March 2020

Synopsis: About half of children who are admitted with community acquired pneumonia develop a parapneumonic effusion. If this becomes infected or loculated, placement of a chest tube for pleural drainage of the empyema is indicated in moderate to severe cases or in patients with significant respiratory compromise. While treatment may include VATS/decortication, protocols using instillation of TPA through a chest tube have shown similar outcomes when clinically feasible. In adults, the addition of Dornase alfa (DNase) to TPA has reported improved outcomes. This randomized trial assessed the addition of DNase to TPA for children. In brief, 97 children were analyzed (ages 6 months to 18 years, mean 5.1 years) over 4 years after tube thoracostomy and instillation of TPA + DNase vs. TPA + placebo (saline). The primary outcome was LOS from insertion to discharge, and secondary outcomes included time to removal, mean fever duration, need for additional procedures, readmissions, and total cost. Treatment with tPA and DNase was not associated with decreased hospital length of stay (mean [SD] LOS: 9.0 [4.9] vs 9.1 [5.3] days). There were no significant differences were observed for any of the secondary outcomes and no difference in the number of serious adverse events. It was concluded that DNase instillation in addition to traditional up front therapy does not improve outcomes in children with empyema. In contrast to adults, children with empyema are often previously healthy.

Synopsis:  Approximately 20% of patients with pancreatic ductal adenocarcinoma (PDAC) have resectable or borderline resectable disease. Standard treatment for these patients is resection followed by adjuvant chemotherapy. This randomized, multicenter Dutch study of 246 patients investigated whether preoperative chemoradiotherapy provides better overall survival (OS) than immediate surgery in patients with resectable or borderline resectable PDAC. Chemoradiotherapy, consisting of 3 courses of gemcitabine, the second combined with 15 × 2.4 Gy radiotherapy, followed by surgery and 4 courses of adjuvant gemcitabine was compared to immediate surgery and 6 courses of adjuvant gemcitabine. Median overall survival by intention to treat analysis was 16.0 months with preoperative chemoradiotherapy and 14.3 months with immediate surgery (HR, 0.78; 95% CI, 0.58 to 1.05; P = .096), with a resection rate of 61% and 72% respectively (P = .058). In patients with predefined borderline resectable PDAC, preoperative chemoradiotherapy significantly improved OS (17.6 months vs 13.2 months; HR 0.62; 95% CI, 0.40 to 0.95; P=.029). Additionally, there were some interesting secondary endpoints. The R0 resection rate was higher in patients treated with preoperative chemoradiotherapy (72% v 40%; P < .001), and fewer patients had pathologic lymph nodes (33% v 78%; P < .001), perineural invasion (39% v 73%; P < .001), or venous invasion (19% v 36%; P = .024). Patients with an R0 resection had a better OS than patients with non-R0 resection (HR, 0.47; 95% CI, 0.31 to 0.72; P < .001). Also, the subgroup of patients with tumor resection who started adjuvant treatment showed a significantly improved median OS of 35.2 months (95% CI, 26.2 months to not available) in the preoperative chemoradiotherapy group compared to the immediate surgery group (19.8 months, 95% CI, 16.8 to 32.2 months; HR, 0.58; 95% CI, 0.35 to 0.95; P = .029). Overall, PDAC has a poor prognosis, and 73% of patients had died by the 27-month mark. Although this study did not show a survival benefit across all resectable and borderline resectable disease, the predefined subgroup analysis showed superior OS after preoperative chemoradiotherapy for borderline resectable disease. Given these findings and the increased compliance of neoadjuvant chemoradiotherapy compared to adjuvant chemotherapy, the neoadjuvant approach should be considered, particularly in patients with borderline resectable disease. 

Synopsis:  It is unclear if the addition of thiamine and vitamin C to hydrocortisone improves mortality and reduces time to shock resolution in septic shock. The VITAMINS trial is a multicenter, open-label, randomized clinical trial conducted in 10 ICUs in Australia, Brazil and New Zealand which randomized 216 patients with septic shock (defined by Sepsis-3 criteria) to receive either high-dose IV vitamin C (1.5g every 6 hours), hydrocortisone (50mg every 6 hours) and thiamine (200mg every 12 hours) or a control group of hydrocortisone (50mg every 6 hours) alone. Both regimens would given until shock resolution or up to 10 days. The primary outcome was time alive and free of vasopressor support at day 7.

The mean age of the cohort was 61.7 years (SD 15.0), 63% were male, with 61% patients receiving mechanical ventilation. Of the 211 patients that completed the primary outcome measurement, the time alive and vasopressor free up to day 7 was not significantly different between the two groups (intervention 122.1 hours (IQR 76.3-145.4 hours) vs. control 124.6 hours (IQR 82.1-147 hours) with median of paired differences -0.6 hours (95% CI, -8.3-7.2 hours, p=0.83). There was no significant difference in 9/10 pre-specified secondary outcomes, including ICU mortality, hospital mortality, 28-day mortality, 90-day mortality or incidence of acute kidney injury. 

Clinical Takeaway:
In patients with septic shock, the addition of vitamin C and thiamine for the treatment of septic shock does no lead to faster shock resolution or reduction in mortality, and therefore, its use as an adjuvant therapy should be strongly discouraged.