Multiorgan Dysfunction After Severe Traumatic Brain Injury

Abstract

Traumatic brain injury (TBI) is a major global health problem and a major contributor to morbidity and mortality following multisystem trauma. Extracranial organ dysfunction is common after severe TBI and significantly impacts clinical care and outcomes following injury. Despite this, extracranial organ dysfunction remains an understudied topic compared with organ dysfunction in other critical care paradigms. In this review, we will: 1) summarize the epidemiology of extracranial multiorgan dysfunction following severe TBI; 2) examine relevant mechanisms that may be involved in the development of multi-organ dysfunction following severe TBI; and 3) discuss clinical management strategies to care for these complex patients.

Traumatic brain injury (TBI) is a major global health problem and a major contributor to morbidity and mortality after trauma.¹ Extracranial organ dysfunction is common after severe TBI and may significantly impact clinical care and outcomes. Consequences of extracranial multiorgan dysfunction on the injured brain include reduced cerebral blood flow (CBF), cerebral hypoxia, altered metabolism, acidosis, and bleeding, all of which may contribute to secondary brain injury and poor clinical outcomes.^2,3 Despite the impact of multiorgan dysfunction on severe TBI outcomes, it remains an understudied topic compared with organ dysfunction in other critical care paradigms, such as sepsis.⁴ In this review, we aim to (1) summarize the epidemiology of extracranial multiorgan dysfunction after severe TBI, (2) examine relevant mechanisms that may be involved in the development of multiorgan dysfunction after severe TBI, and (3) discuss clinical management strategies to care for these complex patients. We hope this serves to provide a framework for physicians and scientists to begin investigations aimed at protecting nonneurologic organ systems after severe TBI, which will ultimately reduce secondary brain injuries and lead to improved neurologic outcomes.

Epidemiology of Multiorgan Dysfunction After Severe TBI

Extracranial organ dysfunction after severe TBI has traditionally been studied on an individual organ system basis; however, data suggest that multisystem organ dysfunction after TBI is common and likely share similar mechanistic and pathophysiologic features with single organ system dysfunction.⁵ We think that correction of organ failures associated with TBI may be an important target to improve clinical outcomes; however, this has not yet been proven. Based on these considerations, this section will first consider the epidemiology of individual organ system dysfunction after severe TBI, followed by a discussion of multiorgan dysfunction associated with severe TBI.

Individual Organ System Dysfunction After Severe TBI

Circulatory dysfunction (shock and cardiac dysfunction) has become an increasingly recognized complication after severe TBI. Shock and cardiac dysfunction are clinically relevant because they can impact early cerebral perfusion in the setting of an impaired vascular autoregulation capacity of the injured brain.^6,7 Although the epidemiology of cardiac dysfunction after severe TBI has become better understood only recently, circulatory shock has long been recognized for its association with deleterious outcomes in patients with severe TBI. Epidemiologic studies have demonstrated a strong association of early hypotension with increased mortality after severe TBI,⁸ suggesting that maintenance of systolic BP (SBP) early after injury may be important to preserving CBF for the injured brain. As early as 1978, Miller et al⁹ demonstrated early hypotension as a predictor of increased mortality after severe TBI. Since that time, several epidemiologic studies have confirmed this association; however, the definition of hypotension has varied from as low as an SBP < 80 mm Hg¹⁰ to as high as an SBP < 120 mm Hg.¹¹ More recent studies have refined BP thresholds for optimizing outcomes in severe TBI, suggesting higher thresholds and age dependence.11, 12, 13 Incorporation of these newer insights are reflected in the most recent Brain Trauma Foundation Guidelines for the Management of Severe Traumatic Brain Injury,¹⁴ which recommend maintenance of an SBP ≥ 100 mm Hg for patients 50 to 69 years of age and an SBP ≥ 110 mm Hg for patients 15 to 49 years of age or > 70 years of age.

With the advent of modern and portable imaging modalities for the heart, cardiac dysfunction has been evaluated more thoroughly after severe TBI over the last decade. Although stress cardiomyopathy has been well recognized after acute brain injuries such as subarachnoid hemorrhage (with 36% of patients affected),¹⁵ the epidemiology in TBI is not as well established. Based on limited studies in TBI, the incidence is reported to be as high as 22% using traditional echocardiographic assessments,^16,17 and between 10% and 38% when more sensitive parameters of left ventricular function, such as global longitudinal strain, are used.^18,19 Cardiac dysfunction is reported to be more common in patients with greater severity of injury,¹⁶ and has a hemodynamic and histologic profile that suggests that sympathetic activation may be the underlying etiology.^20,21 After severe TBI, acute cardiac dysfunction has been postulated to contribute to hypotension, CBF, and secondary brain injuries.²² Importantly, although cardiac dysfunction occurs early after injury (when the injured brain is most sensitive to reduced CBF), cardiac function has been observed to improve over the first week of hospitalization after TBI.¹⁶ Taken together, early cardiac dysfunction and circulatory shock both represent potentially modifiable factors for reducing secondary brain injuries and improving outcomes after severe TBI, through prompt recognition and goal-directed hemodynamic management. Unfortunately, current and past severe TBI guidelines do not comment on evaluating the status of the heart when treating TBI-associated shock, until further evidence accumulates.

TBI is accompanied by a spectrum of pulmonary dysfunction, broadly classified under the clinical umbrella of ARDS. Although the pathophysiologic features of ARDS after acute brain injuries have been described for decades, there are a lack of prospective clinical trials to understand optimal management in the severe TBI population. The heterogeneity of the clinical definition of TBI, along with evolving definitions of ARDS,²³ has also significantly hampered the study of the problem. Available data from retrospective studies suggest an incidence of ARDS after TBI of > 20%, and varies depending on the ARDS definitions that were used.²⁴ Notable risk factors for the development of ARDS after TBI include the following: age, injury severity, and clinical management strategies aimed to induce hypertension.²⁵ The development of ARDS after severe TBI has consistenly been associated with poor clinical and functional outcomes. For example, analysis of the Traumatic Coma Data Bank concluded that development of lung injury after TBI was associated with a nearly three times increased odds of death or persistent vegetative state, independent of the Glasgow Coma Scale²⁶; these clinical observations have been confirmed in more recent studies.²⁷

Acute kidney injury (AKI) is a common organ injury after multiple critical illness paradigms, including TBI. The incidence of AKI after TBI has been reported between 8% and 14%.28, 29, 30 In addition, the development of AKI has consistently been associated with worse clinical and functional outcomes after TBI.28, 29, 30 Etiologies of AKI after TBI include underlying catecholamine excess secondary to sympathetic activation after TBI, and treatments for high intracranial pressures (ICPs) in TBI, such as the use of hyperosmolar solutions that can provide a high chloride load to a kidney that is at risk for injury.^31,32 Ultimately, AKI can lead to several downstream consequences, including acidosis, severe electrolyte disturbances, and difficulty with fluid management; these consequences provide a pathway for AKI to contribute to secondary brain injuries and poor patient outcomes after severe brain injuries.

Multiorgan Dysfunction After Severe TBI

Although individual extracranial organ dysfunction has been evaluated in the literature after severe TBI, fewer studies have considered the incidence and clinical impact of multiorgan dysfunction. A major issue in studying the epidemiology of multiorgan dysfunction is the heterogeneity of definitions used throughout the severe TBI literature. Although prior studies used parameters of individual organ system clinical syndromes (eg, shock, ARDS, pneumonia, sepsis) to describe multiorgan dysfunction,² more recent studies have used clinical scoring systems. Even among clinical scoring systems, there continues to be debate regarding the best system (eg, Denver score, Multiple Organ Dysfunction Syndrome score, Sequential Organ Failure Assessment [SOFA] score). Despite differences in score ascertainment, all scores have comparative discriminative ability to predict outcomes in patients with severe TBI,^5,33 with the SOFA score striking the most balance between sensitivity and specificity characteristics in the general trauma population.³³ Among these multiple scoring systems, the SOFA score has emerged as a widely used scoring system for describing organ dysfunction in critical care in general, it is now incorporated into the global definition of sepsis,³⁴ and it is gaining popularity in studies examining nonneurologic organ dysfunction in multiple neurologic injury paradigms that comprise the field of neurocritical care, including severe TBI.³⁵

Using the SOFA score to describe multiorgan dysfunction after TBI, a composite score of five component systems (cardiovascular, respiratory, coagulation, renal, and hepatic) is calculated. Choosing a cut point of 7 to define multiorgan dysfunction, almost 40% of patients with moderate to severe TBI were observed to experience multiorgan dysfunction within their first 10 days of hospitalization, with cardiopulmonary organ failures comprising most organ dysfunction.³⁵ Among this population, patients with multiorgan dysfunction experienced increased hospital mortality.³⁵

An increased burden of individual organ dysfunction and multiorgan dysfunction has consistently been associated with worse clinical and functional outcomes after TBI, above and beyond the severity of neurologic injury alone. Therefore, understanding the underlying mechanisms of multiorgan dysfunction, developing preventative measures, and examining therapeutic advances in treatment may all represent viable pathways of reducing secondary brain injuries and improving outcomes among patients with severe TBI. In the next section, we discuss some of the known pathophysiologic mechanisms for the development of multiorgan dysfunction after severe TBI.

Mechanisms of Multiorgan Dysfunction After Severe TBI

After severe TBI, a cascade of autonomic and inflammatory mediators is released into the circulation, resulting in widespread organ effects and dysfunction and ultimately secondary brain injuries. Autonomic dysfunction has been implicated as central to the pathophysiology of multiorgan dysfunction after TBI. Severe TBI results in changes in central and peripheral autonomic tone and widespread catecholamine release through activation of the hypothalamic-pituitary-adrenal axis and sympathetic nervous system.36, 37, 38 The resulting activation of the sympathetic nervous system leads to a direct effect on the function of a range of organ systems throughout the body.³⁹ In addition, autonomic dysfunction may contribute to excessive systemic inflammation through adrenergic receptor activation and stimulation of cytokine release from lymphoid organs, such as the spleen^40,41; as subsequently discussed in detail, systemic inflammation can further contribute to secondary brain injuries after severe TBI, above and beyond the effect of autonomic dysfunction alone.

Although sympathetic activation may initially be protective by preserving blood flow to multiple organ beds (including CBF, in the setting of impaired cerebral autoregulation⁴²), this may eventually become maladaptive and result in end-organ dysfunction.²⁰ Cardiopulmonary effects of sympathetic activation include systemic vasoconstriction, increased myocardial workload and oxygen demand,⁴³ and large increases in pulmonary vascular pressures.⁴⁴ GI effects of sympathetic activation can result in alterations in the gut microbiome and mucosal atrophy,^45,46 which may increase intestinal permeability and increase risk of bacterial translocation to the systemic circulation.⁴⁷ Acute kidney injury develops after severe TBI in part from sympathetic activation, which results in decreased renal glomerular perfusion.⁴⁸ Therefore, autonomic dysfunction can result in widespread nonneurologic organ injury and dysfunction after severe TBI, and striking a balance between adaptive and maladaptive sympathetic activation after severe TBI is an important target for future TBI research.

Severe TBI induces a robust inflammatory response that manifests both within locally injured neural tissue and systemically.^49,50 The immune response is initiated in part by neuronal and glial death from the primary injury (either blunt, penetration, or a combination of both). A combination of human and animal data suggests the acute neuroinflammatory response to injury includes increased permeability of the blood-brain barrier, migration of hematogenous macrophages into the injured brain, activation of resident microglial cells, and ultimately the release of inflammatory mediators.^51,52 Although activated resident microglia were historically thought to take on either a proinflammatory subtype (M1) or an antiinflammatory profile (M2), emerging data suggest a more complex and nuanced characterization of their role after brain injury.^53,54 Although intended to be protective, the inflammatory response can ultimately prove to be detrimental if its magnitude, location, and duration are not appropriately regulated. For example, infiltration of activated neutrophils into the lung may make the lungs more susceptible to mechanical stress from ventilation, resulting in a double hit to the lung.⁵⁵ Immune activation can be enduring, with evidence that changes in microglial may persist for years after the initial insult.⁵⁶ Severe TBI results in changes in the levels of inflammatory mediators and cytokines, such as interleukins. In many cases, such as with IL-6, there appears to be a correlation between level and severity of injury.⁵⁰ This is of particular consequence because evidence suggests that elevated levels of IL-6, IL-8, and IL-10 are associated with multisystem organ dysfunction after TBI, above and beyond injury severity characteristics alone.³⁵ Therefore, harnessing the protective aspects of neuroinflammation while limiting the deleterious local and systemic consequences of the inflammatory response are an important research priority in severe TBI.

Maladaptive activation of coagulation pathways may also contribute to ongoing organ dysfunction after severe TBI, and it is strongly associated with adverse outcomes.⁵⁷ Coagulopathy often involves a complex dynamic interaction between patient and injury factors, resulting in massive tissue factor release,⁵⁸ maladaptive protein C responses,⁵⁹ and hyperfibrinolysis.⁶⁰ The incidence of acute coagulopathy after TBI varies widely in the literature (10%-90%); however, meta-analyses suggest that approximately one-third of patients with TBI experience coagulopathy,^61,62 with injury severity as a major risk factor. Examination of the epidemiology of acute coagulopathy after TBI is further complicated by heterogeneity between studies and varying definitions of coagulopathy. For example, in a meta-analysis performed by Epstein et al,⁶² > 19 proposed definitions of acute coagulopathy, using 23 different coagulation values, were used in the examined literature. Ultimately, the maladaptive coagulopathy is a manifestation of a disseminated intravascular coagulation syndrome, and results in bleeding, microthrombosis, and secondary brain injuries from both ischemic and hemorrhagic etiologies.⁶³ This is consistent with the observed association of acute coagulopathy with poor outcomes in patients with TBI, including increased mortality, increased duration of mechanical ventilation, and greater functional disability.^64,65

Relevant mechanisms and clinical consequences are summarized in Figure 1. Although additional mechanisms have been implicated in contributing to extracranial organ dysfunction in other neurologic and critical care injury paradigms, there are little human data in severe TBI. For example, mitochondrial dysfunction is a relevant and increasingly studied mechanism of multiorgan dysfunction in sepsis.⁶⁶ Furthermore, genetic variability may contribute to organ dysfunction, and has been studied in other brain injury paradigms (eg, adrenergic receptor polymorphisms, cardiac dysfunction in subarachnoid hemorrhage).⁶⁷ To gain a more nuanced understanding of how these mechanisms may contribute to multiorgan dysfunction after severe TBI, further research is necessary.

Figure 1.

Relevant mechanisms and clinical consequences of multiorgan dysfunction after severe TBI. DIC = disseminated intravascular coagulation; TBI = traumatic brain injury.

Clinical Management

The widespread systemic effects of severe TBI necessitate multiorgan system management aimed to reduce secondary brain injury. Although initial management is focused around brain-specific goals, prevention and management of extracranial organ dysfunction is a clinical priority. Similar to how severe sepsis requires consideration of multiple organ systems, management of severe TBI requires balancing the optimization of often competing management strategies. Because management of severe sepsis begins with source control to prevent further propagation of the initial insult, management of severe TBI begins with attempts to control ongoing brain damage by removing mass lesions and reducing ICP. Maintenance of adequate CBF is paramount in preventing secondary neurologic injury and promoting functional recovery and is especially relevant when cerebrovascular autoregulation is altered by trauma. CBF is rarely directly measured in a continuous fashion in the clinical setting; therefore, cerebral perfusion pressure (CPP) or mean arterial pressure – ICP is used as a surrogate of appropriate blood flow. Best available evidence, and contemporary guidelines,⁶⁸ suggest maintenance of a CPP between 60 and 70 mm Hg in adults.

The optimal strategy to manage respiratory failure after severe TBI remains undetermined. Despite significant research efforts, the optimal ventilation strategy or oxygenation goal remains unclear. Two particular areas of focus are how positive end-expiratory pressure (PEEP) can be applied safely in the setting of elevated ICP and how mechanical ventilation can be used to augment oxygenation in the damaged brain. In general, moderate levels of PEEP can be safely used without significant risks to increased ICP; however, it can be optimally titrated when ICP monitoring is in place. In addition, protocols for augmentation of cerebral oxygenation by optimization of mechanical ventilator settings have been examined in the phase 2 Brain Oxygen Optimization in Severe TBI Phase-2 (BOOST-2) study⁶⁹ and are currently being further studied in the ongoing phase 3 Brain Oxygen Optimization in Severe TBI Phase-3 (BOOST-3) study. Respiratory failure after severe TBI is of interest because many of the commonly used management strategies for severe respiratory failure are at odds with TBI management. For example, prone positioning after cranial neurosurgery with an incompetent cerebral vault or multiple intracranial monitors is logistically difficult and potentially dangerous. Permissive hypercarbia, and its associated cerebral vasodilation, can lead to refractory intracranial hypertension. Paco₂ is therefore recommended to be kept between 35 and 40 mm Hg. Although a precise acceptable lower limit of normal is debated, prophylactic hyperventilation to manage ICP is discouraged (in the absence of advanced monitoring techniques such as jugular venous oxygen saturation) because it can decrease CBF and result in ischemia.⁷⁰ Oxygen management after TBI is an area of ongoing research with trials assessing whether hyperbaric oxygen or a management strategy guided by brain tissue oxygen tension is beneficial.⁶⁹ Questions regarding oxygen management extend to both Pao₂ goals and the utility of measuring oxygen content within brain tissue itself via the surgical placement of brain tissue oxygen monitors.⁶⁹ Management paradigms using oxygen content within brain tissue may result in the administration of oxygen despite what may be considered acceptable Pao₂ goals, with concerns for possible development of pulmonary oxygen toxicity. Furthermore, the minimal Pao₂ which should be targeted remains unclear; although studies indicate a target of > 90 mm Hg,⁷¹ data are limited. Modes of mechanical ventilation and which factors most affect ICP are largely understudied; however, available data suggest that PEEP may be safely applied without significant changes in ICP.⁷² The management of respiratory failure using lung-protective ventilation, and ventilator failure rescue strategies, in the setting of severe TBI⁷³ presents several unique challenges to the physician and represents an important research priority.

The maintenance of BP allows for adequate CPP to the injured brain with impaired vascular autoregulation. Current guidelines suggest a minimum SBP of 100 mm Hg for patients 50 to 69 years of age or 110 mm Hg for patients either 15 to 49 or > 70 years of age, and is derived from several epidemiologic studies previously discussed, including early data suggesting significant increase in mortality with a single episode of hypotension defined as SBP < 90 mm Hg in adult patients.⁷⁴ When hypotension develops, the particular vasopressor strategy that BP should be augmented is a relatively unexplored arena, and requires further research. Management of coagulopathy is also a controversial area. Although the administration of tranexamic acid within 3 h of injury is associated with reduced head injury-related mortality based on the published CRASH-3 trial,⁷⁵ data on clinical outcomes after the administration of desmopressin or platelets (other than in response to specific laboratory abnormalities or baseline pharmacologic agents) are mixed. A cornerstone of the management of cerebral edema is the use of hypertonic and hyperosmolar agents. Selection of the appropriate agent must take into account the type of baseline serum sodium and osmolarity, hemodynamics, and venous access available. The patient’s renal function must also be considered because diuretics (eg, mannitol) will be less efficacious in the patient with oliguria or anuria.

The multisystem management of severe TBI rests on primary injury management and well-established fundamentals of supportive critical care. This includes the appropriate use of both gastric and venous thromboembolic prophylactic measures in this vulnerable population and early resumption of nutrition, with glucose control. Management of sedation and analgesia can present a challenge because often refractory intracranial hypertension precludes spontaneous awakening trials which have become a mainstay of ICU care. Significant questions remain regarding the best way to apply evidence-based practice of organ failure secondary to other etiologies to that caused by severe TBI. Table 1 summarizes goals and management strategies for nonneurologic organ system dysfunction after severe TBI.

Table 1.

Clinical Management Pearls

Organ System	Management Pearls
Circulatory	• CPP goal 60-70 mm Hg ○ Do not induce hypertension to exceed CPP of 70 mm Hg •SBP minimum of 100 mm Hg (age dependent) •ICP < 22 •Hypertension management – focused on ensuring adequate sedation and that it is not physiological response to elevated ICP prior to artificially lowering
Respiratory	•Paco2 35-40 mm Hg (with exception of rescue therapy for herniation syndrome) •Pao2 > 60 mm Hg (per guidelines, but recent data suggest a Pao2 > 90 mm Hg necessary to prevent brain tissue hypoxia) • Mechanical ventilation ○ Not enough data to recommend specific mode or rescue strategy ○ Mixed data on whether PEEP affects ICP
Hematology and coagulation	•Hemoglobin > 7 g/dL •Normalization of coagulation profile (guided by standard laboratory evaluation or thromboelastography) •Platelet count >100,000/mm3 •Reversal of anticoagulants and antiplatelet agents (controversial)
Endocrine	•Glucose 140-180 mg/dL •Steroid administration contraindicated for the treatment of cerebral edema caused by TBI
Renal	• Hyperosmolar and hypertonic therapies (both used to reduce ICP in the setting of cerebral edema) ○ Both of these agents should be given as bolus as opposed to continuous infusion in response to elevated ICP or clinical herniation syndrome ○ Upper threshold for either agent not well defined ○ Attention to maintenance of adequate CPP

CPP = cerebral perfusion pressure; ICP = intracranial pressure; PEEP = positive end-expiratory pressure; SBP = systolic BP; TBI = traumatic brain injury.

Conclusions

Severe TBI results in significant dysfunction to extracranial organ systems, which contribute to secondary brain injuries and poor clinical outcomes. Although current evidence points to autonomic dysfunction and systemic inflammation as primary causative mechanisms of multiorgan dysfunction after severe TBI, it remains an understudied area. Future research should focus on understanding underlying mechanisms, improving prediction and prevention of multiorgan dysfunction, and clinical trials to identify the best strategies for patient management. Optimal prevention and treatment of multiorgan dysfunction after severe TBI has the potential to improve TBI clinical outcomes worldwide.