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15. Damage Control Resuscitation for Severe Traumatic Brain Injury
Keywords
Damage control resuscitationTraumatic brain injuryLife-threatening hemorrhageResuscitation principlesCrystalloidsColloidsNovel therapeutic strategies in traumatic brain injuryIntroduction
Traumatic brain injury (TBI) remains a leading cause of death and disability worldwide [1, 2]. In the United States alone, approximately 1.7 million people are affected by TBI each year, and TBI ultimately contributes to approximately 30% of all injury-related deaths [3, 4]. In both civilian and military traumatic settings, TBI is frequently accompanied by other traumatic insults, including vascular injury and life-threatening hemorrhage (LTH), which is the leading cause of preventable death in trauma [5]. The presence of severe TBI, in addition to LTH, presents a unique clinical scenario in which providers should be well-versed. Severe TBI alone can contribute to widespread impairment of hemostasis, endothelial function, coagulation, and immune function [6–8]. In the setting of LTH, severe TBI can contribute to potentiation of the lethal triad—acidosis, coagulopathy, and hypothermia—in trauma. To improve patient outcomes, pre- and in-hospital care of patients with LTH and severe TBI requires avoiding hypoxia and hypotension to minimize secondary brain injury and optimizing intracranial hemodynamics [4, 9].
Within recent years, damage control resuscitation (DCR) has become a highly popular treatment strategy with increasing relevance in both military and civilian trauma [10]. Originally termed by the United States Navy, “damage control” refers to providing only those interventions deemed necessary to control hemorrhage and minimize gross contamination [11], with the goal of restoring a patient to a survivable physiologic status through early definitive resuscitation and aggressive correction of metabolic derangements, hypothermia, and acidosis [10]. Achieving these means is possible through application of several key concepts for LTH, including permissive hypotension, prioritizing blood product transfusion over crystalloids, and aggressive correction of shock and coagulopathy with whole blood or blood product component therapy in 1:1:1 unit ratios to simulate whole blood [12, 13]. As TBI and LTH often coexist in severe trauma, both civilian and military providers must be well-versed in the application of DCR in the setting of severe TBI and LTH. Although such a management strategy is well-established for LTH, alternative treatment strategies and management considerations should be applied to patients with concurrent severe TBI.
This chapter highlights [1] the effects of severe TBI on hemostasis, immune function, endothelial function, and shock (oxygen deficit) which results in cell death, [2] resuscitation principles for pre- and in-hospital care of patients with LTH and severe TBI, [3] resuscitation strategies involving blood products and crystalloids/colloids, and [4] novel neurotherapeutic agents which appear promising to improve clinical outcomes in the setting of severe TBI and LTH.
The Impact of TBI on Shock, Coagulopathy, Endotheliopathy, and Immune Dysfunction
Following the direct impact of TBI, normal hemostasis, inflammation, and endothelial cell and immune functions are immediately disrupted. Although these alterations are observed in traumatic injuries without TBI, the presence of concurrent severe TBI and LTH can substantially increase the magnitude of impaired hemostasis, massive inflammation, and endotheliopathy compared to these isolated conditions alone [14–17]. All of these impairments ultimately contribute to the development of impaired hemostasis, which occurs in over 60% of patient with severe TBI [18, 19].
Current understanding of the systemic mechanisms underlying coagulopathy and hemorrhagic contusions after traumatic brain injury. Numerous complex, highly interactive pathways are involved in contributing to the development of coagulopathy following traumatic brain injury including direct impact, microvessel injury, blood-brain barrier disruption, platelet dysfunction, endotheliopathy, protein C activation, hyperfibrinolysis, and iatrogenic coagulopathy. (From Maegele et al. [6], Copyright (2017), with permission with permission of Elsevier)
Initial Injury and Platelet Activation and Disruption
Severe TBI typically results in immediate disruption of brain microvasculature and the blood-brain barrier (BBB) , resulting in an immediate hemorrhagic contusion [6]. The closely surrounding area, known as the penumbra, is also a highly sensitive area which can result in delayed microvessel failure causing progressive hemorrhagic contusion [30]. Following microvasculature and BBB disruption, complex interactions between platelets and damaged endothelium or the subendothelial matrix may occur, leading to the release of massive inflammatory mediators, including prostaglandins, cytokines, and PAF [6, 31, 32]. Such mediators can contribute to additional BBB breakdown along with the release of additional PAF and other procoagulants [33]. As a downstream effect, platelet hyperactivation may ensue followed by subsequent platelet consumption and exhaustion, causing both primary and secondary platelet depletion [20, 34]. Platelet dysfunction secondary to inhibition of adenosine diphosphate or arachidonic acid receptors may also occur, even in the setting of normal platelet counts [20, 23, 34]. Furthermore, this platelet dysfunction can further coagulopathy by influencing coagulation and inflammatory pathways through complement-mediated mechanisms [35–37].
Brain Tissue Factor and Activation of the Coagulation Cascade
Brain tissue factor (TF) release and activation may also play a significant role in the development of inflammation and systemic coagulopathy [6, 38]. In the absence of severe TBI, any brain TF released is normally isolated by the BBB. Following severe TBI, however, TF is shed in the systemic circulation and can be bound extensively by factor VIIa, propagating the extrinsic coagulation pathway [6, 39]. Following subsequent thrombin activation, platelet dysfunction and exhaustion can occur [39]. In severe cases, however, disseminated intravascular coagulation (DIC) may ensue, occurring as early as 6 hours following severe TBI. With the onset of DIC, massive systemic activation of both the intrinsic and extrinsic clotting pathways may occur, resulting in further consumption of coagulation factors and platelets, leading to further coagulopathy. Furthermore, the combination of brain TF and TF released from other associated traumatic injuries can further platelet activation, along with endothelial-derived and platelet-derived micro-particles, enabling formation of procoagulant complexes [14, 24, 40]. As this cascade is propagated, fibrinogen and platelet concentrations may significantly decrease and can result in further coagulopathy and the potentiation of any existing bleeding [41, 42].
Hyperfibrinolysis
Although platelet and coagulation factor consumption contribute to TBI-induced hypocoagulable conditions [41, 42], several alternative mechanisms promoting hyperfibrinolysis have been proposed. In rodent models, both endogenous tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA) , well-known mediators of fibrinolysis, have been demonstrated to be increased in brain tissue following TBI [43]. Furthermore, a depletion of alpha-2-plasmin inhibitor, resulting in an increase in plasmin, has also been demonstrated [24]. As plasmin is the cleavage product of plasminogen and a key mediator of fibrinolysis, its increased levels are suspected to make patients with severe TBI particularly susceptible to impaired hemostasis [6].
Endothelial Dysfunction (Endotheliopathy) and Other Mechanisms
When severe TBI is coupled with polytrauma and LTH, additional mechanisms related to endothelial dysfunction or endotheliopathy also come into play [23]. In this setting, massive endothelial damage secondary to shock and injury can result in severe glycocalyx shedding, which has been shown to induce auto-heparinization [44]. This may ultimately lead to endogenous anticoagulation of TBI patients [44]. In addition, elevated catecholamines often occur secondary to a hyperadrenergic state and endothelial dysfunction, and have been correlated with coagulopathy following TBI [23, 45, 46]. Furthermore, patients with concurrent TBI and LTH have also been shown to exhibit activation of downstream protein C pathways, which can promote further inflammation, hyperfibrinolysis, and inhibition of coagulation factors Va and VIIIa [24, 47].
Lastly, liberal fluid resuscitation for patients with LTH often promotes iatrogenic hypocoagulation secondary to hemodilution, acidosis, and hypothermia (most fluids are room temperature and have a low pH), which can further worsen the lethal triad of trauma—metabolic acidosis, hypothermia, and coagulopathy [48–50]. Acidosis alone can markedly affect the interplay of coagulation factors, while hypothermia is known to inhibit fibrinogen synthesis and thrombin generation [48–50].
Prehospital Resuscitation of the TBI Patient
To achieve optimal patient outcomes, management of severe TBI begins at the time of injury. Initial priorities include in-field triage, stabilization of the patient, and transfer to definitive care facilities. During this process, the major goal should be to minimize secondary brain injury and optimize intracranial hemodynamics. As effective prehospital resuscitation has been linked to short-term and long-term outcomes [51–53], first-responders, emergency medical services, and in-field providers must be well-versed in severe TBI management in the setting of LTH.
Initial prehospital care prioritizes a patient’s “airway” and “breathing.” A definitive airway should be established in all patients with an inability to protect the airway, inability to maintain oxygenation and ventilation, and a Glasgow Coma Scale (GCS) less than nine. Prehospital hypoxia has been shown to worsen severe TBI outcomes along with furthering neuroinflammation and promoting neurobiomarker release potentiating poor TBI outcomes [16, 54–56]. An oxygen saturation level of at least 90% or a pO2 greater than 60 mmHg should be targeted [57]. Oxygen values less than these have been shown to increase TBI-associated mortality fourfold [58]. Furthermore, normal ventilation rates, including an end-tidal CO2 (ETCO2) of 35–40 mmHg, should be targeted for patients with severe TBI. Hyperventilation (ETCO2 <35 mmHg) should be avoided for routine use or elevated intracranial pressure (ICP) prophylaxis [59–61], and only implemented for patients with signs of impending cerebral herniation [62].
Following stabilization of patient’s airway and breathing , the next priority becomes “circulation.” Hemorrhage from trauma is the primary cause of hypovolemia and hypotension. In the prehospital setting, hypotension, which is defined as a systolic blood pressure (SBP) less than 90 mmHg, can be markedly dangerous in patients with severe TBI [63]. Each episode of hypotension has been shown to have deleterious effects on the brain [63]. The goal of fluid resuscitation in this setting is to optimize cerebral hemodynamics and further oxygen delivery to the brain. For patients with concurrent LTH, early and definitive hemorrhage control is key to minimize ongoing hemorrhage. Although the traditional definition of hypotension (<90 mmHg) was previously the target SBP according to the prior Brain Trauma Foundation (BTF) guidelines (3rd edition), new literature has emerged which supports a higher level, which varies by age, to improve outcomes [64–66]. The prior threshold of 90 mmHg is thought to underestimate hypotension-induced secondary brain injury [65]. The 4th edition of the BTF guidelines now states that a SBP greater than 100 mmHg, depending on age, should be targeted for patients with concurrent severe TBI [57]. For patients between 50 and 69 years old, a SBP of greater than 100 mmHg should be targeted [57]. For patients between the ages of 15 and 49 or greater than 70 years old, however, a SBP greater than 110 mmHg should be maintained [57]. Currently, these recommendations remain in contrast with the Tactical Combat Casualty Care (TCCC) guidelines, which still suggest a SBP target of 90 mmHg.
Furthermore, there are no current recommendations regarding the optimal fluid for resuscitation [53]. Isotonic crystalloids are the fluid used most often in the prehospital setting given resource and logistical constraints. However, blood product administration may provide definitive resuscitation for patients with concurrent LTH and can improve neurologic outcomes following severe TBI. Several alternative choices for patients with severe TBI exist and may have logistical advantages. Such resuscitative strategies will be discussed later in the chapter.
Early neurologic assessment, including GCS, should be performed to help guide severe TBI management. Patients should be frequently monitored for signs of Cushing’s triad , including hypertension, bradycardia, and irregular respirations. They should also be monitored for signs of impending cerebral herniation, which includes dilated, unreactive, and asymmetric pupils, and a motor exam with extensor posturing or progressive neurologic deterioration. In patients with concerning signs, hyperventilation (ETCO2 30–35 mmHg) should be employed until clinical improvement is observed and should only be used as a temporizing maneuver [53]. In addition, hypertonic saline, which ranges from 3% to 30%, may be administered to aid in ICP management if deemed a concern [67–70]. A bolus of 250 mL or 2 mL/kg of 7.5% saline has been commonly used in studies. Although found to be inferior to hypertonic saline in ICP reduction, mannitol (0.5–1.0 mg/kg) may be used for patients with cerebral herniation if intravascular volume can be maintained. However, none of these agents have trial evidence supporting improved survival or neurologic outcomes compared to each other. Lastly, combination of hypertonic saline with dextran (250 mL bolus of 7.5% saline/6% dextran) has been studied but also failed to show any clinical benefit compared to normal saline alone [68].
Patients with severe TBI and LTH may also present with hypothermia and is associated with increased fluid resuscitation and blood product transfusions due to severity of their illness. Therefore, prehospital hypothermia should be avoided as much as possible [71, 72]. Furthermore, prehospital hypothermia is independently associated with morbidity and mortality, including pneumonia and adult respiratory distress syndrome (ARDS) [71, 72].
Sedation and analgesia may also be required for transporting patients to a higher level of care. According to the 4th edition of the BTF guidelines, barbiturates and propofol may be used as sedation for patients with TBI. Both agents can reduce ICP and help terminate seizure activity. High-dose barbiturates may be used to control elevated ICP that fails to respond to medical and surgical therapy. However, providers must be aware that it may cause hemodynamic stability during use. Propofol may also be used as a sedative given its rapid onset, short duration of action, ability to decrease ICP, and preservation of CO2 reactivity and cerebral autoregulation [73]. Propofol, however, has failed to show improvement in mortality for 6-month outcomes [74]. Providers must also be aware of propofol infusion syndrome, which can occur at high doses and can cause significant morbidity.
In recent years, there has been an emerging use of ketamine for prehospital induction, maintenance, and sedation for patients with TBI [75]. Ketamine was historically avoided due to concerns that it caused an increase in ICP. However, recent evidence suggests otherwise. A systematic review by Zeiler et al. failed to demonstrate that ketamine increases ICP [76]. In some cases, ketamine use actually decreased ICP. Furthermore, no significant adverse effects were noted related to ketamine administration. Recent studies appear to demonstrate that ketamine may actually have neuroprotective effects in TBI by inhibiting spreading depolarization, decreasing neurotoxic metabolites, and attenuating oxidative stress and apoptosis [75, 77–80]. Although ketamine is currently not listed in the 4th edition BTF guidelines, it appears to be one of the most commonly used prehospital sedatives in the field. Evidence continues to accumulate supporting its use.
Lastly, antibiotics may be administered for patients with associated penetrating injuries related to TBI. Gram positive organisms, including Staphylococcus aureus, and gram-negative bacteria may be involved [81]. As such, cephalosporins are the most preferred antibiotics; however, some recommend ceftriaxone, metronidazole, and vancomycin for extended durations for penetrating brain injury [81].
In-Hospital Resuscitation of the TBI Patient
Once transported to definitive care facilities, severe TBI patient should be transported to the intensive care unit (ICU) for critical care monitoring and management. In the ICU, oxygenation and ventilation should remain key priorities. If not already established, a definitive airway should be considered if indicated (GCS ≤8). Oxygenation should be maintained with a pO2 >60 mmHg or oxygen saturation >90%, while normocapnia (ETCO2 35–40 mmHg) should be targeted in the absence of cerebral herniation [57]. If hyperventilation is indicated for cerebral herniation, it should only be conducted for a period of 24 hours. Following ensuring a secure airway and breathing, a patient’s circulation should be re-evaluated. As stated previously, a SBP of greater than 100 mmHg should be targeted for patients between 50 and 69 years old [57]. However, a SBP greater than 110 mmHg should be maintained for patients between the ages of 15 and 49 or greater than 70 years old [57].
Once stabilized, focus should turn to managing neurologic deficits. Early imaging, including computed tomography (CT), should be obtained to assess the degree intracranial injuries and prognosticate patients. There is some evidence, although weak, to support using ICP monitoring for patients with severe TBI to reduce in-hospital and 2-week post-injury mortality [57]. When ICP monitoring is used, an ICP of less than 22 mmHg should be targeted [57]. Maintaining a cerebral perfusion pressure (CPP) of 60–70 mmHg is critical to provide adequate perfusion to the brain [57]. Several modalities exist to achieve lowering ICP if a concern, including hypertonic saline bullets (30 cc of 23.4% saline), hypertonic saline infusions (3% saline), and mannitol in select patients. An external ventricular drain (EVD) may be used for continuous CSF drainage to lower ICP [57]. This may be used within 12 hours after injury for patients with an initial GCS <6–8 [57, 82]. Other modalities to lower ICP exist, but have weak supporting evidence. According to the BTF guidelines, early hemicraniectomy can be considered in select patients as a last resort [57, 83]. Although long-term outcomes remain controversial and may lead to unfavorable outcomes, this procedure has been shown to reduce ICP and minimize days in the ICU [83]. The latest study suggests that decompressive craniectomy should be used only in patients with refractory intra-cranial hypertension (ICP >25 mmHg) that have failed all medical treatments, rather than as an early treatment [84]. This approach, however, varies widely internationally and different approaches in terms of timing may be considered, especially for adult versus pediatric patients.
Several other management options may be considered. Antiepileptic drugs, including Levetiracetam, have been shown to decrease the incidence of early post-traumatic seizures when administered within 7 days of injury and may be used [85, 86]. Enteral nutrition should be initiated as early as possible to decrease mortality [87, 88]. Lastly, hypothermia [89] and steroids [90] are no longer indicated in these settings, although previously thought to be beneficial.
Resuscitation Strategies for Severe TBI and LTH Patients
Resuscitation strategies remain complex in patients with concurrent LTH and severe TBI. However, initial critical steps for prehospital and in-hospital resuscitation include hemorrhage control and volume expansion to restore systemic perfusion and oxygenation. In the absence of TBI, patients with LTH should receive DCR strategies with focus on hypotensive resuscitation. The injured brain in patients with concurrent TBI, however, is highly susceptible to secondary insult including hypotension and hypoxia . Therefore, maintenance of an adequate SBP and CPP, as previously mentioned, is required [57], and the concept of DCR with hypotensive resuscitation is contraindicated in this setting.
Unfortunately, the optimal resuscitation strategy for patients with LTH and severe TBI in the prehospital setting is rather limited. Crystalloids and colloids are readily available, but blood products are often unavailable in the field due to logistical constraints. In the setting of LTH, blood products can be life-saving and improve outcomes if administered early in ratio-based resuscitation (1:1:1) [12, 91]. For patients with TBI, resuscitation guidelines are not as clear. The BTF guidelines recommend crystalloid for any TBI patient with hypotension in prehospital settings [57]. However, the evidence for this recommendation is weak and warrants further investigation.
Here, we present different resuscitation strategies, including crystalloids, colloids, and blood products, for patients with concurrent LTH and severe TBI. Each strategy has its own benefits and limitations, which providers should consider carefully during the development of their management protocols.
Crystalloid Resuscitation Strategies
Historically, blood products are often unavailable for resuscitation of patients with LTH and severe TBI in the prehospital setting. As such, crystalloids and colloids are the two major types of resuscitative fluids administered to improve circulating volume, shock, and oxygen delivery. Crystalloids are a relatively cheap way to achieve rapid improvement in SBP. However, once administered, crystalloids can decrease oncotic pressure and promote significant interstitial tissue edema when given [92]. As such, a large volume is required to maintain an increase in plasma volume, which can be logistically challenging in an austere environment or resource-constrained settings [93]. Judicious use should always be considered as cerebral edema, a life-threatening complication contributing to TBI-associated mortality, can ensue.
Current Advanced Trauma Life Support (ATLS) guidelines recommend the use of crystalloid, including either normal saline (NS) or lactated ringer’s (LR) , for initial resuscitation [94]. In the setting of LTH, this can be life-saving. However, the optimal fluid for resuscitation in patients with TBI is unknown at this time [95]. Several animal studies suggest that LR resuscitation is associated with improved physiological outcomes and decreased secondary bleeding [96, 97], while NS resuscitation may lead to hypochloremic acidosis, which can cause systemic vasodilation and coagulopathy [98]. Despite this, some consider NS to be the preferred fluid for TBI patient resuscitation given its increased osmolarity compared to LR [95]. Within recent years, prospective observational studies have demonstrated increased mortality with LR use compared with NS in patients with TBI [95]. Although most would consider NS use for patients with TBI, these controversies remain, and randomized controlled clinical trials are needed to further elucidate LR and NS resuscitation for patients with TBI in the prehospital phase.
Colloid Resuscitation Strategies
In contrast to crystalloids , colloids (albumin, dextran, and hydroxyethyl starch) are able to increase intravascular oncotic pressure by drawing water from interstitial tissues and maintain existing volume in the intravascular space [99]. In theory, colloid administration may help prevent over-resuscitation resulting in interstitial edema and aid in maintaining microcirculatory flow [100]. As such, colloids could potentially be used to help minimize the risk of cerebral edema. However, the use of colloids remains controversial in patients with TBI, as some suspect that the increased permeability of a damaged BBB can result in unfavorable outcomes. Despite this, colloids are generally preferred in tactical combat casualty care as they can provide the resuscitative volume needed to improve intravascular volume and “theoretically” minimize the total volume required to achieve this [101].
Although initially thought to be a promising colloid agent, albumin has provided suboptimal results for patients with LTH and severe TBI. The Saline versus Albumin Fluid Evaluation (SAFE) trial demonstrated that 4% albumin can cause increased ICP and mortality among TBI patients [102]. Although not fully explained by the study, some suspect that this increased mortality is attributed to colloid extravasation into the brain parenchyma following TBI-associated BBB damage, which may worsen any initially existing TBI-induced cerebral edema [103, 104]. Some studies, however, have demonstrated benefits when using higher concentrations of albumin (20%), leading to decreased neurologic deficits and brain tissue necrosis in experimental models of TBI.
Hextend, a colloid volume expander consisting of 6% hetastarch in LR, has demonstrated promise in clinically realistic large animal studies. Following administration, Hextend can decrease brain swelling compared to NS resuscitation alone [105]. In small animal studies, 10% hetastarch has demonstrated decreased brain tissue necrosis and neurologic severity scores (NSS) [106]. However, its use has yet to be confirmed in randomized human trials of patients with concurrent LTH and severe TBI. Despite this, Hextend is currently considered the first-line fluid of choice among colloids and crystalloids for use in far-forward combat resuscitation given its markedly beneficial effects in preclinical animal studies and low volume [93, 101]. However, further studies are required to further elucidate its safety and beneficial effects in trauma patients.
Blood Product Resuscitation Strategies
The optimal resuscitation strategy for patients with LTH and severe TBI in the prehospital settings involves early administration of either whole blood or red blood cells (RBCs), fresh frozen plasma (FFP), and platelet concentrates while minimizing crystalloid use. Such blood products and derivatives have demonstrated superiority to crystalloids and colloids by providing definitive resuscitation through improving oxygen-carrying capacity, replacement of clotting factors, and anti-inflammatory mechanisms [12, 107]. Furthermore, blood product administration can mitigate the effects of the lethal triad including trauma-induced coagulopathy, hypothermia, and acidosis. In the setting of isolated LTH, blood products should be administered either as whole blood or in a 1:1:1 fashion to target DCR through hypotensive resuscitation (SBP target of 90 mmHg) for patients with hemoglobin deficits, ongoing hemorrhage, and hemodynamic instability. However, when concurrent severe TBI exists with LTH, achieving DCR requires targeting a SBP greater than 100 mmHg, depending on age, and an adequate CPP, as previously discussed [57]. Currently, no well-defined transfusion thresholds based on evidence guide transfusion practices in patients with severe TBI/closed head injury. It is well known, however, that patients with severe TBI requiring blood product transfusions demonstrate poor clinical outcomes [108]. As such, judicious blood product transfusion should be considered to minimize morbidity and mortality.
Red Blood Cell Transfusion
Within recent years, RBC transfusion for anemia in patients with severe TBI has become a controversial topic. Post-traumatic anemia and poor clinical outcomes in patients with severe TBI has been an inconsistent finding [109]. It is well known that decreased oxygen delivery to the brain following severe TBI can result in progression of ischemia, causing secondary brain injury [108]. As oxygen delivery to the brain is primarily dependent on the hemoglobin (Hb) concentration, decreased Hb has been suspected to cause exacerbation of TBI [108]. However, the exact Hb threshold at which RBCs should be administered for transfusion has remained a matter of debate [110, 111].
Currently, there are clear clinical guidelines indicating that a Hb less than 7 g/dL mandates RBC transfusion [109]. Randomized control trials analyzing the role of restrictive transfusion (Hb <7 g/dL) compared to liberal transfusion (Hb <10 g/dL) demonstrate that patients with restrictive Hb transfusion thresholds had more favorable outcomes and less thromboembolic events [112, 113]. Although previously employed, there appears to be no benefit to liberal transfusions for severe TBI patients targeting a Hb greater than 10 g/dL. In fact, liberal transfusion may be deleterious [114]. Some studies have indicated that liberal transfusion thresholds can even lead to progressive hemorrhagic injury, contributing to higher morbidity and mortality [115]. Although further work to elucidate the optimal Hb threshold is ongoing, most providers would agree that the current standard involves restrictive blood transfusion thresholds in patients with non-active bleeding. For patients with active bleeding, it is reasonable to maintain a Hb of at least 9 g/dL.
Fresh Frozen Plasma Transfusion
Plasma-based resuscitation strategies have demonstrated improved outcomes in trauma patients within recent years. Following LTH, clotting factor levels can decrease by nearly 30% from baseline after replacing a patient’s blood volume with RBC transfusions [116]. Any further hemorrhage beyond this point can severely impact a patient’s ability to maintain hemostasis, leading to trauma-induced coagulopathy, which is present in nearly 25% of trauma patients [18]. Within recent years, the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial assessed clinical outcomes in severely injured trauma patients receiving high and low plasma and platelet transfusion ratios (1:1:1 versus 1:1:2 plasma: platelet: RBC) [117]. Although no differences were found in 24-hour or 30-day mortality, the 1:1:1 group experienced fewer deaths by exsanguination at 24 hours [117]. This improvement has been thought to be secondary to FFP’s ability to decrease vascular permeability and promote improvement in endotheliopathy.
In the setting of concurrent LTH and severe TBI, no randomized control trial data exists for plasma-based resuscitation strategies. However, well-performed preclinical animal and clinical observational and prospective studies appear to suggest a benefit. In porcine models of concurrent LTH and severe TBI, FFP improves secondary brain injury through decreased lesion size and improved neurologic recovery [118]. Lyophilized plasma, an alternative strategy that meets military constraints (e.g., long shelf-life, stable without need for refrigeration, low volume), has also been investigated demonstrating comparable therapeutic effects to FFP on secondary brain injury and neurologic recovery in porcine models [119]. Such benefits are suspected to be due to improvement in volume expansion and cerebral perfusion, attenuation of glutamine-mediated excitotoxicity, decreased mitochondrial dysfunction, as well as repair of endothelial and BBB injury [120]. Repair of endothelial injury following LTH with plasma-based resuscitation strategies has been confirmed in animal lung models [121, 122]. It is also suspected that FFP resuscitation can directly affect gene regulation by upregulating genes involved in metabolic and platelet signaling, and downregulating genes involved in inflammatory pathways [123].
Several human studies have confirmed beneficial effects with plasma-based resuscitation; however, others report detrimental effects. Peininger et al. demonstrated that a high plasma:RBC ratio is an independent predictor of improved survival among 1250 trauma with concurrent LTH and severe TBI [91]. However, others have demonstrated that high plasma:RBC transfusion ratios are associated with improved survival in patients without TBI [124]. A few studies, however, have reported adverse outcomes with FFP transfusion, demonstrating worsening secondary brain injury and higher mortality rates in TBI [125]. Although some controversy remains, further work is required to further elucidate the effects of FFP in human trauma patients with concurrent LTH and severe TBI. Investigation is also needed to compare the safety and efficacy of different formulations of plasma such as FFP, liquid plasma, and solvent detergent plasma. Processing differences for plasma lead to alterations in product characteristics and immune effects [126, 127]. It is unknown if these in vitro differences have any clinical relevance.
Platelet Transfusion
Similar to plasma-based resuscitation strategies, platelet resuscitation strategies have demonstrated improved outcomes in patients with LTH within recent years. Similarly, the PROPPR trial demonstrated that high platelet ratio transfusions (1:1:1 versus 1:1:2 plasma: platelet: RBC) patients can significantly decrease deaths by exsanguination at 24 hours in severely injured trauma patients [117].
Evidence for platelet-based resuscitation strategies has been emerging for patients with concurrent LTH and severe TBI. It is well-known that platelet consumption and dysfunction occurs secondary to alteration in local and systemic coagulation pathways following TBI [6]. In recent years, ratio-based platelet resuscitation strategies have demonstrated improved outcomes in trauma patients with TBI. Spinella et al. conducted a retrospective review analyzing 2,312 trauma patients with massive hemorrhage, with and without TBI, focusing on patients who received high or low platelet to RBC units (<1:2 vs. ≥1:2) [124]. TBI patients who received high platelet ratios were found to have improved 30-day survival compared to patients with low platelet:RBC ratios [124]. Similarly, in a 3-year retrospective analysis of patients with TBI as the only major injury, Oroujikoar et al. found that TBI patients receiving ratio-based platelet resuscitation had higher survival rates compared to patients with non-ratio based resuscitation strategies [128]. For severe TBI patients requiring massive transfusion for concurrent LTH, it is suspected that ratio-based platelet resuscitation can help aid in intravascular volume resuscitation, platelet replenishment, as well as prevention of dilutional coagulopathy [128]. This correction of coagulopathy, through platelet resuscitation, may also help improve clinical outcomes for patients with intracranial bleeding, as well as improve time to definitive operative repair if needed [129]. The benefits of plasma transfusion may also occur with platelet transfusion since there is almost an entire unit of plasma within a unit of apheresis platelets.
Within recent years, several animal studies have attempted to investigate the mechanisms of action by which platelets provide therapeutic effects in TBI at the level of the brain. In a rodent model, platelets have been demonstrated to promote BBB healing by activating oligodendrocyte precursor cells (OPCs) [130]. OPCs are predominantly responsible for differentiation into oligodendrocytes, which can then repair injured areas of demyelination secondary to TBI [130]. Further studies investigating this arena are currently being employed.
Whole Blood Transfusion
Although previously considered the historic resuscitation for LTH, whole blood had, until recently, disappeared from mainstream use for definitive resuscitation. Unfortunately, this transition from whole blood to blood component transfusion had occurred without clinical evidence of superior or equal efficacy and safety. Within recent years, however, there has been a resurgence of whole blood for transfusion in both military and civilian centers for LTH. Currently, there are 20 trauma centers implementing whole blood for transfusion in LTH, and this list is rapidly expanding.
Although data continues to emerge to support its use, whole blood may provide many biological and logistical advantages compared to blood product component therapy [131]. First, whole blood contains balanced and increased cellular components of RBCs, platelets, and plasma [132]. This avoids additives and anticoagulants that can contribute to dilutional coagulopathy noted with individual therapies [132]. Furthermore, whole blood contains a 30% higher oxygen carrying capacity when compared to individual blood component therapy [133]. In terms of hemostatic function, platelets in whole blood stored at 2–6 °C have improved platelet aggregation and stronger clots compared to those stored at 20–24 °C [134–138].
Although there may be may logistical and biological benefits to whole blood transfusion, there is limited data regarding its use in LTH and TBI. Further studies, however, are required to help further support its adoption in the near future.
Complications of Blood Product Transfusion
Although blood products can be life-saving and improve outcomes when administered early and in ratio-based resuscitation, they should be administered judiciously as several possible complications may occur. The most common complications include either acute or delayed, non-hemolytic reactions, which are relatively minor. For patients with severe TBI, transfusion-related acute lung injury (TRALI) and transfusion-associated circulatory overload (TACO) can contribute to significant morbidity and mortality [139–141]. TRALI results from immune complex-mediated damage to the pulmonary vasculature resulting in increased permeability and edema, which can manifest as dyspnea and bilateral pulmonary edema. In TACO, increased hydrostatic pressure results in increased edema, manifesting as respiratory distress, hypoxemia, and volume overload [108]. Treatment for TRALI and TACO involves initial supportive measures and mechanical ventilation, while TACO also mandates diuresis [108].
Novel Therapeutics Agents for Improving Clinical Outcomes
Within recent years, identifying pharmacologic agents to improve outcomes in patients with concurrent LTH and severe TBI has become an area of interest. As far-forward settings and austere environments are often resource-limited and logistically constraining, definitive resuscitative strategies with blood products are not always possible. Pharmacologic agents improving survival and minimizing neurologic injury, coagulopathy, inflammation, and oxidative stress have been investigated. Such agents are low volume, environmentally stable, cheap, and easy-to-use and have the potential to be high impact treatment strategies. Among numerous agents, valproic acid (VPA) appears to be a promising prehospital neurotherapeutic agent which could be used in patients with concurrent LTH and severe TBI. It has demonstrated its significant therapeutic effects in preclinical animal models. Other agents, including anti-inflammatory, anti-edema, and antioxidant agents, have demonstrated promise, although their therapeutic profiles are more selective and targeted. Further studies investigating the therapeutic effects of these agents are ongoing but are likely to be potential treatment strategies in the near future [142].
Valproic Acid
VPA, a historic anti-convulsant drug approved by the Food and Drug Administration (FDA) in 1978, has become a promising agent for patients with LTH and severe TBI in recent years. VPA is a histone deacetylase inhibitor (HDAC inhibitor or HDACI), which causes histone and non-histone acetylation affecting gene expression and protein function. When added to other resuscitative fluids, VPA has been demonstrated to improve outcomes in preclinical models. In rats, NS + VPA (300 mg/kg) resuscitation improved survival to 80% compared to 17% in animals resuscitated with NS alone [143]. In swine subjected to LTH and polytrauma, Hextend + VPA improved survival to 50% compared to 25% in Hextend-treated animals alone [144].
In recent years, large animal models have been used to further demonstrate VPA’s effects in traumatic models including concurrent LTH and severe TBI. In swine subjected to TBI and LTH, animals resuscitated with NS + VPA (150 mg/kg) demonstrated smaller brain lesion size, decreased neurologic injury, improved neurologic recovery, and faster normalization of cognitive function [145]. With the addition of polytraumatic injuries, similar findings have been observed. Animals resuscitated with NS + VPA (150 mg/kg) showed less neurological impairment and smaller brain lesion size after treatment compared to those resuscitated with NS alone [146].
In mediating these effects, VPA has been shown to alter the BBB following injury and promote gene regulation in the brain and peripheral blood mononuclear cells (PBMCs) [147]. Following administration in swine subjected to TBI and LTH, VPA treatment improves protein expression profiles leading to improvement of BBB integrity [148]. Brain tissue harvested at 8 hours following VPA treatment has even demonstrated upregulation of genes involved in neurogenesis and neuroregulation and downregulation of genes involved in apoptosis and inflammation [148]. Similarly, in swine subjected to TBI, polytrauma, and LTH, VPA-treated animals demonstrated altered gene expression in PBMCs [149]. VPA treatment upregulates gene pathways involved in cellular growth and proliferation, and downregulates pathways involved in alteration of cell cycle checkpoints, apoptosis, acute phase reactants, and the inflammatory response [149]. In similar models, VPA treatment has also been demonstrated to reduce collagen, arachidonic acid, and adenosine diphosphate-induced platelet aggregation, suggesting that VPA can decrease platelet aggregation and affect clot dynamics (strength and rate) [150].
Initial human studies have demonstrated great promise as well. The safety and tolerability of high-dose VPA has recently been tested [151] and will be moving to a phase II clinical trial in the coming years.
Anti-inflammatory Agents
Astrocyte and microglial activation, cytokine release, and BBB disruption can contribute significantly to the development of neuroinflammation following TBI. Within recent years, inhibiting neuroinflammation has been a potential target to improve clinical outcomes following TBI. Anti-inflammatory pharmacologic agents, including minocycline, have become promising candidates. Minocycline is a second-generation tetracycline that exhibits potent anti-inflammatory and neuroprotective properties and has been shown to be effective in preclinical models through suppression of IL-1B, IL-6, microgliosis, and neuronal apoptosis [152]. In the past several years, minocycline has been demonstrated to reduce serum neurofilament levels in patients with spinal cord injury (SCI) in clinical trials [153]. Although several studies have demonstrated improvements in long-term behavior following neurologic injury , others have demonstrated only transient effects on recovery [152]. Others, however, are concerned that despite decreasing microglial activation, increased neurodegeneration may be observed with minocycline use [154, 155]. However, further studies in this arena are ongoing.
Synthetic peroxisome proliferator-activated receptor (PPAR) agonists are another potentially efficacious anti-inflammatory agent for the treatment of TBI and SCI. Following activation, PPARs can translocate from the cytoplasm to the nucleus to augment gene expression, suppressing COX2 and iNOS, two pro-inflammatory mediators [156–158]. Fenofibrate has been shown to reduce inflammation, oxidative stress, and cerebral edema following TBI through PPAR-alpha agonism [159]. However, Pioglitazone and Rosiglitazone, PPAR-gamma agonists, have also been demonstrated to decrease astrocytic and microglial activation and to promote neuroprotective proteins HSP27 and Mn-SOD, facilitating improved behavior and histological outcomes following TBI [160, 161]. Such effects have even been observed in various TBI models including cortical impact, diffuse TBI, and lateral percussive injury [160, 162, 163].
Anti-edema Agents
Cerebral edema is a significant contributor to early morbidity and mortality following TBI. It can lead to a significant increase in ICP, preventing the brain from appropriate cerebral perfusion and oxygenation [164]. When severe TBI is coupled with aggressive fluid resuscitation, cerebral edema can worsen even further [164]. Several agents have been used to help prevent against cerebral edema in these settings. In severe TBI, the administration of mannitol, an osmodiuretic, has been demonstrated to decrease brain edema for in-hospital patients [165]. However, prehospital data is currently lacking and mannitol use may be contraindicated for severe TBI patients with concurrent LTH given the risk of hypotension. Other pharmacologic agents, including cannabinoid receptor agonists, have demonstrated promise in the preclinical setting [166–168]. Following TBI, dexanabinol (HU-211) has been shown to reduce brain edema by decreasing neuroinflammation and improving BBB integrity in a murine model of closed head injury. Furthermore, selective activation of cannabinoid receptor-2 has been shown to reduce neuroinflammation, reduce cerebral edema, enhance cerebral blood flow, and even improve neurobehavioral outcomes following murine models of controlled cortical impact-induced TBI and endovascular- induced subarachnoid hemorrhage [168, 169].
Antioxidative Agents
Oxidative damage to the brain can occur as early as minutes following TBI. Several key pathways involve free radical production from the enzyme xanthine oxidase, arachidonic acid cascade, and mitochondrial leak/generation. Following production, these free radicals can cause significant oxidative damage to proteins, DNA, and RNA. In recent years, targeting inhibition of free radical production and scavenging circulating free radicals has been investigated [170].
Cyclosporine A (CsA) , a drug commonly used as immunosuppression in transplantation, inhibits mitochondrial permeability transition pores, which can prevent the production of free radical species [142]. Initial preclinical studies have demonstrated promise, as it has been able to provide neuroprotection in preclinical models by inhibiting lipid peroxidation and mitochondrial damage contributing to neurotoxicity [142]. Other drugs, including phenelzine, an FDA-approved monoamine oxidase inhibitor, have demonstrated similar results and may act synergistically to CsA [171]. These drugs are suspected to act via attenuation of mitochondrial dysfunction and neuronal damage and to decrease glutamate and lactate levels [172–174]. Other promising antioxidant therapies, including dimethyl fumarate, ubiquinol, and N-acetylcysteine, have demonstrated efficacy in preclinical models when administered within several hours following injury [175–177]. Unfortunately, many of these have failed to demonstrate translation into human TBI patients secondary to their limited therapeutic window. However, some view this limitation as an excellent opportunity for prehospital neurotherapeutic resuscitation if able to be administered early [178]. Further studies are required to further refine these therapeutic strategies targeting prevention of oxidative damage.
Conclusions
In conclusion, LTH and severe TBI remain leading causes of preventable deaths in trauma. Although DCR has become a highly popular treatment strategy for LTH, the presence of concurrent severe TBI requires alternative treatment strategies and management considerations. It is important to understand that the presence of severe TBI can significantly contribute to systemic coagulopathy. Improving patient outcomes requires being well-versed in the pre- and in-hospital care of patients with LTH and severe TBI, which aim to minimize secondary brain injury and optimize cerebral hemodynamics. Several novel resuscitative treatment strategies have demonstrated great promise in improving outcomes in patients with LTH and TBI, but require further testing and exploration in the coming years. To ensure streamlined delivery, all of these options should be carefully considered and incorporated into an Institutional TBI-Management Protocol in collaboration with the various stakeholders (emergency medicine, trauma surgeons, neurosurgeons, pharmacy, blood bank, nursing, etc.). These protocols should also be periodically updated as new information becomes available.
