An Official American Thoracic Society/European Society of Intensive Care Medicine/Society of Critical Care Medicine Clinical Practice Guideline: Mechanical Ventilation in Adult Patients with Acute Respiratory Distress Syndrome

BACKGROUND: This document provides evidence-based clinical practice guidelines on the use of mechanical ventilation in adult patients with acute respiratory distress syndrome (ARDS). METHODS: A multidisciplinary panel conducted systematic reviews and metaanalyses of the relevant research and applied Grading of Recommendations, Assessment, Development, and Evaluation methodology for clinical recommendations. RESULTS: For all patients with ARDS, the recommendation is strong for mechanical ventilation using lower tidal volumes (4-8 ml/kg predicted body weight) and lower inspiratory pressures (plateau pressure < 30 cm H2O) (moderate confidence in effect estimates). For patients with severe ARDS, the recommendation is strong for prone positioning for more than 12 h/d (moderate confidence in effect estimates). For patients with moderate or severe ARDS, the recommendation is strong against routine use of high-frequency oscillatory ventilation (high confidence in effect estimates) and conditional for higher positive end-expiratory pressure (moderate confidence in effect estimates) and recruitment maneuvers (low confidence in effect estimates). Additional evidence is necessary to make a definitive recommendation for or against the use of extracorporeal membrane oxygenation in patients with severe ARDS. CONCLUSIONS: The panel formulated and provided the rationale for recommendations on selected ventilatory interventions for adult patients with ARDS. Clinicians managing patients with ARDS should personalize decisions for their patients, particularly regarding the conditional recommendations in this guideline.

High-frequency ventilation versus conventional ventilation for treatment of acute lung injury and acute respiratory distress syndrome.

BACKGROUND: High-frequency ventilation is often used to treat patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) but the effect of this treatment on clinical outcomes has not been well established. OBJECTIVES: The objective of this review is to examine the effect of high-frequency ventilation compared with conventional ventilation as a therapy for ALI or ARDS in children (1 to 17 years old) and adults in order to quantify its effect on patient outcome (mortality, morbidity and other relevant outcomes). SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, issue 4, 2002), MEDLINE (1966 to October Week 5, 2002), EMBASE (1980 to Week 51, 2002), World Wide Web (www.controlled-trials.com, ARDS clinical network), and used Cited Reference Search (Web of Science 1988 to 2002, for specific reference lists of articles). We also contacted authors from each included trial, as well as manufacturers of high-frequency ventilators and other researchers in the field. SELECTION CRITERIA: Randomized controlled clinical trials of children and adults comparing treatment using high-frequency ventilation with conventional ventilation for patients diagnosed with ALI or ARDS. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and extracted data. Study authors were contacted for additional information. MAIN RESULTS: Two trials met the inclusion criteria for this review. One trial recruited children (including some children less than one year old) (n = 58) and the other recruited adults (n = 148). Both trials used a high-frequency oscillatory ventilator as the intervention and included variable use of lung-volume recruitment strategies. The intervention groups showed a trend towards lower 30 day mortality (children relative risk (RR) 0.83, 95% confidence interval (CI) 0.43 to 1.62; adults RR 0.72, 95% CI 0.50 to 1.03), although neither study showed a statistically significant difference. Similarly, there was no statistically significant difference between the intervention and control groups for 'Total length of ventilator days' (WMD) -2.00, 95% CI -18.36 to 14.36; and WMD 2.00, 95% CI -6.55 to 10.55 for the child and adult trials respectively). The studies used only proxies to measure long-term quality of life. There was a statistically significant reduction in the risk of requiring supplemental oxygen amongst survivors at 30 days in the paediatric study (RR 0.36, 95% CI 0.14 to 0.93). REVIEWER'S CONCLUSIONS: There is not enough evidence to conclude whether high-frequency ventilation reduces mortality or long-term morbidity in patients with ALI or ARDS; further trials are needed.

What is an optimal diet? Relationship of macronutrient intake to obesity, glucose tolerance, lipoprotein cholesterol levels and the metabolic syndrome in the Whitehall II study.

OBJECTIVE: Saturated fats have adverse effects on health. To investigate which is more beneficial for energy replacement, we compare the effects of polyunsaturated fatty acid and carbohydrate intake on obesity and metabolic variables (fasting triglycerides, HDL-cholesterol, LDL-cholesterol and 2 h glucose). Further, because the optimum diet may differ according to glucose tolerance, we examine the same associations in glucose tolerant and intolerant groups. Finally, we test the effect of macronutrient intake on the presence or absence of the metabolic syndrome. DESIGN: Cross-sectional analysis. SUBJECTS: A total of 4497 men and 1865 women aged 39--62 in the Whitehall II study. RESULTS: In men, higher intakes of both polyunsaturated fats and carbohydrates were linked to lower waist-hip ratio, triglycerides and LDL-cholesterol. Higher carbohydrate intake alone was linked to decreased body mass index (for 10 g higher carbohydrate intake, -0.12 kg/m(2), P<0.0001) and lower HDL-cholesterol (-0.01 mmol/l, P<0.01). In normoglycaemic men, higher carbohydrate intakes were associated with higher 2 h insulin and glucose levels (0.25 pmol/l, P<0.05 and 0.01 mmol/l, P=0.001, respectively). Dietary effects among women were similar, the exception being a positive association of polyunsaturated fat intake with body mass index and waist--hip ratio (0.47 kg/m(2), P<0.05 and 0.006, P<0.05, respectively). Dietary components, with the exceptions of cholesterol and protein in men, were unrelated to prevalence of the metabolic syndrome, and adjustment for differences in macronutrient intake did not account for the strong inverse association between socioeconomic position and the metabolic syndrome. CONCLUSION: Our observational data provide evidence that both polyunsaturated fatty acids and carbohydrates offer small metabolic benefits with few adverse effects compared with saturated fats. International Journal of Obesity (2001) 25, 45-53

Dissociation of p53-mediated suppression of homologous recombination from G1/S cell cycle checkpoint control.

The tumor suppressor p53 is considered as the guardian of the genome which is activated following genotoxic stress. In many cell types, p53 mediates G1 cell cycle arrest as the predominant cellular response. Inactivation of wild-type p53 leads to loss of G1/S checkpoint control and to genomic instability, including increased spontaneous homologous recombination (HR). To determine whether regulation of the G1/S checkpoint is required for suppression of HR, we assessed recombination events using a plasmid substrate that stably integrated into the genome of p53-null mouse fibroblasts. Exogenous expression of a temperature-sensitive p53 protein (Ala135 to Val), which had lost trans-activation function and could not regulate G1/S transition when in mutant conformation, reduced HR rates to the same extent as wild-type p53. Furthermore, a p53 construct with an alternatively-spliced carboxy terminus also retained this ability in the absence of both activities, G1/S control and non-sequence specific DNA binding as mediated by the carboxy terminus. Our data dissociate regulation of HR by p53 from its role as a cell cycle checkpoint protein. The results support a model which extends p53's role as a guardian of the genome to include transactivation-independent regulatory functions in DNA repair, replication and recombination.

The ability of p53 to activate downstream genes p21(WAF1/cip1) and MDM2, and cell cycle arrest following DNA damage is delayed and attenuated in scid cells deficient in the DNA-dependent protein kinase.

scid mouse embryonic fibroblasts are deficient in DNA-dependent protein kinase activity due to a mutation in the C-terminal domain of the catalytic subunit (DNA-PKcs). When exposed to ionizing radiation, the increase in levels of p53 was the same as in normal mouse embryonic fibroblasts. However, the rise in p21(WAF1/cip1) and mdm2 was found to be delayed and attenuated, which correlated in time with delayed onset of G1/S arrest by flow cytometric analysis. The p53-dependent G1 checkpoint was not eliminated: inactivation of p53 by the E6 protein in scid cells resulted in the complete loss of detectable G1/S arrest after DNA damage. Immunofluorescence analysis of normal cells revealed p53 to be localized predominantly within the cytoplasm prior to irradiation and then translocate to the nucleus after irradiation. In contrast, scid cells show abnormal accumulation of p53 in the nucleus independent of irradiation, which was confirmed by immunoblot analysis of nuclear lysates. Taken together, these data suggest that loss of DNA-PK activity appears to attenuate the kinetics of p53 to activate downstream genes, implying that DNA-PK plays a role in post-translational modification of p53, without affecting the increase in levels of p53 in response to DNA damage.

Diagnosis of iron deficiency anemia in renal failure patients during the post-erythropoietin era.

The purpose of this study was to evaluate the sensitivity and specificity of laboratory methods in the diagnosis of posterythropoietin-era, iron-deficient, chronic renal failure patients. The patient population comprised 25 anemic (hemoglobin < 11 g/dL) patients with creatinine greater than 3 mg/dL; 20 were dialysis patients, two were transplant patients, and three patients had renal failure from other causes. Criteria for study inclusion were as follows: bone marrow iron was the reference standard and was graded 0 to +4, ranging from absent to diffuse homogeneous iron staining; serum ferritin concentration and serum transferrin saturation were tested in terms of sensitivity and specificity. The reference standard indicated that iron deficiency existed in 40% of patients. Neither serum ferritin nor transferrin saturation were completely adequate diagnostic tools. Serum ferritin levels less than 200 ng/dL were 100% specific for the diagnosis but only 41% sensitive. Transferrin saturation of less than 20% was 88% sensitive, but only 63% specific. By excluding patients with hypoproteinemia (transferrin values of < 150 mg/dL), the sensitivity of the test increased to 100% and the specificity to 80%. We conclude that transferrin saturation is an adequate screening tool in anemic chronic renal failure patients, provided that hypoproteinemia is not present. By determining both the serum ferritin concentration and the transferrin saturation, a high sensitivity and specificity can be achieved, even in patients with hypoproteinemia. Furthermore, we believe that on this basis, iron therapy in patients with renal insufficiency can be improved.

DNA aneuploidy and proliferation in spontaneous human and dimethylhydrazine-induced murine colorectal carcinogenesis.

DNA aneuploidy and proliferative abnormalities were studied by flow cytometry in 169 colorectal specimens from 162 patients. Of 37 adenomas, three showed aneuploidy and another seventeen revealed a "near diploid" DNA pattern. The rate of aneuploid and "near diploid" DNA changes in 92 carcinomas was 53.3% and 23.9%, respectively. No correlation was seen between the ploidy distribution and the stage or histologic grade of the carcinomas. The S-phase fractions of both adenomas and carcinomas significantly increased from the diploid (8.1 +/- 0.8% and 7.8 +/- 0.9% respectively; mean +/- SEM) to the "near diploid" (14.9 +/- 1.2% and 12.6 +/- 1.5%) and aneuploid (20.4 +/- 1.3% and 11.4 +/- 1.6%) lesions. To better understand neoplastic progression at very early stages, flow cytometry was also performed on 195 colonic specimens of 44 rats treated by weekly subcutaneous injections of 21 mg/kg Dimethylhydrazine. There was a single "near diploid" carcinoma in this group, and all other induced neoplasms (39 carcinomas and 27 adenomas) revealed a diploid DNA pattern. The S-phase fractions were as follows: controls (38 untreated animals) 8.6 +/- 0.1%, normal mucosa (of Dimethylhydrazine exposed rats) 10.1 +/- 0.25% (p less than 0.0001), adenomas 13.9 +/- 0.6% (p less than 0.01), and carcinomas 14.7 +/- 0.6% (p less than 0.01). These findings support the conclusion that genomic alterations and proliferative abnormalities may already be present in premalignant human colonic lesions. However, despite strong morphological similarities, major biological differences exist between the Dimethylhydrazine-induced murine intestinal carcinogenesis and spontaneously occurring human colorectal neoplasms.

[Experimental comparison of Maxon and chromic catgut in suturing of the urinary bladder]. / Experimenteller Vergleich von Maxon und Chrom-Catgut bei der Naht der Harnblase.

The new monofile absorbable suture material Maxon was compared with Chromic catgut in bladder suturing in rabbits. Comparisons were made after 1, 2, 4, 8 and 12 weeks. The rate of stone formation was mainly determined by the suture technique used and not so much by the suture material. This was demonstrated by the low number of stones formed after using extramucosal suturing technique. Once a suture, be it Maxon or Chromic catgut, comes in contact with urine, concrements may form and the new monofile properties of Maxon do not offer any advantages here. On the other hand, Maxon does not enhance stone formation either. E. coli or Proteus infections did not influence formation of stones. The histological examinations showed Maxon to cause fewer inflammatory reactions. Sutures with Chromic catgut caused inflammation of the bladder wall, subsiding after 4 weeks. An existing urinary infection did not appear to influence the inflammatory process. Maxon offers an advantage over Chromic catgut in extramucosal sutures causing fewer inflammatory reactions.

[Scanning electron microscopy and elementary analytic studies of osteosarcoma]. / Rasterelektronen-mikroskopische und elementaranalytische Untersuchungen am Osteosarkom.

By scanning electron microscopical (SEM) screening analyses of 14 osteosarcomas characteristic three-dimensional structures of tumor osteoid could be demonstrated. These osteoid formations are highly characteristic for osteosarcoma; we did not find them at any other bone tumor or tumor like lesion until now. With these results a better understanding of characteristic growth patterns of bone tumors could be achieved by SEM. No specific results could be found by elementar analysis, x-ray microanalysis, x-ray fluorescence and x-ray diffractometer techniques. The significance of single interesting values has to be evaluated in the future.

Can a substitute for the bladder sphincter be attained by free transplants derived from vesical muscle tissue?

Smooth muscle transplants of the intestinal tract have been tested experimentally as a substitute for the bladder sphincter. An attempt was made to apply the proposed technique to the vesical muscle tissue and to achieve a sphincter replacement with freely transplanted autologous bladder tissue. An internal urethrotomy was performed several times in female sheep until a complete urinary incontinence resulted. For the bladder sphincter substitute a strip of vesical tissue was dissected from the anterior wall and following pre-stretching it was sewed circumferentially around the urethra in order to constrict it. The urethral pressure was registered during the operation before and after application of the sphincter 'graft'. For temporary urinary discharge a suprapubic catheter was inserted. The sheep were examined clinically and urodynamically for up to 3 months. Complete urinary continence was not obtained in any of the cases. The urodynamic examination showed a nearly complete loss of the urethral pressure which had been obtained by the operation. The histological studies showed progressing fibrosis of the desired continence zone. By way of freely transplanted autologous vesical muscle a sphincter substitute could not be achieved.

Three-dimensional shape of a Goormaghtigh cell and its contact with a granular cell in the rabbit kidney.

Goormaghtigh cells of the JGA are characterized by an extensive cellular ramification. In order to elucidate the shape and arrangement of the cell processes a three-dimensional model of a Goormaghtigh cell and of an adjacent granular cell has been constructed based on electron micrographs of a series of ultrathin sections. The model shows that a Goormaghtigh cell has the shape of a flatly pressed cylinder with both ends splitting up into a bunch of parallel processes. The processes maintain a close neighboring position and do not intermingle with processes of other Goormaghtigh cells. This feature is most puzzling when considering that Goormaghtigh cells and their processes are extensively connected by gap junctions. Even processes belonging to the same cell are electrically coupled with each other through gap junctions. The granular cells are clearly different in shape from Goormaghtigh cells. In granular cells bunches of processes are lacking. Granular cells obviously ramify into a few, large processes. The present findings are consistent with the assumption of a functionally central position of Goormaghtigh cells within the feedback mechanism of the JGA.