Mild Hypercapnia or Normocapnia after Out-of-Hospital Cardiac Arrest.

BACKGROUND: Guidelines recommend normocapnia for adults with coma who are resuscitated after out-of-hospital cardiac arrest. However, mild hypercapnia increases cerebral blood flow and may improve neurologic outcomes. METHODS: We randomly assigned adults with coma who had been resuscitated after out-of-hospital cardiac arrest of presumed cardiac or unknown cause and admitted to the intensive care unit (ICU) in a 1:1 ratio to either 24 hours of mild hypercapnia (target partial pressure of arterial carbon dioxide [Paco2], 50 to 55 mm Hg) or normocapnia (target Paco2, 35 to 45 mm Hg). The primary outcome was a favorable neurologic outcome, defined as a score of 5 (indicating lower moderate disability) or higher, as assessed with the use of the Glasgow Outcome Scale-Extended (range, 1 [death] to 8, with higher scores indicating better neurologic outcome) at 6 months. Secondary outcomes included death within 6 months. RESULTS: A total of 1700 patients from 63 ICUs in 17 countries were recruited, with 847 patients assigned to targeted mild hypercapnia and 853 to targeted normocapnia. A favorable neurologic outcome at 6 months occurred in 332 of 764 patients (43.5%) in the mild hypercapnia group and in 350 of 784 (44.6%) in the normocapnia group (relative risk, 0.98; 95% confidence interval [CI], 0.87 to 1.11; P = 0.76). Death within 6 months after randomization occurred in 393 of 816 patients (48.2%) in the mild hypercapnia group and in 382 of 832 (45.9%) in the normocapnia group (relative risk, 1.05; 95% CI, 0.94 to 1.16). The incidence of adverse events did not differ significantly between groups. CONCLUSIONS: In patients with coma who were resuscitated after out-of-hospital cardiac arrest, targeted mild hypercapnia did not lead to better neurologic outcomes at 6 months than targeted normocapnia. (Funded by the National Health and Medical Research Council of Australia and others; TAME ClinicalTrials.gov number, NCT03114033.).

Evaluation of ferritin and the ferritin index as prognostic biomarkers in septic shock.

BACKGROUND: Ferritin, an acute phase reactant, and the ferritin index (FI = observed ferritin level/upper limit of normal level for age and sex) may be prognostic biomarkers in septic shock and cardiac surgery patients. OBJECTIVE: The purpose of this exploratory study is to assess the outcome associations of ferritin and FI levels in septic shock compared to post-cardiac surgery patients. DESIGN: This was a prospective, double-centre, observational study. SETTING: The study setting involved two adult intensive care units (ICUs) in Victoria, Australia. PARTICIPANTS: Sixty-one septic shock and 30 post-cardiac surgery patients participated in this study. MAIN OUTCOME MEASURES: We measured ferritin and FI on ICU admission (T1) and 24 h later (T2) to assess its correlation with mortality, illness severity, and hospital length of stay (LOS). RESULTS: The baseline characteristics of patients in the septic shock group and cardiac surgery group were similar apart from illness severity scores (APACHE III and modified SOFA score). Septic shock patients had more physiological derangements as well as greater use and higher doses of norepinephrine at both T1 and T2. Septic shock patients had significantly higher median ferritin levels (372 µg/L versus 198 µg/L; p < 0.001 at T1, 457 µg/L versus 264 µg/L; p = 0.001 at T2) than post-cardiac surgery patients. Ferritin levels, however, did not have a linear correlation with illness severity or hospital mortality. Instead, there was an association between high ferritin levels at T2 and longer ICU (p = 0.017) and hospital LOS (p = 0.013). Females with septic shock had significantly higher FI (p < 0.001 at T1, p = 0.004 at T2) than males. CONCLUSION: In septic shock patients, ferritin levels and FI were twice the level compared to post-cardiac surgery patients. Both had no association with mortality, but levels above the median at 24 h were associated with longer ICU and hospital LOS.

Accuracy of non-invasive body temperature measurement methods in critically ill patients: a prospective, bicentric, observational study.

Objective: The accuracy of different non-invasive body temperature measurement methods in intensive care unit (ICU) patients is uncertain. We aimed to study the accuracy of three commonly used methods. Design: Prospective observational study. Setting: ICUs of two tertiary Australian hospitals. Participants: Critically ill patients admitted to the ICU. Interventions: Invasive (intravascular and intra-urinary bladder catheter) and non-invasive (axillary chemical dot, tympanic infrared, and temporal scanner) body temperature measurements were taken at study inclusion and every 4 hours for the following 72 hours. Main outcome measures: Accuracy of non-invasive body temperature measurement methods was assessed by the Bland-Altman approach, accounting for repeated measurements and significant explanatory variables that were identified by regression analysis. Clinical adequacy was set at limits of agreement (LoA) of 1°C compared with core temperature. Results: We studied 50 consecutive critically ill patients who were mainly admitted to the ICU after cardiac surgery. From over 375 observations, invasive core temperature (mostly pulmonary artery catheter) ranged from 33.9°C to 39°C. On average, the LoA between invasive and non-invasive measurements methods were about 3°C. The temporal scanner showed the worst performance in estimating core temperature (bias, 0.66°C; LoA, -1.23°C, +2.55°C), followed by tympanic infrared (bias, 0.44°C; LoA, -1.73°C, +2.61°C) and axillary chemical dot methods (bias, 0.32°C; LoA, -1.64°C, +2.28°C). No methods achieved clinical adequacy even accounting for significant explanatory variables. Conclusions: The axillary chemical dot, tympanic infrared and temporal scanner methods are inaccurate measures of core temperature in ICU patients. These non-invasive methods appeared unreliable for use in ICU patients.

Cytokine and lipid metabolome effects of low-dose acetylsalicylic acid in critically ill patients with systemic inflammation: a pilot, feasibility, multicentre, randomised, placebo-controlled trial.

OBJECTIVE: The systemic inflammatory response syndrome (SIRS) is a dysregulated response that contributes to critical illness. Adjunctive acetylsalicylic acid (ASA) treatment may offer beneficial effects by increasing the synthesis of specialised proresolving mediators (a subset of polyunsaturated fatty acid-derived lipid mediators). DESIGN: Pilot, feasibility, multicentre, double-blind, randomised, placebo-controlled trial. SETTING: Four interdisciplinary intensive care units (ICUs) in Australia. PARTICIPANTS: Critically ill patients with SIRS. INTERVENTIONS: ASA 100 mg 12-hourly or placebo, administered within 24 hours of ICU admission and continued until ICU day 7, discharge or death, whichever came first. MAIN OUTCOME MEASURES: Interleukin-6 (IL-6) serum concentration at 48 hours after randomisation and, in a prespecified subgroup of patients, serum lipid mediator concentrations measured by mass spectrometry. RESULTS: The trial was discontinued in December 2017 due to slow recruitment and after the inclusion of 48 patients. Compared with placebo, ASA did not decrease IL-6 serum concentration at 48 hours. In the 32 patients with analysis of lipid mediators, low-dose ASA increased the concentration of 15-hydroxyeicosatetraenoic acid, a proresolving precursor of lipoxin A4, and reduced the concentration of the proinflammatory cytochrome P-dependent mediators 17-HETE (hydroxyeicosatetraenoic acid), 18-HETE and 20-HETE. In the eicosapentaenoic acid pathway, ASA significantly increased the concentration of the anti-inflammatory mediators 17,18-DiHETE (dihydroxyeicosatetraenoic acid) and 14,15-DiHETE. CONCLUSIONS: In ICU patients with SIRS, low-dose ASA did not significantly alter serum IL-6 concentrations, but it did affect plasma concentrations of certain lipid mediators. The ability to measure lipid mediators in clinical samples and to monitor the effect of ASA on their levels unlocks a potential area of biological investigation in critical care. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ACTRN 12614001165673).

The effect of dexmedetomidine on vasopressor requirements in patients with septic shock: a subgroup analysis of the Sedation Practice in Intensive Care Evaluation [SPICE III] Trial.

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 ).

Continuous Magnesium Infusion to Prevent Atrial Fibrillation After Cardiac Surgery: A Sequential Matched Case-Controlled Pilot Study.

OBJECTIVE: The authors aimed to test whether a bolus of magnesium followed by continuous intravenous infusion might prevent the development of atrial fibrillation (AF) after cardiac surgery. DESIGN: Sequential, matched, case-controlled pilot study. SETTING: Tertiary university hospital. PARTICIPANTS: Matched cohort of 99 patients before and intervention cohort of 99 consecutive patients after the introduction of a continuous magnesium infusion protocol. INTERVENTIONS: The magnesium infusion protocol consisted of a 10 mmol loading dose of magnesium sulphate followed by a continuous infusion of 3 mmol/h over a maximum duration of 96 hours or until intensive care unit discharge. MEASUREMENTS AND MAIN RESULTS: The study groups were balanced except for a lower cardiac index in the intervention cohort. The mean duration of magnesium infusion was 27.93 hours (95% confidence interval [CI]: 24.10-31.76 hours). The intervention group had greater serum peak magnesium levels: 1.72 mmol/L ± 0.34 on day 1, 1.32 ± 0.36 on day 2 versus 1.01 ± 1.14 and 0.97 ± 0.13, respectively, in the control group (p < 0.01). Atrial fibrillation occurred in 25 patients (25.3%) in the intervention group and 40 patients (40.4%) in the control group (odds ratio 0.49, 95% CI, 0.27-0.92; p = 0.023). On a multivariate Cox proportional hazards model, the hazard ratio for the development of AF was significantly less in the intervention group (hazard ratio 0.45, 95% CI, 0.26-0.77; p = 0.004). CONCLUSION: The magnesium delivery strategy was associated with a decreased incidence of postoperative AF in cardiac surgery patients. These findings provide a rationale and preliminary data for the design of future randomized controlled trials.

Non-invasive continuous haemodynamic monitoring and response to intervention in haemodynamically unstable patients during rapid response team review.

INTRODUCTION: During rapid response team (RRT) management of haemodynamic instability (HI), continuous non-invasive haemodynamic monitoring may provide supplemental physiological information. OBJECTIVES: To continuously and non-invasively obtain the cardiac index (CI) and mean arterial pressure (MAP) in patients with HI at baseline and during RRT management using the ClearSight™ device. METHODS: We performed a prospective observational study in adult patients managed by the RRT for tachycardia or hypotension or both. We assessed changes from baseline in heart rate (HR), MAP, CI, stroke volume index (SVI) and systemic vascular resistance index (SVRI) (i) at 5-minutely intervals up to 20 min, and (ii) over the entire 20-min period. We analysed patients by RRT trigger (tachycardia/hypotension) and intervention (fluid bolus therapy [FBT]/ no FBT). RESULTS: We successfully recorded the CI in 47 of 50 (94%) patients. RRT reviews triggered by hypotension rather than tachycardia had a lower baseline HR (-45.4 bpm, p = <0.0001), MAP (-16.1 mmHg, p = 0.0007) and CI (1.0 L/min/m2, p = 0.0025). Compared to baseline, in the tachycardia group, there was a small increase in MAP overall and at the 15-20 min time-block from 83.2 mmHg to 87.1 mmHg (+3.9 mmHg, p = 0.0066) and 85.5 mmHg (+2.3 mmHg, p = 0.0061), respectively. In those who received FBT, there was a statistically significant increase in MAP overall and at the 15-20 min time-block compared to baseline, from 70.1 mmHg to 73.5 mmHg (+3.4 mmHg, p = 0.0036) and 74.3 mmHg (+4.2 mmHg, p = 0.0037), respectively. However, there were no statistically significant changes in mean HR, CI, SVI, or SVRI when comparing baseline to the entire 20-min period or 5-min time-blocks within any group. CONCLUSIONS: Continuous non-invasive measurement of haemodynamics during RRT management for HI was possible for 20 min. Patients with hypotension rather than tachycardia had lower baseline HR, MAP and CI values. There was a statistically significant but small increase in MAP at the 15-20 min time-block and overall, for both the tachycardia and FBT groups.

Conservative versus conventional oxygen therapy for cardiac surgical patients: A before-and-after study.

Avoiding hypoxaemia is considered crucial in cardiac surgery patients admitted to the intensive care unit (ICU). However, avoiding hyperoxaemia may also be important. A conservative approach to oxygen therapy may reduce exposure to hyperoxaemia without increasing the risk of hypoxaemia. Using a before-and-after design, we evaluated the introduction of conservative oxygen therapy (target SpO2 88%-92% using the lowest FiO2) for cardiac surgical patients admitted to the ICU. We studied 9041 arterial blood gas (ABG) datasets: 4298 ABGs from 245 'conventional' and 4743 ABGs from 298 'conservative' oxygen therapy patients. During mechanical ventilation (MV) and while in the ICU, compared to the conventional group, conservative group patients had significantly lower FiO2 exposure and PaO2 values ( P < 0.001 for each). Accordingly, using the mean PaO2 during MV, more conservative group patients were classified as normoxaemic (226 versus 62 patients, P < 0.01), fewer as hyperoxaemic (66 versus 178 patients, P < 0.01) and no patient in either group as hypoxaemic or severely hypoxaemic. Moreover, more ABG samples were hyperoxaemic or severely hyperoxaemic during conventional treatment ( P < 0.001). Finally, there was no difference in ICU or hospital length of stay, ICU or hospital mortality or 30-day mortality between the groups. Our findings support the feasibility and physiological safety of conservative oxygen therapy in patients admitted to ICU after cardiac surgery.

Sepsis uncouples serum C-peptide and insulin levels in critically ill patients with type 2 diabetes mellitus.

OBJECTIVE: To assess the effects of sepsis and exogenous insulin on C-peptide levels and C-peptide to insulin ratios in intensive care unit (ICU) patients with type 2 diabetes mellitus (T2DM). DESIGN, SETTING AND PARTICIPANTS: In this prospective, observational, single-centre study, we enrolled 31 ICU-admitted adults with T2DM. We measured serum C-peptide and insulin levels during the first 3 days of ICU stay and recorded characteristics of exogenous insulin therapy. Patients were compared on the basis of the presence of sepsis, and their exposure to exogenous insulin therapy. C-peptide levels were also measured in eight healthy subjects. MAIN OUTCOME MEASURES: Serum insulin and C-peptide levels during the first 3 days in ICU. RESULTS: Median C-peptide levels were higher in the ICU population compared with healthy subjects (10.9 [IQR, 8.2 -14.1] v 4.8 [IQR, 4.6-5.1] nmol/L, P < 0.01). Sepsis was present in 25 ICU patients (81%). Among ICU patients unexposed to exogenous insulin, the 11 patients with sepsis had higher median C-peptide levels compared with the six non-septic patients (2.5 [IQR, 1.8-3.7] v 1.7 [IQR, 0.8-2.2] nmol/L, P = 0.04), and a threefold higher C-peptide to insulin ratio (45 [IQR, 37-62] v 13 [IQR, 11-17], P = 0.03). However, septic patients exposed to exogenous insulin had lower median C-peptide levels (1.2 [IQR, 0.7-2.3] nmol/L, P = 0.01) and C-peptide to insulin ratios (5 [IQR, 2-10], P < 0.01) compared with insulin-free septic patients. The C-peptide to insulin ratio was significantly associated with white cell count and severity of illness in insulin-free septic patients. CONCLUSION: C-peptide levels were elevated in critically ill patients with T2DM. In this population, sepsis increased C-peptide levels and uncoupled serum C-peptide and insulin levels. Exogenous insulin decreased both C-peptide levels and C-peptide to insulin ratios.

Hospital-acquired complications in intensive care unit patients with diabetes: A before-and-after study of a conventional versus liberal glucose control protocol.

BACKGROUND: Critically ill patients with diabetes mellitus (DM) are at increased risk of in-hospital complications and the optimal glycemic target for such patients remains unclear. A more liberal approach to glucose control has recently been suggested for patients with DM, but uncertainty remains regarding its impact on complications. METHODS: We aimed to test the hypothesis that complications would be more common with a liberal glycemic target in ICU patients with DM. Thus, we compared hospital-acquired complications in the first 400 critically ill patients with DM included in a sequential before-and-after trial of liberal (glucose target: 10-14 mmol/L) vs conventional (glucose target: 6-10 mmol/L) glucose control. RESULTS: Of the 400 patients studied, 165 (82.5%) patients in the liberal and 177 (88.5%) in the conventional-control group were coded for at least one hospital-acquired complication (P = 0.09). When comparing clinically relevant complications diagnosed between ICU admission and hospital discharge, we found no difference in the odds for infectious (adjusted odds ratio [aOR] for liberal-control: 1.15 [95% CI: 0.68-1.96], P = 0.60), cardiovascular (aOR 1.40 [95% CI: 0.63-3.12], P = 0.41) or neurological complications (aOR: 1.07 [95% CI: 0.61-1.86], P = 0.81), acute kidney injury (aOR 0.83 [95% CI: 0.43-1.58], P = 0.56) or hospital mortality (aOR: 1.09 [95% CI: 0.59-2.02], P = 0.77) between the liberal and the conventional-control group. CONCLUSION: In this prospective before-and-after study, liberal glucose control was not associated with an increased risk of hospital-acquired infectious, cardiovascular, renal or neurological complications in critically ill patients with diabetes.

Rapid response team review of hemodynamically unstable ward patients: The accuracy of cardiac index assessment.

PURPOSE: Intensive care doctors commonly attend rapid response team (RRT) reviews of hospital-ward patients with hemodynamic instability and estimate the patient's likely cardiac index (CI). We aimed to non-invasively measure the CI of such patients and assess the level of agreement between such measurements and clinically estimated CI categories (low <2L/min/m2, normal 2-2.99L/min/m2 or high ≥3L/min/m2). MATERIALS AND METHODS: A prospective, observational study of non-invasive measurement and clinical estimation of CI categories in 50 adult hospital-ward patients who activated the RRT for 'hemodynamic instability' (tachycardia > 100BPM or hypotension < 90mmHg or both). RESULTS: The CI was measured in 47/50(94%) patients and the mean CI was 3.5(95% CI 3.2-3.7) L/min/m2. Overall, 30(64%) patients had a high CI, 13(28%) and 4(9%) had a normal and a low CI, respectively. The level of agreement between measured and clinically estimated CI categories was low(19.2%). Sensitivity and positive predictive values of clinical estimation were low(0% and 3.3% for high CI, and 0% and 50% for low CI, respectively). CONCLUSIONS: Non-invasive CI measurement was possible in almost all hospital-ward patients triggering RRT review for hemodynamic instability. In such patients, the CI was high, and intensive care clinicians were unable to identify a low or a high CI state.

A Double-Blind Randomized Controlled Trial of High Cutoff Versus Standard Hemofiltration in Critically Ill Patients With Acute Kidney Injury.

OBJECTIVES: In critically ill patients with acute kidney injury receiving vasopressors, high cytokine levels may sustain the shock state. High cutoff hemofiltration achieves greater cytokine removal in ex vivo and in animal models and may reduce the duration of shock but may also increase albumin losses. DESIGN: This was a single-center double-blind randomized controlled trial comparing continuous venovenous hemofiltration-high cutoff to continuous venovenous hemofiltration-standard. SETTING: Tertiary care hospital in Australia. PATIENTS: Vasopressor-dependent patients in acute kidney injury who were admitted to the ICU. INTERVENTIONS: Norepinephrine-free time were calculated in critically ill vasopressor-dependent patients in acute kidney injury, randomized to either continuous venovenous hemofiltration-high cutoff or continuous venovenous hemofiltration-standard. MEASUREMENT AND MAIN RESULTS: A total of 76 patients were randomized with the following characteristics (continuous venovenous hemofiltration-high cutoff vs continuous venovenous hemofiltration-standard); median age of 65 versus 70 year, percentage of males 47% versus 68%, and median Acute Physiology and Chronic Health Evaluation scores of 25 versus 23.5. The median hours of norepinephrine-free time at day 7 were 32 (0-110.8) for continuous venovenous hemofiltration-high cutoff and 56 hours (0-109.3 hr) (p = 0.520) for continuous venovenous hemofiltration-standard. Inhospital mortality was 55.6% with continuous venovenous hemofiltration-high cutoff versus 34.2% with continuous venovenous hemofiltration-standard (adjusted odds ratio, 2.49; 95% CI, 0.81-7.66; p = 0.191). There was no significant difference in time to cessation of norepinephrine (p = 0.358), time to cessation of hemofiltration (p = 0.563), and filter life (p = 0.21). Serum albumin levels (p = 0.192) were similar and the median dose of IV albumin given was 90 grams (20-212 g) for continuous venovenous hemofiltration-high cutoff and 80 grams (15-132 g) for continuous venovenous hemofiltration-standard (p = 0.252). CONCLUSIONS: In critically ill patients with acute kidney injury, continuous venovenous hemofiltration-high cutoff did not reduce the duration of vasopressor support or mortality or change albumin levels compared with continuous venovenous hemofiltration-standard.

High cut-off hemofiltration versus standard hemofiltration: effect on plasma cytokines.

PURPOSE: To study the effects of continuous veno-venous hemofiltration (CVVH) with high cut-off filters (CVVH-HCO) on plasma cytokine levels, sieving coefficient and clearance compared to CVVH using standard filters (CVVH-Std) in a nested cohort within a double-blind randomized controlled trial in severe acute kidney injury (AKI) patients. METHODS: We measured plasma and post-filter levels of IL-6, TNF-alpha, IL-8, IL-1 beta, RANTES, IL-10, IFN-gamma and IFN-alpha in both study groups. We also measured cytokine levels in the ultrafiltrate and calculated sieving coefficients and clearances. RESULTS: By 72 hours of treatment, IL-6 had decreased during both treatments (p = 0.009 and 0.005 respectively). In contrast, IL-10 had decreased with CVVH-Std (p = 0.03) but not CVVH-HCO (p = 0.135). None of the other cytokines showed changes over time. There were also no significant between group differences in plasma levels for each cytokine over the 72-hour treatment period. For all cytokines combined, however, the median sieving coefficient was higher for CVVH-HCO (0.31 vs. 0.16; p = 0.042) as was the mass removal rate by ultrafiltration (p = 0.027). While overall combined cytokine levels had fallen to 62.2% of baseline at 72 hours for CVVH-HCO (p<0.0001) and to 75.9% of baseline with CVVH-Std (p = 0.008) there were no between group differences. CONCLUSIONS: CVVH-HCO achieved greater combined sieving coefficient and mass removal rate by ultrafiltration for a group of key cytokines than CVVH-Std. However, this effect did not differentially lower their plasma level over the first 72 hours. Our study does not support the use of CVVH-HCO to lower cytokines in critically ill patients with AKI.

Targeted therapeutic mild hypercapnia after cardiac arrest: A phase II multi-centre randomised controlled trial (the CCC trial).

BACKGROUND: In intensive care observational studies, hypercapnia after cardiac arrest (CA) is independently associated with improved neurological outcome. However, the safety and feasibility of delivering targeted therapeutic mild hypercapnia (TTMH) for such patients is untested. METHODS: In a phase II safety and feasibility multi-centre, randomised controlled trial, we allocated ICU patients after CA to 24h of targeted normocapnia (TN) (PaCO2 35-45mmHg) or TTMH (PaCO2 50-55mmHg). The primary outcome was serum neuron specific enolase (NSE) and S100b protein concentrations over the first 72h assessed in the first 50 patients surviving to day three. Secondary end-points included global measure of function assessment at six months and mortality for all patients. RESULTS: We enrolled 86 patients. Their median age was 61 years (58, 64 years) and 66 (79%) were male. Of these, 50 patients (58%) survived to day three for full biomarker assessment. NSE concentrations increased in the TTMH group (p=0.02) and TN group (p=0.005) over time, with the increase being significantly more pronounced in the TN group (p(interaction)=0.04). S100b concentrations decreased over time in the TTMH group (p<0.001) but not in the TN group (p=0.68). However, the S100b change over time did not differ between the groups (p(interaction)=0.23). At six months, 23 (59%) TTMH patients had good functional recovery compared with 18 (46%) TN patients. Hospital mortality occurred in 11 (26%) TTMH patients and 15 (37%) TN patients (p=0.31). CONCLUSIONS: In CA patients admitted to the ICU, TTMH was feasible, appeared safe and attenuated the release of NSE compared with TN. These findings justify further investigation of this novel treatment.

Conservative oxygen therapy in mechanically ventilated patients following cardiac arrest: A retrospective nested cohort study.

BACKGROUND: In mechanically ventilated (MV) cardiac arrest (CA) survivors admitted to the intensive care unit (ICU) avoidance of hypoxia is considered crucial. However, avoidance of hyperoxia may also be important. A conservative approach to oxygen therapy may reduce exposure to both. METHODS: We evaluated the introduction of conservative oxygen therapy (target SpO2 88-92% using the lowest FiO2) during MV for resuscitated CA patients admitted to the ICU. RESULTS: We studied 912 arterial blood gas (ABG) datasets: 448 ABGs from 50 'conventional' and 464 ABGs from 50 'conservative' oxygen therapy patients. Compared to the conventional group, conservative group patients had significantly lower PaO2 values and FiO2 exposure (p<0.001, respectively); more received MV in a spontaneous ventilation mode (18% vs 2%; p=0.001) and more were exposed to a FiO2 of 0.21 (19 vs 0 patients, p=0.001). Additionally, according to mean PaO2, more conservative group patients were classified as normoxaemic (36 vs 16 patients, p<0.01) and fewer as hyperoxaemic (14 vs 33 patients, p<0.01). Finally, ICU length of stay was significantly shorter for conservative group patients (p=0.04). There was no difference in the proportion of survivors discharged from hospital with good neurological outcome (14/23 vs 12/22 patients, p=0.67). CONCLUSIONS: Our findings provide preliminary support for the feasibility and physiological safety of conservative oxygen therapy in patients admitted to ICU for MV support after cardiac arrest (Trial registration, NCT01684124).

Bioelectrical impedance vector analysis in critically ill patients: a prospective, clinician-blinded investigation.

INTRODUCTION: Assessment of fluid status in critically ill patients is challenging. We aimed to assess the feasibility and validity of bioelectrical impedance vector analysis (BIVA) as a measure of hydration in critically ill patients. METHODS: We performed twice-daily BIVA measurements and fluid balance calculations and recorded physiological variables in mechanically ventilated patients within 24 h of intensive care unit (ICU) admission for up to 5 days. Treating clinicians were blinded to BIVA results. RESULTS: We performed 344 BIVA measurements in 61 patients. According to BIVA, 14 patients (23%) were dehydrated, 22 (36%) were normally hydrated and 25 (41%) were overhydrated upon ICU admission. Patients with normal BIVA hydration were less sick, had fewer comorbidities and had less deranged physiology than patients found to be dehydrated or overhydrated with BIVA. Cumulative fluid balance increased in patients found to be dehydrated with BIVA by a mean of 3.4±2.2 L, whereas in patients found to be overhydrated with BIVA, it decreased by a mean of 4.5±6.9 L. In patients found to be normally hydrated with BIVA, fluid balance remained unchanged. BIVA-defined hydration increased with 1 L (median change 1.5%, P =0.09) or 2 L (median change 0.7%, P =0.09) of calculated fluid gains. BIVA-defined hydration decreased (median change -0.8%, P =0.02) with a negative cumulative fluid balance of >2 L. BIVA-defined hydration between first and last measurement correlated with the corresponding change in fluid balance (ρ =0.25, P =0.05). CONCLUSIONS: BIVA is feasible in critically ill patients. Its validity is supported by the observed characteristics of patients with different degrees of BIVA hydration upon admission and by different fluid management of such patients by blinded clinicians. The sensitivity of repeated BIVA hydration measurements to detect fluid accumulation or fluid balance changes <2 L was low, however. These contradictory findings provide the rational basis for studies of BIVA-assisted fluid management in ICU patients.

Intensive care nurses' self-reported practice of intravenous fluid bolus therapy.

OBJECTIVE: To describe self-reported practice of fluid bolus therapy by intensive care nurses. RESEARCH METHODOLOGY: Multi-choice questionnaire of intensive care nurses conducted in July, 2014. SETTING: Major university tertiary referral centre. FINDINGS: 141 (64%) intensive care nurses responded. The majority of respondents identified 4% albumin as the commonest fluid bolus type and stated a fluid bolus was 250ml; however fluid bolus volume varied from 100ml to 1000ml. Hypotension was identified as the primary physiological trigger for a fluid bolus. In the hour following a fluid bolus for hypotension almost half of respondents expected an 'increase in mean arterial pressure of 0-10mmHg'; for oliguria, >60% expected an 'increase in urinary output of '0.5-1ml/kg/hour'; for low CVP, 50% expected 'an increase in CVP of 3-4mmHg'; and, for tachycardia, 45% expected a 'decrease in heart rate of 11-20beats/minute'. Finally, 7-10% of respondents were 'unsure' about the physiological response to a fluid bolus. CONCLUSION: Most respondents identified fluid bolus therapy to be at least 250ml of 4% albumin given as quickly as possible; however, volumes from 100 to 1000ml were also accepted. There was much uncertainty about the expected physiological response to fluid bolus therapy according to indication.

High cut-off hemofiltration versus standard hemofiltration: a pilot assessment of effects on indices of apoptosis.

OBJECTIVES: To measure plasma pro-apoptotic and pro-necrotic activity in severe acute kidney injury (AKI) patients within a randomized controlled trial of continuous veno-venous hemofiltration with high cut-off filters (CVVH-HCO) versus standard filters (CVVH-Std). METHODS: We measured pro-apoptotic and pro-necrotic plasma activity by trypan blue exclusion cell viability assay, detection of DNA fragmentation, and by determination of caspase-3 activity and annexin V-based apoptosis and necrosis detection assay. RESULTS: Compared to no apoptosis or necrosis after incubation with healthy plasma, 14-18% of cells showed apoptosis and 4-8% showed necrosis after incubation with plasma from AKI patients. When comparing different measures of pro-apoptotic or pro-necrotic activity, CVVH-HCO and CVVH-Std showed no differential effects on such activity, which remained high over the first 3 days of treatment. However, using annexin V-FITC, there was a significant drop in pro-apoptotic activity across the filter for the CVVH-HCO group (p = 0.043) but not for the CVVH-Std group (p = 0.327) and a significant difference between the two groups (CVVH-HCO vs. CVVH-Std p = 0.006). CONCLUSIONS: Patients with severe AKI have increased pro-apoptotic and pro-necrotic activity. Although on single-pass effect assessment, CVVH-HCO was superior to CVVH-Std in decreasing annexin V-FITC-assessed pro-apoptotic activity, there was no overall attenuation of such activity during the first 3 days of treatment.

Extended normothermic extracorporeal perfusion of isolated human liver after warm ischaemia: a preliminary report.

BACKGROUND: Donation after circulatory death (DCD) livers are at markedly increased risk of primary graft dysfunction and biliary tract ischaemia. Normothermic extracorporeal liver perfusion (NELP) may increase the ability to transplant DCD livers and may allow their use for artificial extracorporeal liver support of patients with fulminant liver failure. OBJECTIVE: We conducted two proof-of-concept experiments using human livers after DCD to assess the feasibility and functional efficacy of NELP over an extended period. METHODS: We applied extracorporeal membrane oxygenation, parenteral nutrition, separate hepatic artery and portal vein perfusion and physiological perfusion pressures to two livers obtained after DCD. RESULTS: We achieved NELP and evidence of liver function (bile production, paracetamol removal and maintenance of normal lactate levels) in both livers; one for 24 hours and the other for 43 hours. Histological examination showed areas of patchy ischaemia but preserved biliary ducts and canaliculi. CONCLUSIONS: Our experiments justify further investigations of the feasibility and efficacy of extended DCD liver preservation by ex-vivo perfusion.

Conservative oxygen therapy in mechanically ventilated patients: a pilot before-and-after trial.

OBJECTIVES: To assess the feasibility and safety of a conservative approach to oxygen therapy in mechanically ventilated ICU patients. DESIGN: Pilot prospective before-and-after study. SETTING: A 22-bed multidisciplinary ICU of a tertiary care hospital in Australia. PATIENTS: A total of 105 adult (18 years old or older) patients required mechanical ventilation for more than 48 hours: 51 patients during the "conventional" before period and 54 after a change to "conservative" oxygen therapy. INTERVENTIONS: Implementation of a conservative approach to oxygen therapy (target SpO2 of 90-92%). MEASUREMENTS AND MAIN RESULTS: We collected 3,169 datasets on 799 mechanical ventilation days. During conservative oxygen therapy the median time-weighted average SpO2 on mechanical ventilation was 95.5% (interquartile range, 94.0-97.3) versus 98.4% (97.3-99.1) (p < 0.001) during conventional therapy. The median PaO2 was 83 torr (71-94) versus 107 torr (94-131) (p < 0.001) with a change to a median FIO2 of 0.27 (0.24-0.30) versus 0.40 (0.35-0.44) (p < 0.001). Conservative oxygen therapy decreased the median total amount of oxygen delivered during mechanical ventilation by about two thirds (15,580 L [8,263-29,351 L] vs 5,122 L [1,837-10,499 L]; p < 0.001). The evolution of the PaO2/FIO2 ratio was similar during the two periods, and there were no difference in any other biochemical or clinical outcomes. CONCLUSIONS: Conservative oxygen therapy in mechanically ventilated ICU patients was feasible and free of adverse biochemical, physiological, or clinical outcomes while allowing a marked decrease in excess oxygen exposure. Our study supports the safety and feasibility of future pilot randomized controlled trials of conventional compared with conservative oxygen therapy.