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Background Septic shock is associated with decreased vasopressor responsiveness. Experimental data suggest that central alpha2-agonists like dexmedetomidine (DEX) increase vasopressor responsiveness and reduce catecholamine requirements in septic shock. However, DEX may also cause hypotension and bradycardia. Thus, it remains unclear whether DEX is hemodynamically safe or helpful in this setting. Methods In this post hoc subgroup analysis of the Sedation Practice in Intensive Care Evaluation (SPICE III) trial, an international randomized trial comparing early sedation with dexmedetomidine to usual care in critically patients receiving mechanical ventilation, we studied patients with septic shock admitted to two tertiary ICUs in Australia and Switzerland. The primary outcome was vasopressor requirements in the first 48 h after randomization, expressed as noradrenaline equivalent dose (NEq [μg/kg/min] = noradrenaline + adrenaline + vasopressin/0.4). Results Between November 2013 and February 2018, 417 patients were recruited into the SPICE III trial at both sites. Eighty-three patients with septic shock were included in this subgroup analysis. Of these, 44 (53%) received DEX and 39 (47%) usual care. Vasopressor requirements in the first 48 h were similar between the two groups. Median NEq dose was 0.03 [0.01, 0.07] μg/kg/min in the DEX group and 0.04 [0.01, 0.16] μg/kg/min in the usual care group ( p  = 0.17). However, patients in the DEX group had a lower NEq/MAP ratio, indicating lower vasopressor requirements to maintain the target MAP. Moreover, on adjusted multivariable analysis, higher dexmedetomidine dose was associated with a lower NEq/MAP ratio. Conclusions In critically ill patients with septic shock, patients in the DEX group received similar vasopressor doses in the first 48 h compared to the usual care group. On multivariable adjusted analysis, dexmedetomidine appeared to be associated with lower vasopressor requirements to maintain the target MAP. Trial registration The SPICE III trial was registered at ClinicalTrials.gov ( NCT01728558 ).

Oxygen (O2) is the most common therapy in mechanically ventilated patients, but targets and dose are poorly understood. We aimed to describe current O2 administration and titration in such patients in an academic intensive care unit. In consecutive ventilated (>48 hours) patients we prospectively obtained fraction of inspired O2 (Fio2), pulse oximetry O2 saturation (Spo2) and arterial O2 tension (Pao2) every 6 hours. We calculated the amount of excess O2 delivery and the intensivists’ response to hyperoxemia (Spo2 >98%). During 358 mechanical ventilation days in 51 critically ill patients, median calculated excess O2 delivery was 3472 L per patient. Patients spent most of their time with their Spo2 >98% (59% [29-83]) and Pao2 between 80 and 120 mm Hg (59% [38–72]). In addition, 50% of all observations showed hyperoxemia and 4% severe hyperoxemia (Pao2 >202.5 mm Hg). Moreover, 71% of the calculated total excess 263,841 L of O2 was delivered when the Fio2 was 0.3 to 0.5. When hyperoxemia occurred with an Fio2 between 0.3 and 0.4, for 88% of episodes, no Fio2 adjustments were made. Excess O2 delivery and liberal O2 therapy were common in mechanically ventilated patients. Current O2 therapy practice may be suboptimal and further investigations are warranted.

We assessed the incidence, characteristics, outcomes and associations of small, short-term point-of-care creatinine increases in critically ill patients. We prospectively identified the first episode of small (>1 μmol/L/h) short-term (3–4 h) point-of-care creatinine increase between two sequential arterial blood gas measurements. We followed patients for the subsequent development of Kidney Disease: Improving Global Outcomes (KDIGO) defined acute kidney injury (AKI) in the intensive care unit (ICU). Of 387 patients, 279 (72.1%) developed an episode of small short-term point-of-care creatinine increase and 212 (54.8%) developed AKI. Such episodes occurred at a median of 5 (IQR 2–10) hours after ICU admission, while AKI occurred at a median of 15 (IQR 9–28) hours after admission. Patients with such episodes were more likely to be mechanically ventilated on admission (83.9 vs. 44.4%; p < .001) and had higher hospital mortality (10.9 vs. 3.7%, p = .03). Creatinine increase episodes had a sensitivity of 86% (95% CI 78–95) and specificity of 31% (95% CI 26–36) for subsequent AKI stages 2 and 3 in 24 h. Small, short-term point-of-care creatinine increase episodes are common. They are associated with illness severity, occur early, precede AKI by 10 h and are sensitive rather than specific markers of AKI. •Small short-term creatinine increases are common in ICU.•They are easily observed with point-of-care testing.•They occur a median of 10 h before AKI in ICU.•They have high sensitivity for subsequent AKI in ICU.•Refining their duration, magnitude and adding oliguria may improve AKI prediction.

Background Different molecular forms of urinary neutrophil gelatinase-associated lipocalin (NGAL) have recently been discovered. We aimed to explore the nature, source and discriminatory value of urinary NGAL in intensive care unit (ICU) patients. Methods We simultaneously measured plasma NGAL (pNGAL), urinary NGAL (uNGAL), and estimated monomeric and homodimeric uNGAL contribution using Western blotting-validated enzyme-linked immunosorbent assays [uNGAL E1 and uNGAL E2 ] and their calculated ratio in 102 patients with the systemic inflammatory response syndrome and oliguria, and/or a creatinine rise of >25 μmol/L. Measurements and main results Bland–Altman analysis demonstrated that, despite correlating well ( r  = 0.988), uNGAL and uNGAL E1 were clinically distinct, lacking both accuracy and precision (bias: 266.23; 95 % CI 82.03–450.44 ng/mg creatinine; limits of agreement: −1,573.86 to 2,106.32 ng/mg creatinine). At best, urinary forms of NGAL are fair (area under the receiver operating characteristic [AUROC] ≤0.799) predictors of renal or patient outcome; most perform significantly worse. The 44 patients with a primarily monomeric source of uNGAL had higher pNGAL (118.5 ng/ml vs. 72.5 ng/ml; p  < 0.001), remaining significant following Bonferroni correction. Conclusions uNGAL is not a useful predictor of outcome in this ICU population. uNGAL patterns may predict distinct clinical phenotypes. The nature and source of uNGAL are complex and challenge the utility of NGAL as a uniform biomarker.

Introduction In this study, we aimed to examine the association between paracetamol administration in the intensive care unit (ICU) and mortality in critically ill patients. Methods We conducted a multicenter retrospective observational study in four ICUs. We obtained information on paracetamol use, body temperature, demographic, clinical and outcome data from each hospital’s clinical information system and admissions and discharges database. We performed statistical analysis to assess the association between paracetamol administration and hospital mortality. Results We studied 15,818 patients with 691,348 temperature measurements at 4 ICUs. Of these patients, 10,046 (64%) received at least 1 g of paracetamol. Patients who received paracetamol had lower in-hospital mortality (10% vs. 20%, P <0.001), and survivors were more likely to have received paracetamol (66% vs. 46%; P <0.001). However, patients treated with paracetamol were also more likely to be admitted to the ICU after surgery (70% vs. 51%; P <0.001) and/or after elective surgery (55% vs. 37%; P <0.001). In multivariate logistic regression analysis including a propensity score for paracetamol treatment, we found a significant and independent association between the use of paracetamol and reduced in-hospital mortality (adjusted odds ratio =0.60 (95% confidence interval (CI), 0.53 to 0.68), P <0.001). Cox proportional hazards analysis showed that patients who received paracetamol also had a significantly longer time to death (adjusted hazard ratio =0.51 (95% CI, 0.46 to 0.56), P <0.001). The association between paracetamol and decreased mortality and/or time to death was broadly consistent across surgical and medical patients. It remained present after adjusting for paracetamol administration as a time-dependent variable. However, when such time-dependent analysis was performed, the association of paracetamol with outcome lost statistical significance in the presence of fever and suspected infection and in patients in the lower tertiles of Acute Physiology and Chronic Health Evaluation II scores. Conclusions Paracetamol administration is common in the ICU and appears to be independently associated with reduced in-hospital mortality and time to death after adjustment for multiple potential confounders and propensity score. This association, however, was modified by the presence of fever, suspected infection and lesser illness severity and may represent the effect of indication bias.

* Mypinder S. Sekhon, * Philip N. Ainslie and * Donald E. Griesdale To the editor: We acknowledge Eastwood et al. for their insightful comments to our narrative review entitled “Clinical pathophysiology of hypoxic ischemic brain injury after cardiac arrest: a “two hit” model”. They identify the importance of preventing secondary cerebral injury after cardiac arrest and the crucial role of arterial carbon dioxide induced modulation of cerebral blood flow and oxygen delivery. This effect occurs through the modulation of extracellular pH and is rendered less effective over time. Clearly, episodes of hypocapnia are associated with adverse outcome, stemming from cerebral vasoconstriction, reduced cerebral blood flow and oxygen delivery [1]. Conversely, in a large multicenter observational study, Schneider et. al demonstrated that patients with hypercapnia (PaCO2 > 45 mmHg on one blood gas in the first 24 hours) had higher rates of discharge home among survivors (OR 1.16, 95%CI: 1.03 - 1.32) [2]. Biologically, the phenomenon of “no reflow”, characterized by cerebral vasoconstriction, microvascular thrombi and subsequent cerebral oligemia early after resuscitation is well established [1]. It follows that mild hypercapnia to induce cerebral vasodilation may augment blood flow during this critical period and mitigate secondary injury. We commend Eastwood et al. for undertaking a foundational randomized control trial to investigate the role of mild hypercapnia (PaCO2 50-55 mmHg) after cardiac arrest compared with normocapnia (PaCO2 35-45 mmHg) (TAME trial; Clinicaltrials.gov NCT03114033) and eagerly await the results. This trial will no doubt provide important insights into the management of post-resuscitative care of cardiac arrest patients. However, it should be noted that there is likely significant within-patient heterogeneity with respect to individual pathophysiology of hypoxic ischemic brain injury [1]. Randomized control trials of single physiological interventions in critical care may fail to account for these nuances. For example, two recent randomized trials of single physiological interventions aimed at mitigating secondary injury after cardiac arrest and traumatic brain injury, specifically targeted temperature management and transfusion thresholds, respectively, were negative [4, 5]. Hence our belief is that we should shift the paradigm to delineating the underlying individualized pathophysiology and establish personalized physiologic resuscitation targets following cardiac arrest. Our research group has recently demonstrated the ability to monitor cerebral autoregulation in real time after cardiac arrest to identify optimal and individualized mean arterial pressure [6]. We acknowledge that it remains unknown if individualized perfusion targets are associated with improved outcome after cardiac arrest. However, this strategy represents an intriguing shift towards personalized physiological resuscitation in the management of this catastrophic and complex disease.

The purpose of the study is to assess the effect of a conservative oxygen therapy (COT) (target SpO2 of 90%-92%) on radiological atelectasis and mechanical ventilation modes. We conducted a secondary analysis of 105 intensive care unit patients from a pilot before-and-after study. The primary outcomes of this study were changes in atelectasis score (AS) of 555 chest radiographs assessed by radiologists blinded to treatment allocation and time to weaning from mandatory ventilation and first spontaneous ventilation trial (SVT). There was a significant difference in overall AS between groups, and COT was associated with lower time-weighted average AS. In addition, in COT patients, change from mandatory to spontaneous ventilation or time to first SVT was shortened. After adjustment for baseline characteristics and interactions between oxygen therapy, radiological atelectasis, and mechanical ventilation management, patients in the COT group had significantly lower “best” AS (adjusted odds ratio, 0.28 [95% confidence interval {CI}, 0.12-0.66]; P = .003) and greater improvement in AS in the first 7 days (adjusted odds ratio, 0.42 [95% CI, 0.17-0.99]; P = .049). Moreover, COT was associated with significantly earlier successful weaning from a mandatory ventilation mode (adjusted hazard ratio, 2.96 [95% CI, 1.73-5.04]; P < .001) and with shorter time to first SVT (adjusted hazard ratio, 1.77 [95% CI, 1.13-2.78]; P = .013). In mechanically ventilated intensive care unit patients, COT might be associated with decreased radiological evidence of atelectasis, earlier weaning from mandatory ventilation modes, and earlier first trial of spontaneous ventilation.

There is controversy about the true coagulation state of acutely ill patients with chronic liver disease (CLD) due to simultaneous pro- and anticoagulant factor deficits and limitations of conventional coagulation tests (CCTs). Thromboelastography (TEG) may provide more physiologically relevant insights. In acutely ill patients with severe (Child-Pugh C) CLD, we conducted a prospective observational study of daily coagulation assessment with both CCTs and TEG. We studied 34 patients with CLD on a total of 109 occasions (median of 3 samples per patient), comparing findings with 157 healthy controls. Conventional coagulation tests and TEG both demonstrated clear hypocoagulability. Thromboelastography-confirmed delayed clot formation was demonstrated by longer reaction time (1.1 minutes vs 0.6 minutes on rapid TEG; P<.01), longer kinetic time (2.9 minutes vs 1.3; P<.01), more acute α angle (65° vs 72.2°; P<.01), and longer activated clotting time (157 seconds vs 105 seconds; P<.01). Patients with CLD demonstrated weaker thrombus strength (maximum amplitude, 43.3 mm vs 61.8 mm; P<.01) and reduced clot lysis (0% vs 1% on rapid TEG; P<.01). In acutely ill patients with CLD, TEG demonstrates delayed clot formation and weaker thrombus strength despite decreased clot lysis. This challenges the notion that such patients experience a balanced coagulation state, highlighting the complexity of their coagulopathies.

Modern near-infrared spectroscopy technology is increasingly adopted to measure cerebral tissue oxygen saturation. However, the normal range of cerebral tissue oxygen saturation in adults with such technology is unknown. We sought to measure cerebral tissue oxygen saturation in healthy volunteers using the novel O3 Regional Oximetry device (Masimo Corporation, Irvine, CA, USA) and assess its relationship with key physical and haemodynamic characteristics. For >=5 minutes, we continuously recorded cerebral tissue oxygen saturation, pulse oximetry, cardiac index and mean arterial pressure. We assessed for differences in cerebral tissue oxygen saturation between hemispheres, sex, skin type, comorbidity or smoking status, and for associations between cerebral tissue oxygen saturation and age, height, weight, SpO2 and haemodynamic parameters. We recorded >32,000 observations in 98 volunteers aged 22 to 60 years, including 41 (42%) males. One-fifth had one or more co morbidities (n1/422, 22.5%), one-tenth were either current or former-smokers (n1/413, 13%), and most had a Fitzpatrick skin type of 3 or lower (n1/484, 86%). The mean combined average cerebral tissue oxygen saturation was 67.6% (95% confidence interval 66.8%-68.6%). We found statistically significant differences in cerebral tissue oxygen saturation according to hemisphere and an association between cerebral tissue oxygen saturation and mean arterial pressure and cardiac index. The combined average cerebral tissue oxygen saturation in 98 healthy volunteers was 67.6% with a narrow confidence interval and no combined average cerebral tissue oxygen saturation was below 56%.We also observed statistically significant yet quantitatively small cerebral tissue oxygen saturation differences between hemispheres, and an association between cerebral tissue oxygen saturation and mean arterial pressure and cardiac index.

Objective: Thromboelastography (TEG) may provide rapid and clinically important coagulation information in acutely ill patients with chronic liver disease (CLD). Our objective was to describe the relationship between TEG and conventional coagulation tests (CCTs), which has not been previously explored in this population. Methods: In acutely ill patients with severe CLD (Child-Pugh score > 9, category C), we conducted a prospective observational study investigating coagulation assessment as measured by both CCTs and TEG. We used quantile regression to explore 30 associations between TEG parameters and corresponding CCTs. We compared TEG and CCT measures of coagulation initiation, clot formation, clot strength, and fibrinolysis. Results: We studied 34 patients on a total of 109 occasions. We observed inconsistent associations between TEG and CCT measures of coagulation initiation: TEG (citrated kaolin [CK] assay) standard reaction time and international normalized ratio: R 2 = 0.117 (P = .044). Conversely, there were strong and consistent associations between tests of clot formation: TEG (CK) kinetics time and fibrinogen: R 2 = 0.202 (P < .0001) and TEG (CK) α angle and fibrinogen 0.263 (P < .0001). We also observed strong associations between tests of clot strength, specifically TEG MA and conventional fibrinogen levels, across all TEG assays: MA (CK) and fibrinogen: R 2 = 0.485 (P < .0001). There were no associations between TEG and D-dimer levels. Conclusions: In acutely ill patients with CLD, there are strong and consistent associations between TEG measures of clot formation and clot strength and conventional fibrinogen levels. There are weak and/or inconsistent associations between TEG and all other conventional measures of coagulation.