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. 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 MEASURESThe 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. RESULTSOf 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.

BackgroundDexmedetomidine 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.MethodsThe 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.ResultsThe 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).ConclusionA sedation strategy with dexmedetomidine is associated with improved renal function and decrease mortality rates among patients with severe sepsis.Trial registrationThis trial was registered on ClinicalTrials.gov (NCT01760967) on January 1, 2013.

Hemorrhage is the most important contributing factor of acute-phase mortality in trauma patients. Previously, traumatologists and investigators identified iatrogenic and resuscitation-associated causes of coagulopathic bleeding after traumatic injury, including hypothermia, metabolic acidosis, and dilutional coagulopathy that were recognized as primary drivers of bleeding after trauma. However, the last 10 years has seen a widespread paradigm shift in the resuscitation of critically injured patients, and there has been a dramatic evolution in our understanding of trauma-induced coagulopathy. Although there is no consensus regarding a definition or an approach to the classification and naming of trauma-associated coagulation impairment, trauma itself and/or traumatic shockinduced endogenous coagulopathy are both referred to as acute traumatic coagulopathy (ATC), and multifactorial trauma-associated coagulation impairment, including ATC and resuscitation-associated coagulopathy is recognized as trauma-induced coagulopathy. Understanding the pathophysiology of trauma-induced coagulopathy is vitally important, especially with respect to the critical issue of establishing therapeutic strategies for the management of patients with severe trauma.

Early aggressive hemodynamic resuscitation using elevated plasma lactate as a marker is an essential component of managing critically ill patients. Therefore, measurement of blood lactate is recommended to stratify patients based on the need for fluid resuscitation and the risks of multiple organ dysfunction syndrome and death. Hyperlactatemia is common among critically ill patients, and lactate levels and their trend may be reliable markers of illness severity and mortality. Although hyperlactatemia has been widely recognized as a marker of tissue hypoxia/hypoperfusion, it can also result from increased or accelerated aerobic glycolysis during the stress response. Additionally, lactate may represent an important energy source for patients in critical condition. Despite its inherent complexity, the current simplified view of hyperlactatemia is that it reflects the presence of global tissue hypoxia/hypoperfusion with anaerobic glycolysis. This review of hyperlactatemia in critically ill patients focuses on its pathophysiological aspects and recent clinical approaches. Hyperlactatemia in critically ill patients must be considered to be related to tissue hypoxia/hypoperfusion. Therefore, appropriate hemodynamic resuscitation is required to correct the pathological condition immediately. However, hyperlactatemia can also result from aerobic glycolysis, unrelated to tissue dysoxia, which is unlikely to respond to increases in systemic oxygen delivery. Because hyperlactatemia may be simultaneously related to, and unrelated to, tissue hypoxia, physicians should recognize that resuscitation to normalize plasma lactate levels could be over-resuscitation and may worsen the physiological status. Lactate is a reliable indicator of sepsis severity and a marker of resuscitation; however, it is an unreliable marker of tissue hypoxia/hypoperfusion.

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.

Paroxysmal sympathetic hyperactivity (PSH) is a distinct syndrome of episodic sympathetic hyperactivities following severe acquired brain injury, characterized by paroxysmal transient fever, tachycardia, hypertension, tachypnea, excessive diaphoresis and specific posturing. PSH remains to be an underrecognized condition with a diagnostic pitfall especially in the intensive care unit (ICU) settings due to the high prevalence of concomitant diseases that mimic PSH. A consensus set of diagnostic criteria named PSH-Assessment Measure (PSH-AM) has been developed recently, which is consisted of two components: a diagnosis likelihood tool derived from clinical characteristics of PSH, and a clinical feature scale assigned to the severity of each sympathetic hyperactivity. We herein present a case series of patients with PSH who were diagnosed and followed by using PSH-AM in our tertiary institutional medical and surgical ICU between April 2015 and March 2017 in order to evaluate the clinical efficacy of PSH-AM. Among 394 survivors of 521 patients admitted with acquired brain injury defined as acute brain injury at all levels of severity regardless of the presence of altered consciousness, including traumatic brain injury, stroke, infectious disease, and encephalopathy, 6 patients (1.5%) were diagnosed as PSH by using PSH-AM. PSH-AM served as a useful scoring system for early objective diagnosis, assessment of severity, and serial evaluation of treatment efficacy in the management of PSH in the ICU settings. In conclusion, critical care clinicians should consider the possibility of PSH and can use PSH-AM as a useful diagnostic and guiding tool in the management of PSH.

Lactate clearance is useful to guide initial resuscitation of patients with septic shock. We conducted this study to evaluate whether dexmedetomidine increases lactate clearance in patients with septic shock. This was a randomized controlled trial that involved a post hoc subgroup analysis. Adult patients with septic shock under ventilation were randomized to receive sedation strategy with or without dexmedetomidine (60 in the dexmedetomidine and 51 in the nondexmedetomidine groups). The primary outcome was the lactate clearance at 6 h, defined as the percent decrease in lactate from randomization to 6 h after. The median Acute Physiology and Chronic Health Evaluation II score was 25 (interquartile range 19-31). The median serum lactate value at randomization was lower in the dexmedetomidine group than in the nondexmedetomidine group (4.0 mmol/L vs. 4.8 mmol/L; P = 0.053). The lactate clearance at 6 h was higher in the dexmedetomidine group, although this was not statistically significant (23.3 ± 29.8 vs. 11.1 ± 54.4, mean difference 12.2, 95% confidence interval (CI), -4.4 to 28.8). After adjusting for the lactate level at randomization, lactate clearance at 6 h was significantly higher in the dexmedetomidine group (adjusted mean difference 18.5, 95% CI, 2.2-34.9). There was no statistically significant difference in the 28-day mortality between the dexmedetomidine and the nondexmedetomidine groups (13 [22%] vs. 18 [35%] patients, P = 0.11). In conclusion, among mechanically ventilated patients with septic shock, sedation with dexmedetomidine resulted in increased lactate clearance compared with sedation without dexmedetomidine.

Circulating endothelial microparticles (EMPs) are considered to be markers of endothelial injury, and lung microvascular endothelial cells express higher levels of angiotensin-converting enzyme (ACE). The aim of this study is to examine whether the number of ACE+ microvascular EMPs could be a prognostic marker for the development of acute respiratory distress syndrome (ARDS) in septic patients.The numbers of EMPs and ACE+ EMPs in the culture supernatant from human microvascular endothelial cells, as well as in the blood of mouse lung injury models and septic patients (n=82), were examined using flow cytometry.ACE+ EMPs in the culture supernatant from pulmonary microvascular endothelial cells increased after exposure to an inflammatory stimulus. In the mouse lung injury models, the circulating ACE+ EMPs and ACE+ EMP/EMP ratio were higher than in the controls (p<0.001). The ACE+ EMP/EMP ratio was correlated with the wet/dry lung ratio (rs=0.775, p<0.001). The circulating ACE+ EMPs and ACE+ EMP/EMP ratio on admission were significantly increased in septic patients who developed ARDS compared with septic patients who did not (p<0.001).Therefore, circulating ACE+ EMPs may be a prognostic marker for the development of ARDS in the septic patients.