination of gabapentin and NSAIDs is effective for postoperative pain and enhances functional recovery after surgery. Intrathecal administration of gabapentin or NSAIDs inhibits hyperalgesia in a rat postoperative pain model. However, there is no information on the effects of intrathecal administration of a combination of gabapentin and NSAIDs. We therefore investigated the effects of intrathecal administration of gabapentin and NSAIDs in a rat model of postoperative pain. METHODS: Rats were prepared for intrathecal catheters under halothane anesthesia. Two days after catheterization, gabapentin (4, 40, or 400 µg per 20 µL of saline), diclofenac sodium, a nonselective cyclooxygenase inhibitor (2, 20, or 200 µg per 20 µL of 6% glucose), 20 µL saline, 20 µL 6% glucose, and a combination of gabapentin and diclofenac (40 µg gabapentin + 20 µg diclofenac and 4 µg gabapentin + 2 µg diclofenac per 20 µL 6% glucose) were injected intrathecally. We performed a hindpaw incision 30 minutes after injection. Each group consisted of 6 rats. The mechanical threshold was measured to evaluate secondary hyperalgesia using von Frey filaments before intrathecal catheterization and at 2 hours, and 1, 3, 5, and 7 days after paw incision. RESULTS: Gabapentin 400 µg attenuated mechanical hyperalgesia for 7 days compared with the control group. Diclofenac 200 µg inhibited hyperalgesia for 5 days compared with the control group. The 40 µg gabapentin + 20 µg diclofenac group had a significantly reduced secondary hyperalgesic response in 2 hours and 1 day compared with 40 µg gabapentin and 20 µg diclofenac, respectively. The 4 µg gabapentin + 2 µg diclofenac group had a significantly reduced secondary hyperalgesic response in 2 hours and 1 day compared with 2 µg diclofenac. The withdrawal threshold on the contralateral paw did not change compared with the preincision threshold. CONCLUSION: Intrathecal administration of gabapentin and diclofenac in combination reduced secondary hyperalgesia at doses having no antihyperalgesic effects when given individually. Our results suggest that gabapentin and diclofenac have an important role in postoperative pain reduction at the spinal level, and that gabapentin augments the antihyperalgesic effects of diclofenac through action in the spinal cord.

Intravenous infusion of remifentanil induces transient withdrawal hyperalgesia depending on administration duration in rats.

BACKGROUND: Recent studies suggest that remifentanil, similar to other µ-opioid agonists, may induce hyperalgesia. We performed animal experiments to determine whether IV remifentanil infusion, the mode of administration used in clinical practice, induces hyperalgesia and the conditions in which this phenomenon occurs. We also determined whether remifentanil-induced hyperalgesia is related to extracellular signal-regulated protein kinase 1/2 (ERK1/2) phosphorylation. METHODS: Remifentanil was administered through a catheter in the tail vein of male Sprague-Dawley rats for 10 minutes (30 µg · kg(-1) · min(-1)), 30 minutes (0.1, 1, and 10 µg · kg(-1) · min(-1)), or 120 minutes (0.1, 1, 3, and 10 µg · kg(-1) · min(-1)). The von Frey test and a tail-flick test were performed, followed by ERK1/2 immunohistochemistry. We examined whether intrathecal preadministration of the mitogen-activated protein kinase inhibitor U0126 suppresses hyperalgesia. RESULTS: Remifentanil had a dose-dependent antinociceptive effect that rapidly diminished. Ten- or 30-minute remifentanil infusion did not induce hyperalgesia. However, tail-flick latency and mechanical pain threshold after infusion termination were significantly lower in the 120-minute remifentanil administration group than those in the control group, regardless of dose. Hyperalgesia duration was no longer than 60 minutes. Significantly more phospho-ERK1/2-immunoreactive neurons in the superficial spinal dorsal horn were observed in the remifentanil 120-minute groups with hyperalgesia than in the 30-minute remifentanil groups without hyperalgesia, although U0126 did not suppress hyperalgesia. CONCLUSIONS: IV remifentanil induces transient withdrawal hyperalgesia soon after its termination. This hyperalgesia is strongly associated with the duration of exposure to remifentanil. Contrary to our hypothesis, ERK1/2 by itself was not the essential factor involved in the induction of the hyperalgesia.