Chronic Critical Illness from Sepsis Is Associated with an Enhanced TCR Response.

Sepsis is characterized by a disproportionate host response to infection that often culminates in multiple organ failure. Current concepts invoke a deregulated immune reaction involving features of hyperinflammation, as well as protracted immune suppression. However, owing to the scarcity of human data, the precise origin of a long-term suppression of adaptive immunity remains doubtful. We report on an explorative clinical study of chronic critical illness (CCI) patients aimed at assessing the long-term consequences of sepsis on T cell function. Blood was drawn from 12 male CCI patients (median age 67 y, range 48-79 y) receiving continuous mechanical ventilation and renal replacement therapy in a long-term care hospital who had been treated in an external acute care hospital for severe sepsis. T cells were purified and subjected to flow cytometric immune-phenotyping and functional assays. We found that T cells from CCI patients featured higher basal levels of activation and stronger expression of the inhibitory surface receptor programmed cell death 1 compared with controls. However, T cells from CCI patients exhibited no suppressed TCR response at the level of proximal TCR signaling (activation/phosphorylation of PLCγ, Erk, Akt, LAT), activation marker upregulation (CD69, CD25, CD154, NUR77), IL-2 production, or clonal expansion. Rather, our data illustrate an augmented response in T cells from CCI patients in response to TCR/coreceptor (CD3/CD28) challenge. Thus, the present findings reveal that CCI sepsis patients feature signs of immune suppression but that their T cells exhibit a primed, rather than a suppressed, phenotype in their TCR response, arguing against a generalized T cell paralysis as a major cause of protracted immune suppression from sepsis.

Fitness and mobility training in patients with Intensive Care Unit-acquired muscle weakness (FITonICU): study protocol for a randomised controlled trial.

BACKGROUND: Critical illness myopathy (CIM) and polyneuropathy (CIP) are a common complication of critical illness. Both cause intensive-care-unit-acquired (ICU-acquired) muscle weakness (ICUAW) which increases morbidity and delays rehabilitation and recovery of activities of daily living such as walking ability. Focused physical rehabilitation of people with ICUAW is, therefore, of great importance at both an individual and a societal level. A recent systematic Cochrane review found no randomised controlled trials (RCT), and thus no supporting evidence, for physical rehabilitation interventions for people with defined CIP and CIM to improve activities of daily living. Therefore, the aim of our study is to compare the effects of an additional physiotherapy programme with systematically augmented levels of mobilisation with additional in-bed cycling (as the parallel group) on walking and other activities of daily living. METHODS/DESIGN: We will conduct a prospective, rater-masked RCT of people with ICUAW with a defined diagnosis of CIM and/or CIP in our post-acute hospital. We will randomly assign patients to one of two parallel groups in a 1:1 ratio and will use a concealed allocation. One intervention group will receive, in addition to standard ICU treatment, physiotherapy with systematically augmented levels of mobilisation (five times per week, over 2 weeks; 20 min each session; with a total of 10 additional sessions). The other intervention group will receive, in addition to standard ICU treatment, in-bed cycle sessions (same number, frequency and treatment time as the intervention group). Standard ICU treatment includes sitting balance exercise, stretching, positioning, and sit-to-stand training, and transfer training to get out of bed, strengthening exercise (in and out of bed), and stepping and assistive standing exercises. Primary efficacy endpoints will be walking ability (defined as a Functional Ambulation Category (FAC) level of ≥3) and the sum score of the Functional Status Score for the Intensive Care Unit (FSS-ICU) (range 0-22 points) assessed by a blinded tester immediately after 2 weeks of additional therapy. Secondary outcomes will include assessment of sit-to-stand recovery, overall limb strength (Medical Research Council, MRC) and grip strength, the Physical Function for the Intensive Care Unit Test-Scored (PFIT-S), the EuroQol 5 Dimensions (EQ-5D) questionnaire and the Reintegration to Normal Living Index (RNL-Index) assessed by a blinded tester. We will measure primary and secondary outcomes with blinded assessors at baseline, immediately after 2 weeks of additional therapy, and at 3 weeks and 6 months and 12 months after the end of the additional therapy intervention. Based on our sample size calculation 108 patients will be recruited from our post-acute ICU in the next 3 to 4 years. DISCUSSION: This will be the first RCT comparing the effects of two physical rehabilitation interventions for people with ICUAW due to defined CIP and/or CIM to improve walking and other activities of daily living. The results of this trial will provide robust evidence for physical rehabilitation of people with CIP and/or CIP who often require long-term care. TRIAL REGISTRATION: We registered the study on 6 April 2016 before enrolling the first patient in the trial at the German Clinical Trials Register ( www.germanctr.de ) with the identifier DRKS00010269 . This is the first version of the protocol (FITonICU study protocol).

Speed-dependent treadmill training in ambulatory hemiparetic stroke patients: a randomized controlled trial.

BACKGROUND AND PURPOSE: A new gait training strategy for patients with stroke seeks to increase walking speed through treadmill training. This study compares the effects of structured speed-dependent treadmill training (STT) (with the use of an interval paradigm to increase the treadmill speed stepwise according to principles of sport physiology) with limited progressive treadmill training (LTT) and conventional gait training (CGT) on clinical outcome measures for patients with hemiparesis. METHODS: Sixty ambulatory poststroke patients were each randomly selected to receive 1 of the 3 different gait therapies: 20 subjects were treated with STT, 20 subjects were trained to walk on a treadmill with a 20% increase of belt speed over the treatment period (LTT), and 20 subjects were treated with CGT. Treatment outcomes were assessed on the basis of overground walking speed, cadence, stride length, and Functional Ambulation Category scores. RESULTS: After a 4-week training period, the STT group scored significantly higher than the LTT and CGT groups for overground walking speed (STT versus LTT, P<0.001; STT versus CGT, P<0.001), cadence (STT versus LTT, P=0.007; STT versus CGT, P<0.001), stride length (STT versus LTT, P<0.001; STT versus CGT, P<0.001), and Functional Ambulation Category scores (STT versus LTT, P=0.007; STT versus CGT, P<0.001). CONCLUSIONS: Structured STT in poststroke patients resulted in better walking abilities than LTT or CGT. This gait training strategy provides a dynamic and integrative approach for the treatment of gait dysfunction after stroke.

Measurement of the effect of a bolus dose of intrathecal baclofen by continuous measurement of force under fibreglass casts.

Continuous intrathecal administration of baclofen with implanted programmable pump systems is recommended in the treatment of severe spasticity of cerebral origin. Prior to pump implantation, a baclofen bolus test (BBT) is used to assess the effectiveness of intrathecal baclofen using the modified Ashworth Scale (MAS) and Penn Spasm Frequency Scales (SFS). The result of a BBT may be difficult to interpret in patients with reduced joint mobility caused by contractures. The aim of this study was to apply a new spasticity measurement which would quantify and visualise the effect of a BBT in 10 patients with severe cerebral spasticity and contractures. Spasticity was recorded continuously by the measurement of force under circular fibreglass casts in 10 knee joint contractures. Force was recorded as net-torque by multiplying the force and distance between sensor and joint axis, thus allowing inter-individual comparison. MAS, SFS, and two three-hour time integrals of net-torque were determined before and after intrathecally administered baclofen. No significant changes in MAS (p = 0.1) and SFS (p = 0.07) were observed; however, a significant reduction of time integrals of net-torque after baclofen administration (p = 0.005) was found. The present study shows that the antispastic effect of intrathecally administered BBT can be quantitatively assessed and visualised using the described method. It also suggests that this method can be helpful in the assessment of the effectiveness of the BBT in patients with severe spasticity of cerebral origin and contractures.

Time course of the effect of a bolus dose of intrathecal baclofen on severe cerebral spasticity.

Continuous intrathecal administration of baclofen with implanted programmable pump systems is recommended in the treatment of severe spasticity of cerebral origin. Prior to pump implantation, a baclofen bolus test (BBT) is used to assess the effectiveness of intrathecal baclofen using clinical scales such as the Modified Ashworth Scale (MAS). In the literature, the time and period of maximum effect of a bolus dose of intrathecally administered baclofen in patients with cerebral spasticity is variously reported. The aim of the study was, therefore, to reveal the time course of the effect of a BBT on severe cerebral spasticity by the use of a recently described spasticity measurement method. Spasticity in knee joints of 13 patients with severe cerebral spasticity was repeatedly assessed using the MAS and also continuously recorded by the measurement of force under circular fibreglass casts. Force was recorded as nettorque by multiplying the force by the distance between sensor and joint axis, thus allowing inter-individual comparison. Half-hour time integrals (TI) of net-torque were determined 9 hours before and 22 hours after intrathecal baclofen administration. Post-BBT half-hour time integrals (TI(+0), TI(+0.5), to TI(+22)) were compared with the mean of 17 pre-BBT half-hour time integrals. Significantly lower post-BBT half-hour time integrals compared with were found between TI(+2) and TI(+8) (Dunnett adjusted p < 0.05). The median lowest TI after BBT of the 13 patients was TI(+4). The lowest mean MAS scores were found 4 hours after BBT. The findings suggest that the greatest effect of BBT on cerebral spasticity occurs between 2 and 8.5 hours, with a maximal effect at 4 hours after intrathecal baclofen injection. Clinical scales used to determine the effect of BBT should thus be carried out during this period-ideally at 4 hours after baclofen injection.

Contractures and involuntary muscle overactivity in severe brain injury.

PRIMARY OBJECTIVE: The aim of the present study was to evaluate the association of contractures with an increase or reduction of non-spastic muscle overactivity due to severe cerebral damage. METHODS AND PROCEDURES: Forty-five patients with tetraparesis after severe cerebral damage were investigated. Three groups were defined based on the presence of spasticity (revealed as resistance to passive stretch (= hypertonia)), and the presence of contracture of the relevant knee joint: Group(s) (17 patients with hypertonia without contracture), Group(s+c) (20 patients with hypertonia and contracture), and Group(c) (eight patients without hypertonia and with contracture). In all groups spontaneous involuntary muscle activity was assessed continuously over a 12-hour period through isometric measurement of knee joint flexion torque. A mathematical algorithm differentiated an hourly muscle activity spectrum (PI(h)). The frequency of peaks (peaks(h)) from the activity spectrum was determined. MAIN OUTCOMES AND RESULTS: We revealed that Group(s) had higher PI(h) and more frequent peaks(h) compared with Group(s+c) and Group(c) (p<0.05). Group(c) had comparable PI(h) and peaks(h) compared with Group(s+c) (p>0.05). CONCLUSION: The presence of contractures was associated with lower involuntary muscle overactivity in terms of lower PI(h) and less frequent peaks(h), indicating that contractures may be associated with reduced non-spastic positive features of the upper motor neurone syndrome in patients with severe brain damage.

The influence of illness duration and level of consciousness on the treatment effect and complication rate of serial casting in patients with severe cerebral spasticity.

OBJECTIVE: To compare the improvement and complication rates for serial casting in patients with shorter as opposed to longer illness duration, and in patients with lower as opposed to higher levels of consciousness. DESIGN: A retrospective case-comparison study. SETTING: A rehabilitation centre for adult persons with neurological disorders. SUBJECTS: Sixty-eight patients with cerebral spasticity of different aetiologies were treated with serial casting to relieve fixed contractures. INTERVENTION: Serial casting with either < 90 days (group A, 36 joints, 24 patients) or > or = 90 days (group B, 85 joints, 44 patients) duration of illness and either < 12 (group 1, 49 joints, 25 patients) or > or = 12 (group 2, 72 joints, 43 patients) Glasgow Coma Scale (GCS) scores. MAIN OUTCOME MEASURES: Percentage of normal maximum range of motion (ROM) at the completion of casting and one month after discontinuation, and number of complications due to casting procedure. RESULTS: No differences in ROM improvement between duration groups (F = 0.43, p = 0.51) and GCS groups (F = 1.3, p = 0.26) were observed. Complications in serial casting were found in 25.0% in group A, in 10.6% in group B (chi-squared = 4.2, p = 0.042), in 24.5% in group 1, and in 8.3% in group 2 (chi-squared = 6.0, p = 0.014). CONCLUSION: This study suggests that serial casting in patients with longer illness duration and higher levels of consciousness provides improvements in ROM comparable with an earlier treatment in patients with more impaired consciousness, but results in a lower occurrence of complications.

Effectiveness of serial casting in patients with severe cerebral spasticity: a comparison study.

OBJECTIVE: To compare the improvement and complication rate between a technique using a short casting interval and a more conventional changing interval. DESIGN: A retrospective case-comparison study. SETTING: A rehabilitation center for adults with neurologic disorders. PARTICIPANTS: One hundred five patients with cerebral spasticity of different etiologies treated with serial casting to relieve fixed contractures caused by increased muscle tone. INTERVENTION: Serial casting of 172 joints (42 elbow, 41 wrist, 21 knee, 68 ankle joints), with cast-changing intervals of 5 to 7 days (group 1:92 joints, 56 patients), or 1 to 4 days (group 2:80 joints, 49 patients). MAIN OUTCOME MEASURES: Percentage of normal maximum range of motion (ROM) at the completion of casting and 1 month after discontinuation, and the number of complications resulting from casting procedure. RESULTS: Improved percentage ROM immediately after serial casting and 1 month later in both groups (F=1469.5, P<.001). No differences in ROM improvement between groups were observed (F=0.3, P=.72). Complications in serial casting were found in 19.8% of 172 casting procedures, in 29.3% in group 1 and in 8.8% in group 2 (chi(2)=10.2, P=.001). Discontinuations of treatment because of casting complications or other reasons were observed in 12.8% of the entire sample, in 18.5% in group 1 and in 6.3% in group 2 (chi(2)=4.7 P=.03). CONCLUSION: Casting is effective in the treatment of fixed contractures of the upper and lower extremities caused by increased muscle tone of cerebral origin. Short changing intervals in serial casting provide improvements in ROM comparable with conventional changing intervals, and result in fewer complications.

Treatment of pressure ulcers by serial casting in patients with severe spasticity of cerebral origin.

OBJECTIVE: To assess the effectiveness of serial casting in the treatment of pressure ulcers caused by severe spasticity. DESIGN: Case series. SETTING: A clinic for the rehabilitation of persons with neurologic disorders. PATIENTS: Nine patients with 11 pressure ulcers resulting from severe cerebral spasticity, the ulcers being intractable to conventional management because of repeated friction and/or inaccessibility. INTERVENTION: Serial casting of the limb(s) with the pressure ulcer(s), with either fenestration or a cast arch providing access to the wound. MAIN OUTCOME MEASURES: Improved healing of pressure ulcers, as quantified with the National Pressure Ulcer Advisory Panel classification system. RESULTS: Within a mean of 4.6 weeks, 7 ulcers healed completely and 4 improved markedly. The casting caused no complications. Moreover, extension deficits improved markedly in all patients (105 degrees +/- 27 degrees to 17 degrees +/- 10 degrees ). CONCLUSION: Serial casting may be a valuable tool in the treatment of pressure ulcers at the extremities of patients with severe cerebral spasticity.

Immediate effects of speed-dependent treadmill training on gait parameters in early Parkinson's disease.

OBJECTIVE: To compare the immediate effects of different training interventions on gait parameters in patients with early Parkinson's disease (PD). DESIGN: Randomized, multiple intervention crossover pilot study. SETTING: A rehabilitation center for adult persons with neurologic disorders. PARTICIPANTS: Seventeen patients with early PD (Hoehn and Yahr stages I through III) and gait disturbances. INTERVENTION: Patients were randomly assigned to varying sequences of the following interventions over 4 consecutive days: structured speed-dependent treadmill training (STT), limited progressive treadmill training (LTT), conventional gait training (CGT), and a control intervention. MAIN OUTCOME MEASURES: Basic gait parameters (overground walking speed and stride length at self-adapted speeds) and parameters of gait analysis based on vertical ground reaction forces. RESULTS: STT and LTT improved all basic gait parameters and the double stance duration compared with preintervention values (P<.05). No changes were found after CGT and the control intervention (P<.05). Significantly higher gains were observed in all basic gait parameters after STT and LTT when compared with CGT and the control intervention (P<.05). Additionally, a greater reduction of double stance duration was found after STT than after the control intervention (P<.001). No significant differences in gains were observed between STT and LTT, or between CGT and the control intervention, in all gait parameters. CONCLUSION: The main disturbances of gait in PD, namely, speed and stride length, can be improved through a single intervention of STT or LTT, but not through CGT and the control intervention.