Gustavo Petroni

A Trial of Intracranial-Pressure Monitoring in Traumatic Brain Injury

BACKGROUND Intracranial-pressure monitoring is considered the standard of care for severe traumatic brain injury and is used frequently, but the efficacy of treatment based on monitoring in improving the outcome has not been rigorously assessed. METHODS We conducted a multicenter, controlled trial in which 324 patients 13 years of age or older who had severe traumatic brain injury and were being treated in intensive care units (ICUs) in Bolivia or Ecuador were randomly assigned to one of two specific protocols: guidelines-based management in which a protocol for monitoring intraparenchymal intracranial pressure was used (pressure-monitoring group) or a protocol in which treatment was based on imaging and clinical examination (imaging-clinical examination group). The primary outcome was a composite of survival time, impaired consciousness, and functional status at 3 months and 6 months and neuropsychological status at 6 months; neuropsychological status was assessed by an examiner who was unaware of protocol assignment. This composite measure was based on performance across 21 measures of functional and cognitive status and calculated as a percentile (with 0 indicating the worst performance, and 100 the best performance). RESULTS There was no significant between-group difference in the primary outcome, a composite measure based on percentile performance across 21 measures of functional and cognitive status (score, 56 in the pressure-monitoring group vs. 53 in the imaging-clinical examination group; P=0.49). Six-month mortality was 39% in the pressure-monitoring group and 41% in the imaging-clinical examination group (P=0.60). The median length of stay in the ICU was similar in the two groups (12 days in the pressure-monitoring group and 9 days in the imaging-clinical examination group; P=0.25), although the number of days of brain-specific treatments (e.g., administration of hyperosmolar fluids and the use of hyperventilation) in the ICU was higher in the imaging-clinical examination group than in the pressure-monitoring group (4.8 vs. 3.4, P=0.002). The distribution of serious adverse events was similar in the two groups. CONCLUSIONS For patients with severe traumatic brain injury, care focused on maintaining monitored intracranial pressure at 20 mm Hg or less was not shown to be superior to care based on imaging and clinical examination. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01068522.).

Mortality and morbidity from moderate to severe traumatic brain injury in Argentina

After adopting the Guidelines for the Management of Severe Head Injury, critical care physicians in Argentina reduced the mortality rate of patients with traumatic brain injury (TBI). However, there is no in-hospital or postdischarge rehabilitation services for persons with TBI in Argentina. Thus, severely disabled survivors were being discharged to home without follow-up or long-term care. ObjectivesThe objectives of this project were to establish a structure for conducting research about TBI in Argentina, and to conduct a prospective, observational study of outcomes from TBI in hospitals that had adopted the acute care guidelines. The goal was to document outcomes for people treated in a medical system that does not provide TBI rehabilitation. The focus of this report is mortality and morbidity during the acute care and hospital ward treatment of TBI in Argentina. MethodsWe established a data-collection system in 5 hospitals in Argentina, using instruments and protocols developed by the NIDRR-funded TBI Model System program. Data-collection intervals were established to be comparable with intervals used in the TBI Model System program. The Argentine team consists of 11 neurocritical care physicians and 1 project manager/translator. All patient evaluation, data collection and entry, quality control, and local administration were conducted by this group. ResultsOver 31 months, 278 patients were entered into the study. Approximately 61% were discharged from acute care directly to home. The in-hospital mortality rate was 31%. Seventy-six percent of expired patients died from secondary complications such as sepsis and pneumonia, and 93% while in the hospital. DiscussionTBI is a major public health concern in Argentina. However, rehabilitation for TBI is not a part of this countrys medical system. The greatest proportion of expired patients in the Argentine sample died of secondary complications such as pneumonia or sepsis, which may have been avoided employing basic medical rehabilitation. The next research questions to be addressed in this population should be designed to identify solutions to the immediate need for rehabilitation, including treatment efficacy questions as well as questions about systems for delivering treatments.

Intracranial Pressure Monitoring in Severe Traumatic Brain Injury in Latin America: Process and Methods for a Multi-Center Randomized Controlled Trial

In patients with severe traumatic brain injury (TBI), the influence on important outcomes of the use of information from intracranial pressure (ICP) monitoring to direct treatment has never been tested in a randomized controlled trial (RCT). We are conducting an RCT in six trauma centers in Latin America to test this question. We hypothesize that patients randomized to ICP monitoring will have lower mortality and better outcomes at 6-months post-trauma than patients treated without ICP monitoring. We selected three centers in Bolivia to participate in the trial, based on (1) the absence of ICP monitoring, (2) adequate patient accession and data collection during the pilot phase, (3) preliminary institutional review board approval, and (4) the presence of equipoise about the value of ICP monitoring. We conducted extensive training of site personnel, and initiated the trial on September 1, 2008. Subsequently, we included three additional centers. A total of 176 patients were entered into the trial as of August 31, 2010. Current enrollment is 81% of that expected. The trial is expected to reach its enrollment goal of 324 patients by September of 2011. We are conducting a high-quality RCT to answer a question that is important globally. In addition, we are establishing the capacity to conduct strong research in Latin America, where TBI is a serious epidemic. Finally, we are demonstrating the feasibility and utility of international collaborations that share resources and unique patient populations to conduct strong research about global public health concerns.

Traumatic brain injury in Latin America: lifespan analysis randomized control trial protocol*.

BACKGROUND Although in the developed world the intracranial pressure (ICP) monitor is considered the standard of care for patients with severe traumatic brain injury (TBI), its usefulness to direct treatment decisions has never been tested rigorously. OBJECTIVE The primary focus was to conduct a high-quality, randomized, controlled trial to determine whether ICP monitoring used to direct TBI treatment improves patient outcomes. By providing education, equipment, and structure, the project will enhance the research capacity of the collaborating investigators and will foster the collaborations established during earlier studies. METHODS Study centers were selected that routinely treated ICP based on clinical examination and computed tomography imaging using internal protocols. We randomized patients to either an ICP monitor group or an imaging and clinical examination group. Treatment decisions for the ICP monitor group are guided by ICP monitoring based on established guidelines. Treatment decisions for the imaging and clinical examination group are made using a single protocol derived from those previously being used at those centers. EXPECTED OUTCOMES There are 2 study hypotheses: (1) patients with severe TBI whose acute care treatment is managed using ICP monitors will have improved outcomes and 2) incorporating ICP monitoring in the care of patients with severe TBI will minimize complications and decrease length of intensive care unit stay. DISCUSSION This clinical trial tests the effectiveness of a management protocol based on technology considered pivotal to brain trauma treatment in the developed world: the ICP monitor. A randomized, controlled trial of ICP monitoring has never been performed-a critical gap in the evidence base that supports the role of ICP monitoring in TBI care. As such, the results of this randomized, controlled trial will have global implications regardless of the level of development of the trauma system.

Postdischarge Care of Pediatric Traumatic Brain Injury in Argentina: A Multicenter Randomized Controlled Trial.

Objective: To develop, in partnership with families of children with traumatic brain injury, a postdischarge intervention that is effective, simple, and sustainable. Design: Randomized Controlled Trial. Setting: Seven Level 1 Pediatric Trauma Centers in Argentina. Patients: Persons less than 19 years of age admitted to one of the study hospitals with a diagnosis of severe, moderate, or complicated mild traumatic brain injury and were discharged alive. Interventions: Patients were randomly assigned to either the intervention or standard care group. A specially trained Community Resource Coordinator was assigned to each family in the intervention group. We hypothesized that children with severe, moderate, and complicated mild traumatic brain injury who received the intervention would have significantly better functional outcomes at 6 months post discharge than those who received standard care. We further hypothesized that there would be a direct correlation between patient outcome and measures of family function. Measurements and Main Results: The primary outcome measure was a composite measured at 6 months post injury. There were 308 patients included in the study (61% men). Forty-four percent sustained a complicated mild traumatic brain injury, 18% moderate, and 38% severe. Sixty-five percent of the patients were 8 years old or younger, and over 70% were transported to the hospital without ambulance assistance. There was no significant difference between groups on the primary outcome measure. There was a statistically significant correlation between the primary outcome measure and the scores on the Family Impact Module of the Pediatric Quality of Life Inventory (&rgr; = 0.57; p < 0.0001). Children with better outcomes lived with families reporting better function at 6 months post injury. Conclusions: Although no significant effect of the intervention was demonstrated, this study represents the first conducted in Latin America that documents the complete course of treatment for pediatric patients with traumatic brain injury spanning hospital transport through hospital care and into the postdischarge setting.

Benchmarking prehospital and emergency department care for Argentine children with traumatic brain injury: for the South American Guideline Adherence Group

Objective 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. Methods 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). Results 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. Conclusion 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.

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

Objective 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. Methods 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. Results 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]). Conclusion 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.

Ethical and methodological considerations on conducting clinical research in poor and low-income countries: Viewpoint of the authors of the BEST TRIP ICP randomized trial in Latin America.

We read with interest the editorial critique of Sahuquillo and Biestro[10] regarding the BEST TRIP trial,[2] and appreciate Hunts editorial response.[6] However, we believe that the several oversights and misinterpretations that flaw the structure of the editorial, although resolvable by careful reading of the paper, will benefit by clarification by us who were directly involved with the study. Our major concerns are regarding the misrepresentation of the studys focus and the sterile analysis of equipoise. As stated in the BEST TRIP report, this was not a study of intracranial pressure (ICP) monitoring per se. It was designed as an investigation of two protocols of aggressive treatment of intracranial hypertension, one driven by monitored ICP and based on recommendations from the Guidelines for the Management of Acute Brain Injury in Adults[1] and the other based on current practices at the study (non-monitoring) institutions, which were guided by serial neurological examination and CT imaging. There was no placebo group in this study; both groups were afforded highly aggressive neurological management. As presented in the BEST TRIP report, there was no difference in the incidence of pre-specified clinical neurological deterioration criteria (one hallmark of inadequate ICP management) between the monitor-driven and the non–monitor-driven protocols. Recognizing the absence of a placebo control group renders specious the suggested parallels between the BEST TRIP trial and ethically questionable studies such as the African zidovudine studies and the Tuskegee and Willowbrook investigations. From a position of academics in high-income countries (HICs), it is argued that ICP monitoring is the standard of care. However, the guidelines themselves note that the weakness of the literature supporting ICP monitoring reflects the lack of randomized control trial (RCT)-level data. There is no doubt that elevated ICP is a bad prognostic indicator; the evidentiary frisson exists because it has not been definitively shown that lowering ICP improves recovery. The correlative nature of the available Class II and III studies cannot differentiate treatment-related selection of patient subgroups with different prognoses versus actually increasing recovery. An objective indication that there is no consensus on ICP monitoring, even in HICs, is the wide variation of its routine use in actual practice (77.4% in the US,[5] 44.5% in Australia and New Zealand,[7] 63% in Canada,[9] and 37% in Europe[12]). Perhaps naively, we believe that these frequencies reflect clinical or global equipoise at HIC centers rather than non-compliance with a true standard of practice. In low- and-middle-income countries (LMICs), although ICP monitoring is generally available (via ventriculostomy), it is rarely used, with availability of neurological surgeons, expense, complications, and labor intensity quoted as reasons. As a result, aggressive treatment of suspected intracranial hypertension is based on serial imaging and neurological examination. The widespread environment of competition for funding and resources in LMICs places the implications of the lack of scientific rigor in a unique context quite different from that in HICs. It is perhaps germane to realize that most, if not all, of the authors of the guidelines have never managed a severe traumatic brain injury (TBI) patient without an ICP monitor. This brings us to our second major area of concern with the Sahuquillo and Biestro critique, which revolves around the sterility of their analysis of equipoise. As noted in the commentary of Hunt, equipoise may be considered to have superficial and deep aspects. Superficially, it is likely true that our Latin American investigators would have been using ICP monitoring before the trial if it were readily available. Of course, cardiac surgeons would have routinely employed internal mammary artery ligation for angina in the 1950s[3] and intensivists would have chosen pulmonary artery catheterization for managing critically ill ICU patients four decades later.[4,8,11] We would all likely benefit from confessing to “medical magpie-ism” and admitting that practice in the high-resource environment of HICs greatly facilitates (and obscures) such a non-scientific proclivity. However, the benefits of living in a high-resource environment also strongly inhibits us from understanding the profoundly different visceral viewpoint that arises from having experienced ones entire medical career in LMICs. Indeed, the BEST TRIP investigators from the US and Argentina were initially taken aback when the site investigators involved in designing a multicenter prospective observational study suggested that they would be interested in performing an RCT involving ICP-monitor-driven care. Not until after much discussion among ourselves and with our site PIs did we realize that their position of equipoise, although difficult for us initially to understand, was internally valid. Without the indispensable experience that we had gained over a decade of working in Latin America, learning and experiencing their reality, it is quite possible that some of the BEST TRIP authors might have co-authored the editorial critique of Sahuquillo and Biestro. It is notable that this trial was evaluated and approved by ethical committees and FWA-approved IRBs in all participating Latin American institutions, as well as by the IRB at the University of Washington in the US. Although there were myriad ethical questions from each entity during these reviews, none found the study unacceptable based on ethical concerns. As far as conflict of interest is concerned, the site PIs who suggested and performed this study had no interest in its implications in HICs, but were very much interested in finding whether the application of our current ICP-monitor-driven protocols in their environment would warrant the required resources. Although the editorial states that “BEST TRIP is a good example of research that has no practical relevance to the health needs of the host country, but it is apparently important to the foreign sponsors and researchers …,” we fail to see how demonstrating inadequacies in our use of an important monitoring device is not relevant to the health needs of both the US and Latin American countries involved in the study. We also take issue with their strong implication that this study was influenced by industry. Given the highly limited funding that comes with Fogarty International Center directed/NIH sponsored research awards, there was no way for us to purchase the required monitors. Integra Life Sciences responded positively to our request that they would supply the necessary hardware, despite explicit prohibitions against their having input into the design, execution, analysis, or publication of the study results. This is collaboration, not collusion, and allegations otherwise would benefit from supporting evidence. In contrast to the implications of the editorial, the BEST TRIP publication explicitly cautions against ready generalization of the results to HIC centers. This is based on the many important differences between these environments and our inability to adequately control for them in our analyses. As the editorial correctly states, the logical next step would be repeating the study at trauma centers in HICs. However, it also posits, “these countries would never allow such a trial to be conducted,” which we believe is incorrect. As noted above, there were sizeable percentages of HIC trauma centers not monitoring prior to the trial, and we perceive an increasing willingness for practitioners who do not routinely monitor to publically admit this following the BEST TRIP publication. A shift in HIC-equipoise balance might not be required to perform such a study. Finally, our site PIs almost to a person took umbrage at the implication in this editorial that the study ICUs were of limited quality due to lack of resources. Anyone who has spent time in these ICUs will immediately recognize the high level of education, diligence, and application represented by the involved intensivists, which is clearly reflected in the data presented in the BEST TRIP publication and the online supplement. We offer a standing invitation to Professor Sahuquillo and Dr. Biestro to visit any or all of the BEST TRIP ICUs toward rectifying their difficulty in differentiating resource limitations and quality of care. We believe that proper response to a careful, thorough reading of the BEST TRIP report is to recognize the critical value of aggressive and attentive management of TBI patients in all settings and to admit that our fields employment of ICP monitoring is under-developed at present, rather than to deny the studys findings. Refinements in threshold setting, TBI subgroup identification, and integration of ICP data with other monitored values and trends appear wanting, but there is no evidence that ICP monitoring should be abandoned. On the larger stage, it is also important to realize that the medical and ethical literature almost exclusively emanates from academic centers in HICs. The only valid method for assessing the generalizability of this literature to LMICs is to make an unbiased, protracted effort to understand their reality, as perceived by them. In this light, it is notable that none of our Latin American colleagues have ever expressed regret that they suggested this study or participated in its execution.