Optimizing subgroup selection in two-stage adaptive enrichment and umbrella designs.

We design two-stage confirmatory clinical trials that use adaptation to find the subgroup of patients who will benefit from a new treatment, testing for a treatment effect in each of two disjoint subgroups. Our proposal allows aspects of the trial, such as recruitment probabilities of each group, to be altered at an interim analysis. We use the conditional error rate approach to implement these adaptations with protection of overall error rates. Applying a Bayesian decision-theoretic framework, we optimize design parameters by maximizing a utility function that takes the population prevalence of the subgroups into account. We show results for traditional trials with familywise error rate control (using a closed testing procedure) as well as for umbrella trials in which only the per-comparison type 1 error rate is controlled. We present numerical examples to illustrate the optimization process and the effectiveness of the proposed designs

Intensive care treatments associated with favorable discharge outcomes in Argentine children with severe traumatic brain injury: For the South American Guideline Adherence Group.

Little is known about the critical care management of children with traumatic brain injury (TBI) in low middle income countries. We aimed to identify indicators of intensive care unit (ICU) treatments associated with favorable outcomes in Argentine children with severe TBI.We conducted a secondary analysis of data from patients previously enrolled in a prospective seven center study of children with severe TBI who were admitted to an ICU in one of the seven study centers. Severe TBI was defined by head AIS ≥ 3, head CT with traumatic lesion, and admission GCS < 9. Seven indicators of best practice TBI care were examined. The primary outcome was discharge Pediatric Cerebral Performance Category Scale [PCPC] and Pediatric Overall Performance category Scale [POPC]. We also examined variation in ICU care and in-patient mortality.Of the 117 children, 67% were male and 7.5 (4.3) years on average, 92% had isolated TBI. Hypotension (54%) was more common than hypoxia (28%) and clinical or radiographic signs of high intracranial pressure (ICP) were observed in 92%. Yet, ICP monitoring occurred in 60% and hyperosmolar therapy was used in only 36%. Adherence to indicators of best TBI practice ranged from 55.6% to 83.7% across the seven centers and adherence was associated with favorable discharge PCPC (aRR 0.98; 95% CI [0.96, 0.99]), and POPC (aRR 0.98; 95% CI [0.96, 0.99]). Compared to patients whose adherence rates were below 65%, patients whose adherence rates were higher between 75%-100% had better discharge PCPC (aRR 0.28; 95% CI [0.10, 0.83]) and POPC (aRR 0.32; 95% CI [0.15, 0.73]. Two indicators were associated with favorable discharge PCPC: Avoidance of hypoxia (aRR 0.46; 95% CI [0.23, 0.93]), and Nutrition started in 72 hours (aRR 0.45; 95% CI [0.21, 0.99]). Avoiding hypoxia was also associated with favorable discharge POPC (aRR 0.47; 95% CI [0.22, 0.99]).There is variation in Argentine ICU practice in the care of children with severe TBI. Second insults are common and hyperosmolar therapy use is uncommon. Adherence to best practice TBI care by avoiding hypoxia and providing timely nutrition were associated with significantly favorable discharge outcomes. Implementing strategies that prevent hypoxia and facilitate early nutrition in the ICUs are urgently needed to improve pediatric TBI outcomes

Benchmarking Prehospital and Emergency Department Care for Argentine Children with Traumatic Brain Injury: For the South American Guideline Adherence Group

<div><p>Objective</p><p>There is little information on the type of early care provided to children with traumatic brain injury (TBI) in low middle income countries. We benchmarked early prehospital [PH] and emergency department [ED] pediatric TBI care in Argentina.</p><p>Methods</p><p>We conducted a secondary analysis of data from patients previously enrolled in a prospective seven center study of children with TBI. Eligible participants were patients 0–18 years, and had diagnosis of TBI (admission Glasgow Coma scale score [GCS] < 13 or with GCS 14–15 and abnormal head CT scan within 48 hours of admission, and head AIS > 0). Outcomes were transport type, transport time, PH and ED adherence to best practice, and discharge Pediatric Cerebral Performance Category Scale (PCPC) and Pediatric Overall Performance category Scale (POPC).</p><p>Results</p><p>Of the 366 children, mean age was 8.7 (5.0) years, 58% were male, 90% had isolated TBI and 45.4% were transported by private vehicle. 50 (34.7%) of the 144 children with severe TBI (39.3% of all TBI patients) were transported by private vehicle. Most (267; 73%) patients received initial TBI care at an index hospital prior to study center admission, including children with severe (81.9%) TBI. Transport times were shorter for those patients who were directly transported by ambulance to study center than for the whole cohort (1.4 vs.5.5 hours). Ambulance blood pressure data were recorded in 30.9%. ED guideline adherence rate was higher than PH guideline adherence rate (84.8% vs. 26.4%). For patients directly transferred from scene to study trauma centers, longer transport time was associated with worse discharge outcome (PCPC aOR 1.10 [1.04, 1.18] and (POPC aOR 1.10 [1.04, 1.18]). There was no relationship between PH or ED TBI guideline adherence rate and discharge POPC and PCPC.</p><p>Conclusion</p><p>This study benchmarks early pediatric TBI care in Argentina and shows that many critically injured children with TBI do not receive timely or best practice PH care, that PH guideline adherence rate is low and that longer transport time was associated with poor discharge outcomes for patients with direct transfer status. There is an urgent need to improve the early care of children with TBI in Argentina, especially timely transportation to a hospital.</p></div

Box Plot of Transport Time hours from Scene to Study Centers by Direct and Indirect Transfer Status for TBI Patients.

<p>* Among 366 study sample, 27 patients had missing transport time, and 3 patients had unknown direct transfer status (Center1 [N = 70]; Center2 [N = 79]; Center3 [N = 19]; Center4 [N = 78]; Center5 [N = 40]; Center6 [N = 24]; Center7 [N = 26]).</p

Association between Transport Time (hours) from Scene to Study Centers (Including Transfers) and Discharge Outcomes in 366^* Children with Traumatic Brain Injury.

<p>Association between Transport Time (hours) from Scene to Study Centers (Including Transfers) and Discharge Outcomes in 366^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0166478#t005fn001" target="_blank">*</a>} Children with Traumatic Brain Injury.</p

Outcomes of 117 children with severe traumatic brain injury admitted to seven study centers.

<p>Outcomes of 117 children with severe traumatic brain injury admitted to seven study centers.</p

Box Plot of Transport Time hours from Scene to Study Centers by Direct and Indirect Transfer Status for Severe TBI Patients.

<p>* Among 144 study sample with severe TBI, 20 patients had missing transport time (Center1 [N = 16]; Center2 [N = 35]; Center3 [N = 14]; Center4 [N = 27]; Center5 [N = 13]; Center6 [N = 9]; Center7 [N = 10]).</p

Transfer and Transport Characteristics of 366^* Children with Traumatic Brain Injury Admitted to Seven Study Centers.

<p>Transfer and Transport Characteristics of 366^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0166478#t003fn001" target="_blank">*</a>} Children with Traumatic Brain Injury Admitted to Seven Study Centers.</p

Association between ICU indicators of adherence to best practice and discharge PCPC and POPC.

<p>Association between ICU indicators of adherence to best practice and discharge PCPC and POPC.</p