This was a retrospective cohort study conducted to evaluate the effect of vasopressor use on mortality among patients with severe TBI, using a nationwide trauma database in Japan. With robust analyses to adjust for severity, it was found that the use of vasopressors was significantly associated with higher mortality, not only on hospital discharge but also in the ED. Subgroup analysis also reiterated the same and suggested that the use of vasopressors for severe TBI was associated with higher mortality on hospital discharge in almost all cases.
Hypotension (defined as a systolic blood pressure < 90 mmHg) is a well-known risk factor associated with the occurrence of secondary cerebral damage and poor outcome, especially after TBI [7–9]. In contrast, the large IMPACT prospective database found that a systolic blood pressure < 120 mmHg is also a strong predictor of unfavorable neurological recovery . Based on these findings, major guidelines or studies, including those of the Brain Trauma Foundation or the SAFE-TBI randomized study in Australia, recommend maintaining a systolic blood pressure > 90 mmHg with a vasopressor after severe TBI [2, 5]. The purpose of maintaining consistent cerebral perfusion with vasopressors is to prevent hypotensive cerebral ischemia. Further, vasopressors may be used as volume-sparing resuscitating agents to prevent brain edema. However, our study showed that neither mortality nor the occurrence of cognitive dysfunction was improved by the use of vasopressors, suggesting that vasopressors should be avoided in most cases of severe TBI. A similar recommendation was provided by Lund, although the guideline was not supported by strong levels of evidence .
Only a few studies have tried to assess whether the use of vasopressors is beneficial for severe TBI . However, a number of studies have focused on which type of vasopressor should be used [24, 25]. Our findings could pave the way for future guidelines regarding the use of vasopressors for the treatment of severe TBI.
The penumbra, the brain tissue surrounding the impacted core of the TBI, becomes particularly vulnerable to cell death by hypoxic insults, and preservation of this area is one of the important objectives for using vasopressors. The overall effects of vasopressor use on the brain are probably a consequence of systemic arterial contraction but are also influenced by other factors such as brain injury, integrity of the blood–brain barrier, and the status of cerebral autoregulation . In the abnormal state of autoregulation after severe TBI, excessive elevation of intracranial pressure favors edema formation by increased capillary hydrostatic pressure across the blood–brain barrier, causing brain herniation . This may also result in unwanted hemodynamic effects, such as intracranial hemorrhage, leading to increased mortality [28, 29]. Additionally, vasopressors cause an array of adverse effects among other organs of the body [30, 31]. Catecholamine surge after TBI can lead to peripheral insults induced by the release of proinflammatory substances and result in increased vascular permeability . In this situation, the accentuated proinflammatory response could trigger the development of acute respiratory distress syndrome . Other potential negative systemic side effects of vasopressors include arrhythmia, diuresis, and increased left ventricular afterload.
In patients with severe TBI, low arterial blood pressure, major surgery with bleeding, and blood transfusion can contribute to secondary insults to the brain and aggravate the primary insults and cerebral edema, increasing the risk of developing severe lung injury, or even multiple organ failure. Traditionally, it has been suggested that the clinical effects of brain injuries vary depending on individual characteristics such as sex, age, past medical history, and type of TBI. With multiple confounding factors, planning treatment for TBI is especially challenging. In this study, we used the largest trauma dataset in Japan that allowed us to adjust for confounding factors. To the best of our knowledge, our study included the largest cohort of its kind, to date, that has focused on patients with severe TBI. This study also reveals the utility of vasopressors in some specific conditions (e.g., in patients with TBI with a history of stroke). In cases of stroke, structural cerebrovascular changes may increase resistance; thus, normal cerebral blood flow can be maintained using vasopressors. However, the use of vasopressors in such a subgroup did not reduce mortality at the time of hospital discharge. These results suggest that vasopressors should be avoided in most cases of severe TBI.
The authors acknowledge a few limitations of this observational study. First, PS matching analysis has the risk of residual selection bias. Some differences in the two groups may still exist, even after PS matching, particularly if data on important confounding factors are not included in the analysis. Second, although the use of vasopressors (mainly catecholamine) for resuscitation was recorded in the JTDB, important information such as the type and dose of vasopressors used and the timing of vasopressor administration was not included, leading to selection bias. Detailed information about the dose, type of vasopressor, mode of administration (bolus and/or continuous), and patients’ vital signs when the vasopressor was initiated was not included in the JTDB. However, all TBI patients transported to JTDB-participating hospitals were treated based on the guidelines for the management of severe TBI, which state that vasopressors are recommended to maintain a systolic blood pressure > 110 mmHg . Third, the incidence of cognitive disorders could have been underestimated in our study as the JTDB includes clinical data until hospital discharge, which would largely cater to the acute phase of the injury. Cognitive symptoms after TBI would be accurately evaluated only after recovering from an altered state of consciousness in the acute phase. Additionally, the data included in this study primarily involved cases of blunt trauma, which cannot be extended to penetrating TBI. Lastly, this was an observational study, and there may be other unknown confounding factors. The results of this investigation could not establish causality and remain limited to associations. Ideally, the results should be validated in a randomized study.
Blood pressure augmentation to avoid hypotension has been considered to attenuate secondary cerebral damage. Therefore, the management of blood pressure using vasopressors during the emergent phase and intensive care unit phase is based on low-quality evidence and strong recommendations according to recent guidelines for the management of severe TBI [5, 9, 32, 33]. However, our results suggest that vasopressors should be avoided in most cases of severe TBI. Our study has the potential to result in policy and guideline changes for the treatment and management of severe TBI.