Critical care beyond organ support: the importance of geriatric rehabilitation.

Very old critically ill patients pose a growing challenge for intensive care. Critical illness and the burden of treatment in the intensive care unit (ICU) can lead to a long-lasting decline of functional and cognitive abilities, especially in very old patients. Multi-complexity and increased vulnerability to stress in these patients may lead to new and worsening disabilities, requiring careful assessment, prevention and rehabilitation. The potential for rehabilitation, which is crucial for optimal functional outcomes, requires a systematic, multi-disciplinary approach and careful long-term planning during and following ICU care. We describe this process and provide recommendations and checklists for comprehensive and timely assessments in the context of transitioning patients from ICU to post-ICU and acute hospital care, and review the barriers to the provision of good functional outcomes.

The trajectory of very old critically ill patients.

The demographic shift, together with financial constraint, justify a re-evaluation of the trajectory of care of very old critically ill patients (VIP), defined as older than 80 years. We must avoid over- as well as under-utilisation of critical care interventions in this patient group and ensure the inclusion of health care professionals, the patient and their caregivers in the decision process. This new integrative approach mobilises expertise at each step of the process beginning prior to intensive care unit (ICU) admission and extending to long-term follow-up. In this review, several international experts have contributed to provide recommendations that can be universally applied. Our aim is to define a minimum core dataset of information to be shared and discussed prior to ICU admission and to facilitate the shared-decision-making process with the patient and their caregivers, throughout the patient journey. Documentation of uncertainty may contribute to a tailored level of care and ultimately to discussions around possible limitations of life sustaining treatments. The goal of ICU care is not only to avoid death, but more importantly to maintain an acceptable quality of life and functional autonomy after hospital discharge. Societal consideration is important to highlight, together with alternatives to ICU admission. We discuss challenges for the future and potential areas of research. In summary, this review provides a state-of-the-art current overview and aims to outline future directions to address the challenges in the treatment of VIP.

A Comparison of High and Usual Protein Dosing in Critically Ill Patients With Obesity: A Post Hoc Analysis of an International, Pragmatic, Single-Blinded, Randomized Clinical Trial.

OBJECTIVES: Across guidelines, protein dosing for critically ill patients with obesity varies considerably. The objective of this analysis was to evaluate whether this population would benefit from higher doses of protein. DESIGN: A post hoc subgroup analysis of the effect of higher protein dosing in critically ill patients with high nutritional risk (EFFORT Protein): an international, multicenter, pragmatic, registry-based randomized trial. SETTING: Eighty-five adult ICUs across 16 countries. PATIENTS: Patients with obesity defined as a body mass index (BMI) greater than or equal to 30 kg/m 2 ( n = 425). INTERVENTIONS: In the primary study, patients were randomized into a high-dose (≥ 2.2 g/kg/d) or usual-dose protein group (≤ 1.2 g/kg/d). MEASUREMENTS AND MAIN RESULTS: Protein intake was monitored for up to 28 days, and outcomes (time to discharge alive [TTDA], 60-d mortality, days of mechanical ventilation [MV], hospital, and ICU length of stay [LOS]) were recorded until 60 days post-randomization. Of the 1301 patients in the primary study, 425 had a BMI greater than or equal to 30 kg/m 2 . After adjusting for sites and covariates, we observed a nonsignificant slower rate of TTDA with higher protein that ruled out a clinically important benefit (hazard ratio, 0.78; 95% CI, 0.58-1.05; p = 0.10). We found no evidence of difference in TTDA between protein groups when subgroups with different classes of obesity or patients with and without various nutritional and frailty risk variables were examined, even after the removal of patients with baseline acute kidney injury. Overall, 60-day mortality rates were 31.5% and 28.2% in the high protein and usual protein groups, respectively (risk difference, 3.3%; 95% CI, -5.4 to 12.1; p = 0.46). Duration of MV and LOS in hospital and ICU were not significantly different between groups. CONCLUSIONS: In critically ill patients with obesity, higher protein doses did not improve clinical outcomes, including those with higher nutritional and frailty risk.

The clinical frailty scale - does it predict outcome of the very-old in UK ICUs?

Introduction: The age of patients admitted into critical care in the UK is increasing. Clinical decisions for very-old patients, usually defined as over 80, can be challenging. Clinicians are frequently asked to predict outcomes as part of discussions around the pros and cons of an intensive care unit (ICU) admission. Measures of overall health in old age, such as the clinical frailty scale (CFS), are increasingly used to help guide these discussions. We aimed to understand the characteristics of the very-old critically unwell population in the UK and the associations between frailty and outcome of an ICU admission in our healthcare system (National Health Service, NHS). Methods: Baseline characteristics, ICU interventions and outcomes (ICU- and 30-day mortality) were recorded for sequential admissions of very old patients to UK ICUs as part of the European VIP 1 and 2 studies. Patient characteristics, interventions and outcome measures were compared by frailty group using standard statistical tests. Multivariable logistic regression modelling was undertaken to test association between baseline characteristics, admission type and outcome. Results: 1858 participants were enrolled from 95 ICUs in the UK. The median age was 83. The median CFS was 4 (IQR 3-5). 30-day survival was significantly lower in the frail group (CFS > 4, 58%) compared to vulnerable (CFS = 4, 65%) and fit (CFS < 4 68%, p = .004). Sequential organ failure assessment (SOFA) score, reason for admission and CFS were all independently associated with increased 30-day mortality (p < .01). Conclusion: In the UK, frailty is associated with an increase in mortality at 30-days following an ICU admission. At moderate frailty (CFS 5-6), three out of every five patients admitted survived to 30-days. This is a similar mortality to septic shock.

Differences in lipopolysaccharide- and lipoteichoic acid-induced cytokine/chemokine expression.

PURPOSE: To investigate differences in cytokine/chemokine release in response to lipoteichoic acid (LTA) or lipopolysaccharide (LPS) and contributing cellular mechanisms, in order to improve understanding of the pathogenesis of sepsis. METHODS: Levels of cytokines/chemokines were measured in plasma and peritoneal lavage fluid of 10-week-old male mice (C57/B16) following intraperitoneal injection of LTA or LPS (250 µg), and in supernatants of murine J774.2 cells, immortalised blood monocytes, or isolated human monocytes treated with LTA or LPS (0-10 µg/ml). The role of cytokine/chemokine messenger RNA (mRNA) stability versus nuclear factor-kappaB (NF-κB) and activator protein-1 (AP-1) in mediating cytokine/chemokine release in J774 cells was also assessed. RESULTS: In mice, plasma levels of keratinocyte-derived chemokine (KC), macrophage inflammatory protein (MIP)-2, interleukin (IL)-10, interferon (IFN)-γ and tumour necrosis factor-alpha (TNF-α) and peritoneal lavage fluid levels of KC, MIP-2 and TNF-α increased significantly 1 h after LPS. Only KC and MIP-2 levels increased 1 h after LTA. LPS-treated (10 µg/ml) J774 cells released MIP-2, IL-10, IFN-γ and TNF-α but not KC (24 h), whereas cells treated with 10 µg/ml LTA released only MIP-2. LPS-stimulated human monocytes released IL-10 and IL-8 (24 h); by contrast, LTA-treated cells released only IL-8. LPS and LTA activated NF-κB and AP-1 in J774 cells. The protein synthesis inhibitor cycloheximide abolished LPS-induced IL-10 mRNA expression and increased LTA- and LPS-induced mRNA for MIP-2 in J774 cells. CONCLUSION: LTA and LPS, at clinically relevant concentrations, induced differential cytokine/chemokine release in vitro and in vivo, via effects distal to activation of NF-κB/AP-1 that might include chromatin remodelling or mRNA stability.

Increased plasma thioredoxin levels in patients with sepsis: positive association with macrophage migration inhibitory factor.

PURPOSE: To establish the relationship between plasma levels of thioredoxin (Trx) and macrophage migration inhibitory factor (MIF) in systemic inflammatory stress syndrome (SIRS)/sepsis. METHODS: Enzyme-linked immunosorbent assay measurements of Trx, MIF, IL-6, -8, and -10 and enzyme-linked fluorescent assay determination of procalcitonin (PCT) in plasma from patients with SIRS/sepsis, neutropenic sepsis, healthy volunteers and pre-oesophagectomy patients. RESULTS: Thioredoxin was significantly higher in SIRS/sepsis patients [101.3 ng ml(-1), interquartile range (IQR) 68.7-155.6, n = 32] compared with that in healthy controls (49.5 ng ml(-1), IQR 31.4-71.1, P < 0.001, n = 17) or pre-oesophagectomy patients (40.5 ng ml(-1), IQR 36.9-63.2, P < 0.01, n = 7), but was not raised in neutropenics (n = 5). MIF levels were also significantly higher in SIRS/sepsis patients (12.1 ng ml(-1), IQR 9.5-15.5, n = 35), but not in the neutropenic group, when compared with healthy controls (9.3 ng ml(-1), IQR 7.3-10.7, P < 0.01, n = 20). Trx levels correlated, positively, with MIF levels and APACHE II scores. Plasma levels of IL-6, -8 and -10 and PCT increased significantly in patients with SIRS/sepsis (P < 0.001) and with neutropenic sepsis, but did not correlate with Trx or MIF levels. CONCLUSION: Plasma levels of Trx, MIF, IL-6, -8, -10 and PCT were raised in patients with SIRS/sepsis. Comparisons between mediators suggest a unique correlation of Trx with MIF. Moreover, Trx and MIF differed from cytokines and PCT in that levels were significantly lower in patients with neutropenia compared with the main SIRS/sepsis group. By contrast, IL-8 and PCT levels were significantly greater in the neutropenic patient group. The link between MIF and Trx highlighted in this study has implications for future investigations into the pathogenesis of SIRS/sepsis.

Severe sepsis and Toll-like receptors.

Severe sepsis dominates the mortality of non-cardiac intensive care units. The ingenious Toll-like receptor (TLR) system can recognise many infectious organisms through relatively few receptors to trigger pro-inflammatory and anti-inflammatory cytokine release. Further complexity arises from positive and negative signalling feedback loops. Severe sepsis may be a consequence of an inappropriately excessive response or inadequate endogenous negative feedback. Therapies targeting these pathways are currently being evaluated. Alternatively, in clinical scenarios such as compensatory anti-inflammatory response syndrome, chronic viral sepsis or inadequate vaccine function, TLR signalling may be inadequate. TLR agonists may augment the innate response and are being investigated.

Sepsis since the discovery of Toll-like receptors: disease concepts and therapeutic opportunities.

OBJECTIVE: Sepsis and its sequelae are the leading cause of death in critically ill patients. Discovery in the late 1990s of Toll-like receptors as primary sensors of microbial infection led to significant advances in understanding the pathogenesis of sepsis, including emerging differences between Gram-positive and Gram-negative infection and the potential for the manipulation of Toll-like receptors for the treatment of sepsis. This review describes these advances. METHODS: Bibliographic search of the literature since 1999, with particular emphasis on the conceptual and therapeutic implications of Toll-like receptors for patients with systemic sepsis. RESULTS AND CONCLUSIONS: Toll-like receptors initiate the inflammatory processes that underlie the clinical response to infection and therefore represent an important putative target for therapeutic intervention.

An unusual case of abdominal pain in a patient with cystic fibrosis.

We report the case of a 19 year old man with cystic fibrosis (CF) who presented with atypical abdominal pain precipitated by pressing his ribs. This was subsequently discovered to be referred pain from an intercostal schwannoma. Surgical resection led to a resolution of his symptoms.