The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

AIM: The SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery. METHODS: This was an international prospective cohort study of consecutive colorectal cancer patients with a decision for curative surgery (January-April 2020). Surgical delay was defined as an operation taking place more than 4 weeks after treatment decision, in a patient who did not receive neoadjuvant therapy. A subgroup analysis explored the effects of delay in elective patients only. The impact of longer delays was explored in a sensitivity analysis. The primary outcome was complete resection, defined as curative resection with an R0 margin. RESULTS: Overall, 5453 patients from 304 hospitals in 47 countries were included, of whom 6.6% (358/5453) did not receive their planned operation. Of the 4304 operated patients without neoadjuvant therapy, 40.5% (1744/4304) were delayed beyond 4 weeks. Delayed patients were more likely to be older, men, more comorbid, have higher body mass index and have rectal cancer and early stage disease. Delayed patients had higher unadjusted rates of complete resection (93.7% vs. 91.9%, P = 0.032) and lower rates of emergency surgery (4.5% vs. 22.5%, P < 0.001). After adjustment, delay was not associated with a lower rate of complete resection (OR 1.18, 95% CI 0.90-1.55, P = 0.224), which was consistent in elective patients only (OR 0.94, 95% CI 0.69-1.27, P = 0.672). Longer delays were not associated with poorer outcomes. CONCLUSION: One in 15 colorectal cancer patients did not receive their planned operation during the first wave of COVID-19. Surgical delay did not appear to compromise resectability, raising the hypothesis that any reduction in long-term survival attributable to delays is likely to be due to micro-metastatic disease

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Antimicrobial dosing strategies in critically ill patients with acute kidney injury and high-dose continuous veno-venous hemofiltration

Purpose of review Delivery of appropriate antimicrobial therapy is a great challenge during continuous veno-venous hemofiltration (CVVH), particularly if the recommended higher doses are applied. The present contribution discusses the principles of drug dosing during CVVH and compares the various proposed dosing strategies. Recent findings The basic principles underlying removal of antibiotics during CVVH and the published dosing strategies are reviewed. The key factor to consider is the fractional CVVH clearance (Fr-CVVH), Critical illness and acute kidney injury, however, may dramatically affect the pharmacokinetic properties of a drug and thus Fr-CVVH. Five dosing strategies have been proposed on the basis of either available references, total creatinine clearance, the reduction in total body clearance, the maintenance dose multiplication factor, or therapeutic drug monitoring. Dose predictions according to the various strategies show reasonable approximations for some but not all antibiotics. Summary The delivery of appropriate antimicrobial therapy during CVVH leaves us with uncertainty and presents a great challenge. To ensure efficacy and prevent toxicity, therapeutic drug monitoring is highly recommended. In the absence of therapeutic drug monitoring, adequate concentrations can only be inferred from clinical response. For nontoxic antibiotics overdosing is preferred to underdosing because the danger of underdosing is far greater than that of overdosin

Timing of renal replacement therapy in critically ill patients with acute kidney injury

PURPOSE OF REVIEW: Timing of renal replacement therapy in critically ill patients with acute kidney injury is highly subjective, and may influence outcome. We discuss renal and nonrenal criteria for timing considering the recent literature. RECENT FINDINGS: Two randomized and four nonrandomized controlled trials investigated the effects of timing on patient outcome. All but one randomized controlled trial indicated better outcome with early renal replacement therapy but had poor methodological quality. The heterogeneity of timing definition, study population and mode of therapy, however, hampered comparison among studies. SUMMARY: In the absence of large randomized controlled trials we can make no firm recommendations for timing of renal replacement therapy in acute kidney injury. Since rapid recovery of renal function is unlikely when other organ failure persists and the consequences of acute kidney injury may be more severe in critically ill patients, we suggest other organ failure is also considered. Patients with acute kidney injury, persisting shock and poorly recovering functions of other organs may benefit from early therapy. For future studies, we recommend describing renal replacement therapy timing according to the 'RIFLE' classification, as modified by the Acute Kidney Injury Network, and quantifying the severity of other organ failure. Biomarkers may refine acute kidney injury and timing definitions in the futur