OPTIMAL PLASMA CONCENTRATION OF THROMBOMODULIN ALFA TO TREAT SEPSIS-INDUCED DISSEMINATED INTRAVASCULAR COAGULATION.

ABSTRACT: Thrombomodulin alfa (TM alfa) has been shown effective for treatment of disseminated intravascular coagulation (DIC) associated with sepsis, although the optimal therapeutic plasma concentration has not been clarified. In the present study, the plasma trough concentration of TM alfa in septic patients with DIC was determined, then the cutoff value for that concentration showing influence on treatment outcome was calculated using a receiver operating characteristic curve. With a cutoff value of 1,010, the area under the curve of the receiver operating characteristic was 0.669 (95% confidence interval, 0.530-0.808), with sensitivity of 0.458 and specificity of 0.882. To evaluate its accuracy, patients were divided into those above or below the cutoff value, and 90-day survival rates were compared. The above-cutoff group showed a significantly higher 90-day survival rate (91.7%) as compared with the below-cutoff group (63.4%) ( P = 0.017), with a hazard ratio of 0.199 (95% confidence interval, 0.045-0.871). Interestingly, the incidence of hemorrhagic adverse effects was not significantly different between the groups. Based on these results, the recommended plasma trough concentration of TM alfa for treatment of septic DIC is 1,010 ng/mL, which should minimize the risk of severe bleeding while maximizing the therapeutic effect.

Usefulness of criteria for intraoperative Management of Postoperative Nausea and Vomiting.

BACKGROUND: Postoperative nausea and vomiting (PONV) delays postoperative recovery, prolongs hospital stays, and hinders patients' return to society, thus making it a major cause of increased healthcare costs. It is also the most troubling postoperative complication in female patients undergoing surgery. However, in Japan, guidelines for the management of PONV have not been established, and the management protocol for PONV is left to each institution and anesthesiologist. Therefore, we developed criteria for intraoperative management of PONV. METHODS: In female surgical patients, the usefulness of the criteria was evaluated by comparing the implementation rate of intraoperative management and PONV incidence before and after the establishment of the criteria. An Apfel simplified score (Apfel score) ≥2 was set as an indication for intraoperative management of PONV. RESULTS: The implementation rate of intraoperative management increased from 91.2 to 96.0% after the introduction of the criteria. In patients with an Apfel score of 2, the intraoperative management implementation rate significantly increased from 81.1 to 94.7% (p = 0.016), while PONV incidence significantly decreased from 44.6 to 34.1% after the introduction of the criteria (p = 0.040). CONCLUSIONS: The criteria for intraoperative management of PONV increased the implementation rate of intraoperative management and decreased PONV incidence, indicating the usefulness of the criteria.

Therapeutic and Adverse Effects of Thrombomodulin Alfa to Treat Sepsis-Induced Disseminated Intravascular Coagulation.

In the treatment of disseminated intravascular coagulation (DIC), which is a complication of underlying diseases such as infections and malignant tumors, effective plasma concentrations of thrombomodulin (TM) alfa range from 300 to 900 ng/mL; however, appropriate concentrations when treating sepsis-induced DIC are unknown. Thus, our aim was to determine the relationship between plasma concentrations of TM alfa and its therapeutic effects, and hemorrhagic adverse events. First, we calculated the plasma trough concentrations of TM alfa in septic DIC patients. Next, we divided patients into two groups according to their plasma concentrations into a low- and high-concentration group based on a cut-off value of 600 ng/mL. Fourteen and 35 patients were included in the low- and high-concentration groups, respectively. The Japanese Association for Acute Medicine DIC diagnostic criteria score 4 days after TM alfa administration decreased significantly by 2.06 points from baseline in the high-concentration group compared with 0.71 points in the low-concentration group. The 90-day survival rate was significantly higher in the high-concentration group (85.4%) than in the low-concentration group (49.0%) (hazard ratio, 0.27; 95% confidence interval: 0.09-0.86). In contrast, the incidence of serious hemorrhage was not significantly different between the groups. The recommended plasma concentration of TM alfa in the treatment of septic DIC was determined to be higher than 600 ng/mL, and a dose of 380 U/kg (0.06 mg/kg) was necessary to achieve this concentration.

Method for Prediction of Efficacy of Sugammadex Administered to Recover from Rocuronium-Induced Neuromuscular Blockade in Gynecological Laparoscopic Surgery Cases.

Sugammadex (SDX), a neuromuscular blocking-reversal agent, quickly reverses neuromuscular blockade induced by rocuronium (RCR). SDX dosage is set according to the state of neuromuscular blockade determined with a neuromuscular monitoring device. However, in clinical situations, such a devise is not frequently used. Here, we report construction of a method for theoretically setting SDX dose by which the optimum reverse time (RT) can be obtained for individual patients even when the device is not available. The subjects were 42 adult female patients who underwent laparoscopic surgery from 1 August 2015 to 31 March 2016, during which RCR and SDX were administered. We formulated an equation for theoretically calculating the RCR residual ratio (RR) in blood after SDX administration. Furthermore, we examined the relationship between RR and RT. Based on the results obtained, we developed a method for predicting RT using RR. We excluded 1 subject as the RT value was detected as an outlier in our analysis. Multiple regression analysis was performed using standard body weight, serum creatinine, total bilirubin, and RR as explanatory variables. The number of subjects with a prediction error of RT within ±1 min was 36 (87.8%) of 41 in multiple regression analysis. We could predict RT following SDX administration by using the RT prediction expression with RR obtained for subjects administered RCR during the surgery. Furthermore, our results suggest that the SDX dose able to achieve optimum RT may be set prior to surgery on the basis of the present methodology.

[Effects of Pharmacist Intervention on the Treatment of Infectious Diseases in Critically Ill Patients].

The pathological conditions of patients who require intensive care are usually complex and extremely severe; their health and life are in a critical state. Therefore, correct, rapid treatment of these conditions is indispensable. Furthermore, the selection of drugs and adjustment of their dosage for an immediate effect are important. Moreover, most patients are immunocompromised and present an extremely high level of risk for complications involving infectious diseases. Since such complications may lead to life-threatening outcomes, a rational dosage regimen to achieve sufficient antimicrobial activity from the initial stage of treatment is essential. However, most critically ill cases are complicated by several factors: fluid retention including edema, pleural effusion, and ascites; increased vascular permeability and hypoalbuminemia; and dysfunction of various organs. These factors cause significant changes in the pharmacokinetics of antimicrobials, making it particularly difficult to design a dosage regimen at the time of initial administration. Thus, we focused on the importance of a rational dosage regimen for antimicrobial drugs in the treatment of infectious diseases. We conducted a retrospective study of severe cases of pneumonia with a high death rate; patients were divided into two groups according to the pharmacist intervention procedures and a comparative study of treatment efficacy was performed. Furthermore, for antimicrobial agents to exert a sufficient effect from the initial stage of treatment, we examined the theoretical methodology underlying the initial administration.

Evaluation of the Effects of Pharmacist Intervention for Adverse Drug Reaction Detection and Exacerbation Avoidance.

We evaluated the effects of pharmacist intervention for adverse drug reaction detection and exacerbation avoidance, as well as the severity and outcome of reactions based on analyses of pharmacist involvement in a collaborative approach to medicine. Of 5436 cases with pharmacist involvement, adverse drug reaction prevention was seen in 440, accounting for 8.1%, and exacerbation avoidance in 213, accounting for 3.9%. We concluded that pharmacist involvement contributes to detect adverse drug reactions and avoid exacerbation, and improves pharmacotherapy safety. We also analyzed 131 cases in which the course after intervention was followed. When categorized by adverse drug reaction severity, Grade 1 and 2 were the same at 45.8%, Grade 3 at 8.4%, respectively. Those findings suggested that pharmacist intervention contributes to early detection of an adverse drug reaction. Also, the relationship between clues for detecting adverse drug reactions by a pharmacist and their severity showed that objective evaluations such as clinical laboratory test results, physical assessments and medication history were important for detecting reactions that became more serious. Patients recovered or recovering from an adverse reaction comprised 76.4%, indicating that pharmacist intervention contributed to exacerbation avoidance and improvement. Our findings revealed the effects of pharmacist intervention for adverse drug reaction detection and exacerbation avoidance, and for safety improvement of pharmacotherapy. Additionally, we considered it necessary for the future pharmacist intervention to improve skills of assessing an adverse drug reaction objectively.

Initial dosing regimen of vancomycin to achieve early therapeutic plasma concentration in critically ill patients with MRSA infection based on APACHE II score.

It is essential to assure the efficacy of antimicrobials at the initial phase of therapy. However, increasing the volume of distribution (Vd) of hydrophilic antimicrobials in critically ill patients leads to reduced antimicrobial concentration in plasma and tissue, which may adversely affect the efficacy of that therapy. The aim of the present study was to establish a theoretical methodology for setting an appropriate level for initial vancomycin therapy in individual patients based on Acute Physiology and Chronic Health Evaluation (APACHE) II score. We obtained data from patients who received intravenous vancomycin for a suspected or definitively diagnosed Gram-positive bacterial infection within 72 h after admission to the intensive care unit. The Vd and elimination half-life (t 1/2) of vancomycin values were calculated using the Bayesian method, and we investigated the relationship between them and APACHE II score. There were significant correlations between APACHE II scores and Vd/actual body weight (ABW), as well as t 1/2 (r = 0.58, p < 0.05 and r = 0.74, p < 0.01, respectively). Our results suggested that the Vd and t 1/2 of vancomycin could be estimated using the following regression equations using APACHE II score.[Formula: see text] [Formula: see text]We found that APACHE II score was a useful index for predicting the Vd and t 1/2 of vancomycin, and used that to establish an initial vancomycin dosing regimen comprised of initial dose and administration interval for individual patients.

[Effects of early pharmacist intervention on antimicrobial therapy for severe hospital-acquired pneumonia].

Hospital-acquired pneumonia (HAP) is defined as pneumonia that occurs 48 hours or more after admission, and is an important factor in the high mortality seen in hospital-acquired infections. Recently, pharmacist intervention, such as adjustment of dosing and monitoring for adverse effects, has been reported to improve the effects of infectious disease therapy. The aim of this study was to evaluate the usefulness of early pharmacist intervention during antimicrobial therapy for severe HAP. We retrospectively investigated the reduction rate of C-reactive protein (CRP) levels and duration of antibiotics administration. Patients with severe HAP were classified into 2 groups according to pharmacist intervention from the initial phase of therapy, with 15 in the intervention group and 23 in the control group (no pharmacist intervention). The reduction rate of CRP levels during the 7-day period after initiating antimicrobial therapy was 66.5 ± 17.3% in the intervention group and 35.9 ± 53.9% in the control group, which was significantly different (p<0.05). In addition, the average duration of antibiotics administration in the intervention group was significantly decreased as compared to the control group: the decreased period was 8 days. Our results suggest that pharmacist intervention contributed to reduce inflammation in the early phase and to shorten the duration of antimicrobial therapy.

Prediction of distribution volume of vancomycin in critically ill patients using extravascular lung water and pulmonary vascular permeability indices.

OBJECTIVE: Alterations in distribution volume affect the concentrations of hydrophilic drugs in plasma and tissues at the time of initial therapy. When the distribution volume of hydrophilic antimicrobials is increased in critically ill patients with a serious infection, antimicrobial concentrations are reduced, which may adversely affect the efficacy of antimicrobial therapy. A transpulmonary thermodilution technique system (PiCCO) enables measurements of pulmonary vascular permeability index (PVPI) and extravascular lung water index (EVLWI), which are related to pulmonary edema and pulmonary vascular permeability, respectively. In addition, those indices may also be related to the distribution volume of hydrophilic antimicrobials. The aim of this study was to investigate the relationships of PVPI and EVLWI with the distribution volume of vancomycin (Vss), as well as to establish a method for estimating Vss for planning an appropriate initial dose for individual patients. METHODS: Seven patients were administered vancomycin intravenously and underwent extended hemodynamic monitoring with the PiCCO system in the intensive care unit (ICU) from April 2009 to March 2011. Vss was calculated using the Bayesian method, and the relationships of PVPI and EVLWI with Vss were investigated. RESULTS: The relationship between Vss/actual body weight (ABW) and median EVLWI on days when blood levels were measured was significant (r = 0.900, p = 0.0057), whereas the relationship between Vss/ABW and PVPI was not significant (r = 0.649, p = 0.1112). CONCLUSION: EVLWI determined by the PiCCO system is useful to predict Vss and should lead to more effective vancomycin therapy for critically ill patients at the initial stage.

[Effect of pharmacists' intervention on the antibiotic therapy for the methicillin-resistant Staphylococcus aureus (MRSA) infectious diseases in the intensive care unit].

Pharmacists are providing pharmaceutical care in general wards, but it is still not common in the intensive care unit (ICU). However, we have worked in ICU, and recommended the rational dosage regimen of the antibiotics to the physicians during the treatment period. Especially, the patients who were infected with methicillin-resistant Staphylococcus aureus (MRSA) in ICU should be provided appropriate antibiotic therapy, otherwise they have a poor prognosis. The aim of this study is to evaluate usefulness of the pharmacists' intervention on the antibiotic therapy for MRSA infectious diseases in the ICU. We investigated retrospectively the period of anti MRSA drugs administration, the medical cost, which includes cost of anti MRSA drugs and hospital charge, and the initial trough concentration of vancomycin (VCM). The patients with MRSA pneumonia were classified into two groups according to the pharmacists' intervention. The number of the patients who the pharmacists performed dosage regimen of anti MRSA drug was 11 (intervention group) and that of the patients who the pharmacists performed no intervention was 47 (control group). The average period of administration of anti MRSA drugs in the intervention group was significantly decreased in 5 days. Furthermore, if the pharmacists performed dosage regimen of anti MRSA drug to the patients in control group, the medical cost of 10 million yen would be saved. The initial trough concentrations of VCM were not significantly different between two groups. However, the achievement rates are 75.0% in intervention group and 66.7% in control group, if the goal of trough level of VCM is set from 5 to 15 µg/ml. Moreover, there are 75.0% in intervention group and 20.8% in control group, if the goal of trough level of VCM is set from 10 to 20 µg/ml, which is significantly different between the two groups. Therefore, it was suggested that the pharmacists in the ICU contributed to optimize the anti MRSA therapy and reduce the medical cost.

[Clinical evaluation of drug information provided by the pharmacists in the intensive care unit].

Pharmacists working in the intensive care unit (ICU) in Saiseikai Yokohamashi Tobu Hospital are mainly responsible for managing the stock of drugs, providing drug information to other medical staff, educating them for rational drug therapy, and providing pharmaceutical care to the patients. In order to evaluate the contribution to the rational drug therapy, we investigated the acceptance rate of the drug information that the pharmacists in the ICU provided to the physicians from February to May in 2009. The number of cases in which drug information was provided by the pharmacists to the physicians during the period was 288. It was suggested that more than half of the information could optimize the drug dosage regimens and correct the inadequate prescriptions. Furthermore, 98.9% of the information provided by pharmacists was accepted by physicians. We questioned 5 intensivists to evaluate the information with a 5 point scale (maximum score was 4, minimum score was 0) and then the average of score was 3.3. In addition, their evaluation of the information about optimizing the drug dosage regimens marked the highest point (over 3.5). Meanwhile, providing drug information which led the physicians to correct the inadequate prescriptions contributed to reduce the cost of the drug therapy by 900000 yen during the period. As a result, it was suggested that the intensivists highly appreciated the information offered by the pharmacists and the information contributed to enhance high-quality drug therapy. Additionally, the economic impact was identified through the cost reduction in drug therapy.

[Clinically significant drug-drug and drug-food interactions associated with calcium channel blockers].

Calcium channel blockers have been widely used for treatment of hypertension, angina pectoris, arrhythmia, and other heart diseases. Nowadays, combination therapy is widely common for these diseases. However, combination therapy is associated with increasing risks of pharmacokinetic or pharmacodynamic drug-drug interaction, and therefore clinicians should pay attention to prevent it. Furthermore, in addition to drug-drug interactions, we need to be cautions for drug interaction with food and drink including health-food and supplement.