The effect of conservative oxygen therapy on mortality in adult critically ill patients: A systematic review and meta-analysis of randomised controlled trials.

Background: Oxygen is the commonest intervention provided to critically ill patients requiring mechanical ventilation. Despite this, it is unclear how much oxygen should be administered to patients in order to promote the best clinical outcomes and it has been suggested that a strategy of conservative oxygen therapy (COT) may be advantageous. We therefore sought to answer the question of whether COT versus usual or liberal oxygen therapy was beneficial to adult patients receiving mechanical ventilation on an intensive care unit (ICU) by performing a systematic review and meta-analysis. Methods: Studies were included if they were randomised controlled trials comparing COT to liberal or usual oxygen therapy strategies in acutely ill adults (aged ⩾18 years) admitted to an ICU, and reported an outcome of interest. Studies were excluded if they were limited to a specific single disease diagnosis. The review was registered on PROSPERO (CRD42022308436). Risk of bias was assessed using a modified Cochrane Risk of Bias assessment tool. Effect estimates were pooled using a random effects model with the between study variance estimated using restricted maximum likelihood and standard errors calculated using the method of Hartung-Knapp/Sidik-Jonkman. Between study heterogeneity was quantified using the I2 statistic. The certainty in the body of evidence was assessed using GRADE criteria. Results: Nine eligible studies with 5727 participants fulfilled all eligibility criteria. Trials varied in their definitions of COT and liberal or usual oxygen therapy. The pooled estimate of risk ratio for 90 day mortality for COT versus comparator was 0.99 (95% confidence interval 0.88-1.12, 95% prediction interval 0.82-1.21). There was low heterogeneity among studies (I2 = 22.4%). The finding that mortality was similar for patients managed with COT or usual/liberal oxygen therapy was graded as moderate certainty. Conclusions: In critically ill adults admitted to an ICU, COT is neither beneficial nor harmful when compared to usual or liberal oxygen therapy. Trials to date have been inconsistent in defining both COT and liberal or usual oxygen therapy, which may have had an impact on the results of this meta-analysis. Future research should focus on unifying definitions and outcome measures.

Perioperative redox changes in patients undergoing hepato-pancreatico-biliary cancer surgery.

BACKGROUND: Tissue injury induces inflammation and the surgical stress response, which are thought to be central to the orchestration of recovery or deterioration after surgery. Enhanced formation of reactive oxygen and nitrogen species accompanies the inflammatory response and triggers separate but integrated reduction/oxidation (redox) pathways that lead to oxidative and/or nitrosative stress (ONS). Quantitative information on ONS in the perioperative period is scarce. This single-centre exploratory study investigated the effects of major surgery on ONS and systemic redox status and their potential associations with postoperative morbidity. METHODS: Blood was collected from 56 patients at baseline, end of surgery (EoS) and the first postoperative day (day-1). Postoperative morbidity was recorded using the Clavien-Dindo classification and further categorised into minor, moderate and severe. Plasma/serum measures included markers of lipid oxidation (thiobarbituric acid-reactive substances; TBARS, 4-hydroxynonenal; 4-HNE, 8-iso-prostaglandin F2⍺; 8-isoprostanes). Total reducing capacity was measured using total free thiols (TFTs) and ferric-reducing ability of plasma (FRAP). Nitric oxide (NO) formation/metabolism was measured using cyclic guanosine monophosphate (cGMP), nitrite, nitrate and total nitroso-species (RxNO). Interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF-⍺) were measured to evaluate inflammation. RESULTS: Both oxidative stress (TBARS) and nitrosative stress (total nitroso-species) increased from baseline to EoS (+14%, P = 0.003 and +138%, P < 0.001, respectively), along with an increase in overall reducing capacity (+9%, P = 0.03) at EoS and protein-adjusted total free thiols (+12%, P = 0.001) at day-1 after surgery. Nitrite, nitrate and cGMP concentrations declined concomitantly from baseline to day-1. Baseline nitrate was 60% higher in the minor morbidity group compared to severe (P = 0.003). The increase in intraoperative TBARS was greater in severe compared to minor morbidity (P = 0.01). The decline in intraoperative nitrate was more marked in the minor morbidity group compared to severe (P < 0.001), whereas the cGMP decline was greatest in the severe morbidity group (P = 0.006). CONCLUSION: In patients undergoing major HPB surgery, intraoperative oxidative and nitrosative stress increased, with a concomitant increase in reductive capacity. Baseline nitrate was inversely associated with postoperative morbidity, and the hallmarks of poor postoperative outcome include changes in both oxidative stress and NO metabolism.

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.

Human adaptation to hypoxia in critical illness.

The syndrome of critical illness is a complex physiological stressor that can be triggered by diverse pathologies. It is widely believed that organ dysfunction and death result from bioenergetic failure caused by inadequate cellular oxygen supply. Teleologically, life has evolved to survive in the face of stressors by undergoing a suite of adaptive changes. Adaptation not only comprises alterations in systemic physiology but also involves molecular reprogramming within cells. The concept of cellular adaptation in critically ill patients is a matter of contention in part because medical interventions mask underlying physiology, creating the artificial construct of "chronic critical illness," without which death would be imminent. Thus far, the intensive care armamentarium has not targeted cellular metabolism to preserve a temporary equilibrium but instead attempts to normalize global oxygen and substrate delivery. Here, we review adaptations to hypoxia that have been demonstrated in cellular models and in human conditions associated with hypoxia, including the hypobaric hypoxia of high altitude, the intrauterine low-oxygen environment, and adult myocardial hibernation. Common features include upregulation of glycolytic ATP production, enhancement of respiratory efficiency, downregulation of mitochondrial density, and suppression of energy-consuming processes. We argue that these innate cellular adaptations to hypoxia represent potential avenues for intervention that have thus far remained untapped by intensive care medicine.

Correction to: Intraoperative oxygenation in adult patients undergoing surgery (iOPS): a retrospective observational study across 29 UK hospitals.

[This corrects the article DOI: 10.1186/s13741-018-0098-3.].

The case for a chronobiological approach to neonatal care.

Time of day is a critical factor for most biological functions, but concepts from the field of chronobiology have yet to be fully translated to clinical practice. Circadian rhythms, generated internally and synchronised to the external environment, promote function and support survival in almost every living species. Fetal circadian rhythms can be observed in utero from 30weeks gestation, coupled to the maternal rhythm, but synchronise to the external environment only after birth. Important cues for synchronisation include the light/dark cycle, the timing of feeding, and exposure to melatonin in breast milk. Disruption to these cues may occur during admission to the neonatal intensive care unit. This can impair the development of circadian rhythms, and influence survival and function in the neonatal period, with a potential to impact health and well-being throughout adult life. Here we outline the rationale and evidence to support a chronobiological approach to neonatal care.

Intraoperative oxygenation in adult patients undergoing surgery (iOPS): a retrospective observational study across 29 UK hospitals.

Background: Considerable controversy remains about how much oxygen patients should receive during surgery. The 2016 World Health Organization (WHO) guidelines recommend that intubated patients receive a fractional inspired oxygen concentration (FIO2) of 0.8 throughout abdominal surgery to reduce the risk of surgical site infection. However, this recommendation has been widely criticised by anaesthetists and evidence from other clinical contexts has suggested that giving a high concentration of oxygen might worsen patient outcomes. This retrospective multi-centre observational study aimed to ascertain intraoperative oxygen administration practice by anaesthetists across parts of the UK. Methods: Patients undergoing general anaesthesia with an arterial catheter in situ across hospitals affiliated with two anaesthetic trainee audit networks (PLAN, SPARC) were eligible for inclusion unless undergoing cardiopulmonary bypass. Demographic and intraoperative oxygenation data, haemoglobin saturation and positive end-expiratory pressure were retrieved from anaesthetic charts and arterial blood gases (ABGs) over five consecutive weekdays in April and May 2017. Results: Three hundred seventy-eight patients from 29 hospitals were included. Median age was 66 years, 205 (54.2%) were male and median ASA grade was 3. One hundred eight (28.6%) were emergency cases. An anticipated difficult airway or raised BMI was documented preoperatively in 31 (8.2%) and 45 (11.9%) respectively. Respiratory or cardiac comorbidity was documented in 103 (27%) and 83 (22%) respectively. SpO2 < 96% was documented in 83 (22%) patients, with 7 (1.9%) patients desaturating < 88% at any point intraoperatively. The intraoperative FIO2 ranged from 0.25 to 1.0, and median PaO2/FIO2 ratios for the first four arterial blood gases taken in each case were 24.6/0.5, 23.4/0.49, 25.7/0.46 and 25.4/0.47 respectively. Conclusions: Intraoperative oxygenation currently varies widely. An intraoperative FIO2 of 0.5 currently represents standard intraoperative practice in the UK, with surgical patients often experiencing moderate levels of hyperoxaemia. This differs from both WHO's recommendation of using an FIO2 of 0.8 intraoperatively, and also, the value most previous interventional oxygen therapy trials have used to represent standard care (typically FIO2 = 0.3). These findings should be used to aid the design of future intraoperative oxygen studies.

Clinical chronobiology: a timely consideration in critical care medicine.

A fundamental aspect of human physiology is its cyclical nature over a 24-h period, a feature conserved across most life on Earth. Organisms compartmentalise processes with respect to time in order to promote survival, in a manner that mirrors the rotation of the planet and accompanying diurnal cycles of light and darkness. The influence of circadian rhythms can no longer be overlooked in clinical settings; this review provides intensivists with an up-to-date understanding of the burgeoning field of chronobiology, and suggests ways to incorporate these concepts into daily practice to improve patient outcomes. We outline the function of molecular clocks in remote tissues, which adjust cellular and global physiological function according to the time of day, and the potential clinical advantages to keeping in time with them. We highlight the consequences of "chronopathology", when this harmony is lost, and the risk factors for this condition in critically ill patients. We introduce the concept of "chronofitness" as a new target in the treatment of critical illness: preserving the internal synchronisation of clocks in different tissues, as well as external synchronisation with the environment. We describe methods for monitoring circadian rhythms in a clinical setting, and how this technology may be used for identifying optimal time windows for interventions, or to alert the physician to a critical deterioration of circadian rhythmicity. We suggest a chronobiological approach to critical illness, involving multicomponent strategies to promote chronofitness (chronobundles), and further investment in the development of personalised, time-based treatment for critically ill patients.

Tackling delirium: a crucial target for improving clinical outcomes.

Delirium is a common and debilitating syndrome in hospitalized patients, and its impact on mortality, morbidity and duration of hospital admission is increasingly apparent. Delirium is a complex phenomenon, for which there is no specific treatment, but research over the last decade has revealed contributing factors, many of which are modifiable, and preventative strategies have demonstrated benefit. This review highlights the importance of reducing the impact of delirium on hospitalized patients, and summarizes the current evidence for strategies to achieve this. Current recommendations focus on the pre-emptive implementation of multi-modal non-pharmacological interventions to reduce the occurrence of delirium in the first place, and routine monitoring using validated tools to identify delirious patients early. Potential therapies for established delirium remain controversial.

The significance of circadian rhythms and dysrhythmias in critical illness.

Many physiological and cellular processes cycle with time, with the period between one peak and the next being roughly equal to 24 h. These circadian rhythms underlie 'permissive homeostasis', whereby anticipation of periods of increased energy demand or stress may enhance the function of individual cells, organ systems or whole organisms. Many physiological variables related to survival during critical illness have a circadian rhythm, including the sleep/wake cycle, haemodynamic and respiratory indices, immunity and coagulation, but their clinical significance remains underappreciated. Critically ill patients suffer from circadian dysrhythmia, manifesting overtly as sleep disturbance and delirium, but with widespread covert effects on cellular and organ function. Environmental and pharmacological strategies that ameliorate or prevent circadian dysrhythmia have demonstrated clinical benefit. Harnessing these important biological phenomena to match metabolic supply to demand and bolster cell defenses at the apposite time may be a future therapeutic strategy in the intensive care unit.

The human physiological impact of global deoxygenation.

There has been a clear decline in the volume of oxygen in Earth's atmosphere over the past 20 years. Although the magnitude of this decrease appears small compared to the amount of oxygen in the atmosphere, it is difficult to predict how this process may evolve, due to the brevity of the collected records. A recently proposed model predicts a non-linear decay, which would result in an increasingly rapid fall-off in atmospheric oxygen concentration, with potentially devastating consequences for human health. We discuss the impact that global deoxygenation, over hundreds of generations, might have on human physiology. Exploring the changes between different native high-altitude populations provides a paradigm of how humans might tolerate worsening hypoxia over time. Using this model of atmospheric change, we predict that humans may continue to survive in an unprotected atmosphere for ~3600 years. Accordingly, without dramatic changes to the way in which we interact with our planet, humans may lose their dominance on Earth during the next few millennia.

Five- to 18-year follow-up for treatment of trapeziometacarpal osteoarthritis: a prospective comparison of excision, tendon interposition, and ligament reconstruction and tendon interposition.

PURPOSE: To investigate whether palmaris longus interposition or flexor carpi radialis ligament reconstruction and tendon interposition improve the outcome of trapezial excision for the treatment of basal joint arthritis after a minimum follow-up of 5 years. METHODS: We randomized 174 thumbs with trapeziometacarpal osteoarthritis into 3 groups to undergo simple trapeziectomy, trapeziectomy with palmaris longus interposition, or trapeziectomy with ligament reconstruction and tendon interposition using 50% of the flexor carpi radialis tendon. A K-wire was passed across the trapezial void and retained for 4 weeks, and a thumb spica was used for 6 weeks in all 3 groups. We reviewed 153 thumbs after a minimum of 5 years (median, 6 y; range, 5-18 y) after surgery with subjective and objective assessments of thumb pain, function, and strength. RESULTS: There was no difference in the pain relief achieved in the 3 treatment groups, with good results in 120 (78%) patients. Grip strength and key and tip pinch strengths did not differ among the 3 groups and range of movement of the thumb was similar. Few complications persisted after 5 years, and these were distributed evenly among the 3 groups. Compared with the results at 1 year in the same group of patients, the good pain relief achieved was maintained in the longer term, irrespective of the type of surgery. While improvements in grip strength achieved at 1 year after surgery were preserved, the key and tip pinch strengths deteriorated with time, but the type of surgery did not influence this. CONCLUSIONS: The outcomes of these 3 variations of trapeziectomy were similar after a minimum follow-up of 5 years. There appears to be no benefit to tendon interposition or ligament reconstruction in the longer term.