Monitoring for adverse drug events of high-risk medications with a computerized clinical decision support system: a prospective cohort study.

Monitoring is recommended to prevent severe adverse drug events, but such examinations are often missed. To increase the number of monitoring that should be ordered for high-risk medications, we introduced a clinical decision support system (CDSS) that alerts and orders the monitoring for high-risk medications in an outpatient setting. We conducted a 2-year prospective cohort study at a tertiary care teaching hospital before (phase 1) and after (phase 2) the activation of a CDSS. The CDSS automatically provided alerts for liver function tests for vildagliptin, thyroid function tests for immune checkpoint inhibitors (ICIs) and multikinase inhibitors (MKIs), and a slit-lamp examination of the eyes for oral amiodarone when outpatients were prescribed the medications but not examined for a fixed period. The order of laboratory tests automatically appeared if alert was accepted. The alerts were hidden and did not appear on the display before activation of the CDSS. The outcomes were the number of prescriptions with alerts and examinations. During the study period, 330 patients in phase 1 and 307 patients in phase 2 were prescribed vildagliptin, 20 patients in phase 1 and 19 patients in phase 2 were prescribed ICIs or MKIs, and 72 patients in phase 1 and 66 patients in phase 2 were prescribed oral amiodarone. The baseline characteristics were similar between the phases. In patients prescribed vildagliptin, the proportion of alerts decreased significantly (38% vs 27%, P < 0.0001), and the proportion of examinations increased significantly (0.9% vs 4.0%, P < 0.0001) after activation of the CDSS. In patients prescribed ICIs or MKIs, the proportion of alerts decreased significantly (43% vs 11%, P < 0.0001), and the proportion of examinations increased numerically, but not significantly (2.6% vs 7.0%, P = 0.13). In patients prescribed oral amiodarone, the proportion of alerts decreased (86% vs 81%, P = 0.055), and the proportion of examinations increased (2.2% and 3.0%, P = 0.47); neither was significant. The CDSS has potential to increase the monitoring for high-risk medications. Our study also highlighted the limited acceptance rate of monitoring by CDSS. Further studies are needed to explore the generalizability to other medications and the cause of the limited acceptance rates among physicians.

Effect of dexmedetomidine on inflammation in patients with sepsis requiring mechanical ventilation: a sub-analysis of a multicenter randomized clinical trial.

BACKGROUND: Administration of dexmedetomidine has been reported to improve inflammatory response in animals. We explored the effects of administering dexmedetomidine on the levels of C-reactive protein (CRP) and procalcitonin, and thus on inflammation, in patients with sepsis enrolled in a randomized clinical trial. METHODS: The DESIRE trial was a multicenter randomized clinical trial in which adult patients with sepsis were sedated with (DEX group) or without (non-DEX group) dexmedetomidine while on mechanical ventilators. As a prespecified sub-analysis, we compared CRP and procalcitonin levels during the first 14 days of treatment between the two groups. The 14-day mortality rate, albumin level, and the number of patients with disseminated intravascular coagulation (DIC) were also assessed. We used generalized linear models to estimate the differences in these outcomes between groups. We also used the Kaplan-Meier method to estimate the 14-day mortality rate and the log-rank test to assess between-group differences. RESULTS: Our study comprised 201 patients: 100 in the DEX group and 101 in the non-DEX group. CRP and procalcitonin levels were lower in the DEX vs. non-DEX group during the 14-day treatment period [CRP-range, 5.6-20.3 vs. 8.3-21.1 mg/dL (P = 0.03); procalcitonin-range, 1.2-37.4 vs. 1.7-52.9 ng/mL (P = 0.04)]. Albumin levels were higher in the DEX group (range, 2.3-2.6 g/dL) than in the non-DEX group (range, 2.1-2.7 g/dL; P = 0.01). The percentage of patients with DIC did not significantly differ between the groups (range, 21-59% and 17-56% for the DEX and non-DEX groups, respectively; P = 0.49). The 14-day mortality rates in the DEX and non-DEX groups were 13 and 21%, respectively (P = 0.16). CONCLUSION: Sedation using dexmedetomidine reduced inflammation in patients with sepsis requiring mechanical ventilation. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01760967 . Registered on 4 January 2013.

Mortality Effects of Prolonged Hemoperfusion Therapy Using a Polymyxin B-Immobilized Fiber Column for Patients with Septic Shock: A Sub-Analysis of the DESIRE Trial.

BACKGROUND/AIMS: The optimal duration of hemoperfusion therapy with a polymyxin B-immobilized fiber column has not yet been verified. METHODS: This analysis examined whether hemoperfusion therapy with a polymyxin B-immobilized fiber column lasting longer than 2 h (prolonged polymyxin) improved outcomes for patients with septic shock compared to 2-h polymyxin therapy (sub-analysis of data from the DESIRE trial). RESULTS: The 2-h and prolonged polymyxin groups contained 22 and 14 patients, respectively. Both groups had similar characteristics. The polymyxin duration per session in the prolonged polymyxin group was significantly longer (median, 5.5 h) than in the 2-h polymyxin group (p < 0.01). The 28-day mortality rate was significantly higher in the 2-h polymyxin group (7, 31.8%) than in the prolonged polymyxin group (0, 0%; p = 0.019). CONCLUSION: Prolonged polymyxin therapy might be associated with better clinical outcomes than 2-h polymyxin therapy in patients with septic shock. Video Journal Club "Cappuccino with Claudio Ronco" at http://www.karger.com/?doi=491744.

Effect of Dexmedetomidine on Mortality and Ventilator-Free Days in Patients Requiring Mechanical Ventilation With Sepsis: A Randomized Clinical Trial.

Importance: Dexmedetomidine provides sedation for patients undergoing ventilation; however, its effects on mortality and ventilator-free days have not been well studied among patients with sepsis. Objectives: To examine whether a sedation strategy with dexmedetomidine can improve clinical outcomes in patients with sepsis undergoing ventilation. Design, Setting, and Participants: Open-label, multicenter randomized clinical trial conducted at 8 intensive care units in Japan from February 2013 until January 2016 among 201 consecutive adult patients with sepsis requiring mechanical ventilation for at least 24 hours. Interventions: Patients were randomized to receive either sedation with dexmedetomidine (n = 100) or sedation without dexmedetomidine (control group; n = 101). Other agents used in both groups were fentanyl, propofol, and midazolam. Main Outcomes and Measures: The co-primary outcomes were mortality and ventilator-free days (over a 28-day duration). Sequential Organ Failure Assessment score (days 1, 2, 4, 6, 8), sedation control, occurrence of delirium and coma, intensive care unit stay duration, renal function, inflammation, and nutrition state were assessed as secondary outcomes. Results: Of the 203 screened patients, 201 were randomized. The mean age was 69 years (SD, 14 years); 63% were male. Mortality at 28 days was not significantly different in the dexmedetomidine group vs the control group (19 patients [22.8%] vs 28 patients [30.8%]; hazard ratio, 0.69; 95% CI, 0.38-1.22; P = .20). Ventilator-free days over 28 days were not significantly different between groups (dexmedetomidine group: median, 20 [interquartile range, 5-24] days; control group: median, 18 [interquartile range, 0.5-23] days; P = .20). The dexmedetomidine group had a significantly higher rate of well-controlled sedation during mechanical ventilation (range, 17%-58% vs 20%-39%; P = .01); other outcomes were not significantly different between groups. Adverse events occurred in 8 (8%) and 3 (3%) patients in the dexmedetomidine and control groups, respectively. Conclusions and Relevance: Among patients requiring mechanical ventilation, the use of dexmedetomidine compared with no dexmedetomidine did not result in statistically significant improvement in mortality or ventilator-free days. However, the study may have been underpowered for mortality, and additional research may be needed to evaluate this further. Trial Registration: clinicaltrials.gov Identifier: NCT01760967.

Influence of adverse drug events on morbidity and mortality in intensive care units: the JADE study.

OBJECTIVE: To identify the influence of adverse drug events (ADEs) on morbidity and mortality in intensive care units (ICUs). DESIGN: A prospective cohort study. SETTING: ICU setting at three acute care hospitals in Japan. PARTICIPANTS: All patients aged ≥15 years were admitted to all ICUs during a 6-month study period. INTERVENTION: No intervention. MAIN OUTCOME MEASURES: Mortality in the ICUs and the length of the ICU stay. . RESULTS: We included 459 patients with a total of 3231 patient-days. Ninety-nine ADEs occurred in 70 patients (15%), so that the incidence of ADEs was 30.6 per 1000 patient-days and 21.6 ADEs per 100 admissions. Seventy-three patients (16%) died during their ICU stay. Excluding 38 deaths within 3 days after admission, 12 patients (17%) died among the 70 patients who had at least one ADE during their ICU stay and 23 (7%) died among 351 without an ADE (P = 0.003). The median ICU length of stay was 3 days. Excluding 73 patients who died during their ICU stay, the median ICU stay of patients with at least one ADE was 13 days, while it was only 2 days in the remainder (P < 0.0001). ADEs were associated with longer length of ICU stay but not with mortality even after adjusting for patients' severity of illness. CONCLUSIONS: ADEs were common in ICUs and significantly associated with longer length of ICU stay but did not influence on mortality.

Adverse Events in Pediatric Inpatients: The Japan Adverse Event Study.

OBJECTIVES: Adverse events (AEs) represent an important cause of morbidity and mortality for pediatric inpatients; however, reports on their epidemiology in pediatrics, especially outside Western countries, are scarce. We investigated the incidence and nature of AEs in pediatric inpatients in Japan. METHODS: Trained pediatrician and pediatric nurses reviewed all medical documents of 1126 pediatric inpatients in 2 tertiary care teaching hospitals in Japan, and potential incidents were collected with patients' characteristics. Age was categorized into 6 groups (neonates, infants, preschoolers, school-aged children, teenagers, and over-aged pediatric patients), and medical care when potential incidents occurred was classified into drug, operation, procedure/examinations, nursing, management, and judgment. Physician reviewers independently evaluated all collected incidents into AEs, potential AEs, medical errors, and exclusions and assessed their severity and preventability. RESULTS: A total of 1126 patients with 12,624 patient-days were enrolled, and 953 AEs, with an incidence of 76 (95% confidence interval, 71-80) per 1000 patient-days, were identified. Preventable AEs accounted for 23% (218/953) of AEs. The incidence of AEs tended to decrease with increasing age. The proportion of AEs that were preventable was highest in neonates (40%), and this proportion decreased as children aged. Both judgment and management-related AEs were considered preventable AEs, and judgment-related AEs were more severe AEs than no-judgment-related AEs; 43% were life-threatening. CONCLUSIONS: Adverse events were common in Japanese pediatric inpatients, and their preventability and severity varied considerably by age category and medical care. Further investigation is needed to address which strategies might most improve pediatric patient safety.

[Case report of anesthesia with veno-veno extracorporeal membrane oxygenation (V-V ECMO) during one-lung ventilation for acute respiratory distress syndrome (ARDS) complicated with severe sepsis due to spontaneous esophageal rupture].

A 55-year-old man was transferred to our hospital with spontaneous esophageal rupture. An emergency operation of mediastinum drainage by thoracotomy was performed. On postoperative day 8, he had new abcesses located at the upper mediastinum around the esophagus, and required another operation. But one-lung ventilation for the operation was difficult, because of profound hypoxia caused by the acute respiratory distress syndrome (ARDS) with severe sepsis. Therefore we introduced V-V ECMO for the treatment of severe hypoxia and could anesthetize him safely during surgical operation. Intraoperative and post-operative hemodynamics was stable. His respiratory condition improved, and he was weaned from V-V ECMO. Unfortunately, postoperative day 11, he died because of sudden intrathoracic bleeding from the thoracic aorta which might have been infected by the severe mediastinitis.

Comparison between midazolam and propofol in acute phase for ventilated patients with sepsis: a post-hoc analysis of the DESIRE trial.

Aim: There are few assessments of sedatives during the acute phase under sedation protocols for patients with sepsis. We aimed to compare the influence of different sedation strategies using midazolam and propofol under light sedation on clinical outcomes of ventilated patients with sepsis. Methods: This study was a post-hoc analysis of data from the dexmedetomidine for sepsis in the ICU Randomized Evaluation (DESIRE) trial. Patients were divided into propofol and midazolam groups based on continuously used drug, and sedation control between groups compared on day three. We assessed the incidence of delirium, length of ICU stay, number of ventilator-free days within the first 28 days, and mortality after 28 days. Results: The midazolam and propofol groups consisted of 51 and 66 patients, respectively. Both groups had similar characteristics, except for age and emergency surgery. The number of well-controlled sedation patients in the propofol group on day three was significantly higher than that in the midazolam group (odds ratio [OR] 3.9, 95% CI [1.30, 11.7]). The incidence of daily coma and delirium within the initial week was different between groups and increased with midazolam administration (P = 0.0138). The number of Confusion Assessment Method for ICU-positive patients was significantly higher in the midazolam group than in the propofol group (OR 5.71, 95% CI [2.30, 14.2]). Conclusion: In patients with sepsis required mechanical ventilation, sedation with midazolam based on a light sedation protocol may be associated with inappropriate sedation during the acute phase, with increased coma and delirium as compared to propofol.

Effectiveness of a computerized clinical decision support system for prevention of glucocorticoid-induced osteoporosis.

Glucocorticoids are widely used for a variety of diseases, but the prevention of glucocorticoid-induced osteoporosis is sometimes neglected. Therefore, the effectiveness of a computerized clinical decision support system (CDSS) to improve the performance rate of preventive care for glucocorticoid-induced osteoporosis was evaluated. We conducted a prospective cohort study of outpatients who used glucocorticoids for three months or longer and who met the indication for preventive care based on a guideline. The CDSS recommended bisphosphonate (BP) prescription and bone mineral density (BMD) testing based on the risk of osteoporosis. The observation period was one year (phase 1: October 2017-September 2018) before implementation and the following one year (phase 2: October 2018-September 2019) after implementation of the CDSS. Potential alerts were collected without displaying them during phase 1, and the alerts were displayed during phase 2. We measured BP prescriptions and BMD testing for long-term prescription of glucocorticoids. A total of 938 patients (phase 1, 457 patients; phase 2, 481 patients) were included, and the baseline characteristics were similar between the phases. The median age was 71 years, and men accounted for 51%. The primary disease for prescription of glucocorticoids was rheumatic disease (28%), followed by hematologic diseases (18%). The prevalence of patients who needed an alert for BP prescription (67% vs. 63%, P = 0.24) and the acceptance rate of BP prescription (16% vs. 19%, P = 0.33) were similar between the phases. The number of patients who had orders for BMD testing was significantly increased (4% vs. 24%, P < 0.001) after CDSS implementation. The number of patients who needed an alert for BMD testing was significantly decreased from 93% in phase 1 to 87% in phase 2 (P = 0.004). In conclusion, the CDSS significantly increased BMD testing in patients with a higher risk of glucocorticoid-induced osteoporosis, but did not increase BP prescription.

Effect of Gram Stain-Guided Initial Antibiotic Therapy on Clinical Response in Patients With Ventilator-Associated Pneumonia: The GRACE-VAP Randomized Clinical Trial.

Importance: Gram staining should provide immediate information for detecting causative pathogens. However, the effect of Gram staining on restricting the initial antibiotic choice has not been investigated in intensive care units (ICUs). Objective: To compare the clinical response to Gram stain-guided restrictive antibiotic therapy vs guideline-based broad-spectrum antibiotic treatment in patients with ventilator-associated pneumonia (VAP). Design, Setting, and Participants: This multicenter, open-label, noninferiority randomized clinical trial (Gram Stain-Guided Antibiotics Choice for VAP) was conducted in the ICUs of 12 tertiary referral hospitals in Japan from April 1, 2018, through May 31, 2020. Patients aged 15 years or older with a VAP diagnosis and a modified Clinical Pulmonary Infection Score of 5 or higher were included. The primary analysis was based on the per-protocol analysis population. Interventions: Patients were randomized to Gram stain-guided antibiotic therapy or guideline-based antibiotic therapy (based on the 2016 Infectious Disease Society of America and American Thoracic Society clinical practice guidelines for VAP). Main Outcomes and Measures: The primary outcome was the clinical response rate; clinical response was defined as completion of antibiotic therapy within 14 days, improvement or lack of progression of baseline radiographic findings, resolution of signs and symptoms of pneumonia, and lack of antibiotic agent readministration, with a noninferiority margin of 20%. Secondary outcomes were the proportions of antipseudomonal agents and anti-methicillin-resistant Staphylococcus aureus (MRSA) agents as initial antibiotic therapies; 28-day mortality, ICU-free days, ventilator-free days; and adverse events. Results: In total, 206 patients (median [IQR] age, 69 [54-78] years; 141 men [68.4%]) were randomized to the Gram stain-guided group (n = 103) or guideline-based group (n = 103). Clinical response occurred in 79 patients (76.7%) in the Gram stain-guided group and 74 patients (71.8%) in the guideline-based group (risk difference, 0.05; 95% CI, -0.07 to 0.17; P < .001 for noninferiority). Reduced use of antipseudomonal agents (30.1%; 95% CI, 21.5%-39.9%; P < .001) and anti-MRSA agents (38.8%; 95% CI, 29.4%-48.9%; P < .001) was observed in the Gram stain-guided group vs guideline-based group. The 28-day cumulative incidence of mortality was 13.6% (n = 14) in the Gram stain-guided group vs 17.5% (n = 18) in the guideline-based group (P = .39). Escalation of antibiotics according to culture results was performed in 7 patients (6.8%) in the Gram stain-guided group and 1 patient (1.0%) in the guideline-based group (P = .03). There were no significant differences between the groups in ICU-free days, ventilator-free days, and adverse events. Conclusions and Relevance: Results of this trial showed that Gram stain-guided treatment was noninferior to guideline-based treatment and significantly reduced the use of broad-spectrum antibiotics in patients with VAP. Gram staining can potentially ameliorate the multidrug-resistant organisms in the critical care setting. Trial Registration: ClinicalTrials.gov Identifier: NCT03506113.

Effect of age on dexmedetomidine treatment for ventilated patients with sepsis: a post-hoc analysis of the DESIRE trial.

AIM: There are no definitive data to determine whether age influences the effects of dexmedetomidine (DEX) treatment. Thus, we investigated whether older age was associated with more favorable sedative action by DEX in sepsis patients who required mechanical ventilation. METHODS: This study involved a post-hoc analysis of data from the Dexmedetomidine for Sepsis in the ICU Randomized Evaluation (DESIRE) trial. The patients were categorized based on median age into elderly and younger groups. The two groups were then compared during the first 7 days after ventilation based on proportion of patients with well-controlled sedation (Richmond Agitation-Sedation Scale score between -3 and +1), days free from delirium (based on the Confusion Assessment Method for ICU), and days free from coma (Richmond Agitation-Sedation Scale score between -4 and -5). RESULTS: One hundred and one patients were assigned to the elderly group and 100 patients were assigned to the younger group. In the elderly group, 50 patients received DEX treatment and 51 patients received non-DEX treatment, with the DEX arm having significantly better-controlled sedation (range, 14-52% versus 16-27%; P = 0.01). In the younger group, 50 patients received DEX treatment and 50 patients received non-DEX treatment, with no significant difference in the proportions of well-controlled sedation (range, 20-64% versus 24-60%; P = 0.73). There were no significant differences in the numbers of days free from delirium or coma between the groups. CONCLUSION: In elderly sepsis patients who require ventilation, dexmedetomidine could be more effective than other sedative agents for achieving proper sedation.

Adverse Drug Events due to Central Nervous System Depressant Drugs in Pediatric Patients With or Without Surgery.

OBJECTIVES: To identify differences in the incidence and severity of adverse drug events (ADEs) due to CNS depressant drugs among pediatric patients with and without surgery. METHODS: The Japan Adverse Drug Events Study was a cohort study enrolling pediatric inpatients. Potential ADEs were identified by onsite review of medical charts, incident reports, and prescription queries. Two independent physicians classified ADEs and severity. We compared the incidence and characteristics of ADEs between pediatric patients with surgery (surgery group) and without surgery (non-surgery group). We evaluated severity of ADEs due to CNS depressant drugs among both groups. RESULTS: We enrolled 944 patients, 234 in surgery group and 710 in non-surgery group. A total of 480 ADEs due to any drugs occurred in 225 patients. Among 81 ADEs due to CNS depressant drugs, 42 ADEs were in surgery group, whereas 39 were in non-surgery group. The risk of fatal or life-threatening ADEs due to CNS depressant drugs was significantly higher than other drugs (12% vs. 2%, p < 0.001). In the surgery group, anesthetics led to 2 fatal or life-threatening, 8 serious, and 30 significant ADEs, whereas in the non-surgery group anesthetics led to 2 fatal or life-threatening, 5 serious, and 4 significant ADEs. Anesthetics were higher risk in the non-surgery group (p = 0.049). CONCLUSIONS: The risks of fatal and life-threatening ADEs were significantly higher with CNS depressant drugs than other drugs. Pediatric patients without surgery have higher risks of fatal or life-threatening ADEs due to anesthetics than those with surgery.

Incidence, risk factors, and outcomes for sepsis-associated delirium in patients with mechanical ventilation: A sub-analysis of a multicenter randomized controlled trial.

PURPOSE: This study aimed to investigate incidence, risk factors, and outcomes for sepsis-associated delirium (SAD) in mechanically ventilated patients. MATERIALS AND METHODS: We performed a retrospective post-hoc analysis of the DExmedetomidine for Sepsis in Intensive care unit Randomized Evaluation (DESIRE) trial. Outcomes included 28-day mortality, ventilator-free days, length of ICU stay, self-extubation, and re-intubation. Multivariable analysis was performed to identify variables independently associated with SAD. RESULTS: We retrospectively divided the patients into two groups: delirium group (n = 89) and non-delirium group (n = 98). There were no significant differences between the groups in 28-day mortality, self-extubation, and re-intubation. The number of ventilator-free days was significantly less in the delirium vs. non-delirium group (17 vs. 22 days, p = .006), and the length of ICU stay was significantly longer in the delirium group (10 vs. 5 days, p = .04). Multivariable analyses revealed that emergency surgery, more doses of midazolam, and fentanyl were independent predictors for SAD. CONCLUSIONS: SAD was associated with a less number of ventilator-free days and longer length of ICU stay. Emergency surgery, more doses of midazolam, and fentanyl may be independent risk factors for SAD in mechanically ventilated patients with sepsis.

Clinical Decision Support System with Renal Dose Adjustment Did Not Improve Subsequent Renal and Hepatic Function among Inpatients: The Japan Adverse Drug Event Study.

BACKGROUND: Medication dose adjustment is crucial for patients with renal dysfunction (RD). The assessment of renal function is generally mandatory; however, the renal function may change during the hospital stay and the manual assessment is sometimes challenging. OBJECTIVE: We developed the clinical decision support system (CDSS) that provided a recommended dose based on automated calculated renal function. METHODS: We conducted a prospective cohort study in a single teaching hospital in Japan. All hospitalized patients were included except for obstetrics/gynecology and pediatric wards between September 2013 and February 2015. The CDSS was implemented on December 2013. Renal and hepatic dysfunction (HD) were defined as changes in the estimated glomerular filtration rate (eGFR) and alanine aminotransferase or alkaline phosphatase levels based on these measurements during hospital stay. These measurements were obtained before (phase I), after (phase II), and 1 year after (phase III) the CDSS implementation. RESULTS: We included 6,767 patients (phase I: 2,205; phase II: 2,279; phase III: 2,283). The patients' characteristics were similar among phases. Changes in eGFR were similar among phases, but the incidence of RD increased in phase III (phase I: 228 [10.3%]; phase II: 260 [11.4%]; phase III: 296 [13.0%], p = 0.02). However, the differences in incidences of RD were not statistically significant after adjusting for eGFR at baseline and age. The incidences of HD were also similar among phases (phase I: 175 [13.2%]; phase II: 171 [12.9%]; phase III: 167 [12.2%], p = 0.72). CONCLUSION: The CDSS implementation did not affect the incidence of renal and HD and changes in renal and hepatic function among hospitalized patients. The effectiveness of the CDSS with renal-guided doses should be investigated with respect to other endpoints.

Utility of a prediction model for delirium in intensive care unit patients (PRE-DELIRIC) in mechanically ventilated patients with sepsis.

AIM: Delirium frequently develops in patients with sepsis during their intensive care unit (ICU) stay, which is associated with increased morbidity and mortality. A prediction model for delirium in patients in ICU, PRE-DELIRIC, has been utilized in overall ICU patients, but its utility is uncertain among patients with sepsis. This study aims to examine the utility of PRE-DELIRIC to predict delirium in mechanically ventilated patients with sepsis. METHODS: This is a post hoc analysis of a randomized clinical trial in eight Japanese ICUs, which aimed to evaluate the sedative strategy with/without dexmedetomidine in adult mechanically ventilated patients with sepsis. The Confusion Assessment Method for the ICU was used every day to assess for delirium throughout their ICU stay. We excluded patients who were delirious on the first day of ICU, those who were under sustained coma throughout their ICU stay, and those who stayed in the ICU less than 24 h. The discriminative ability of PRE-DELIRIC was evaluated by measuring the area under the receiver operating characteristic curve (AUROC). RESULTS: Of the 201 patients enrolled in the trial, we analyzed 158 patients. The mean age was 69.4 ± 14.0 years, and 99 patients (63%) were men. Delirium occurred at least once during the ICU stay of 63 patients (40%). The AUROC of PRE-DELIRIC was 0.60 (95% confidence interval, 0.50-0.69). Subgroup analyses indicated that PRE-DELIRIC was useful in those with Sequential Organ Failure Assessment score >8 with AUROC of 0.65 (95% confidence interval, 0.51-0.77). CONCLUSIONS: The PRE-DELIRIC model could not predict delirium in mechanically ventilated patients with sepsis.

Dexmedetomidine improved renal function in patients with severe sepsis: an exploratory analysis of a randomized controlled trial.

BACKGROUND: Dexmedetomidine has been reported to improve organ dysfunction in critically ill patients. In a recent randomized controlled trial (Dexmedetomidine for Sepsis in Intensive Care Unit (ICU) Randomized Evolution [DESIRE]), we demonstrated that dexmedetomidine was associated with reduced mortality risk among patients with severe sepsis. We performed this exploratory sub-analysis to examine the mechanism underlying improved survival in patients sedated with dexmedetomidine. METHODS: The DESIRE trial compared a sedation strategy with and without dexmedetomidine among 201 mechanically ventilated adult patients with sepsis across eight ICUs in Japan. In the present study, we included 104 patients with Acute Physiology and Chronic Health Evaluation II (APACHE II) scores of ≥ 23 (54 in the dexmedetomidine [DEX] group and 50 in the non-dexmedetomidine [non-DEX] group). Initially, we compared the changes in the sequential organ failure assessment (SOFA) scores from the baseline within 6 days after randomization between groups. Subsequently, we evaluated the variables comprising the organ component of the SOFA score that showed relevant improvement in the initial comparison. RESULTS: The mean patient age was 71.0 ± 14.1 years. There was no difference in the median APACHE II score between the two groups (29 [interquartile range (IQR), 25-31] vs. 30 [IQR, 25-33]; p = 0.35). The median SOFA score at the baseline was lower in the DEX group (9 [IQR, 7-11] vs. 11 [IQR, 9-13]; p = 0.01). While the renal SOFA subscore at the baseline was similar for both groups, it significantly decreased in the DEX group on day 4 (p = 0.02). During the first 6 days, the urinary output was not significantly different (p = 0.09), but serum creatinine levels were significantly lower (p = 0.04) in the DEX group. The 28-day and in-hospital mortality rates were significantly lower in the DEX group (22% vs. 42%; p = 0.03, 28% vs. 52%; p = 0.01, respectively). CONCLUSION: A sedation strategy with dexmedetomidine is associated with improved renal function and decrease mortality rates among patients with severe sepsis. TRIAL REGISTRATION: This trial was registered on ClinicalTrials.gov (NCT01760967) on January 1, 2013.

Association between heart rate on admission and in-hospital mortality among general inpatients: Insights from Japan Adverse Drug Events (JADE) study.

Association between heart rate (HR) and in-hospital mortality in general patients irrespective of underlying diseases were not well scrutinized. We assessed the relationship between HR on admission and in-hospital mortality among general inpatients.We used data from Japan Adverse Drug Events (JADE) study, a prospective cohort study. One tertiary care hospital in Japan with 13 medical and 12 surgical wards, and an intensive care unit (ICU). Patients (n = 2360) were ≥12 years old and admitted to this hospital within 3 months; and pregnant women were excluded. We assessed the relationship between HR and mortality in five (<60, 60-79, 80-99, 100-119, ≥120 beats per minutes [bpm]) groups. We also compared the five HR groups according to the age (<70 years; ≥70 years) and wards (medical; surgical; ICU).We enrolled 2360 patients (median age, 71 [interquartile range (IQR) 58-81] years) including 1147, 1068, and 145 patients in the medical and surgical wards, and the ICU, respectively. The median (IQR) HR on admission was 78 (68-91) bpm. Ninety-five patients died during hospitalization. Mortalities in the <60, 60-79, 80-99, 100-119, and ≥120 bpm groups were 2.9% (5/175), 2.7% (28/1047), 3.4% (26/762), 8.2% (24/291), and 14.3% (12/84), respectively (P < .001). The adjusted odds ratios of in-hospital mortality was 3.64 (95% CI 1.88-7.05, P < .001) when HR was ≥100 bpm in the medical ward; and 5.69 (95% CI 1.72-18.82, P = .004) when HR ≥120 bpm in the surgical ward. There was no statistically significant relationship with the ICU.In conclusion, higher HR should be associated with in-hospital mortality among patients with general diseases. Even with less severe condition or outside ICU, HR should be directed attention to and patients with high HR on admission should be taken additional therapy to reduce the further risk of deterioration.

Epidemiology of Adverse Events and Medical Errors in the Care of Cardiology Patients.

OBJECTIVES: There have been epidemiological studies of adverse events (AEs) among general patients but those of patients cared by cardiologist are not well scrutinized. We investigated the occurrence of AEs and medical errors (MEs) among adult patients with cardiology in Japan. METHODS: We conducted a cross-sectional study of adult outpatients at a Japanese teaching hospital from February through November 2006. We measured AE and ME incidents from patient report, which were verified by medical records, laboratory data, incident reports, and prescription queries. Two independent physicians reviewed the incidents to determine whether they were AEs or MEs and to assess severity and symptoms. RESULTS: We identified 144 AEs and 30 MEs (16.3 and 3.9 per 100 patients, respectively). Of the 144 AEs, 99 were solely adverse drug events (ADEs), 20 were solely non-ADEs, and the remaining 25 were both causes. The most frequent symptoms of ADEs were skin and allergic reactions due to medication. The most frequent symptoms of non-ADEs were bleeding due to therapeutic interventions. Among AEs, 12% was life threatening. Life-threatening AEs were 25% of non-ADEs and 5% of ADEs (P = 0.0003). Among the 30 MEs, 21MEs (70%) were associated with drugs. CONCLUSIONS: Adverse events were common among cardiology patients. Adverse drug events were the most frequent AEs, and non-ADEs were more critical than ADEs. Such data should be recognized among practicing physicians to improve the patients' outcomes.

GRam stain-guided Antibiotics ChoicE for Ventilator-Associated Pneumonia (GRACE-VAP) trial: rationale and study protocol for a randomised controlled trial.

BACKGROUND: Optimising the use of antibiotic agents is a pressing challenge to overcoming the rapid emergence and spread of multidrug-resistant pathogens in intensive care units (ICUs). Although Gram staining may possibly provide immediate information for predicting pathogenic bacteria, Gram stain-guided initial antibiotic treatment is not well established in the ICU setting. We planned the GRam stain-guided Antibiotics ChoicE for Ventilator-Associated Pneumonia (GRACE-VAP) trial to investigate whether Gram staining can safely restrict the use of broad-spectrum antibiotics in patients with ventilator-associated pneumonia (VAP), which is one of the most common hospital-acquired infections in ICUs. METHODS/DESIGN: The GRACE-VAP trial is a multicentre, randomised, open-label parallel-group trial to assess the non-inferiority of Gram stain-guided initial antibiotic treatment to guidelines-based initial antibiotic treatment for the primary endpoint of clinical response rate in patients with VAP. Secondary endpoints include the coverage rates of initial antibiotic therapies, the selected rates of anti-pseudomonal agents and anti-methicillin-resistant Staphylococcus aureus (anti-MRSA) agents as initial antibiotic therapies, 28-day all-cause mortality, ICU-free days, ventilator-free days and adverse events. Patients are randomly assigned to receive Gram stain-guided treatment or guidelines-based treatment at a ratio of 1:1. In the Gram stain group, results of Gram staining of endotracheal aspirate are used to guide the selection of antibiotics. In the guidelines group, the combination of an anti-pseudomonal agent and an anti-MRSA agent is administered. A total sample size of 200 was estimated to provide a power of 80% with a one-sided alpha level of 2.5% and a non-inferiority margin of 20%, considering 10% non-evaluable patients. DISCUSSION: The GRACE-VAP trial is expected to reveal whether Gram staining can reduce the use of broad-spectrum antibiotics without impairing patient outcomes and thereby provide evidence for an antibiotic selection strategy in patients with VAP. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03506113 . Registered on 29 March 2018. University Hospital Medical Information Network, UMIN000031933. Registered on 26 March 2018.

Effect of norepinephrine dosage on mortality in patients with septic shock.

BACKGROUND: Use of high-dose norepinephrine is thought to have an immunosuppressive action that increases mortality. This study aimed to evaluate the correlation between norepinephrine dosage and prognosis of patients with septic shock. METHODS: This study was a nested cohort of the DExmedetomidine for Sepsis in Intensive Care Unit Randomized Evaluation (DESIRE) trial. We evaluated 112 patients with septic shock and an initial Sequential Organ Failure Assessment Cardiovascular (SOFA-C) category score > 2 and initial lactate level > 2 mmol/L. We divided the patients into two groups according to the norepinephrine dosage administered over the initial 7 days: high dose (≥ 416 µg/kg/week) (H group, n = 56) and low dose (< 416 µg/kg/week) (L group, n = 56). The primary outcome of interest was 28-day mortality. Secondary outcomes were ventilator-free days, initial 24-h infusion volume, initial 24- to 48-h infusion volume, and the need for renal replacement therapy. For comparisons between the H group and L group, we used the chi-square test or Fisher's exact test for categorical variables and the t test or Wilcoxon rank sum test for continuous variables. For time-to-event outcomes, Cox proportional hazards models were used. Kaplan-Meier survival curves were created for graphical representation. RESULTS: Patient characteristics appeared to be similar between the two groups except for the SOFA-C score and fibrinogen degradation product level. The cumulative incidence of death at 28 days was 29.9% (16 patients) in the L group and 29.7% (15 patients) in the H group (p = 0.99). The median number of 28-day ventilator-free days was 20 (0, 25) in the L group and 16 (0, 22) in the H group (p < 0.05). Initial infusion volume at 0-24 h in the H group was significantly higher than that in the L group (p = 0.004). Infusion volume at 24-48 h in the H group was also significantly higher than that in the L group (p = 0.03). CONCLUSIONS: No statistically significant difference was observed in 28-day mortality between patients with septic shock treated with high-dose norepinephrine compared with those treated with low-dose norepinephrine. However, the number of ventilator-free days in the L group was higher than that in the H group. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01760967 Date of trial registration: January 4, 2013.