From NELA to EPOCH and beyond: enhancing the evidence base for emergency laparotomy.

Around 35,000 patients undergo emergency laparotomy surgery in the UK each year with an in-hospital 30-day mortality estimated as between 11 and 15 %. The recent publication of the First Patient Report of the National Emergency Laparotomy Audit (NELA) has provided a detailed description of individual hospital performance against national standards of care in emergency laparotomy in England and Wales. Although the standards used for audit purposes in NELA are based upon the best currently available evidence, none of the source data derives from randomised controlled studies. This commentary explores the evidence base for the standards evaluated by NELA and highlights recent and forthcoming studies that may substantially contribute to improving the evidence base in this area, thereby improving patient care and strengthening the validity of the NELA audit standards

Enhanced flow-motion complexity of skin microvascular perfusion in Sherpas and lowlanders during ascent to high altitude

An increased and more effective microvascular perfusion is postulated to play a key role in the physiological adaptation of Sherpa highlanders to the hypobaric hypoxia encountered at high altitude. To investigate this, we used Lempel-Ziv complexity (LZC) analysis to explore the spatiotemporal dynamics of the variability of the skin microvascular blood flux (BF) signals measured at the forearm and finger, in 32 lowlanders (LL) and 46 Sherpa highlanders (SH) during the Xtreme Everest 2 expedition. Measurements were made at baseline (BL) (LL: London 35 m; SH: Kathmandu 1300 m) and at Everest base camp (LL and SH: EBC 5,300 m). We found that BF signal content increased with ascent to EBC in both SH and LL. At both altitudes, LZC of the BF signals was significantly higher in SH, and was related to local slow-wave flow-motion activity over multiple spatial and temporal scales. In SH, BF LZC was also positively associated with LZC of the simultaneously measured tissue oxygenation signals. These data provide robust mechanistic information of microvascular network functionality and flexibility during hypoxic exposure on ascent to high altitude. They demonstrate the importance of a sustained heterogeneity of network perfusion, associated with local vaso-control mechanisms, to effective tissue oxygenation during hypobaric hypoxia

Divergent trajectories of cellular bioenergetics, intermediary metabolism and systemic redox status in survivors and non-survivors of critical illness.

BACKGROUND: Numerous pathologies result in multiple-organ failure, which is thought to be a direct consequence of compromised cellular bioenergetic status. Neither the nature of this phenotype nor its relevance to survival are well understood, limiting the efficacy of modern life-support. METHODS: To explore the hypothesis that survival from critical illness relates to changes in cellular bioenergetics, we combined assessment of mitochondrial respiration with metabolomic, lipidomic and redox profiling in skeletal muscle and blood, at multiple timepoints, in 21 critically ill patients and 12 reference patients. RESULTS: We demonstrate an end-organ cellular phenotype in critical illness, characterized by preserved total energetic capacity, greater coupling efficiency and selectively lower capacity for complex I and fatty acid oxidation (FAO)-supported respiration in skeletal muscle, compared to health. In survivors, complex I capacity at 48 h was 27% lower than in non-survivors (p = 0.01), but tended to increase by day 7, with no such recovery observed in non-survivors. By day 7, survivors' FAO enzyme activity was double that of non-survivors (p = 0.048), in whom plasma triacylglycerol accumulated. Increases in both cellular oxidative stress and reductive drive were evident in early critical illness compared to health. Initially, non-survivors demonstrated greater plasma total antioxidant capacity but ultimately higher lipid peroxidation compared to survivors. These alterations were mirrored by greater levels of circulating total free thiol and nitrosated species, consistent with greater reductive stress and vascular inflammation, in non-survivors compared to survivors. In contrast, no clear differences in systemic inflammatory markers were observed between the two groups. CONCLUSION: Critical illness is associated with rapid, specific and coordinated alterations in the cellular respiratory machinery, intermediary metabolism and redox response, with different trajectories in survivors and non-survivors. Unravelling the cellular and molecular foundation of human resilience may enable the development of more effective life-support strategies

Design and conduct of Caudwell Xtreme Everest: an observational cohort study of variation in human adaptation to progressive environmental hypoxia

Background: The physiological responses to hypoxaemia and cellular hypoxia are poorly understood, and inter-individual differences in performance at altitude and outcome in critical illness remain unexplained. We propose a model for exploring adaptation to hypoxia in the critically ill: the study of healthy humans, progressively exposed to environmental hypobaric hypoxia (EHH). The aim of this study was to describe the spectrum of adaptive responses in humans exposed to graded EHH and identify factors (physiological and genetic) associated with inter-individual variation in these responses.MethodsDesign: Observational cohort study of progressive incremental exposure to EHH.Setting: University human physiology laboratory in London, UK (75 m) and 7 field laboratories in Nepal at 1300 m, 3500 m, 4250 m, 5300 m, 6400 m, 7950 m and 8400 m.Participants: 198 healthy volunteers and 24 investigators trekking to Everest Base Camp (EBC) (5300 m). A subgroup of 14 investigators studied at altitudes up to 8400 m on Everest.Main outcome measures: Exercise capacity, exercise efficiency and economy, brain and muscle Near Infrared Spectroscopy, plasma biomarkers (including markers of inflammation), allele frequencies of known or suspected hypoxia responsive genes, spirometry, neurocognitive testing, retinal imaging, pupilometry. In nested subgroups: microcirculatory imaging, muscle biopsies with proteomic and transcriptomic tissue analysis, continuous cardiac output measurement, arterial blood gas measurement, trans-cranial Doppler, gastrointestinal tonometry, thromboelastography and ocular saccadometry.Results: Of 198 healthy volunteers leaving Kathmandu, 190 reached EBC (5300 m). All 24 investigators reached EBC. The completion rate for planned testing was more than 99% in the investigator group and more than 95% in the trekkers. Unique measurements were safely performed at extreme altitude, including the highest (altitude) field measurements of exercise capacity, cerebral blood flow velocity and microvascular blood flow at 7950 m and arterial blood gas measurement at 8400 m.Conclusions: This study demonstrates the feasibility and safety of conducting a large healthy volunteer cohort study of human adaptation to hypoxia in this difficult environment. Systematic measurements of a large set of variables were achieved in 222 subjects and at altitudes up to 8400 m. The resulting dataset is a unique resource for the study of genotype: phenotype interactions in relation to hypoxic adaptation

Sublingual microcirculatory blood flow and vessel density in Sherpas at high altitude

Anecdotal reports suggest that Sherpa highlanders demonstrate extraordinary tolerance to hypoxia at high altitude despite exhibiting a lower arterial oxygen content than acclimatised Lowlanders. This study tested the hypothesis that Sherpas exposed to hypobaric hypoxia on ascent to 5300m, develop increased microcirculatory blood flow as a means of maintaining normal tissue oxygen delivery. Images of the sublingual microcirculation were obtained from 64 Sherpas and 69 Lowlanders using incident dark field imaging. Serial measurements were obtained from participants undertaking an ascent from baseline testing (35m or 1300m) to Everest base camp (5300m), and following subsequent descent in Kathmandu (1300m). Microcirculatory flow index and heterogeneity index were used to provide indices of microcirculatory flow, whilst capillary density was assessed using small vessel density. Sherpas, when compared to Lowlanders, demonstrated significantly greater microcirculatory blood flow at Everest Base Camp, but not at baseline testing or on return in Kathmandu. Additionally, Sherpa blood flow exhibited greater homogeneity at 5300m and 1300m (descent) when compared to Lowlanders. Sublingual small vessel density was not different between the two cohorts at baseline testing or at 1300m, however at 5300m Sherpas capillary density was up to 30% greater. These data suggest that Sherpas have the ability to maintain a significantly greater microcirculatory flow per unit time, and flow per unit volume of tissue at high altitude, when compared to Lowlanders. These findings support the notion that peripheral vascular factors at the microcirculatory level may be important in the process of adaptation to hypoxia

A feasibility randomised controlled trial of targeted oxygen therapy in mechanically ventilated critically ill patients.

Background: Despite oxygen being the commonest drug administered to critically ill patients we do not know which oxygen saturation (SpO2) target results in optimal survival outcomes in those receiving mechanical ventilation. We therefore conducted a feasibility randomised controlled trial in the United Kingdom (UK) to assess whether it would be possible to host a larger national multi-centre trial to evaluate oxygenation targets in mechanically ventilated patients. Methods: We set out to recruit 60 participants across two sites into a trial in which they were randomised to receive conservative oxygenation (SpO2 88-92%) or usual care (control - SpO2 ≥96%). The primary outcome was feasibility; factors related to safety and clinical outcomes were also assessed. Results: A total of 34 patients were recruited into the study until it was stopped due to time constraints. A number of key barriers to success were identified during the course of the study. The conservative oxygenation intervention was feasible and appeared to be safe in this small patient cohort and it achieved wide separation of the median time-weighted average (IQR) SpO2 at 91% (90-92%) in conservative oxygenation group versus 97% (96-97%) in control group. Conclusion: Whilst conservative oxygenation was a feasible and safe intervention which achieved clear group separation in oxygenation levels, the model used in this trial will require alterations to improve future participant recruitment rates in the UK

Arterial oxygen content is precisely maintained by graded erythrocytotic responses in settings of high/normal serum iron levels, and predicts exercise capacity: an observational study of hypoxaemic patients with pulmonary arteriovenous malformations.

Oxygen, haemoglobin and cardiac output are integrated components of oxygen transport: each gram of haemoglobin transports 1.34 mls of oxygen in the blood. Low arterial partial pressure of oxygen (PaO2), and haemoglobin saturation (SaO2), are the indices used in clinical assessments, and usually result from low inspired oxygen concentrations, or alveolar/airways disease. Our objective was to examine low blood oxygen/haemoglobin relationships in chronically compensated states without concurrent hypoxic pulmonary vasoreactivity.165 consecutive unselected patients with pulmonary arteriovenous malformations were studied, in 98 cases, pre/post embolisation treatment. 159 (96%) had hereditary haemorrhagic telangiectasia. Arterial oxygen content was calculated by SaO2 x haemoglobin x 1.34/100.There was wide variation in SaO2 on air (78.5-99, median 95)% but due to secondary erythrocytosis and resultant polycythaemia, SaO2 explained only 0.1% of the variance in arterial oxygen content per unit blood volume. Secondary erythrocytosis was achievable with low iron stores, but only if serum iron was high-normal: Low serum iron levels were associated with reduced haemoglobin per erythrocyte, and overall arterial oxygen content was lower in iron deficient patients (median 16.0 [IQR 14.9, 17.4]mls/dL compared to 18.8 [IQR 17.4, 20.1]mls/dL, p<0.0001). Exercise tolerance appeared unrelated to SaO2 but was significantly worse in patients with lower oxygen content (p<0.0001). A pre-defined athletic group had higher Hb:SaO2 and serum iron:ferritin ratios than non-athletes with normal exercise capacity. PAVM embolisation increased SaO2, but arterial oxygen content was precisely restored by a subsequent fall in haemoglobin: 86 (87.8%) patients reported no change in exercise tolerance at post-embolisation follow-up.Haemoglobin and oxygen measurements in isolation do not indicate the more physiologically relevant oxygen content per unit blood volume. This can be maintained for SaO2 ≥78.5%, and resets to the same arterial oxygen content after correction of hypoxaemia. Serum iron concentrations, not ferritin, seem to predict more successful polycythaemic responses