Jennifer K. Clune

Cognitive and physical rehabilitation of intensive care unit survivors: results of the RETURN randomized controlled pilot investigation.

Background:Millions of patients who survive medical and surgical general intensive care unit care every year experience newly acquired long-term cognitive impairment and profound physical and functional disabilities. To overcome the current reality in which patients receive inadequate rehabilitation, we devised a multifaceted, in-home, telerehabilitation program implemented using social workers and psychology technicians with the goal of improving cognitive and functional outcomes. Methods:This was a single-site, feasibility, pilot, randomized trial of 21 general medical/surgical intensive care unit survivors (8 controls and 13 intervention patients) with either cognitive or functional impairment at hospital discharge. After discharge, study controls received usual care (sporadic rehabilitation), whereas intervention patients received a combination of in-home cognitive, physical, and functional rehabilitation over a 3-month period via a social worker or master’s level psychology technician utilizing telemedicine to allow specialized multidisciplinary treatment. Interventions over 12 wks included six in-person visits for cognitive rehabilitation and six televisits for physical/functional rehabilitation. Outcomes were measured at the completion of the rehabilitation program (i.e., at 3 months), with cognitive functioning as the primary outcome. Analyses were conducted using linear regression to examine differences in 3-month outcomes between treatment groups while adjusting for baseline scores. Results:Patients tolerated the program with only one adverse event reported. At baseline both groups were well-matched. At 3-month follow-up, intervention group patients demonstrated significantly improved cognitive executive functioning on the widely used and well-normed Tower test (for planning and strategic thinking) vs. controls (median [interquartile range], 13.0 [11.5–14.0] vs. 7.5 [4.0–8.5]; adjusted p < .01). Intervention group patients also reported better performance (i.e., lower score) on one of the most frequently used measures of functional status (Functional Activities Questionnaire at 3 months vs. controls, 1.0 [0.0 –3.0] vs. 8.0 [6.0–11.8], adjusted p = .04). Conclusions:A multicomponent rehabilitation program for intensive care unit survivors combining cognitive, physical, and functional training appears feasible and possibly effective in improving cognitive performance and functional outcomes in just 3 months. Future investigations with a larger sample size should be conducted to build on this pilot feasibility program and to confirm these results, as well as to elucidate the elements of rehabilitation contributing most to improved outcomes.

Low levels of tissue factor lead to alveolar haemorrhage, potentiating murine acute lung injury and oxidative stress

Background Systemic blockade of tissue factor (TF) attenuates acute lung injury (ALI) in animal models of sepsis but the effects of global TF deficiency are unknown. We used mice with complete knockout of mouse TF and low levels (∼1%) of human TF (LTF mice) to test the hypothesis that global TF deficiency attenuates lung inflammation in direct lung injury. Methods LTF mice were treated with 10 μg of lipopolysaccharide (LPS) or vehicle administered by direct intratracheal injection and studied at 24 h. Results Contrary to our hypothesis, LTF mice had increased lung inflammation and injury as measured by bronchoalveolar lavage cell count (3.4×105 wild-type (WT) LPS vs 3.3×105 LTF LPS, p=0.947) and protein (493 μg/ml WT LPS vs 1014 μg/ml LTF LPS, p=0.006), proinflammatory cytokines (TNF-α, IL-10, IL-12, p<0.035 WT LPS vs LTF LPS) and histology compared with WT mice. LTF mice also had increased haemorrhage and free haemoglobin in the airspace accompanied by increased oxidant stress as measured by lipid peroxidation products (F2 isoprostanes and isofurans). Conclusions These findings indicate that global TF deficiency does not confer protection in a direct lung injury model. Rather, TF deficiency causes increased intra-alveolar haemorrhage following LPS leading to increased lipid peroxidation. Strategies to globally inhibit TF may be deleterious in patients with ALI.

Regulation of Alveolar Procoagulant Activity and Permeability in Direct Acute Lung Injury by Lung Epithelial Tissue Factor

Tissue factor (TF) initiates the extrinsic coagulation cascade in response to tissue injury, leading to local fibrin deposition. Low levels of TF in mice are associated with increased severity of acute lung injury (ALI) after intratracheal LPS administration. However, the cellular sources of the TF required for protection from LPS-induced ALI remain unknown. In the current study, transgenic mice with cell-specific deletions of TF in the lung epithelium or myeloid cells were treated with intratracheal LPS to determine the cellular sources of TF important in direct ALI. Cell-specific deletion of TF in the lung epithelium reduced total lung TF expression to 39% of wild-type (WT) levels at baseline and to 29% of WT levels after intratracheal LPS. In contrast, there was no reduction of TF with myeloid cell TF deletion. Mice lacking myeloid cell TF did not differ from WT mice in coagulation, inflammation, permeability, or hemorrhage. However, mice lacking lung epithelial TF had increased tissue injury, impaired activation of coagulation in the airspace, disrupted alveolar permeability, and increased alveolar hemorrhage after intratracheal LPS. Deletion of epithelial TF did not affect alveolar permeability in an indirect model of ALI caused by systemic LPS infusion. These studies demonstrate that the lung epithelium is the primary source of TF in the lung, contributing 60-70% of total lung TF, and that lung epithelial, but not myeloid, TF may be protective in direct ALI.

Cognitive and Physical Rehabilitation of ICU Survivors: results of the RETURN randomized, controlled pilot investigation

Background:Millions of patients who survive medical and surgical general intensive care unit care every year experience newly acquired long-term cognitive impairment and profound physical and functional disabilities. To overcome the current reality in which patients receive inadequate rehabilitation, we devised a multifaceted, in-home, telerehabilitation program implemented using social workers and psychology technicians with the goal of improving cognitive and functional outcomes. Methods:This was a single-site, feasibility, pilot, randomized trial of 21 general medical/surgical intensive care unit survivors (8 controls and 13 intervention patients) with either cognitive or functional impairment at hospital discharge. After discharge, study controls received usual care (sporadic rehabilitation), whereas intervention patients received a combination of in-home cognitive, physical, and functional rehabilitation over a 3-month period via a social worker or master’s level psychology technician utilizing telemedicine to allow specialized multidisciplinary treatment. Interventions over 12 wks included six in-person visits for cognitive rehabilitation and six televisits for physical/functional rehabilitation. Outcomes were measured at the completion of the rehabilitation program (i.e., at 3 months), with cognitive functioning as the primary outcome. Analyses were conducted using linear regression to examine differences in 3-month outcomes between treatment groups while adjusting for baseline scores. Results:Patients tolerated the program with only one adverse event reported. At baseline both groups were well-matched. At 3-month follow-up, intervention group patients demonstrated significantly improved cognitive executive functioning on the widely used and well-normed Tower test (for planning and strategic thinking) vs. controls (median [interquartile range], 13.0 [11.5–14.0] vs. 7.5 [4.0–8.5]; adjusted p < .01). Intervention group patients also reported better performance (i.e., lower score) on one of the most frequently used measures of functional status (Functional Activities Questionnaire at 3 months vs. controls, 1.0 [0.0 –3.0] vs. 8.0 [6.0–11.8], adjusted p = .04). Conclusions:A multicomponent rehabilitation program for intensive care unit survivors combining cognitive, physical, and functional training appears feasible and possibly effective in improving cognitive performance and functional outcomes in just 3 months. Future investigations with a larger sample size should be conducted to build on this pilot feasibility program and to confirm these results, as well as to elucidate the elements of rehabilitation contributing most to improved outcomes.

Myeloid tissue factor does not modulate lung inflammation or permeability during experimental acute lung injury.

Tissue factor (TF) is a critical mediator of direct acute lung injury (ALI) with global TF deficiency resulting in increased airspace inflammation, alveolar-capillary permeability, and alveolar hemorrhage after intra-tracheal lipopolysaccharide (LPS). In the lung, TF is expressed diffusely on the lung epithelium and intensely on cells of the myeloid lineage. We recently reported that TF on the lung epithelium, but not on myeloid cells, was the major source of TF during intra-tracheal LPS-induced ALI. Because of a growing body of literature demonstrating important pathophysiologic differences between ALI caused by different etiologies, we hypothesized that TF on myeloid cells may have distinct contributions to airspace inflammation and permeability between direct and indirect causes of ALI. To test this, we compared mice lacking TF on myeloid cells (TF∆mye, LysM.Cre+/−TFflox/flox) to littermate controls during direct (bacterial pneumonia, ventilator-induced ALI, bleomycin-induced ALI) and indirect ALI (systemic LPS, cecal ligation and puncture). ALI was quantified by weight loss, bronchoalveolar lavage (BAL) inflammatory cell number, cytokine concentration, protein concentration, and BAL procoagulant activity. There was no significant contribution of TF on myeloid cells in multiple models of experimental ALI, leading to the conclusion that TF in myeloid cells is not a major contributor to experimental ALI.

Cognitive and physical rehabilitation of intensive care unit survivors

Background:Millions of patients who survive medical and surgical general intensive care unit care every year experience newly acquired long-term cognitive impairment and profound physical and functional disabilities. To overcome the current reality in which patients receive inadequate rehabilitation, we devised a multifaceted, in-home, telerehabilitation program implemented using social workers and psychology technicians with the goal of improving cognitive and functional outcomes. Methods:This was a single-site, feasibility, pilot, randomized trial of 21 general medical/surgical intensive care unit survivors (8 controls and 13 intervention patients) with either cognitive or functional impairment at hospital discharge. After discharge, study controls received usual care (sporadic rehabilitation), whereas intervention patients received a combination of in-home cognitive, physical, and functional rehabilitation over a 3-month period via a social worker or master’s level psychology technician utilizing telemedicine to allow specialized multidisciplinary treatment. Interventions over 12 wks included six in-person visits for cognitive rehabilitation and six televisits for physical/functional rehabilitation. Outcomes were measured at the completion of the rehabilitation program (i.e., at 3 months), with cognitive functioning as the primary outcome. Analyses were conducted using linear regression to examine differences in 3-month outcomes between treatment groups while adjusting for baseline scores. Results:Patients tolerated the program with only one adverse event reported. At baseline both groups were well-matched. At 3-month follow-up, intervention group patients demonstrated significantly improved cognitive executive functioning on the widely used and well-normed Tower test (for planning and strategic thinking) vs. controls (median [interquartile range], 13.0 [11.5–14.0] vs. 7.5 [4.0–8.5]; adjusted p < .01). Intervention group patients also reported better performance (i.e., lower score) on one of the most frequently used measures of functional status (Functional Activities Questionnaire at 3 months vs. controls, 1.0 [0.0 –3.0] vs. 8.0 [6.0–11.8], adjusted p = .04). Conclusions:A multicomponent rehabilitation program for intensive care unit survivors combining cognitive, physical, and functional training appears feasible and possibly effective in improving cognitive performance and functional outcomes in just 3 months. Future investigations with a larger sample size should be conducted to build on this pilot feasibility program and to confirm these results, as well as to elucidate the elements of rehabilitation contributing most to improved outcomes.