Cefepime vs Piperacillin-Tazobactam in Adults Hospitalized With Acute Infection: The ACORN Randomized Clinical Trial.

Importance: Cefepime and piperacillin-tazobactam are commonly administered to hospitalized adults for empirical treatment of infection. Although piperacillin-tazobactam has been hypothesized to cause acute kidney injury and cefepime has been hypothesized to cause neurological dysfunction, their comparative safety has not been evaluated in a randomized clinical trial. Objective: To determine whether the choice between cefepime and piperacillin-tazobactam affects the risks of acute kidney injury or neurological dysfunction. Design, Setting, and Participants: The Antibiotic Choice on Renal Outcomes (ACORN) randomized clinical trial compared cefepime vs piperacillin-tazobactam in adults for whom a clinician initiated an order for antipseudomonal antibiotics within 12 hours of presentation to the hospital in the emergency department or medical intensive care unit at an academic medical center in the US between November 10, 2021, and October 7, 2022. The final date of follow-up was November 4, 2022. Interventions: Patients were randomized in a 1:1 ratio to cefepime or piperacillin-tazobactam. Main Outcomes and Measures: The primary outcome was the highest stage of acute kidney injury or death by day 14, measured on a 5-level ordinal scale ranging from no acute kidney injury to death. The 2 secondary outcomes were the incidence of major adverse kidney events at day 14 and the number of days alive and free of delirium and coma within 14 days. Results: There were 2511 patients included in the primary analysis (median age, 58 years [IQR, 43-69 years]; 42.7% were female; 16.3% were Non-Hispanic Black; 5.4% were Hispanic; 94.7% were enrolled in the emergency department; and 77.2% were receiving vancomycin at enrollment). The highest stage of acute kidney injury or death was not significantly different between the cefepime group and the piperacillin-tazobactam group; there were 85 patients (n = 1214; 7.0%) in the cefepime group with stage 3 acute kidney injury and 92 (7.6%) who died vs 97 patients (n = 1297; 7.5%) in the piperacillin-tazobactam group with stage 3 acute kidney injury and 78 (6.0%) who died (odds ratio, 0.95 [95% CI, 0.80 to 1.13], P = .56). The incidence of major adverse kidney events at day 14 did not differ between groups (124 patients [10.2%] in the cefepime group vs 114 patients [8.8%] in the piperacillin-tazobactam group; absolute difference, 1.4% [95% CI, -1.0% to 3.8%]). Patients in the cefepime group experienced fewer days alive and free of delirium and coma within 14 days (mean [SD], 11.9 [4.6] days vs 12.2 [4.3] days in the piperacillin-tazobactam group; odds ratio, 0.79 [95% CI, 0.65 to 0.95]). Conclusions and Relevance: Among hospitalized adults in this randomized clinical trial, treatment with piperacillin-tazobactam did not increase the incidence of acute kidney injury or death. Treatment with cefepime resulted in more neurological dysfunction. Trial Registration: ClinicalTrials.gov Identifier: NCT05094154.

Effect of resistance training during hemodialysis on circulating cytokines: a randomized controlled trial.

The purpose of this study was to evaluate the effect of a 12-week intradialytic progressive resistance training (PRT) regimen on circulating pro- and anti-inflammatory cytokines. Forty-nine patients (62.6 ± 14.2 years) were recruited from the outpatient hemodialysis unit of the St. George Public Hospital, Sydney, Australia. Patients were randomized to: PRT + usual care (n = 24) or usual care control (n = 25). The PRT group performed two sets of 10 exercises at high intensity using free-weights, 3 times per week for 12 weeks during dialysis, while the control group did not exercise. Tumor necrosis factor-alpha, interleukin-1b, interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10, and interleukin-12 were measured in serum before and after the intervention period. Muscle cross-sectional area (CSA), intramuscular lipid, intermuscular adipose tissue, and subcutaneous and total thigh fat, evaluated via computed tomography of the non-dominant mid-thigh, were also collected at both time points. All cytokines were significantly elevated in the total cohort at baseline compared with normative data. There were no cytokine changes over time or between groups (p > 0.05). In secondary analyses pooling the groups, changes in logIL-6 and IL-8 were inversely related to changes subcutaneous thigh fat (p < 0.05) while changes in logIL-6 were also inversely related to changes in thigh muscle CSA, and total thigh fat (p < 0.03). These data suggest that 12 weeks of intradialytic progressive resistance training does not improve circulating pro- and anti-inflammatory markers. Further research is required to elucidate the implications and mechanisms of the relationships between IL-6 and IL-8 and body composition in ESRD.

Investigation of skeletal muscle quantity and quality in end-stage renal disease.

AIM: A more precise understanding of the aetiology and sequelae of muscle wasting in end-stage renal disease (ESRD) is required for the development of effective interventions to target this pathology. METHODS: We investigated 49 patients with ESRD (62.6 +/- 14.2 years, 0.3-16.7 years on haemodialysis). Thigh muscle cross-sectional area (CSA), intramuscular lipid and intermuscular adipose tissue (IMAT) were measured via computed tomography as indices of muscle quantity (i.e. CSA) and quality (i.e. intramuscular lipid and IMAT). Additional health and clinical measures were investigated to determine associations with these variables. RESULTS: Age, energy intake, disease burden, pro-inflammatory cytokines, nutritional status, strength and functioning were related to muscle quantity and quality. Potential aetiological factors entered into forward stepwise regression models indicated that hypoalbuminaemia and lower body mass index accounted significantly and independently for 32% of the variance in muscle CSA (r = 0.56, P < 0.001), while older age and interleukin-8 accounted for 41% of the variance in intramuscular lipid (r = 0.64, P < 0.001) and body mass index accounted for 45% of the variance in IMAT (r = 0.67, P < 0.001). Stepwise regression models revealed that intramuscular lipid was independently predictive of habitual gait velocity and 6 min walk distance, while CSA was independently predictive of maximal isometric strength (P < 0.05). CONCLUSION: Ageing, poor nutritional status and elevated interleukin-8 are factors potentially contributing to the loss of muscle quality and quantity in ESRD. These deficits can predict functional impairments, with intramuscular lipid accumulation most closely related to decline of submaximal musculoskeletal performance (walking), and low muscle CSA most closely related to decline of maximal performance (peak isometric strength).

Estimation of thigh muscle cross-sectional area by dual-energy X-ray absorptiometry in frail elderly patients.

BACKGROUND: Thigh muscle mass and cross-sectional area (CSA) are useful indexes of sarcopenia and the response to treatment in older patients. Current criterion methods are computed tomography (CT) and magnetic resonance imaging. OBJECTIVE: The objective was to compare thigh muscle mass estimated by dual-energy X-ray absorptiometry (DXA), a less expensive and more accessible method, with thigh muscle CSA determined by CT in a group of elderly patients recovering from hip fracture. DESIGN: Midthigh muscle CSA (in cm(2)) was assessed from a 1-mm CT slice and midthigh muscle mass (g) from a 1.3-cm DXA slice in 30 patients (24 women) aged 81 +/- 8 y during 12 mo of follow-up. Fat-to-lean soft tissue ratios were calculated with each technique to permit direct comparison of a variable in the same units. RESULTS: Baseline midthigh muscle CSA was highly correlated with midthigh muscle mass (r = 0.86, P < 0.001) such that DXA predicted CT-determined CSA with an SEE of 10 cm(2) (an error of approximately 12% of the mean CSA value). CT- and DXA-determined ratios of midthigh fat to lean mass were similarly related (intraclass correlation coefficient = 0.87, P < 0.001). When data were expressed as the changes from baseline to follow-up, CT and DXA changes were weakly correlated (intraclass correlation coefficient = 0.51, P = 0.019). CONCLUSIONS: Assessment of sarcopenia by DXA midthigh slice is a potential low-radiation, accessible alternative to CT scanning of older patients. The errors inherent in this technique indicate, however, that it should be applied to groups of patients rather than to individuals or to evaluate the response to interventions.

Randomized controlled trial of intradialytic resistance training to target muscle wasting in ESRD: the Progressive Exercise for Anabolism in Kidney Disease (PEAK) study.

BACKGROUND: To determine whether prolonged (24 weeks) intradialytic progressive resistance training (PRT) could counteract muscle wasting more effectively than short-duration training (12 weeks) in patients with end-stage renal disease. STUDY DESIGN: Randomized controlled trial. SETTING & PARTICIPANTS: 49 patients (age, 62.6 +/- 14.2 years; 0.3 to 16.7 years on hemodialysis therapy) were randomly assigned to PRT plus usual care for 24 weeks (24WK group) or a crossover control group that received usual care for the first 12 weeks, then PRT plus usual care for the latter 12 weeks (12WK group). INTERVENTION: Two sets of 10 free-weight PRT exercises were performed at a high intensity during routine thrice-weekly hemodialysis treatment under direct supervision. OUTCOMES & MEASUREMENTS: Primary outcomes include thigh muscle cross-sectional area by means of computed tomography and intramuscular lipid content estimated through attenuation. Secondary outcomes include muscular strength, exercise capacity, and C-reactive protein level. RESULTS: The 24WK group increased muscle cross-sectional area (+1.82 +/- 3.25 cm(2)) compared with losses in the 12WK group (-1.37 +/- 6.87 cm(2); relative effect size, 0.59; 95% confidence interval [CI], -0.27 to 6.65; P = 0.04). However, this outcome did not achieve the level of statistical significance required (P = 0.025) after Bonferroni correction for multiple primary outcomes. There was no significant change in intramuscular lipid content between groups (+0.19 +/- 1.32 versus +0.16 +/- 1.69 Hounsfield units in the 24WK and 12WK groups, respectively; P = 0.31). Log C-reactive protein level tended to decrease in the 24WK group compared with the 12WK group (relative effect size, -0.63; 95% CI, -0.27 [-0.54 to 0.00]; P = 0.05). The 24WK group improved muscular strength measures and exercise capacity throughout the trial. LIMITATIONS: Single geographic site used; no control group without exercise exposure; unblinded assessment of some secondary outcome measures. CONCLUSIONS: Prolonged intradialytic PRT did not significantly improve muscle cross-sectional area or intramuscular lipid content compared with a shorter duration of exercise. Future trials are required to more thoroughly investigate the clinical importance and magnitude of myogenic adaptations to PRT in this cohort.

Progressive exercise for anabolism in kidney disease (PEAK): a randomized, controlled trial of resistance training during hemodialysis.

Skeletal muscle wasting is common and insidious in patients who receive maintenance hemodialysis treatment for the management of ESRD. The objective of this study was to determine whether 12 wk of high-intensity, progressive resistance training (PRT) administered during routine hemodialysis treatment could improve skeletal muscle quantity and quality versus usual care. Forty-nine patients (62.6 +/- 14.2 yr; 0.3 to 16.7 yr on dialysis) were recruited from the outpatient hemodialysis unit of the St. George Public Hospital (Sydney, Australia). Patients were randomized to PRT + usual care (n = 24) or usual care control only (n = 25). The PRT group performed two sets of 10 exercises at a high intensity (15 to 17/20 on the Borg Scale) using free weights, three times per week for 12 wk during routine hemodialysis treatment. Primary outcomes included thigh muscle quantity (cross-sectional area [CSA]) and quality (intramuscular lipid content via attenuation) evaluated by computed tomography scan. Secondary outcomes included muscle strength, exercise capacity, body circumference measures, proinflammatory cytokine C-reactive protein, and quality of life. There was no statistically significant difference in muscle CSA change between groups. However, there were statistically significant improvements in muscle attenuation, muscle strength, mid-thigh and mid-arm circumference, body weight, and C-reactive protein in the PRT group relative to the nonexercising control group. These findings suggest that patients with ESRD can improve skeletal muscle quality and derive other health-related adaptations solely by engaging in a 12-wk high-intensity PRT regimen during routine hemodialysis treatment sessions. Longer training durations or more sensitive analysis techniques may be required to document alterations in muscle CSA.