Effectiveness of prone position in spontaneously breathing patients with COVID-19: A prospective cohort study.

We present a single centre study describing the effect of awake prone position (PP) on oxygenation and clinical outcomes in spontaneously breathing patients with novel coronavirus disease (COVID-19). Between 1st March and 30th April 2020, forty eight of 138 patients managed outside of the critical care unit with facemask oxygen, high flow nasal oxygen (HFNO) or continuous positive airway pressure (CPAP), underwent PP. Prone position was associated with significant improvement in oxygenation, lower ICU admission, tracheal intubation, and shorter ICU length of stay. Lack of response to PP may be an indicator of treatment failure, requiring early escalation.

Long term outcomes following rib fracture fixation in patients with major chest trauma.

BACKGROUND: Severe chest injuries are associated with significant morbidity and mortality. Surgical rib fixation has become a more commonplace procedure to improve chest wall mechanics, pain, and function. The aim of this study was to characterise the epidemiology and long-term functional outcomes of chest trauma patients who underwent rib fixation in a major trauma centre (MTC). METHODOLOGY: This was a retrospective review (2014-19) of all adult patients with significant chest injury who had rib fixation surgery following blunt trauma to the chest. The primary outcome was functional recovery after hospital discharge, and secondary outcomes included length of intensive care unit (ICU) and hospital stay, maximum organ support, tracheostomy insertion, ventilator days. RESULTS: 60 patients underwent rib fixation. Patients were mainly male (82%) with median age 52 (range 24-83) years, injury severity score (ISS) of 29 (21-38), 10 (4-19) broken ribs, and flail segment in 90% of patients. Forty-six patients (77%) had a good outcome (GOSE grade 6-8). Patients in the poor outcome group (23%; GOSE 1-5) tended to be older [55 (39-83) years vs. 51 (24-78); p = 0.05] and had longer length of hospital stay [42 (19-82) days vs. 24 (7-90); p<0.01]. Injury severity, rate of mechanical ventilation or organ dysfunction did not affect long term outcome. Nineteen patients (32%) were not mechanically ventilated. CONCLUSIONS: Rib fixation was associated with good long-term outcomes in severely injured patients. Age was the only predictor of long-term outcome. The results suggest that rib fixation be considered in patients with severe chest injuries and may also benefit those who are not mechanically ventilated but are at risk of deterioration.

Relationship between norepinephrine dose, tachycardia and outcome in septic shock: A multicentre evaluation.

PURPOSE: Septic shock is associated with massive release of endogenous catecholamines. Adrenergic agents may exacerbate catecholamine toxicity and contribute to poor outcomes. We sought to determine whether an association existed between tachycardia and mortality in septic shock patients requiring norepinephrine for more than 6 h despite adequate volume resuscitation. MATERIALS AND METHODS: Multicentre retrospective observational study on 730 adult patients in septic shock consecutively admitted to eight European ICUs between 2011 and 2013. Three timepoints were selected: T1 (first hour of infusion of norepinephrine), Tpeak (time of highest dose during the first 24 h of treatment), and T24 (24-h post-T1). Binary logistic regression models were constructed for the three time-points. RESULTS: Overall ICU mortality was 38.4%. Mortality was higher in those requiring high-dose (≥0.3 mcg/kg/min) versus low-dose (<0.3 mcg/kg/min) norepinephrine at T1 (53.4% vs 30.6%; p < 0.001) and T24 (61.4% vs 20.4%; p < 0.0001). Patients requiring high-dose with concurrent tachycardia had higher mortality at T1; in the low-dose group tachycardia was not associated with mortality. Resolving tachycardia (from T1 to T24) was associated with lower mortality compared to patients where tachycardia persisted (27.8% vs 46.4%; p = 0.001). CONCLUSIONS: Use of high-dose norepinephrine and concurrent tachycardia are associated with poor outcomes in septic shock.

Elevated urea-to-creatinine ratio provides a biochemical signature of muscle catabolism and persistent critical illness after major trauma.

PURPOSE: Muscle wasting is common amongst patients with persistent critical illness and associated with increased urea production, but reduced creatinine production. We hypothesised that elevated urea:creatinine ratio would provide a biochemical signature of muscle catabolism and characterise prolonged intensive care (ICU) admissions after major trauma. METHODS: Using pre-specified hypotheses, we analysed two existing data sets of adults surviving ≥ 10 days following admission to ICU after major trauma. We analysed trauma-ICU admissions to the major trauma centre serving the North East London and Essex Trauma Network, with a verification cohort of trauma-ICU cases from the MIMIC-III database. We compared serum urea, creatinine, and urea:creatinine ratio (ratio of concentrations in mmol/L) between patients with persistent critical illness (defined as ICU stay of ≥ 10 days) and those discharged from ICU before day 10. In a sub-group undergoing sequential abdominal computerised tomography (CT), we measured change in cross-sectional muscle area (psoas muscle at L4 vertebral level and total muscle at L3 level) and assessed for relationships with urea:creatinine ratio and ICU stay. Results are provided as median [interquartile range]. RESULTS: We included 1173 patients between February 1st, 2012 and May 1st, 2016. In patients with ICU stay ≥ 10 days, day 10 urea:creatinine ratio had increased by 133% [72-215], from 62 [46-78] to 141 [114-178], p < 0.001; this rise was larger (p < 0.001) than in patients discharged from ICU before day 10, 59% [11-122%], 61 [45-75] to 97 [67-128], p < 0.001. A similar separation in trajectory of urea:creatinine ratio was observed in 2876 trauma-ICU admissions from MIMIC-III. In 107 patients undergoing serial CTs, decrease in L4 psoas and L3 muscle cross-sectional areas between CTs significantly correlated with time elapsed (R2 = 0.64 and R2 = 0.59, respectively). Rate of muscle decrease was significantly greater (p < 0.001 for interaction terms) in 53/107 patients with the second CT during evolving, current or recent persistent critical illness. In this group, at the second CT urea:creatinine ratio negatively correlated with L4 psoas and L3 muscle cross-sectional areas (R2 0.39, p < 0.001 and 0.44, p < 0.001). CONCLUSION: Elevated urea:creatinine ratio accompanies skeletal muscle wasting representing a biochemical signature of persistent critical illness after major trauma. If prospectively confirmed, urea:creatinine ratio is a potential surrogate of catabolism to examine in epidemiological and interventional studies.

Acute Kidney Injury in Trauma Patients Admitted to Critical Care: Development and Validation of a Diagnostic Prediction Model.

Acute Kidney Injury (AKI) complicating major trauma is associated with increased mortality and morbidity. Traumatic AKI has specific risk factors and predictable time-course facilitating diagnostic modelling. In a single centre, retrospective observational study we developed risk prediction models for AKI after trauma based on data around intensive care admission. Models predicting AKI were developed using data from 830 patients, using data reduction followed by logistic regression, and were independently validated in a further 564 patients. AKI occurred in 163/830 (19.6%) with 42 (5.1%) receiving renal replacement therapy (RRT). First serum creatinine and phosphate, units of blood transfused in first 24 h, age and Charlson score discriminated need for RRT and AKI early after trauma. For RRT c-statistics were good to excellent: development: 0.92 (0.88-0.96), validation: 0.91 (0.86-0.97). Modelling AKI stage 2-3, c-statistics were also good, development: 0.81 (0.75-0.88) and validation: 0.83 (0.74-0.92). The model predicting AKI stage 1-3 performed moderately, development: c-statistic 0.77 (0.72-0.81), validation: 0.70 (0.64-0.77). Despite good discrimination of need for RRT, positive predictive values (PPV) at the optimal cut-off were only 23.0% (13.7-42.7) in development. However, PPV for the alternative endpoint of RRT and/or death improved to 41.2% (34.8-48.1) highlighting death as a clinically relevant endpoint to RRT.

Skeletal muscle dysfunction is associated with derangements in mitochondrial bioenergetics (but not UCP3) in a rodent model of sepsis.

Muscle dysfunction is a common feature of severe sepsis and multiorgan failure. Recent evidence implicates bioenergetic dysfunction and oxidative damage as important underlying pathophysiological mechanisms. Increased abundance of uncoupling protein-3 (UCP3) in sepsis suggests increased mitochondrial proton leak, which may reduce mitochondrial coupling efficiency but limit reactive oxygen species (ROS) production. Using a murine model, we examined metabolic, cardiovascular, and skeletal muscle contractile changes following induction of peritoneal sepsis in wild-type and Ucp3(-/-) mice. Mitochondrial membrane potential (Δψm) was measured using two-photon microscopy in living diaphragm, and contractile function was measured in diaphragm muscle strips. The kinetic relationship between membrane potential and oxygen consumption was determined using a modular kinetic approach in isolated mitochondria. Sepsis was associated with significant whole body metabolic suppression, hypothermia, and cardiovascular dysfunction. Maximal force generation was reduced and fatigue accelerated in ex vivo diaphragm muscle strips from septic mice. Δψm was lower in the isolated diaphragm from septic mice despite normal substrate oxidation kinetics and proton leak in skeletal muscle mitochondria. Even though wild-type mice exhibited an absolute 26 ± 6% higher UCP3 protein abundance at 24 h, no differences were seen in whole animal or diaphragm physiology, nor in survival rates, between wild-type and Ucp3(-/-) mice. In conclusion, this murine sepsis model shows a hypometabolic phenotype with evidence of significant cardiovascular and muscle dysfunction. This was associated with lower Δψm and alterations in mitochondrial ATP turnover and the phosphorylation pathway. However, UCP3 does not play an important functional role, despite its upregulation.

The metabolic phenotype of rodent sepsis: cause for concern?

PURPOSE: Rodent models of sepsis are frequently used to investigate pathophysiological mechanisms and to evaluate putative therapeutic strategies. However, preclinical efficacy in these models has failed to translate to the clinical setting. We thus questioned the representativeness of such models and herein report a detailed comparison of the metabolic and cardiovascular phenotypes of long-term faecal peritonitis in fluid-resuscitated rats and mice with similar mortality profiles. METHODS: We conducted prospective laboratory-controlled studies in adult male Wistar rats and C57 black mice. Animals were made septic by intraperitoneal injection of faecal slurry. Rats received continuous intravenous fluid resuscitation, whereas mice received intermittent fluid boluses subcutaneously. Sham-treated animals served as controls. Survival was assessed over 72 h. In separate studies, whole body metabolism (O2 consumption, CO2 production) was measured over 24 h with echocardiography performed at early (6 h) and established (24 h) phases of sepsis. Blood gas analysis was performed at 6 h (rats) and 24 h (rats, mice). RESULTS: Similar survival curves were seen in both rodent models with approximately 75% mortality at 72 h. In mice, sepsis caused severity-dependent falls in core temperature and global metabolism. Oxygen consumption in severely septic mice fell by 38% within 2 h, and 80% at 22 h compared with baseline values. This was only partially restored by external warming. By contrast, septic rats maintained core temperature; only severely affected animals showed a pre-mortem decline in oxygen consumption. Significant myocardial dysfunction was seen in mice during early and established sepsis, whereas peak velocity and other hemodynamic variables in rats were similar at 6 h and significantly worse by 24 h in severely septic animals only. CONCLUSIONS: Markedly differing metabolic and cardiovascular profiles were seen in long-term fluid-resuscitated rat and mouse models of bacterial sepsis despite similar mortality. The mouse model, in particular, does not represent the human condition. We urge caution in applying findings in murine models to septic patients, both with regard to our understanding of pathophysiology and the failure to translate preclinical efficacy into successful clinical trials.

The tracheal tube: gateway to ventilator-associated pneumonia.

Ventilator-associated pneumonia (VAP) is a major healthcare-associated complication with considerable attributable morbidity, mortality and cost. Inherent design flaws in the standard high-volume low-pressure cuffed tracheal tubes form a major part of the pathogenic mechanism causing VAP. The formation of folds in the inflated cuff leads to microaspiration of pooled oropharyngeal secretions into the trachea, and biofilm formation on the inner surface of the tracheal tube helps to maintain bacterial colonization of the lower airways. Improved design of tracheal tubes with new cuff material and shape have reduced the size and number of these folds, which together with the addition of suction ports above the cuff to drain pooled subglottic secretions leads to reduced aspiration of oropharyngeal secretions. Furthermore, coating tracheal tubes with antibacterial agents reduces biofilm formation and the incidence of VAP. In this Viewpoint article we explore the published data supporting the new tracheal tubes and their potential contribution to VAP prevention strategies. We also propose that it may now be against good medical practice to continue to use a 'standard cuffed tube' given what is already known, and the weight of evidence supporting the use of newer tube designs.

BK large conductance Ca²+-activated K+ channel-deficient mice are not resistant to hypotension and display reduced survival benefit following polymicrobial sepsis.

Nitric oxide-mediated activation of large conductance calcium-activated potassium (BK) channels is considered an important underlying mechanism of sepsis-induced hypotension. Indeed, the nonselective K-channel inhibitor, tetraethylammonium chloride (TEA), has been proposed as a potential treatment to raise blood pressure in septic shock by virtue of its ability to inhibit BK channels. As experimental evidence has so far relied on pharmacological inhibition, we examined the effects of channel deletion using BKα subunit knockout (α, Slo) mice in two mouse models of polymicrobial sepsis, namely, intraperitoneal fecal slurry and cecal ligation and puncture. Comparison was made against TEA treatment in wild-type (WT) mice. Following slurry, BKα and WT mice developed similar degrees of hypotension over 10 h with no difference in cardiac output as assessed by echocardiography between groups. Tetraethylammonium chloride raised blood pressure significantly in septic WT mice, but had no effect on survival. However, following cecal ligation and puncture, a significantly reduced survival was seen in both BKα mice and (high-dose) TEA-treated WT mice compared with untreated WT animals. In conclusion, the BK channel does not appear to be integral to sepsis-induced hypotension but does affect survival through other mechanisms. The pressor effect of TEA may be related to effects on other potassium channels.

Hypovolaemic hypotension after abdominal aortic surgery is predicted by initial distribution volume of glucose.

BACKGROUND AND OBJECTIVE: Evaluation of volaemia is a crucial question for the management of patients during anaesthesia and in the ICU. Numerous methods have been described, but there is as yet no single ideal parameter. Another way to approach this problem is to predict the extent of hypovolaemia. The initial distribution volume of glucose (IDVG) has been shown to predict the development of hypovolaemic hypotension following oesophageal surgery. In this study, we evaluated the use of the IDVG in predicting hypovolemic hypotension after abdominal aortic surgery. METHODS: All patients undergoing elective abdominal aortic surgery had IDVG measured following admission to the ICU. Other haemodynamic parameters, such as heart rate, blood pressure, urine output and central venous pressure, were also collected during the first postoperative day. Patients were divided into two groups depending on the occurrence of hypovolaemic hypotension, indicated by a SBP lower than 90 mmHg rapidly corrected by administration of intravenous fluid boluses. RESULTS: Out of the 27 patients who underwent aortic surgery, 13 developed hypovolaemic hypotension. IDVG was significantly lower in this group when compared with the haemodynamically stable group, that is, 78 (59-122) vs. 120 (63-151) ml kg(-1). This was despite similar haemodynamic parameters between the two groups. The best area under the receiver-operating characteristic curve was obtained for an IDVG value of 91.1 ml kg(-1). CONCLUSION: In this study, IDVG predicts the occurrence of hypovolaemic hypotension after elective abdominal aortic surgery.

In vivo killing of Staphylococcus aureus using a light-activated antimicrobial agent.

BACKGROUND: The widespread problem of antibiotic resistance in pathogens such as Staphylococcus aureus has prompted the search for new antimicrobial approaches. In this study we report for the first time the use of a light-activated antimicrobial agent, methylene blue, to kill an epidemic methicillin-resistant Staphylococcus aureus (EMRSA-16) strain in two mouse wound models. RESULTS: Following irradiation of wounds with 360 J/cm(2) of laser light (670 nm) in the presence of 100 microg/ml of methylene blue, a 25-fold reduction in the number of viable EMRSA was seen. This was independent of the increase in temperature of the wounds associated with the treatment. Histological examination of the wounds revealed no difference between the photodynamic therapy (PDT)-treated wounds and the untreated wounds, all of which showed the same degree of inflammatory infiltration at 24 hours. CONCLUSION: The results of this study demonstrate that PDT is effective at reducing the total number of viable EMRSA in a wound. This approach has promise as a means of treating wound infections caused by antibiotic-resistant microbes as well as for the elimination of such organisms from carriage sites.