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Neuromuscular weakness resulting in severe functional impairment is common in critical care survivors. This study aimed to evaluate effects of an early progressive rehabilitation intervention in mechanically ventilated adults at risk. This was a parallel, two-arm, assessor-blinded, randomised controlled trial with 6-months follow-up that was conducted in a mixed ICU of an academic centre in Switzerland. Previously independent, mechanically ventilated, critically ill adults with expected critical care stay ≥72 hours (n = 115) were randomised to a control group receiving standard physiotherapy including early mobilisation or to an experimental group with early endurance and resistance training combined with mobilisation. Primary endpoints were functional capacity (6-Minute Walk Distance) and functional independence (Functional Independence Measure) at hospital discharge. Secondary endpoints including muscle strength were assessed at critical care discharge. Safety was monitored closely by standard monitoring and predefined adverse events. Physiotherapy started within 48 hours of critical care admission while 97% of participants were still ventilated and 68% on inotropes. Compared to the control group (n = 57), the experimental group (n = 58) received significantly more physiotherapy (sessions: 407 vs 377, p<0.001; time/session: 25min vs 18min, p<0.001) and had less days with sedation (p<0.001). Adverse events were rare (0.6%) and without consequences. There were no significant between-group differences in 6-Minute Walk Distance (experimental 123m (IQR 25-280) vs control 100m (IQR 0-300); p = 0.542) or functional independence (98 (IQR 66-119) vs 98 (IQR 18-115); p = 0.308). Likewise, no differences were found for the secondary outcomes, except a trend towards improved mental health in the experimental group after 6 months (84 (IQR 68-88) vs 70 (IQR 64-76); p = 0.023). Early endurance and resistance training in mechanically ventilated, intensive care patients does not improve functional capacity or independence at hospital discharge compared to early standard physiotherapy but may improve mental health 6-months after critical care discharge. German Clinical Trials Register (DRKS): DRKS00004347, registered on 10 September 2012.

After prolonged stay in an intensive care unit (ICU) patients often complain about cognitive impairments that affect health-related quality of life after discharge. The aim of this proof-of-concept study was to test the feasibility and effects of controlled visual and acoustic stimulation in a virtual reality (VR) setup in the ICU. The VR setup consisted of a head-mounted display in combination with an eye tracker and sensors to assess vital signs. The stimulation consisted of videos featuring natural scenes and was tested in 37 healthy participants in the ICU. The VR stimulation led to a reduction of heart rate (p = 0. 049) and blood pressure (p = 0.044). Fixation/saccade ratio (p < 0.001) was increased when a visual target was presented superimposed on the videos (reduced search activity), reflecting enhanced visual processing. Overall, the VR stimulation had a relaxing effect as shown in vital markers of physical stress and participants explored less when attending the target. Our study indicates that VR stimulation in ICU settings is feasible and beneficial for critically ill patients.

Intensive care unit acquired weakness (ICUAW) may contribute to functional disability in ICU survivors, yet performance-based data for general ICU patients are lacking. This study explored functional outcomes of (1) and risk factors for (2) weakness at ICU discharge. Data from a randomised controlled trial that investigated two early exercise regimes in previously independent, ventilated adults (n = 115) without any significant outcome-differences were used for the present analysis. ICUAW was clinically diagnosed in cooperative participants (n = 83) at ICU discharge with the Medical Research Council sum-score (MRC-SS) using a cut-off <48 for moderate or <36 for severe weakness. Primary outcomes were the 6-Minute Walk Test and Functional Independence Measure at hospital discharge. Secondary outcomes included health-related quality of life after six months. Risk factors during the ICU stay were explored for their effect on MRC-SS with linear regression. Functional outcomes and length of hospital stay significantly differed in patients with severe, moderate to no weakness (6-Minute Walk test: p = 0.013; 110m [IQR 75-240], 196m [90-324.25], 222.5m [129-378.75], Functional Independence Measure: p = 0.001; 91[IQR 68-101], 113[102.5-118.5], 112[97-123], length of stay after ICU discharge: p = 0.008; 20.9d [IQR 15.83-30.73], 16.86d [13.07-27.10], 11.16d [7.35-19.74]). However, after six months participants had similar values for quality of life regardless of their strength at ICU discharge (Short-Form 36 sum-scores physical health: p = 0.874, mental health: p = 0.908). In-bed immobilisation was the most significant factor associated with weakness at ICU discharge in the regression models (MRC-SS: -24.57(95%CI [-37.03 to -12.11]); p<0.001). In this general, critically ill cohort, weakness at ICU discharge was associated with short-term functional disability and prolonged hospital length of stay, but not with quality of life, which was equivalent to the values for patients without ICUAW within six months. Immobilisation may be a modifiable risk factor to prevent ICUAW. Prospective trials are needed to validate these results. German Clinical Trials Register (DRKS) identification number: DRKS00004347, registered on September 10, 2012.

Purpose Acute gastrointestinal (GI) dysfunction and failure have been increasingly recognized in critically ill patients. The variety of definitions proposed in the past has led to confusion and difficulty in comparing one study to another. An international working group convened to standardize the definitions for acute GI failure and GI symptoms and to review the therapeutic options. Methods The Working Group on Abdominal Problems (WGAP) of the European Society of Intensive Care Medicine (ESICM) developed the definitions for GI dysfunction in intensive care patients on the basis of the available evidence and current understanding of the pathophysiology. Results Definitions for acute gastrointestinal injury (AGI) with its four grades of severity, as well as for feeding intolerance syndrome and GI symptoms (e.g. vomiting, diarrhoea, paralysis, high gastric residual volumes) are proposed. AGI is a malfunctioning of the GI tract in intensive care patients due to their acute illness. AGI grade I = increased risk of developing GI dysfunction or failure (a self-limiting condition); AGI grade II = GI dysfunction (a condition that requires interventions); AGI grade III = GI failure (GI function cannot be restored with interventions); AGI grade IV = dramatically manifesting GI failure (a condition that is immediately life-threatening). Current evidence and expert opinions regarding treatment of acute GI dysfunction are provided. Conclusions State-of-the-art definitions for GI dysfunction with gradation as well as management recommendations are proposed on the basis of current medical evidence and expert opinion. The WGAP recommends using these definitions for clinical and research purposes.

Stress is a part of everyday life which can be counteracted by evoking the relaxation response via nature scenes presented using immersive virtual reality (VR). The aim of this study was to determine which sensory aspect of immersive VR intervention is responsible for the greatest relaxation response. We compared four conditions: auditory and visual combined (audiovisual), auditory only, visual only, and no artificial sensory input. Physiological changes in heart rate, respiration rate, and blood pressure were recorded, while participants reported their preferred condition and awareness of people, noise, and light in the real-world. Over the duration of the stimulation, participants had the lowest heart rate during the audiovisual and visual only conditions. They had the steadiest decrease in respiration rate and the lowest blood pressure during the audiovisual condition, compared to the other conditions, indicating the greatest relaxation. Moreover, ratings of awareness indicated that participants reported being less aware of their surroundings (i.e., people, noise, light, real environment) during the audiovisual condition versus the other conditions (p < 0.001), with a preference for audiovisual inputs. Overall, the use of audiovisual VR stimulation is more effective at inducing a relaxation response compared to no artificial sensory inputs, or the independent inputs.

Background Diarrhea is frequent in patients in intensive care units (ICU) and is associated with discomfort and complications and may increase the length of stay and nursing workload. Methods This was a prospective, double-blind, randomized, controlled single-center pilot study to assess the incidence and frequency of diarrhea and the respective effects of a modified enteral diet (intervention: Peptamen® AF, rich in proteins, medium chain triglycerides and fish oil) compared to a standard diet (control: Isosource® Energy) in 90 randomized adult patients (intervention, n  = 46; control, n  = 44) with an ICU stay ≥5 days and tube feeding ≥3 days. Tube feeding was initiated within 72 h of ICU admission and continued up to 10 days. The caloric goal was adjusted to needs by indirect calorimetry. Gastrointestinal function, nutritional intake, and nursing workload were recorded. Follow-up was until 28 days after randomization. Results Median age was 63.3 (interquartile range (IQR) 51.0–73.2) years and Simplified Acute Physiology Score (SAPS) II was 61.0 (IQR 47.8–74). Time to reach caloric goal (intervention: 2.2 (0.8–3.7) days (median, IQR); control: 2.0 (1.3–2.7) days; p  = 0.16), length of time on study nutrition (intervention: 5.0 (3.6–6.4) days; control: 7.0 (5.3–8.7) days; p  = 0.26), and calorie intake (intervention: 18.0 (12.5–20.9) kcal/kg/day; control 19.7 (17.3–23.1) kcal/kg/day; p  = 0.08) did not differ between groups, with a higher protein intake for Peptamen® group (1.13 (0.78–1.31) g/kg/day vs 0.80 (0.70–0.94); p  < 0.001). No difference in diarrhea incidence (intervention group: 29 (64%); control group: 31 (70%); p  = 0.652), use of fecal collectors (23 (51%) vs. 24 (55%); p  = 0.83), or diarrhea-free days (161 (64%) vs 196 (68%); p  = 0.65) was found. Nursing workload and cost for diarrhea care were not different between the groups. In a post-hoc analysis, adjusted for treatment group, age, sex, and SAPS II score, diarrhea was associated with length of mechanical ventilation (9.5 (6.0–13.1) vs. 3.9 (3.2–4.6) days; p  = 0.006) and length of ICU stay (11.0 (8.9–13.1) vs. 5.0 (3.8–6.2) days; p  = 0.001). Conclusions In this pilot study, we found a high incidence of diarrhea, which was not attenuated by Peptamen® AF. Patients with diarrhea stayed longer in the ICU. Trial registration ClinicalTrials.gov identifier, NCT01581957 . Registered on 18 April 2012.

Background The aim was to describe transfusion practice in critically ill patients at an international level and evaluate the effects of red blood cell (RBC) transfusion on outcomes in these patients. Methods This was a pre-planned sub-study of the Intensive Care Over Nations audit, which involved 730 ICUs in 84 countries and included all adult patients admitted between 8 May and 18 May 2012, except admissions for routine postoperative surveillance. Results ICU and hospital outcomes were recorded. Among the 10,069 patients included in the audit, data related to transfusion had been completed for 9553 (mean age 60 ± 18 years, 60% male); 2511 (26.3%) of these had received a transfusion, with considerable variation among geographic regions. The mean lowest hemoglobin on the day of transfusion was 8.3 ± 1.7 g/dL, but varied from 7.8 ± 1.4 g/dL in the Middle East to 8.9 ± 1.9 g/dL in Eastern Europe. Hospital mortality rates were higher in transfused than in non-transfused patients (30.0% vs. 19.6%, p  < 0.001) and increased with increasing numbers of transfused units. In an extended Cox proportional hazard analysis, the relative risk of in-hospital death was slightly lower after transfusion in the whole cohort (hazard ratio 0.98, confidence interval 0.96–1.00, p  = 0.048). There was a stepwise decrease in the hazard ratio for mortality after transfusion with increasing admission severity scores. Conclusions More than one fourth of critically ill patients are transfused during their ICU stay, with considerable variations in transfusion practice among geographic regions. After adjustment for confounders, RBC transfusions were associated with a slightly lower relative risk of in-hospital death, especially in the most severely ill patients, highlighting the importance of taking the severity of illness into account when making transfusion decisions.

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 ).

Early rehabilitation is indicated in critically ill adults to counter functional complications. However, the physiological response to rehabilitation is poorly understood. This study aimed to determine the cardiorespiratory response to rehabilitation and to investigate the effect of explanatory variables on physiological changes during rehabilitation and recovery. In a prospectively planned, secondary analysis of a randomised controlled trial conducted in a tertiary, mixed intensive care unit (ICU), we analysed the 716 physiotherapy-led, pragmatic rehabilitation sessions (including exercise, cycling and mobilisation). Participants were previously functionally independent, mechanically ventilated, critically ill adults (n = 108). Physiological data (2-minute medians) were collected with standard ICU monitoring and indirect calorimetry, and their medians calculated for baseline (30min before), training (during physiotherapy) and recovery (15min after). We visualised physiological trajectories and investigated explanatory variables on their estimated effect with mixed-effects models. This study found a large range of variation within and across participants' sessions with clinically relevant variations (>10%) occurring in more than 1 out of 4 sessions in mean arterial pressure, minute ventilation (MV) and oxygen consumption (VO2), although early rehabilitation did not generally affect physiological values from baseline to training or recovery. Active patient participation increased MV (mean difference 0.7l/min [0.4-1.0, p<0.001]) and VO2 (23ml/min [95%CI: 13-34, p<0.001]) during training when compared to passive participation. Similarly, session type 'mobilisation' increased heart rate (6.6bpm [2.1-11.2, p = 0.006]) during recovery when compared to 'exercise'. Other modifiable explanatory variables included session duration, mobilisation level and daily medication, while non-modifiable variables were age, gender, body mass index and the daily Sequential Organ Failure Assessment. A large range of variation during rehabilitation and recovery mirrors the heterogenous interventions and patient reactions. This warrants close monitoring and individual tailoring, whereby the best option to stimulate a cardiorespiratory response seems to be active patient participation, shorter session durations and mobilisation. German Clinical Trials Register (DRKS) identification number: DRKS00004347, registered on 10 September 2012.

Autonomic and vascular failures are common phenotypes of sepsis, typically characterized by tachycardia despite corrected hypotension/hypovolemia, vasopressor resistance, increased arterial stiffness and decreased peripheral vascular resistance. In a 5-day swine experiment of polymicrobial sepsis we aimed at characterizing arterial properties and autonomic mechanisms responsible for cardiovascular homeostasis regulation, with the final goal to verify whether the resuscitation therapy in agreement with standard guidelines was successful in restoring a physiological condition of hemodynamic profile, cardiovascular interactions and autonomic control. Twenty pigs were randomized to polymicrobial sepsis and protocol-based resuscitation or to prolonged mechanical ventilation and sedation without sepsis. The animals were studied at baseline, after sepsis development, and every 24 h during the 3-days resuscitation period. Beat-to-beat carotid blood pressure (BP), carotid blood flow, and central venous pressure were continuously recorded. The two-element Windkessel model was adopted to study carotid arterial compliance, systemic vascular resistance and characteristic time constant τ. Effective arterial elastance was calculated as a simple estimate of total arterial load. Cardiac baroreflex sensitivity (BRS) and low frequency (LF) spectral power of diastolic BP were computed to assess autonomic activity. Sepsis induced significant vascular and autonomic alterations, manifested as increased arterial stiffness, decreased vascular resistance and τ constant, reduced BRS and LF power, higher arterial afterload and elevated heart rate in septic pigs compared to sham animals. This compromised condition was persistent until the end of the experiment, despite achievement of recommended resuscitation goals by administered vasopressors and fluids. Vascular and autonomic alterations persist 3 days after goal-directed resuscitation in a clinically relevant sepsis model. We hypothesize that the addition of these variables to standard clinical markers may better profile patients’ response to treatment and this could drive a more tailored therapy which could have a potential impact on long-term outcomes.