Moritoki Egi

Renal blood flow in sepsis

IntroductionTo assess changes in renal blood flow (RBF) in human and experimental sepsis, and to identify determinants of RBF.MethodUsing specific search terms we systematically interrogated two electronic reference libraries to identify experimental and human studies of sepsis and septic acute renal failure in which RBF was measured. In the retrieved studies, we assessed the influence of various factors on RBF during sepsis using statistical methods.ResultsWe found no human studies in which RBF was measured with suitably accurate direct methods. Where it was measured in humans with sepsis, however, RBF was increased compared with normal. Of the 159 animal studies identified, 99 reported decreased RBF and 60 reported unchanged or increased RBF. The size of animal, technique of measurement, duration of measurement, method of induction of sepsis, and fluid administration had no effect on RBF. In contrast, on univariate analysis, state of consciousness of animals (P = 0.005), recovery after surgery (P < 0.001), haemodynamic pattern (hypodynamic or hyperdynamic state; P < 0.001) and cardiac output (P < 0.001) influenced RBF. However, multivariate analysis showed that only cardiac output remained an independent determinant of RBF (P < 0.001).ConclusionThe impact of sepsis on RBF in humans is unknown. In experimental sepsis, RBF was reported to be decreased in two-thirds of studies (62 %) and unchanged or increased in one-third (38%). On univariate analysis, several factors not directly related to sepsis appear to influence RBF. However, multivariate analysis suggests that cardiac output has a dominant effect on RBF during sepsis, such that, in the presence of a decreased cardiac output, RBF is typically decreased, whereas in the presence of a preserved or increased cardiac output RBF is typically maintained or increased.

Renal Vascular Resistance in Sepsis

Aims: To assess changes in renal vascular resistance (RVR) in human and experimental sepsis and to identify determinants of RVR. Methods: We performed a systematic interrogation of two electronic reference libraries using specific search terms. Subjects were animals and patients involved in experimental and human studies of sepsis and septic acute renal failure, in which the RVR was assessed. We obtained all human and experimental articles reporting RVR during sepsis. We assessed the role of various factors that might influence the RVR during sepsis using statistical methods. Results: We found no human studies, in which the renal blood flow (and, therefore, the RVR) was measured with suitably accurate direct methods. Of the 137 animal studies identified, 52 reported a decreased RVR, 16 studies reported no change in RVR, and 69 studies reported an increased RVR. Consciousness of animals, duration of measurement, method of induction of sepsis, and fluid administration had no effect on the RVR. On the other hand, on univariate analysis, size of the animals (p<0.001), technique of measurement (p = 0.017), recovery after surgery (p = 0.004), and cardiac output (p <0.001) influenced the RVR. Multivariate analysis, however, showed that only cardiac output (p = 0.028) and size of the animals (p = 0.031) remained independent determinants of the RVR. Conclusions: Changes in RVR during sepsis in humans are unknown. In experimental sepsis, several factors not directly related to sepsis per se appear to influence the RVR. A high cardiac output and the use of large animals predict a decreased RVR, while a decreased cardiac output and the use of small animals predict an increased RVR.

Low-dose citrate continuous veno-venous hemofiltration (CVVH) and acid-base balance.

Objective To evaluate the acid-base effect of low-dose regional citrate anticoagulation (RCA) during continuous veno-venous hemofiltration (CVVH). Design Prospective observational study. Setting ICUs of tertiary public and private hospitals. Subjects Thirty critically ill patients with acute renal failure at risk of bleeding or with a major contraindication to heparin-CVVH and/or short filter life. Methods We used a commercial citrate-based fluid (11 mmol/L, sodium: 140 mmol/L, chloride: 108 mmol/L and 1 mol/L of potassium) as pre-dilution replacement fluid during CVVH. Further potassium was added according to serum potassium levels. We measured all relevant variables for acid-base analysis according to the Stewart-Figge methodology. Results Before treatment, study patients had a slight metabolic acidosis, which worsened over 6 hours of RCA-CVVH (pH from 7.39 to 7.38, p<0.005; bicarbonate from 23.2 to 21.6 mmol/L, p<0.0001 and base excess from −2.0 to −3.0 mEq/L, p<0.0001) due to a significant increase in SIG (from 5.8 to 6.6 mEq/L, p<0.05) and a decrease in SIDa (from 37.5 to 36.6 mEq/L, p<0.05). These acidifying effects were attenuated by hypoalbuminemia and a decrease in lactate (from 1.48 to 1.34 mmol/L, p<0.005) and did not lead to progressive acidosis. On cessation of treatment, this acidifying effect rapidly self-corrected within six hours. Conclusions Low dose RCA-CVVH induces a mild acidosis secondary to an increased strong ion gap and decreased SIDa which fully self-corrects at cessation of therapy. Clinicians need to be aware of these effects to correctly interpret changes in acid-base status in such patients.

Comparison of nafamostat mesilate and unfractionated heparin as anticoagulants during continuous renal replacement therapy

Purpose Nafamostat mesilate (NM) can be used as a regional anticoagulant for continuous renal replacement therapy (CRRT). The primary aim of this study was to assess the association of the use of NM with risk of bleeding complications and compare it with the use of unfractionated heparin (UFH). Methods We conducted a single-center retrospective observational study. We included adult patients who required CRRT in our intensive care unit from 2011 to 2013. The primary outcome was the risk of bleeding complications during CRRT and the secondary outcome was filter life for the first filter of CRRT. Results We included 101 patients (76 with NM, 25 with UFH). Among the 101 patients, use of NM tended to be associated with lower risk of bleeding complications (6.6% vs. 16%; odds ratio, 0.37; p = 0.16). Propensity score matching generated 30 patients with NM and 15 patients with UFH with well-balanced baseline characteristics. Among the propensity score-matched cohorts, use of NM was significantly associated with decreased risk of bleeding complications (3.3% vs. 27%; odds ratio, 0.09; p = 0.04). In multivariate logistic analysis using the inverse probability of treatment weighting for sensitive analysis, the use of NM was independently associated with reduced risk of bleeding complications (p = 0.02). The median filter life was not significantly different for patients with NM and patients with UFH (25.5 hours vs. 30.5 hours, p = 0.16). Conclusions In our retrospective analysis, the use of NM as an anticoagulant during CRRT was associated with decreased incidence of bleeding complications compared with the use of UFH.

Impact of Milrinone Administration in Adult Cardiac Surgery Patients: Updated Meta-Analysis

OBJECTIVE To determine the effects of milrinone on short-term mortality in cardiac surgery patients with focus on the presence or absence of heterogeneity of the effect. DESIGN A systematic review and meta-analysis. SETTING AND PARTICIPANTS Five hundred thirty-seven adult cardiac surgery patients from 12 RCTs. INTERVENTIONS Milrinone administration. MEASUREMENTS AND MAIN RESULTS The authors conducted a systematic Medline and Pubmed search to assess the effect of milrinone on short-term mortality in adult cardiac surgery patients. Subanalysis was performed according to the timing for commencement of milrinone administration and the type of comparators. The primary outcome was any short-term mortality. Overall analysis showed no difference in mortality rates in patients who received milrinone and patients who received comparators (odds ratio = 1.25, 95% CI 0.45-3.51, p = 0.67). In subanalysis for the timing to commence milrinone administration and the type of comparators, odds ratio for mortality varied from 0.19 (placebo as control drug, start of administration after cardiopulmonary bypass) to 2.58 (levosimendan as control drug, start of administration after cardiopulmonary bypass). CONCLUSIONS Among RCTs to assess the effect of milrinone administration in adult cardiac surgery patients, there are wide variations of the odds ratios of administration of milrinone for short-term mortality according to the comparators and the timing of administration. This fact may suggest that a simple pooling meta-analysis is not applicable for assessing the risk and benefit of milrinone administration in an adult cardiac surgery cohort.

The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2016 (J‐SSCG 2016)

The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2016 (J‐SSCG 2016), a Japanese‐specific set of clinical practice guidelines for sepsis and septic shock created jointly by the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine, was first released in February 2017 in Japanese. An English‐language version of these guidelines was created based on the contents of the original Japanese‐language version.

Quantitative relationships among plasma lactate, inorganic phosphorus, albumin, unmeasured anions and the anion gap in lactic acidosis

Background: Quantitative relationships among plasma [Lactate], [Pi], [Albumin], unmeasured anions ([UA]) and the anion gap (AGK) in lactic acidosis (LA) are not well defined. Methods: A mathematical model featuring compensatory potassium and chloride shifts and respiratory changes in LA demonstrated: (1) AGK = [Lactate] + Zp × [Pi] + 2.4 × [Albumin] + constant1 + e, where Zp is a function of pH, and e reflects unmeasured anions and cations plus pH‐related variations. Eq. (1) can be algebraically rearranged to incorporate the albumin‐corrected anion gap, cAGK: (2) cAGK = [Lactate] + Zp × [Pi] + constant2 + e. Eq. (1) was tested against 948 data sets from critically ill patients with [Lactate] 4.0 mEq/L or greater. AGK and cAGK were evaluated against 12,341 data sets for their ability to detect [Lactate] > 4.0 mEq/L. Results: Analysis of Eq. (1) revealed r2 = 0.5950, p < 0.001. cAGk > 15 mEq/L exhibited a sensitivity of 93.0% [95% CI: 91.3–94.5] in detecting [Lactate] > 4.0 mEq/L, whereas AGK > 15 mEq/L exhibited a sensitivity of only 70.4% [67.5–73.2]. Additionally, [Lactate] > 4.0 mEq/L and cAGK > 20 mEq/L were each strongly associated with intensive care unit mortality (χ2 > 200, p < 0.0001 for each). Conclusions: In LA, cAGK is more sensitive than AGK in predicting [Lactate] > 4.0 mEq/L.

Acetaminophen for febrile patients with suspected infection: potential benefit and further directions

Fever, increased body temperature, is a physiological expression of the host’s response to an infective (1) or non-infective pathology (2-6). Non-infective fever is common in critically ill patients, which includes ones related with post-surgical reaction, acute myocardial infarction, cerebral infarction, cerebral hemorrhage, acute pancreatitis, malignant tumor, post-transfusion reaction, transplant rejection and drug fever. Fever is also common in infective patients. In multicenter observational study, among the patients who developed body temperature equal or more than 38.5 ℃, approximately 63% of patients were diagnosed as sepsis (7).

The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2016 (J-SSCG 2016)

Background and purposeThe Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2016 (J-SSCG 2016), a Japanese-specific set of clinical practice guidelines for sepsis and septic shock created jointly by the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine, was first released in February 2017 and published in the Journal of JSICM, [2017; Volume 24 (supplement 2)] https://doi.org/10.3918/jsicm.24S0001 and Journal of Japanese Association for Acute Medicine [2017; Volume 28, (supplement 1)] http://onlinelibrary.wiley.com/doi/10.1002/jja2.2017.28.issue-S1/issuetoc.This abridged English edition of the J-SSCG 2016 was produced with permission from the Japanese Association of Acute Medicine and the Japanese Society for Intensive Care Medicine.MethodsMembers of the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine were selected and organized into 19 committee members and 52 working group members. The guidelines were prepared in accordance with the Medical Information Network Distribution Service (Minds) creation procedures. The Academic Guidelines Promotion Team was organized to oversee and provide academic support to the respective activities allocated to each Guideline Creation Team. To improve quality assurance and workflow transparency, a mutual peer review system was established, and discussions within each team were open to the public. Public comments were collected once after the initial formulation of a clinical question (CQ) and twice during the review of the final draft. Recommendations were determined to have been adopted after obtaining support from a two-thirds (> 66.6%) majority vote of each of the 19 committee members.ResultsA total of 87 CQs were selected among 19 clinical areas, including pediatric topics and several other important areas not covered in the first edition of the Japanese guidelines (J-SSCG 2012). The approval rate obtained through committee voting, in addition to ratings of the strengths of the recommendation, and its supporting evidence were also added to each recommendation statement. We conducted meta-analyses for 29 CQs. Thirty-seven CQs contained recommendations in the form of an expert consensus due to insufficient evidence. No recommendations were provided for five CQs.ConclusionsBased on the evidence gathered, we were able to formulate Japanese-specific clinical practice guidelines that are tailored to the Japanese context in a highly transparent manner. These guidelines can easily be used not only by specialists, but also by non-specialists, general clinicians, nurses, pharmacists, clinical engineers, and other healthcare professionals.

The clinical practice guideline for the management of ARDS in Japan

BackgroundThe Japanese Society of Respiratory Care Medicine and the Japanese Society of Intensive Care Medicine provide here a clinical practice guideline for the management of adult patients with ARDS in the ICU.MethodThe guideline was developed applying the GRADE system for performing robust systematic reviews with plausible recommendations. The guideline consists of 13 clinical questions mainly regarding ventilator settings and drug therapies (the last question includes 11 medications that are not approved for clinical use in Japan).ResultsThe recommendations for adult patients with ARDS include: we suggest against early tracheostomy (GRADE 2C), we suggest using NPPV for early respiratory management (GRADE 2C), we recommend the use of low tidal volumes at 6-8 mL/kg (GRADE 1B), we suggest setting the plateau pressure at 30cmH20 or less (GRADE2B), we suggest using PEEP within the range of plateau pressures less than or equal to 30cmH2O, without compromising hemodynamics (Grade 2B), and using higher PEEP levels in patients with moderate to severe ARDS (Grade 2B), we suggest using protocolized methods for liberation from mechanical ventilation (Grade 2D), we suggest prone positioning especially in patients with moderate to severe respiratory dysfunction (GRADE 2C), we suggest against the use of high frequency oscillation (GRADE 2C), we suggest the use of neuromuscular blocking agents in patients requiring mechanical ventilation under certain circumstances (GRADE 2B), we suggest fluid restriction in the management of ARDS (GRADE 2A), we do not suggest the use of neutrophil elastase inhibitors (GRADE 2D), we suggest the administration of steroids, equivalent to methylprednisolone 1-2mg/kg/ day (GRADE 2A), and we do not recommend other medications for the treatment of adult patients with ARDS (GRADE1B; inhaled/intravenous β2 stimulants, prostaglandin E1, activated protein C, ketoconazole, and lisofylline, GRADE 1C; inhaled nitric oxide, GRADE 1D; surfactant, GRADE 2B; granulocyte macrophage colony-stimulating factor, N-acetylcysteine, GRADE 2C; Statin.)ConclusionsThis article was translated from the Japanese version originally published as the ARDS clinical practice guidelines 2016 by the committee of ARDS clinical practice guideline (Tokyo, 2016, 293p, available from http://www.jsicm.org/ARDSGL/ARDSGL2016.pdf). The original article, written for Japanese healthcare providers, provides points of view that are different from those in other countries.