Case report of pharmacokinetic analysis of continuous intravenous infusion of fentanyl in a patient with severe burn: burn shock stage complicates pain management.

BACKGROUND: Fentanyl is widely used as an analgesic and sedative for patients with severe burn injuries in intensive care units. However, pharmacokinetic (PK) data for fentanyl, particularly for continuous intravenous infusion during the acute phase of burn injuries, are limited. Here, we report the clinical course and changes in blood fentanyl concentrations during the acute phase in a patient with severe burns treated with continuous intravenous infusion of fentanyl. CASE PRESENTATION: A woman in her 40s, with burns caused by a gas cylinder explosion, was transported to our hospital. The patient had burn wounds on face, neck, shoulders, and all four extremities, with a total burn area of 39.0%. For pain relief, the patient received a continuous infusion of 0.01 mg/mL fentanyl (20-30 µg/h) with a target blood concentration of 1.0-1.5 ng/mL, but continued to suffer from pain due to burning during the acute phase. We measured the blood fentanyl concentrations and found that all concentrations obtained during the acute phase were subtherapeutic. Notably, during the burn shock stage, blood concentrations of fentanyl were 0.50 ng/mL on day 1 and 0.66 ng/mL on day 2, indicating that the blood concentration did not rise sufficiently for the dosage. From days 0 to 2, the patient was administered a massive fluid load for burn shock. After the burn shock stage resolved, fentanyl concentrations gradually approached the target range, and the pain rating scale improved, even though the fentanyl administration rate remained unchanged (30 µg/h). CONCLUSIONS: Major changes in the fluid volumes of body compartments that occur with large burns might increase the volume of fentanyl distribution, thereby lowering its concentration when a standard dose is administered. Our findings indicate that the PK of fentanyl in patients with severe burns can be substantially affected, especially during the shock phase, implying the importance of titrating analgesics for clinical efficacy in the acute phase.

Clinical pharmacokinetics of oxaliplatin in a hemodialysis patient with advanced gastric cancer.

We administered FOLFOX (oxaliplatin (L-OHP) plus infusional 5-fluorouracil (5-FU) and leucovorin) to an hemodialysis (HD) patient with advanced gastric cancer (AGC), and investigated pharmacokinetics (PKs) and dialyzability of L-OHP. The patient was a 54-year-old Japanese man with a diagnosis of inoperable AGC. FOLFOX was instituted 3 h prior to the start of a 4 h HD period with the L-OHP and 5-FU doses reduced by 50% for the first cycle, and 30% reduced dose was administered for the second cycle. We performed an analysis of the PKs of L-OHP during these two cycles. Volume of distribution and area under the curve of the 30% reduced L-OHP dose were 56.7 L and 30.0 µg·h/mL, respectively. A dose reduction of L-OHP by 30%-50% may be advisable for the initial administration, given the need for careful administration of chemotherapy in HD patients, with particular attention to the development of hematological toxicities and neuropathy.

Vancomycin pharmacokinetics in critically ill patients receiving continuous haemodiafiltration with a polyethyleneimine-coated polyacrylonitrile membrane.

WHAT IS KNOWN AND OBJECTIVE: We investigated the elimination efficiency and pharmacokinetics (PK) parameters of vancomycin (VCM) in patients undergoing continuous haemodiafiltration (CHDF) using a polyethyleneimine-coated polyacrylonitrile membrane (AN69ST) for dosage adjustment. METHODS: We conducted a retrospective study of CHDF patients treated with VCM from December 2017 to August 2019. We calculated PK parameters of VCM and determined the 24-hour dose required to maintain the target trough concentration of VCM (VCM_trough ). RESULTS AND DISCUSSION: The average (95% CI) volume of distribution and total clearance of VCM were 75.5 L (63.7-87.3 L) and 1.84 L/h (1.38-2.30 L/h), respectively, and the elimination rate constant and half-life were 0.026/h (0.017-0.034/h) and 31.2 h (22.8-39.5 h), respectively. The average AN69ST clearance of VCM (CL_CHDF ) was 0.69 L/h (0.52-0.86 L/h). The estimated average doses required to maintain VCM_trough of 10, 15 and 20 µg/mL were 623.1 mg (379.8-866.4 mg), 934.6 mg (569.7-1299.5 mg) and 1246.2 mg (759.6-1732.8 mg), respectively. WHAT IS NEW AND CONCLUSION: The PK of VCM and CL_CHDF of AN69ST were clarified. These results suggest that it is possible to adjust the dose of VCM in using AN69ST, which efficiently removes cytokines, and contributes to improvement of serious infections.

[A Case of Advanced Esophageal Cancer Treated with Nedaplatin in a Patient Undergoing Maintenance Hemodialysis].

Herein, we investigated the pharmacokinetic (PK) profile of nedaplatin (cis-diamine-glycolateplatinum; CDGP) in a hemodialysis (HD) patient with advanced esophageal squamous cell carcinoma (ESCC) by administering the CDGP immediately prior to HD. Our patient was treated with CDGP (45 mg/m2 for a total dose of 60.2 mg) and 5-fluorouracil (560 mg/m2 for a total dose of 750 mg) before initiating HD. The total platinum (Pt) concentration (Pt_total) and free Pt concentration (Pt_free) 2 h after completion of HD were 0.4 µg/mL and 0.3 µg/mL, respectively. The removal rates of Pt_total and Pt_free by the dialyzer were 76.5% and 84.6%, respectively. Twenty-four hours after CDGP administration, the Pt_free was below the detection limit of the method of analysis. Pt_free within the range of the recommended CDGP target AUC0-24 was 8-10 µg/mL•h, the AUC0-24 of Pt_total and Pt_free were 16.5 µg/mL•h and 8.8 µg/mL•h, respectively. We conclude that HD should be performed after the end of CDGP infusion as part of the CDGP chemotherapy regimen for HD patients with ESCC, and suggest that HD is effective for obtaining a PK profile of CDGP similar to patients with normal renal function.

[Evaluation of Intervention by an Antimicrobial Stewardship Team for Patients with Bacteremia].

In this study, antimicrobial stewardship team (AST) intervention was evaluated by comparing patient outcomes and consumption of broad-spectrum antibiotics [carbapenem antibiotics and tazobactam/piperacillin (TAZ/PIPC)] before and after the intervention. There was no fluctuation in the consumption rate of carbapenem, TAZ/PIPC and other antibiotics, but there was a decreased annual consumption of antibiotics after AST intervention compared to before intervention. For the carbapenems, antimicrobial use density (AUD) of meropenem (MEPM) was highest in both periods, at 20.1 and 20.4 before and after AST intervention, respectively, with no significant change after AST intervention. However, the days of therapy (DOT) for MEPM were 27.4 and 24.8 d, respectively, with a decreasing trend after AST intervention. AUD and DOT for TAZ/PIPC after AST intervention were 6.5 and 8.1 d, respectively, which were lower than the pre-intervention values. Rapid identification of the causative strain enables early de-escalation and may improve the economics of antibiotic use, but there was no difference from before to after AST intervention. Compared with before and after strain identification, the carbapenem administration rate after AST intervention was significantly lower than the pre-intervention rate (p<0.01). There was no difference in 28-day mortality and treatment period before and after AST intervention, and there were no differences in outcomes such as resolution of bacteremia, mortality, exacerbation and no change from before to after AST intervention. Based on these results, we suggest that AST intervention can reduce consumption of antibiotics without altering patient outcomes.

Pharmacokinetics and pharmacodynamics of daptomycin in a clinical setting.

We investigated achievement of a target 24-h area under the concentration-time curve to minimum inhibitory concentration ratio (AUC/MIC) ≥666 and the factors influencing this ratio in patients who received daptomycin (DAP) for infectious disease treatment in a clinical setting. The target AUC/MIC was obtained in 6 patients (35.3%) at a 4-6 mg/kg dose (Group_4-6 mg/kg) and in 4 (18.2%) at a >6 mg/kg dose (Group_>6 mg/kg). There was a significant difference in clearance of DAP (CL_DAP) between these groups, but no other difference in characteristics. Multiple linear regression analysis was performed for prediction of AUC ≥666 based on patient factors and the presence or absence of sepsis. In a stepwise analysis, serum creatinine (SCr) was a significant predictor of AUC, but this parameter explained only 13% of the variance in achievement of the target AUC. These results show that the target AUC/MIC may or may not be achieved at the doses used in Group_4-6 mg/kg and Group_>6 mg/kg. Receiver operating characteristic analysis suggested that a CL_DAP >0.450 L/hr may lead to failure to reach the target AUC/MIC. Therefore, regardless of dose, the efficacy of DAP should be monitored closely to prevent failure of infectious disease treatment, particularly because therapeutic drug monitoring of DAP is limited by difficulty measuring the DAP serum concentration at many medical facilities. Our findings are preliminary, and a further study is required to identify factors that increase CL_DAP and to enable dose adjustment of DAP.

Preparation and Evaluation of a Modified Mohs Paste Mixed with Zinc Oxide 10% Topical Oil-Based Ointment.

BACKGROUND: The skin fixative used in Mohs chemosurgery contains zinc chloride and is referred to as Mohs paste (MP). However, MP shows a remarkable change in rheological characteristics after its preparation. OBJECTIVE: To prepare an MP with stable rheological characteristics, we prepared a modified MP (mMP) using zinc oxide 10% single ointment (Zn_ointment), which is an oil-based ointment. METHODS: We evaluated mMP by determining its rheological characteristics, depth of tissue fixation, and observation of the tissue surface after treatment. RESULTS: The viscosity of mMP increased after three months. However, the treatment-dependent viscosity of mMP could be obtained by mixing with glycerin. The viscosity and spreadability of mMP_3mth, which was three months after preparation, were 1992.0 ± 376.5 Pa·s and 2.1 ± 0.1 cm, respectively. In contrast, the viscosity and spreadability of MP mixed with glycerin were 436.9 ± 0.0 Pa·s and 2.8 ± 0.0 cm, respectively. The fixed invasion depth of MP was significantly higher than that of mMP (p < 0.05). CONCLUSION: This study of a mixture of MP and Zn_ointment showed that the viscosity of mMP could be adjusted with glycerin. Also, the tissue fixation of mMP progressed slowly compared with that of MP. This finding suggests that mMP is effective and safe for Mohs treatment.

Investigation of the Efficacy of an Administration Plan for Tazobactam/Piperacillin (TAZ/PIPC) and the Incidence of Kidney and Hepatic Disorders.

Tazobactam/piperacillin (TAZ/PIPC) is widely used in the treatment of infectious disease. In this study, three hundred and sixty-three patients who were treated with the recommended dose of TAZ/PIPC were investigated for the proportion of time above the minimum inhibitory concentration (%TAM) and the frequency of renal and liver dysfunction. Of the whole patient population, 5.23%, exhibited increased creatinine levels, 9.37% and 8.82% exhibited increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, respectively. The patients who exhibited high serum creatinine (SCr) levels before administration, exhibited significant increases of AST (p=0.0121). The patients who exhibited low albumin levels before administration, exhibited significant decreases in renal function (p=0.0041). In the case of a breakpoint (BP) of 64 µg/mL, the arrival probabilities of %TAM of 30% and 50% were 99.4% and 76.9%, respectively. We suggested that the dose of TAZ/PIPC should be adjusted according to the interview form finding and a %TAM>50% (maximal bactericidal action).

Pharmacokinetics of linezolid during continuous hemodiafiltration: A case report.

The pharmacokinetics of linezolid clearance (CLLZD) during continuous hemodiafiltration (CHDF) has not been comprehensively analyzed. Here, we examined CLLZD by CHDF in a patient with septic shock and disseminated intravascular coagulation due to methicillin-resistant Staphylococcus aureus. The extraction ratio of LZD by CHDF was 22.6%, and the protein-binding rate was 17.9% ± 7.7%. In addition, it was determined that the calculated total body clearance of LZD was 30.2 mL/min, plasma elimination half-life was 8.66 h, and the CLLZD by the dialyzer used for CHDF was 23.0 mL/min. From the obtained pharmacokinetics, the CLLZD of patients continuing CHDF was estimated to be approximately half of the reported CLLZD for healthy subjects. In addition, the LZD concentration of the sepsis patient who underwent CHDF remained higher than the minimum inhibitory concentration and was similar to the LZD concentrations reported in normal renal function patients. Although further studies are warranted, when LZD is administered to patients treated with CHDF, the present findings suggest that dose regulation is not required.