David M. Griffith

Objectives Microcirculatory dysfunction drives the end-organ pathophysiology of circulatory shock but is not reflected within existing clinical indices of perfusion, such as blood pressure. The choroidal vasculature of the retina can be measured non-invasively and we hypothesised that this may reflect dysfunction in other organs. We tested the feasibility of measuring the choroid in intensive care and explored associations between choroidal measurements and clinical parameters. Design A pilot study of optical coherence tomography conducted in a sample of general intensive care unit (ICU) patients. Setting A tertiary mixed ICU within the UK. Participants 15 patients were recruited. One patient was excluded following withdrawal of active treatment. 12/14 (86%) of the remaining patients had successful baseline imaging and 6 (40%) of these had follow-up imaging within intensive care. These patients had a mean age of 56.3 years, were 71% (10/14) male and mean Acute Physiology and Chronic Health Evaluation 2 (APACHE2) score on ICU admission was 20.4. Outcome measures Choroidal anatomy, including choroidal and suprachoroidal thickness, as well as volumetric analysis of intrachoroidal blood vessels, was assessed using automated image segmentation along with clinical, physiological and biochemical data at ICU admission and after an interval of 12–72 hours. Feasibility and safety data were assessed throughout ICU admission. Results Baseline choroidal vascular index and choroidal thickness were positively associated with fluid balance, and negatively with APACHE2 score, haematocrit and albumin content. A measurable suprachoroidal space was seen in nine (75%) patients (range 25.0–110.0 microns) and was inversely associated with heart rate. There was substantial intraindividual variation in choroidal measurements over time. There were no safety concerns. Conclusions Measuring the choroid is feasible in patients with Intensive Care Society Level 2 or Level 3 requirements. The suprachoroidal space may be markedly enlarged in these patients. Exploratory associations with systemic variables suggest that the choroid may provide information about the microvascular function of other major organs. Size and change of choroidal measurements may reflect perfusion pressure and vascular leakage.

The long-term impact of systemic hypoxia resulting from acute respiratory distress syndrome (ARDS) on the function of short-lived innate immune cells is unclear. We show that patients 3–6 months after recovering from ARDS have persistently impaired circulating neutrophil effector functions and an increased susceptibility to secondary infections. These defects are linked to a widespread loss of the activating histone mark H3K4me3 in genes that are crucial for neutrophil activities. By studying healthy volunteers exposed to altitude-induced hypoxemia, we demonstrate that oxygen deprivation alone causes this long-term neutrophil reprogramming. Mechanistically, mouse models of systemic hypoxia reveal that persistent loss of H3K4me3 originates in proNeu and preNeu progenitors within the bone marrow and is linked to N-terminal histone 3 clipping, which removes the lysine residue for methylation. Thus, we present new evidence that systemic hypoxia initiates a sustained maladaptive reprogramming of neutrophil immunity by triggering histone 3 clipping and H3K4me3 loss in neutrophil progenitors.

Objectives: To synthesize the existing use, definitions, and variation in the application of hospital-free days (HFDs) as an outcome measure in randomized controlled trials (RCTs) of critically ill adults. Data Sources: Trial registries (ISRCTN, ClinicalTrials.gov) and electronic databases (CENTRAL, MEDLINE, Embase, and CINAHL PLUS). Study Selection: We included trial registrations, protocols, or articles reporting RCTs that included patients admitted to an adult ICU and had any variation of HFD as a primary or secondary outcome. Data Extraction: Data collected included definition of HFD, statistical analysis, minimal clinically important difference, method of data collection, and loss to follow-up. Risk of bias in the included studies was assessed using the relevant domains of the Cochrane Risk of Bias 2 tool (blinding of outcome assessment, incomplete outcome data, and selective reporting). Data were synthesized quantitatively using frequencies and percentages. Data Synthesis: We identified 110 eligible studies. We found considerable variability in how HFD was defined and reported. Incomplete reporting was common, with 69 studies (62.7%) not reporting all three individual components of HFD. Length of stay was omitted most frequently. Risk of bias related to outcome assessment and measurement was considered low. Fifty-two studies (47.3%) collected HFD data from routine healthcare records. The most common follow-up time points were 28 and 90 days. Over half of all studies (56 [50.9%]) did not report the number of HFD counted if a patient died during follow-up. Conclusions: This systematic review highlights the heterogeneity in the definition, reporting, and analysis of HFD. We propose guidance for the use of HFD and highlight areas for future research to allow standardization in the use and reporting of HFD in critical care research.

Background Shock involves microcirculatory dysfunction that is not suitably captured well by measurements of large vessels, such as systemic blood pressure. The outer retinal microcirculation (the choroid) can be measured non-invasively and may reflect dysfunction in other organs. We tested the feasibility of measuring the retinal choroid in an intensive care setting and explored associations between choroidal measurements and severity of disease. Methods We performed optical coherence tomography on patients admitted to the intensive treatment unit, and repeated imaging once 12-72 hours later. We measured choroidal anatomy using automated image segmentation, compared this to routine clinical data, and described change over time. Results Of fifteen patients recruited, 80% (12) had successful baseline imaging and 40% (6) of these had follow-up imaging within intensive care. At baseline, patients with thicker choroids and larger vascularity had larger cumulative fluid balance, and lower disease severity (Acute Physiology and Chronic Health Evaluation II) score, haematocrit, and albumin. A measurable suprachoroidal space was seen in 75% (9) patients and the size of this space tended to be larger in patients with lower heart rates. There was substantial intraindividual variation in choroidal measurements over time. Comment Measuring the retinal choroid is feasible in patients with critical illness. Exploratory associations with systemic variables suggest that the choroid may provide information about the microvascular function of other major organs. Size and change of choroidal measurements may reflect perfusion pressure or vascular leak in response to inflammation.

Hypoxemia is a defining feature of acute respiratory distress syndrome (ARDS), an often-fatal complication of pulmonary or systemic inflammation, yet the resulting tissue hypoxia, and its impact on immune responses, is often neglected. In the present study, we have shown that ARDS patients were hypoxemic and monocytopenic within the first 48 h of ventilation. Monocytopenia was also observed in mouse models of hypoxic acute lung injury, in which hypoxemia drove the suppression of type I interferon signaling in the bone marrow. This impaired monopoiesis resulted in reduced accumulation of monocyte-derived macrophages and enhanced neutrophil-mediated inflammation in the lung. Administration of colony-stimulating factor 1 in mice with hypoxic lung injury rescued the monocytopenia, altered the phenotype of circulating monocytes, increased monocyte-derived macrophages in the lung and limited injury. Thus, tissue hypoxia altered the dynamics of the immune response to the detriment of the host and interventions to address the aberrant response offer new therapeutic strategies for ARDS.