Mayuki Aibiki

Post–Cardiac Arrest Syndrome

The contributors to this statement were selected to ensure expertise in all the disciplines relevant to post–cardiac arrest care. In an attempt to make this document universally applicable and generalizable, the authorship comprised clinicians and scientists who represent many specialties in many regions of the world. Several major professional groups whose practice is relevant to post–cardiac arrest care were asked and agreed to provide representative contributors. Planning and invitations took place initially by e-mail, followed a series of telephone conferences and face-to-face meetings of the cochairs and writing group members. International writing teams were formed to generate the content of each section, which corresponded to the major subheadings of the final document. Two team leaders from different countries led each writing team. Individual contributors were assigned by the writing group cochairs to work on 1 or more writing teams, which generally reflected their areas of expertise. Relevant articles were identified with PubMed, EMBASE, and an American Heart Association EndNote master resuscitation reference library, supplemented by hand searches of key papers. Drafts of each section were written and agreed on by the writing team authors and then sent to the cochairs for editing and amalgamation into a single document. The first draft of the complete document was circulated among writing team leaders for initial comment and editing. A revised version of the document was circulated among all contributors, and consensus was achieved before submission of the final version for independent peer review and approval for publication. This scientific statement outlines current understanding and identifies knowledge gaps in the pathophysiology, treatment, and prognosis of patients who regain spontaneous circulation after cardiac arrest. The purpose is to provide a resource for optimization of post–cardiac arrest care and to pinpoint the need for research focused on gaps in knowledge that would potentially improve outcomes …

Moderate hypothermia improves imbalances of thromboxane A2 and prostaglandin I2 production after traumatic brain injury in humans.

ObjectiveTo examine the levels of thromboxane B2 (TXB2) and 6-keto prostaglandin F1&agr; (6-keto PGF1&agr;) production in arterial and internal jugular bulb sera in patients with traumatic brain injury (TBI). TBI is associated with arachidonate release and may be associated with an imbalance of vasoconstricting and vasodilating cyclooxygenase metabolites. DesignA prospective, randomized study. SettingThe intensive care unit of a medical university hospital. InterventionsTwenty-six ventilated TBI patents (Glasgow Coma Scale score on admission, ≤8 points) were divided randomly into two groups: a hypothermic group (n = 15), in which the patients were cooled to 32 to 33°C after being giving vecuronium, midazolam, and buprenorphine; and a normothermic group (n = 11), in which the patients’ body temperature was controlled at 36 to 37°C by surface cooling using the same treatment as the hypothermic group. Body temperature control including normothermia was started 3 to 4 hrs after injury. The duration of hypothermia usually lasted for 3 to 4 days, after which the patients were rewarmed at a rate of approximately 1°C per day. Measurements and Main ResultsBlood sampling for TXB2 and 6-keto PGF1&agr; was started shortly after admission in both groups. Arterial TXB2 levels on admission in both groups were elevated remarkably, but not 6-keto PGF1&agr;, thereby causing an imbalance of the prostanoids after injury. In the normothermic group, TXB2 decreased transiently, but this prostanoid increased again 3 days after the injury. In the hypothermic group, such prostanoid differences disappeared shortly after therapy, and the condition was sustained for 10 days. Hypothermia attenuated differences in TXB2 levels between arterial and internal jugular bulb sera, which may reflect reduced cerebral prostanoid production. The Glasgow Outcome Scale score 6 months after the insult in the hypothermic group was significantly higher than that in the normothermic group (p = .04). ConclusionThe current results from a limited number of patients suggest that moderate hypothermia may reduce prostanoid production after TBI, thereby attenuating an imbalance of thromboxane A2 and prostaglandin I2. However, it must be clarified whether the changes in the prostanoid after moderate hypothermia are a secondary effect of other mediator changes or whether they simply represent an epiphenomenon that is mechanistically unrelated to damage in TBI.

Part 4: Advanced life support

The International Liaison Committee on Resuscitation (ILCOR) Advanced Life Support (ALS) Task Force performed detailed systematic reviews based on the recommendations of the Institute of Medicine of the National Academies1 and using the methodological approach proposed by the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) Working Group.2 Questions to be addressed (using the PICO [population, intervention, comparator, outcome] format)3 were prioritized by ALS Task Force members (by voting). Prioritization criteria included awareness of significant new data and new controversies or questions about practice. Questions about topics no longer relevant to contemporary practice or where little new research has occurred were given lower priority. The ALS Task Force prioritized 42 PICO questions for review. With the assistance of information specialists, a detailed search for relevant articles was performed in each of 3 online databases (PubMed, Embase, and the Cochrane Library). By using detailed inclusion and exclusion criteria, articles were screened for further evaluation. The reviewers for each question created a reconciled risk of bias assessment for each of the included studies, using state-of-the-art tools: Cochrane for randomized controlled trials (RCTs),4 Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 for studies of diagnostic accuracy,5 and GRADE for observational studies that inform both therapy and prognosis questions.6 GRADE evidence profile tables7 were then created to facilitate an evaluation of the evidence in support of each of the critical and important outcomes. The quality of the evidence (or confidence in the estimate of the effect) was categorized as high, moderate, low, or very low,8 based on the study methodologies and the 5 core GRADE domains of risk of bias, inconsistency, indirectness, imprecision, and other considerations (including publication bias).9 These evidence profile tables were then used to create a …

ABANDON THE MOUSE RESEARCH SHIP? NOT JUST YET!

ABSTRACT Many preclinical studies in critical care medicine and related disciplines rely on hypothesis-driven research in mice. The underlying premise posits that mice sufficiently emulate numerous pathophysiologic alterations produced by trauma/sepsis and can serve as an experimental platform for answering clinically relevant questions. Recently, the lay press severely criticized the translational relevance of mouse models in critical care medicine. A series of provocative editorials were elicited by a highly publicized research report in the Proceedings of the National Academy of Sciences (PNAS; February 2013), which identified an unrecognized gene expression profile mismatch between human and murine leukocytes following burn/trauma/endotoxemia. Based on their data, the authors concluded that mouse models of trauma/inflammation are unsuitable for studying corresponding human conditions. We believe this conclusion was not justified. In conjunction with resulting negative commentary in the popular press, it can seriously jeopardize future basic research in critical care medicine. We will address some limitations of that PNAS report to provide a framework for discussing its conclusions and attempt to present a balanced summary of strengths/weaknesses of use of mouse models. While many investigators agree that animal research is a central component for improved patient outcomes, it is important to acknowledge known limitations in clinical translation from mouse to man. The scientific community is responsible to discuss valid limitations without overinterpretation. Hopefully, a balanced view of the strengths/weaknesses of using animals for trauma/endotoxemia/critical care research will not result in hasty discount of the clear need for using animals to advance treatment of critically ill patients.

Post-cardiac arrest syndrome: Epidemiology, pathophysiology, treatment, and prognostication: A Scientific Statement from the International Liaison Committee on Resuscitation; the American Heart Association Emergency Cardiovascular Care Committee; the Council on Cardiovascular Surgery and Anesthesia; the Council on Cardiopulmonary, Perioperative, and Critical Care; the Council on Clinical Cardiology; the Council on Stroke (Part II)

AIM OF THE REVIEW To review the epidemiology, pathophysiology, treatment and prognostication in relation to the post-cardiac arrest syndrome. METHODS Relevant articles were identified using PubMed, EMBASE and an American Heart Association EndNote master resuscitation reference library, supplemented by hand searches of key papers. Writing groups comprising international experts were assigned to each section. Drafts of the document were circulated to all authors for comment and amendment. RESULTS The 4 key components of post-cardiac arrest syndrome were identified as (1) post-cardiac arrest brain injury, (2) post-cardiac arrest myocardial dysfunction, (3) systemic ischaemia/reperfusion response, and (4) persistent precipitating pathology. CONCLUSIONS A growing body of knowledge suggests that the individual components of the postcardiac arrest syndrome are potentially treatable.

Effects of dexmedetomidine, an α2-adrenoceptor agonist, on renal sympathetic nerve activity, blood pressure, heart rate and central venous pressure in urethane-anesthetized rabbits

To clarify the role of the neural blood pressure control system in hemodynamic changes after dexmedetomidine (DXM) administration, we examined the effects of an intravenous injection of DXM (10 microg/kg) on heart rate (HR), mean blood pressure (MBP), central venous pressure (CVP) and renal sympathetic nerve activity (RNA) in urethane-anesthetized rabbits using direct recordings of RNA. The animals were divided into four groups: animals with an intact neuraxis (intact group; n = 12), cervical vagotomized animals (vagotomy group; n = 5), sino-aortic denervated animals (SAD group; n = 5), and animals with SAD plus vagotomy (SADV group; n = 5). An initial HR decrease, which occurred in the intact group, did not occur in the other three groups, suggesting the mediation of the baroreflex. A subsequent HR decrease occurred in the three groups other than the vagotomy group, in which RNA recovered earlier than in the other groups. RNA in the intact group, associated with transient hypertension, was suppressed shortly after the injection. Such an RNA drop was not eliminated even in the SADV group. Despite recovery of RNA, hypotension lasted until the end of experiment in the intact and vagotomy groups. However, sustained depression of RNA associated with lasting hypotension was found in the SAD and SADV groups. CVP in all groups did not change significantly after the injection. These results suggest the following: (1) Initial bradycardia after DXM is mediated via the baroreflex. Subsequently, HR reductions may result mainly from central sympathetic depression. (2) An initial reduction in RNA is not mediated via the baroreceptor reflex, unlike HR responses, but by central sympatho-inhibitory effects. (3) Long-lasting hypotension after DXM is likely to be attributable to its peripheral vascular effects including the stimulation of pre-synaptic alpha2-adrenoceptors, rather than to central sympathetic depression.

Reversible hypophosphatemia during moderate hypothermia therapy for brain-injured patients.

ObjectiveBecause plasma potassium, which may similarly change as plasma phosphate (P), decreases during moderate hypothermia, plasma P, a requisite electrolyte for the cell function, may alter during therapeutic moderate hypothermia for brain-injured patients. In 22 such patients who underwent moderate hypothermia or were treated with normothermia, plasma concentrations of P and other chemicals were examined. DesignA prospective study. SettingThe intensive care unit of a medical university hospital. Patients and Interventions In 15 consecutive patients with brain injury who underwent moderate hypothermia and 7 serial patients treated with normothermia, plasma concentrations of P, potassium, glucose, blood gas tension and pH, daily urine volume, and water balance were examined. Inequality in the numbers of patients of the two groups was the result of patient exclusion because of multiple trauma, aluminum hydroxide administrations, hyperventilation, preexisting diabetes mellitus, or administration of insulin. Daily blood sampling was done around 8 am. Inclusion criteria included a Glasgow Coma Scale score assessment ≤8 at admission to the emergency room and evidence of injury on computerized tomography scanning of the brain. Measurement and Main Results Hypothermia decreased plasma P levels as compared with those of normothermia within 4 days after the injury (this period was similar to the duration of the hypothermic phase in the hypothermia group). Such reduction related to changes in blood glucose levels, but not to any in the urine volume, or water balance. The P decrease occurred during the hypothermic phase, but subsequently there was a recovery of P after the rewarming phase. The changes in plasma potassium levels were similar to those in plasma P concentrations during the course. Such changes were accompanied by a recovery of decreased heart rate that occurred during the hypothermic phase. ConclusionThe results suggest that moderate hypothermia of 32–33°C decreases plasma P levels. Further studies are required to examine whether P repletion may overcome certain hemodynamic derangements during moderate hypothermia in brain-injured patients.

The Japanese guidelines for the management of sepsis

SummaryThis is a guideline for the management of sepsis, developed by the Sepsis Registry Committee of The Japanese Society of Intensive Care Medicine (JSICM) launched in March 2007. This guideline was developed on the basis of evidence-based medicine and focuses on unique treatments in Japan that have not been included in the Surviving Sepsis Campaign guidelines (SSCG), as well as treatments that are viewed differently in Japan and in Western countries. Although the methods in this guideline conform to the 2008 SSCG, the Japanese literature and the results of the Sepsis Registry Survey, which was performed twice by the Sepsis Registry Committee in intensive care units (ICUs) registered with JSICM, are also referred. This is the first and original guideline for sepsis in Japan and is expected to be properly used in daily clinical practice.This article is translated from Japanese, originally published as “The Japanese Guidelines for the Management of Sepsis” in the Journal of the Japanese Society of Intensive Care Medicine (J Jpn Soc Intensive Care Med), 2013; 20:124–73. The original work is at http://dx.doi.org/10.3918/jsicm.20.124.

Activated cytokine production in patients with accidental hypothermia

We have demonstrated recently that therapeutic moderate hypothermia of 32-33 degrees C, induced by surface cooling under the administration of narcotics, sedatives and muscle relaxant, suppresses cytokine production after traumatic brain injury. We present here the first documented case report of augmented cytokine production in two accidental hypothermia patients, unconscious 84- (acute immersion) and 87- (non-immersion) year-old women, whose rectal temperatures were below 28 degrees C. The victims were artificially ventilated after sedation with midazolam and buprenorphine in accordance with our protocol. Rewarming at the rate of approximately 1 degrees C/h was done by blowing forced-air with appropriate fluid resuscitation. Plasma interleukin(IL)-6 and/or IL-8 levels were measured using ELISA in the patients. In both patients, plasma IL-6 levels on admission were already elevated and the cytokine levels further increased during and after the rewarming period. In the patient with the poorer prognosis, the plasma IL-8 level on admission was not elevated remarkably but after rewarming the level rose significantly. Augmented IL-6 production in accidental hypothermia was sustained for 6 days in the patient with the poorer prognosis but not in the subject with good recovery, who was treated with anti-thrombin III in the early phase. Since the mechanisms for developing accidental hypothermia were different, simple comparisons between the two cases should be limited. But, these findings may suggest a need for testing a hypothesis whether cytokine modulation could be a therapeutic approach worthy of consideration. The results presented here also suggest that in hypothermia, changes in cytokine release may vary depending on procedures such as the anesthetic drugs used, the duration of the therapy, or the rate of rewarming from hypothermia.

Ulinastatin, a human trypsin inhibitor, inhibits endotoxin-induced thromboxane B2 production in human monocytes

OBJECTIVES Ulinastatin has an inhibitory effect on certain cytokines produced from lipopolysaccharide (endotoxin)-stimulated human monocytes. However, the effects of ulinastatin on arachidonic acid metabolism in monocytes have not been determined. This study examined the effects of ulinastatin on the arachidonic acid metabolite, thromboxane B2, in response to endotoxin-, phorbol 12-myristate 13-acetate-, or arachidonic acid-stimulated human peripheral blood monocytes. DESIGN Controlled, human laboratory investigation of monocyte function in vitro. SETTING Research facility of a health science university. SUBJECTS Five normal volunteers. INTERVENTIONS Mononuclear cells were separated from blood using Histopaque. Monocytes were stimulated with endotoxin (0.1 to 10 micrograms/mL) or other stimulatory agents, which were added simultaneously with or without ulinastatin (25 to 1000 U/mL). None of the compounds in this study altered the cell viability of adherent cellular protein content. Ulinastatin alone did not affect basal thromboxane B2. MEASUREMENTS AND MAIN RESULTS Endotoxin induced dose-dependent increases in thromboxane B2 production by the monocytes. Ulinastatin (100 U/mL) maximally decreased endotoxin (1.0 microgram/mL)-stimulated thromboxane B2 production, which was not further suppressed with higher ulinastatin concentrations. Increases in thromboxane B2, stimulated by phorbol myristic acid (10 nM) or arachidonic acid (16 microM), were also suppressed by ulinastatin at 100 to 1000 U/mL. CONCLUSIONS These results indicate that ulinastatin may nonspecifically but moderately down-regulate stimulated arachidonic acid metabolism in human monocytes. Therefore, the present results warrant further clinical studies to examine the beneficial effects of ulinastatin in the treatment of patients with sepsis syndrome.