Early, Goal-Directed Therapy for Septic Shock - A Patient-Level Meta-Analysis

BACKGROUND: After a single-center trial and observational studies suggesting that early, goal-directed therapy (EGDT) reduced mortality from septic shock, three multicenter trials (ProCESS, ARISE, and ProMISe) showed no benefit. This meta-analysis of individual patient data from the three recent trials was designed prospectively to improve statistical power and explore heterogeneity of treatment effect of EGDT. METHODS: We harmonized entry criteria, intervention protocols, outcomes, resource-use measures, and data collection across the trials and specified all analyses before unblinding. After completion of the trials, we pooled data, excluding the protocol-based standard-therapy group from the ProCESS trial, and resolved residual differences. The primary outcome was 90-day mortality. Secondary outcomes included 1-year survival, organ support, and hospitalization costs. We tested for treatment-by-subgroup interactions for 16 patient characteristics and 6 care-delivery characteristics. RESULTS: We studied 3723 patients at 138 hospitals in seven countries. Mortality at 90 days was similar for EGDT (462 of 1852 patients [24.9%]) and usual care (475 of 1871 patients [25.4%]); the adjusted odds ratio was 0.97 (95% confidence interval, 0.82 to 1.14; P=0.68). EGDT was associated with greater mean (±SD) use of intensive care (5.3±7.1 vs. 4.9±7.0 days, P=0.04) and cardiovascular support (1.9±3.7 vs. 1.6±2.9 days, P=0.01) than was usual care; other outcomes did not differ significantly, although average costs were higher with EGDT. Subgroup analyses showed no benefit from EGDT for patients with worse shock (higher serum lactate level, combined hypotension and hyperlactatemia, or higher predicted risk of death) or for hospitals with a lower propensity to use vasopressors or fluids during usual resuscitation. CONCLUSIONS: In this meta-analysis of individual patient data, EGDT did not result in better outcomes than usual care and was associated with higher hospitalization costs across a broad range of patient and hospital characteristics. (Funded by the National Institute of General Medical Sciences and others; PRISM ClinicalTrials.gov number, NCT02030158.

Mean ergodicity and spectrum of the Cesàro operator on weighted c0 spaces

[EN] A detailed investigation is made of the continuity, the compactness and the spectrum of the Cesàro operator C acting on the weighted Banach sequence space c0(w) for a bounded, strictly positive weight w. New features arise in the weighted setting (e.g. existence of eigenvalues, compactness, mean ergodicity) which are not present in the classical setting of c0.The research of the first two authors was partially supported by the Projects MTM2013-43540-P, GVA Prometeo II/2013/013 and ACOMP/2015/186 (Spain).Albanese, AA.; Bonet Solves, JA.; Ricker, WJ. (2016). Mean ergodicity and spectrum of the Cesàro operator on weighted c0 spaces. Positivity. 20:761-803. https://doi.org/10.1007/s11117-015-0385-xS76180320Akhmedov, A.M., Başar, F.: On the fine spectrum of the Cesàro operator in $$c_0$$ c 0 . Math. J. Ibaraki Univ. 36, 25–32 (2004)Akhmedov, A.M., Başar, F.: The fine spectrum of the Cesàro operator $$C_1$$ C 1 over the sequence space $$bv_p, (1 \le p < \infty )$$ b v p , ( 1 ≤ p < ∞ ) . Math. J. Okayama Univ. 50, 135–147 (2008)Albanese, A.A., Bonet, J., Ricker, W.J.: Convergence of arithmetic means of operators in Fréchet spaces. J. Math. Anal. Appl. 401, 160–173 (2013)Albanese, A.A., Bonet, J., Ricker, W.J.: Spectrum and compactness of the Cesàro operator on weighted $$\ell _p$$ ℓ p spaces. J. Aust. Math. Soc. 99, 287–314 (2015)Albanese, A.A., Bonet, J., Ricker, W.J.: The Cesàro operator in the Fréchet spaces $$\ell ^{p+}$$ ℓ p + and $$L ^{p-}$$ L p - . Glasg. Math. J (to appear)Ansari, S.I., Bourdon, P.S.: Some properties of cyclic operators. Acta Sci. Math. Szeged 63, 195–207 (1997)Brown, A., Halmos, P.R., Shields, A.L.: Cesàro operators. Acta Sci. Math. Szeged 26, 125–137 (1965)Curbera, G.P., Ricker, W.J.: Spectrum of the Cesàro operator in $$\ell ^p$$ ℓ p . Arch. Math. 100, 267–271 (2013)Curbera, G.P., Ricker, W.J.: Solid extensions of the Cesàro operator on $$\ell ^p$$ ℓ p and $$c_0$$ c 0 . Integr. Equ. Oper. Theory 80, 61–77 (2014)Curbera, G.P., Ricker, W.J.: The Cesàro operator and unconditional Taylor series in Hardy spaces. Integr. Equ. Oper. Theory 83, 179–195 (2015)Diestel, J.: Sequences and Series in Banach Spaces. Springer, New York (1984)Dowson, H.R.: Spectral Theory of Linear Operators. Academic Press, London (1978)Dunford, N., Schwartz, J.T.: Linear Operators I: General Theory, 2nd Printing. Wiley Interscience Publ, New York (1964)Emilion, R.: Mean-bounded operators and mean ergodic theorems. J. Funct. Anal. 61, 1–14 (1985)Goldberg, S.: Unbounded Linear Operators: Theory and Applications. Dover Publ, New York (1985)Hille, E.: Remarks on ergodic theorems. Trans. Am. Math. Soc. 57, 246–269 (1945)Jarchow, H.: Locally Convex Spaces. Teubner, Stuttgart (1981)Krengel, U.: Ergodic Theorems. de Gruyter, Berlin (1985)Leibowitz, G.: Spectra of discrete Cesàro operators. Tamkang J. Math. 3, 123–132 (1972)Lin, M.: On the uniform ergodic theorem. Proc. Am. Math. Soc. 43, 337–340 (1974)Megginson, R.E.: An Introduction to Banach Space Theory. Springer, New York (1998)Mureşan, M.: A Concrete Approach to Classical Analysis. Springer, Berlin (2008)Okutoyi, J.I.: On the spectrum of $$C_1$$ C 1 as an operator on $$bv_0$$ b v 0 . J. Aust. Math. Soc. Ser. A 48, 79–86 (1990)Radjavi, H., Tam, P.-W., Tan, K.-K.: Mean ergodicity for compact operators. Studia Math. 158, 207–217 (2003)Reade, J.B.: On the spectrum of the Cesàro operator. Bull. Lond. Math. Soc. 17, 263–267 (1985)Rhoades, B.E., Yildirim, M.: The spectra and fine spectra of factorable matrices on $$c_0$$ c 0 . Math. Commun. 16, 265–270 (2011)Taylor, A.E.: Introduction to Functional Analysis. Wiley, New York (1958

In Search of the Optimal Surgical Treatment for Velopharyngeal Dysfunction in 22q11.2 Deletion Syndrome: A Systematic Review

<div><h3>Background</h3><p>Patients with the 22q11.2 deletion syndrome (22qDS) and velopharyngeal dysfunction (VPD) tend to have residual VPD following surgery. This systematic review seeks to determine whether a particular surgical procedure results in superior speech outcome or less morbidity.</p> <h3>Methodology/ Principal Findings</h3><p>A combined computerized and hand-search yielded 70 studies, of which 27 were deemed relevant for this review, reporting on a total of 525 patients with 22qDS and VPD undergoing surgery for VPD. All studies were levels 2c or 4 evidence. The methodological quality of these studies was assessed using criteria based on the Cochrane Collaboration's tool for assessing risk of bias. Heterogeneous groups of patients were reported on in the studies. The surgical procedure was often tailored to findings on preoperative imaging. Overall, 50% of patients attained normal resonance, 48% attained normal nasal emissions scores, and 83% had understandable speech postoperatively. However, 5% became hyponasal, 1% had obstructive sleep apnea (OSA), and 17% required further surgery. There were no significant differences in speech outcome between patients who underwent a fat injection, Furlow or intravelar veloplasty, pharyngeal flap pharyngoplasty, Honig pharyngoplasty, or sphincter pharyngoplasty or Hynes procedures. There was a trend that a lower percentage of patients attained normal resonance after a fat injection or palatoplasty than after the more obstructive pharyngoplasties (11–18% versus 44–62%, p = 0.08). Only patients who underwent pharyngeal flaps or sphincter pharyngoplasties incurred OSA, yet this was not statistically significantly more often than after other procedures (p = 0.25). More patients who underwent a palatoplasty needed further surgery than those who underwent a pharyngoplasty (50% versus 7–13%, p = 0.03).</p> <h3>Conclusions/ Significance</h3><p>In the heterogeneous group of patients with 22qDS and VPD, a grade C recommendation can be made to minimize the morbidity of further surgery by choosing to perform a pharyngoplasty directly instead of only a palatoplasty.</p> </div

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

Consensus guidelines for the use and interpretation of angiogenesis assays

The formation of new blood vessels, or angiogenesis, is a complex process that plays important roles in growth and development, tissue and organ regeneration, as well as numerous pathological conditions. Angiogenesis undergoes multiple discrete steps that can be individually evaluated and quantified by a large number of bioassays. These independent assessments hold advantages but also have limitations. This article describes in vivo, ex vivo, and in vitro bioassays that are available for the evaluation of angiogenesis and highlights critical aspects that are relevant for their execution and proper interpretation. As such, this collaborative work is the first edition of consensus guidelines on angiogenesis bioassays to serve for current and future reference

Prevention of acute kidney injury and protection of renal function in the intensive care unit

Acute renal failure on the intensive care unit is associated with significant mortality and morbidity. To determine recommendations for the prevention of acute kidney injury (AKI), focusing on the role of potential preventative maneuvers including volume expansion, diuretics, use of inotropes, vasopressors/vasodilators, hormonal interventions, nutrition, and extracorporeal techniques. A systematic search of the literature was performed for studies using these potential protective agents in adult patients at risk for acute renal failure/kidney injury between 1966 and 2009. The following clinical conditions were considered: major surgery, critical illness, sepsis, shock, and use of potentially nephrotoxic drugs and radiocontrast media. Where possible the following endpoints were extracted: creatinine clearance, glomerular filtration rate, increase in serum creatinine, urine output, and markers of tubular injury. Clinical endpoints included the need for renal replacement therapy, length of stay, and mortality. Studies are graded according to the international Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) group system Several measures are recommended, though none carries grade 1A. We recommend prompt resuscitation of the circulation with special attention to providing adequate hydration whilst avoiding high-molecular-weight hydroxy-ethyl starch (HES) preparations, maintaining adequate blood pressure using vasopressors in vasodilatory shock. We suggest using vasopressors in vasodilatory hypotension, specific vasodilators under strict hemodynamic control, sodium bicarbonate for emergency procedures administering contrast media, and periprocedural hemofiltration in severe chronic renal insufficiency undergoing coronary intervention

Harmonizing international trials of early goal-directed resuscitation for severe sepsis and septic shock: methodology of ProCESS, ARISE, and ProMISe

ProCESS/ARISE/ProMISe methodology writing committee members: Sandra L. Peake and Patricia Williams for the University of Adelaide, South Australia.PURPOSE To describe and compare the design of three independent but collaborating multicenter trials of early goal-directed resuscitation for severe sepsis and septic shock. METHODS We reviewed the three current trials, one each in the USA (ProCESS: protocolized care for early septic shock), Australasia (ARISE: Australasian resuscitation in sepsis evaluation), and the UK (ProMISe: protocolised management in sepsis). We used the 2010 CONSORT (consolidated standards of reporting trials) statement and the 2008 CONSORT extension for trials assessing non-pharmacologic treatments to describe and compare the underlying rationale, commonalities, and differences. RESULTS All three trials conform to CONSORT guidelines, address the same fundamental questions, and share key design elements. Each trial is a patient-level, equal-randomized, parallel-group superiority trial that seeks to enroll emergency department patients with inclusion criteria that are consistent with the original early goal-directed therapy (EGDT) trial (suspected or confirmed infection, two or more systemic inflammatory response syndrome criteria, and refractory hypotension or elevated lactate), is powered to detect a 6–8 % absolute mortality reduction (hospital or 90-day), and uses trained teams to deliver EGDT. Design differences appear to primarily be driven by between-country variation in health care context. The main difference between the trials is the inclusion of a third, alternative resuscitation strategy arm in ProCESS. CONCLUSIONS Harmonization of study design and methods between severe sepsis trials is feasible and may facilitate pooling of data on completion of the trials.The ProCESS/ARISE/ProMISe Methodology Writing Committe

A systematic review and meta-analysis of early goal-directed therapy for septic shock: the ARISE, ProCESS and ProMISe Investigators.

PURPOSE: To determine whether early goal-directed therapy (EGDT) reduces mortality compared with other resuscitation strategies for patients presenting to the emergency department (ED) with septic shock. METHODS: Using a search strategy of PubMed, EmBase and CENTRAL, we selected all relevant randomised clinical trials published from January 2000 to January 2015. We translated non-English papers and contacted authors as necessary. Our primary analysis generated a pooled odds ratio (OR) from a fixed-effect model. Sensitivity analyses explored the effect of including non-ED studies, adjusting for study quality, and conducting a random-effects model. Secondary outcomes included organ support and hospital and ICU length of stay. RESULTS: From 2395 initially eligible abstracts, five randomised clinical trials (n = 4735 patients) met all criteria and generally scored high for quality except for lack of blinding. There was no effect on the primary mortality outcome (EGDT: 23.2% [495/2134] versus control: 22.4% [582/2601]; pooled OR 1.01 [95% CI 0.88-1.16], P = 0.9, with heterogeneity [I(2) = 57%; P = 0.055]). The pooled estimate of 90-day mortality from the three recent multicentre studies (n = 4063) also showed no difference [pooled OR 0.99 (95% CI 0.86-1.15), P = 0.93] with no heterogeneity (I(2) = 0.0%; P = 0.97). EGDT increased vasopressor use (OR 1.25 [95% CI 1.10-1.41]; P < 0.001) and ICU admission [OR 2.19 (95% CI 1.82-2.65); P < 0.001]. Including six non-ED randomised trials increased heterogeneity (I(2) = 71%; P < 0.001) but did not change overall results [pooled OR 0.94 (95% CI 0.82 to 1.07); P = 0.33]. CONCLUSION: EGDT is not superior to usual care for ED patients with septic shock but is associated with increased utilisation of ICU resources