Masamitsu Sanui

Association of body temperature and antipyretic treatments with mortality of critically ill patients with and without sepsis: multi-centered prospective observational study

IntroductionFever is frequently observed in critically ill patients. An independent association of fever with increased mortality has been observed in non-neurological critically ill patients with mixed febrile etiology. The association of fever and antipyretics with mortality, however, may be different between infective and non-infective illness.MethodsWe designed a prospective observational study to investigate the independent association of fever and the use of antipyretic treatments with mortality in critically ill patients with and without sepsis. We included 1,425 consecutive adult critically ill patients (without neurological injury) requiring > 48 hours intensive care admitted in 25 ICUs. We recorded four-hourly body temperature and all antipyretic treatments until ICU discharge or 28 days after ICU admission, whichever occurred first. For septic and non-septic patients, we separately assessed the association of maximum body temperature during ICU stay (MAXICU) and the use of antipyretic treatments with 28-day mortality.ResultsWe recorded body temperature 63,441 times. Antipyretic treatment was given 4,863 times to 737 patients (51.7%). We found that treatment with non-steroidal anti-inflammatory drugs (NSAIDs) or acetaminophen independently increased 28-day mortality for septic patients (adjusted odds ratio: NSAIDs: 2.61, P = 0.028, acetaminophen: 2.05, P = 0.01), but not for non-septic patients (adjusted odds ratio: NSAIDs: 0.22, P = 0.15, acetaminophen: 0.58, P = 0.63). Application of physical cooling did not associate with mortality in either group. Relative to the reference range (MAXICU 36.5°C to 37.4°C), MAXICU ≥ 39.5°C increased risk of 28-day mortality in septic patients (adjusted odds ratio 8.14, P = 0.01), but not in non-septic patients (adjusted odds ratio 0.47, P = 0.11).ConclusionsIn non-septic patients, high fever (≥ 39.5°C) independently associated with mortality, without association of administration of NSAIDs or acetaminophen with mortality. In contrast, in septic patients, administration of NSAIDs or acetaminophen independently associated with 28-day mortality, without association of fever with mortality. These findings suggest that fever and antipyretics may have different biological or clinical or both implications for patients with and without sepsis.Trial registrationClinicalTrials.gov: NCT00940654

Effects of arginine vasopressin during resuscitation from hemorrhagic hypotension after traumatic brain injury

Objective:Two series of experiments were designed to evaluate whether early arginine vasopressin improves acute outcome following resuscitation from traumatic brain injury and severe hemorrhagic hypotension Design:Prospective randomized, blinded animal study. Setting:University laboratory. Subjects:Thirty-three swine. Interventions:In series 1 (n = 19), after traumatic brain injury with hemorrhage and 12 mins of shock (mean arterial pressure ≈20 mm Hg), survivors (n = 16) were initially resuscitated with 10 mL/kg crystalloid. After 30 mins, crystalloid and blood with either 0.1 unit·kg−1·hr−1 arginine vasopressin or placebo was titrated to a mean arterial pressure target ≥60 mm Hg. After 90 mins, all received mannitol and the target was cerebral perfusion pressure ≥60 mm Hg. To test cerebrovascular function, 7.5% inhaled CO2 was administered periodically. In series 2 (n = 14), the identical protocol was followed except the shock period was 20 mins and survivors (n = 10) received a bolus of either arginine vasopressin (0.2 units/kg) or placebo during the initial fluid resuscitation. Measurements and Main Results:In series 1, by 300 mins after traumatic brain injury with arginine vasopressin (n = 8) vs. placebo (n = 8), the fluid and transfusion requirements were reduced (both p < .01), intracranial pressure was improved (11 ± 1 vs. 23 ± 2 mmHg; p < .0001), and the CO2-evoked intracranial pressure elevation was reduced (7 ± 2 vs. 26 ± 3 mm Hg, p < .001), suggesting improved compliance. In series 2, with arginine vasopressin vs. placebo, cerebral perfusion pressure was more rapidly corrected (p < .05). With arginine vasopressin, five of five animals survived 300 mins, whereas three of five placebo animals died. The survival time with placebo was 54 ± 4 mins (p < .05 vs. arginine vasopressin). Conclusions:Early supplemental arginine vasopressin rapidly corrected cerebral perfusion pressure, improved cerebrovascular compliance, and prevented circulatory collapse during fluid resuscitation of hemorrhagic shock after traumatic brain injury.

Recombinant human soluble thrombomodulin and mortality in sepsis-induced disseminated intravascular coagulation : a multicentre retrospective study

Recombinant human soluble thrombomodulin (rhTM) is a novel class of anticoagulants for treating disseminated intravascular coagulation (DIC). Although rhTM is widely used in clinical settings throughout Japan, there is limited clinical evidence supporting the use of rhTM in patients with sepsis-induced DIC. Furthermore, rhTM is not approved for DIC treatment in other countries. This study aimed to clarify the survival benefits of rhTM administration in critically ill patients. Data from 3,195 consecutive adult patients who were admitted to 42 intensive care units for the treatment of severe sepsis or septic shock between January 2011 and December 2013 were retrospectively analysed, and 1,784 patients were diagnosed with DIC based on the scoring algorithm from the Japanese Association for Acute Medicine DIC (n = 645, rhTM group; n = 1,139, control group). Propensity score matching created 452 matched pairs, and logistic regression analysis revealed a significant association between rhTM administration and lower in-hospital all-cause mortality in the propensity score-matched groups (odds ratio, 0.757; 95 % confidence interval, 0.574-0.999, p = 0.049). Inverse probability of treatment weighted and quintile-stratified analyses also revealed significant associations between rhTM administration and lower in-hospital all-cause mortality. Survival time in the propensity score-matched rhTM group was significantly longer than that in the propensity score-matched control group (hazard ratio, 0.781; 95 % confidence interval, 0.624-0.977, p = 0.03). Bleeding complications were not more frequent in the rhTM groups. In conclusion, this study demonstrated that rhTM administration is associated with reduced in-hospital all-cause mortality among patients with sepsis-induced DIC.

Intraoperative hydroxyethyl starch 70/0.5 is not related to acute kidney injury in surgical patients: retrospective cohort study.

BACKGROUND: Although high-molecular-weight hydroxyethyl starch (HES) has been reported to cause acute kidney injury (AKI), it is not clear whether low-molecular-weight HES (6% HES 70/0.5) can be a risk for AKI or not. We hypothesized that intraoperative 6% HES 70/0.5 administration is not related to postoperative AKI. METHODS: A retrospective chart review was conducted to identify adult surgical patients with intraoperative blood loss of ≥1000 mL at a university hospital. AKI was defined as >50% increase in serum creatinine from the preoperative value within 7 days after the operation according to the RIFLE (Risk, Injury, Failure, Loss, or End-stage kidney disease) criteria. We compared the incidence of AKI between patients with and without intraoperative HES administration. Multivariate logistic regression analysis and propensity score matching were also conducted to elucidate the impact of HES on postoperative AKI. RESULTS: Among 14,332 surgical cases, 846 patients met the inclusion criteria. In patients given HES (a median dose of 1000 mL, n = 635), 12.9% developed AKI, compared with 16.6% (−3.7%, −1.7% to 9.1%) in patients without HES (n = 211). Multivariate logistic regression analysis showed that HES was not an independent risk factor for postoperative AKI (odds ratio: 0.76, 0.48–1.21). Using the propensity score, 179 pairs were matched. In patients with HES, 12.3% developed AKI, compared with 14.5% in patients without HES (−2.2%, −4.9% to 9.3%). CONCLUSION: In this uncontrolled retrospective chart review, intraoperative 6% HES 70/0.5 in a low dose was not related to postoperative AKI in patients with major intraoperative blood loss. Randomized controlled trials are warranted to further evaluate the safety and efficacy of low-molecular-weight HES.

Antithrombin Supplementation and Mortality in Sepsis-induced Disseminated Intravascular Coagulation: A Multicenter Retrospective Observational Study

ABSTRACT Supplemental doses of antithrombin (AT) are widely used to treat sepsis-induced disseminated intravascular coagulation (DIC) in Japan. However, evidence on the benefits of AT supplementation for DIC is insufficient. This multicenter retrospective observational study aimed to clarify the effect of AT supplementation on sepsis-induced DIC using propensity score analyses. Data from 3,195 consecutive adult patients admitted to 42 intensive care units for severe sepsis treatment were retrospectively analyzed; 1,784 patients were diagnosed with DIC (n = 715, AT group; n = 1,069, control group). Inverse probability of treatment-weighted propensity score analysis indicated a statistically significant association between AT supplementation and lower in-hospital all-cause mortality (n = 1,784, odds ratio [95% confidence intervals]: 0.748 [0.572–0.978], P = 0.034). However, quintile-stratified propensity score analysis (n = 1,784, odds ratio: 0.823 [0.646–1.050], P = 0.117) and propensity score matching analysis (461 matching pairs, odds ratio: 0.855 [0.649–1.125], P = 0.263) did not show this association. In the early days after intensive care unit admission, the survival rate was statistically higher in the propensity score-matched AT group than in the propensity score-matched control group (P = 0.007). In DIC patients without concomitant heparin administration, similar results were observed. In conclusion, AT supplementation may be associated with reduced in-hospital all-cause mortality in patients with sepsis-induced DIC. However, the statistical robustness of this connection was not strong. In addition, although the number of transfusions needed in patients with AT supplementation increased, severe bleeding complications did not.

Utility of the Penn Classification in Predicting Outcomes of Surgery for Acute Type A Aortic Dissection

The Penn classification, a risk assessment system for acute type A aortic dissection (AAAD), is based on preoperative ischemic conditions. We investigated whether Penn classes predict outcomes after surgery for AAAD. Three hundred fifty-one patients with DeBakey type I AAAD treated surgically, January 1997 to January 2011, were divided into 4 groups per Penn class: Aa (no ischemia, n = 187), Ab (localized ischemia with branch malperfusion, n = 67), Ac (generalized ischemia with circulatory collapse, n = 46), and Abc (localized and generalized ischemia, n = 51). Early and late outcomes were compared between groups. In-hospital mortality was 3% (6 of 187) for Penn Aa, 6% (4 of 67) for Penn Ab, 17% (8 of 46) for Penn Ac, and 22% (11 of 51) for Penn Abc. Multivariate logistic regression analysis showed Penn classes Ac and Abc, operation time >6 hours, and entry in the descending thoracic aorta to be risk factors for in-hospital mortality. Incidences of neurologic, respiratory, and hepatic complications differed between groups. Five-year cumulative survival was 85% in the Penn Aa group, 74% in the Penn Ab group (p = 0.027 vs Penn Aa), 78% in the Penn Ac group, and 67% in the Penn Abc group (p <0.001 vs Penn Aa). In conclusion, morbidity and mortality are high in patients with generalized ischemia. The Penn classification appears to be a useful risk assessment system for AAAD, predictive of outcomes.

The Dose-Response Relationship Between Body Mass Index and Mortality in Subjects Admitted to the ICU With and Without Mechanical Ventilation

BACKGROUND: Obesity has been associated with increased mortality in the general population, whereas a paradoxical relationship between higher body mass index and lower mortality has been referred to as the obesity paradox in critically ill patients. However, it remains unknown whether a particular subgroup is most affected. The aim of the present study is to elucidate whether obesity is associated with lower mortality in the ICU population by comparing subjects with and without mechanical ventilation. METHODS: A total of 334,238 subjects from a nationwide database who were discharged between July 2010 and March 2012 and who were admitted to general ICUs during their hospitalization were included in this study. The primary outcome was in-hospital mortality. RESULTS: Of all subjects evaluated, 23.3% were started on mechanical ventilation within the first 2 d after ICU admission. Compared with the non-ventilated group, the ventilated group was more likely to have sepsis, pneumonia, or coma. The ventilated group underwent more procedures within the first 2 d after ICU admission compared with the non-ventilated group. A restricted cubic spline function showed lower mortality in subjects with a higher body mass index among the ventilated group, whereas mortality was increased with increasing body mass index in the non-ventilated group. CONCLUSIONS: This study shows that a high body mass index is associated with low mortality in the mechanically ventilated group, whereas the non-ventilated group showed a reverse J-shaped association. There was a higher mortality rate in underweight subjects in both groups.

The Volume-Outcome Relationship in Critically Ill Patients in Relation to the ICU-to-Hospital Bed Ratio.

Objectives:A volume-outcome relationship in ICU patients has been suggested in recent studies. However, it is unclear whether the ICU-to-hospital bed ratio affects the volume-outcome relationship. The aim of this study is to investigate the relationship between hospital volume and in-hospital mortality of adult ICU patients in relation to the ratio of ICU beds to regular hospital beds. Design:Retrospective cohort study. Setting:Four hundred seventy-seven Japanese hospitals from 2007 to 2012 in the Japanese Diagnosis Procedure Combination database. Patients:A total of 596,143 patients discharged from acute care hospitals. Interventions:None. Measurements and Main Results:We analyzed data from 596,143 ICU patients from 2007 through 2012 using a nationwide administrative database. Patients were categorized into nine subgroups (the tertiles of hospital volume of ICU patients combined with the tertiles of ICU-to-hospital bed ratio). Multivariable logistic regression analyses were performed to examine the concurrent effects of hospital volume of ICU patients and ICU-to-hospital bed ratio on in-hospital mortality, with adjustment for patient and hospital characteristics. Higher hospital volume of ICU patients and a higher ICU-to-hospital bed ratio were independently associated with lower mortality. When patients were stratified by ICU-to-hospital bed ratio categories, in-hospital mortality was significantly lower in the high-volume subgroup (odds ratio, 0.74; 95% CI, 0.58–0.93) compared with the low-volume subgroup in hospitals with a high ICU-to-hospital bed ratio. However, these relationships were not significant in hospitals with low ICU-to-hospital bed ratios (odds ratio, 0.94; 95% CI, 0.59–1.50) or in hospitals with intermediate ICU-to-hospital bed ratios (odds ratio, 0.80; 95% CI, 0.71–1.08). Conclusions:An inverse relationship between hospital volume of ICU patients and mortality was seen only when the ICU-to-hospital bed ratio was sufficiently high. Regionalization and increasing the number of ICU beds in referral centers may improve patient outcomes.

A fatal infection caused by sequence type 398 methicillin-resistant Staphylococcus aureus carrying the Panton-Valentine leukocidin gene: A case report in Japan.

Methicillin-resistant Staphylococcus aureus (MRSA) has now been recognized as a common pathogen in the community. Sequence type (ST) 398 MRSA is generally considered as an emerging zoonotic agent spreading among livestock and personnel who have direct contact with animals, mainly in Europe. A 37-year-old Chinese woman receiving steroid therapy for systemic lupus erythematosus with general fatigue and myalgia was brought to the emergency department in critical condition. Her condition deteriorated despite aggressive management and she died on day 7. Her blood culture revealed ST398 MRSA-SCCmec V with Panton-Valentine Leukocidin (PVL) gene. This is the first case report of a fatal infection caused by this lineage. According to the results of molecular analyses, the isolate from this particular patients blood was genetically close to a lineage detected in China, and is less likely to be related to an animal-associated lineage.

Reliability and validity assessment of the Japanese version of the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU)

OBJECTIVE Delirium may lead to adverse outcomes in patients with serious conditions, but is often under-diagnosed due to inadequate screening. The Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) is an established method for assessing delirium in the ICU. The validity and reliability of the Japanese version of the CAM-ICU has not, however, been verified, and we undertook this study to verify these parameters. RESEARCH METHODOLOGY CAM-ICU validity and reliability were assessed in two Japanese ICUs. Using the evaluation of the DMS-IV-TR in the psychiatrists group as the standard criteria for delirium diagnosis, we compared the evaluation of the Japanese version of the CAM-ICU between the research nurses group and the staff nurses group. RESULTS According to DSM-IV-TR criteria, the prevalence of delirium was 22.0%, and according to CAM-ICU delirium was found in 22.0% with Research Nurses and 19.5% with Staff Nurses. CAM-ICU sensitivity ratings were 83% and 78%, while their specificity ratings were 95% and 97%, respectively. The Kappa inter-rater reliability was good (κ=0.85), and Cronbachs alpha coefficient was 0.69 (95% CI: 0.57-0.79). Mean rating time for the CAM-ICU was 2.5-2.8 minutes for Research Nurses and Staff Nurses, respectively. CONCLUSION The Japanese version of the CAM-ICU has comparable validity and reliability as a delirium assessment tool in surgical patients in two Japanese ICUs. With training, CAM-ICU can be incorporated into daily clinical practice.