Anoxia Complicating TBI

Caroline Sizer and Gary Goldberg

INTRODUCTION

This chapter addresses clinical concerns when hypoxic/ischemic brain injury (HIBI) and traumatic brain injury (TBI) overlap. Simultaneous HIBI and TBI are known to occur [1–3], although research on the incidence and prevalence of coinciding HIBI and TBI is limited. To this date, there are no published studies that specifically investigate overlapping HIBI and TBI (O/HIBI+TBI). This lack of focused study may be due to difficulty in establishing the diagnosis of both HIBI and TBI concurrently. Nevertheless, it is expected that early recognition and diagnosis of O/HIBI+TBI may increase with more sophisticated neurointensive care techniques, such as brain tissue oxygenation measurements [4]. This chapter aims to describe the epidemiology, diagnosis, selected medical complications, treatment, and prognostication of patients suspected to have O/HIBI+TBI through examination of existing literature describing HIBI and case-control studies comparing HIBI and TBI.

DEFINITIONS

• Hypoxic brain injury: Hypoxic brain injury (HBI) is defined as a global disturbance in brain function due to a decrease or loss of oxygen supply to the brain. Since tissue oxygenation is related to the product of deliverable blood oxygen content and blood flow, tissue hypoxia can result from a significant reduction in either or both of these factors (i.e., hypoxemia and ischemia, respectively). The resultant effect of brain hypoxia depends on the degree to which the tissue oxygen supply is reduced, and the duration of the reduction. Hypoxia thus leads to a continuum of injury severity. Mild hypoxia produces reversible tissue dysfunction. However, prolonged hypoxia induces neuronal cell death resulting in irreversible brain injury. The term “anoxia” is intended to refer to a complete loss of tissue oxygenation. This condition can result from hypoxemia (i.e., a severe reduction in deliverable blood oxygen content) but more often is due to ischemia (i.e., a severe disruption in blood flow, e.g., as a result of cardiac arrest or hypovolemic shock—see the following). Brain hypoxia can result from hypoxemia alone in the presence of normal brain perfusion, as in the case of carbon monoxide poisoning or suffocation.

• Ischemic brain injury: Ischemic brain injury (IBI) occurs when there is decreased brain oxygenation due to reduced brain perfusion. Brain ischemia can be either focal (i.e., due to blockade of flow through a particular cerebral artery as occurs most commonly in thrombo-embolic cerebrovascular pathology) or global (i.e., due to pump failure, e.g., in cardiac arrest), each of which produces characteristic clinical presentations [5].

• Hypoxic/ischemic brain injury: In their purest forms, hypoxemic and ischemic brain injuries can have very different presentations: in hypoxemic injury, the more active oxygen-sensitive areas of the brain are especially susceptible, whereas with ischemic injury, brain regions supplied through specific vascular structures are more vulnerable. Most often, these disorders clinically overlap.

To illustrate this concept, consider the following example:

Imagine the case of a person sustaining carbon monoxide poisoning. Blood circulates through the cardiovascular system with markedly reduced oxygen content. Cardiac myocytes lose their ability to function optimally due to very reduced cellular ATP production via anaerobic rather than aerobic metabolism, ultimately leading to decreased cardiac output. Decreased cardiac output leads to reduced vascular flow and tissue perfusion, which, in turn, results in a compounding of the hypoxemic and ischemic insult to the brain and other tissues. It is for this reason that many experts refer to these brain injuries as HIBI. For the purposes of this chapter, we will focus on HIBI, and where appropriate, we will identify information that relates to the pure syndromes of either IBI or HBI.

EPIDEMIOLOGY

• HIBI can complicate TBI, and has been reported to occur in 35% to 44% of individuals who sustain moderate-to-severe TBI based on demonstration of hypoxia on initial Emergency Medical Services (EMS) pulse oximetry measurements [3–5].

• This prevalence of O/HIBI+TBI is anticipated to rise with advancements in critical care medicine, which improve survival rates after HIBI [6], as well as with improved diagnosis and management. While the presence of moderate-to-severe TBI is often clinically apparent, coexisting HIBI is not as easily diagnosed in the setting of concurrent TBI.

• Frequently, O/HIBI+TBI is seen in the setting of polytrauma, which is regularly complicated by hypotension/shock, airway obstruction, and respiratory failure due to chest injury (such as hemopneumothorax and lung contusion). Furthermore, the TBI itself can potentially exacerbate the HIBI by a directly consequent reduced respiratory drive due to brainstem injury, thereby causing a concurrent HBI [4,7].

• Recognition and diagnosis of O/HIBI+TBI is important in guiding treatment decisions, projecting expected outcome, and predicting the course of recovery, for example, when responding to queries from family.

• A handful of studies have directly assessed outcome from HIBI and TBI in case-controlled designs, offering a glimpse into differences in outcomes from pure HIBI referenced to expected outcome from TBI under otherwise equivalent conditions. The results of those studies will be discussed further in the “Prognosis” section [6,8–10].

MAKING THE DIAGNOSIS

Comparisons can be drawn readily between TBI and HIBI in the rehabilitation setting, due to the current pragmatic practice of admitting individuals who carry diagnoses of either traumatic or hypoxic encephalopathy to the same brain injury rehabilitation unit, utilizing the same treatment team [6,8–13]. Key areas of diagnostic differentiation between TBI and HIBI patients have been noted in the following areas of clinical assessment: medical history, physical examination, neuropsychological testing, and neuroimaging. A number of key clinical factors can distinguish HIBI from TBI, or suggest concomitant HIBI and TBI with the production of additional superimposed impairment.

History

Risk factors for concomitant HIBI and TBI include documented hypoxic pulse oximetry at initial presentation, seizures, cardiac or respiratory arrest, chest trauma, near drowning, attempted hanging, anaesthetic accidents, vehicular trauma with prolonged extrication, carbon monoxide poisoning, and various metabolic encephalopathies [6,8,9]. Available medical records should be carefully reviewed for evidence of impaired oxygenation, respiratory insufficiency, and/or reduced cerebral perfusion as well as the timing and duration of such impairment. Circumstantial evidence such as initial vital signs in the field, delays in initiation of resuscitation, cyanosis, and evidence of systemic hypoperfusion (e.g., hypovolemic shock) can also suggest superimposed HIBI-related impairment.

Physical Examination

Abnormal or ataxic gait, movement disorders [8], significantly poorer performance on the mental status exam in the realms of construction, attention, calculation, and memory (particularly short-term memory and visual memory) [14], spastic quadriparesis in the absence of spinal trauma, profound and fluctuating anosognosia, and prolonged disorders of consciousness, all suggest possible concomitant HIBI [10].

Neuropsychological Testing

Moderate to severe memory impairment, psychomotor slowing, profound and fluctuating memory deficits, decreased psychomotor speed, impaired insight, and abnormal visuospatial perception are all more characteristic of O/HIBI+TBI than TBI alone. Executive function and attention appears to be less severely affected in HIBI patients [8,10,14].

Neuroimaging

HIBI is associated with characteristic patterns of disproportionate damage to more highly metabolic areas of the brain and areas more vulnerable to globally reduced perfusion, namely, specific gray matter structures (cerebral cortex, basal ganglia, pyramidal cell loss in the hippocampi, and Purkinje cell loss in the cerebellum) [6,8,15,16]. In IBI specifically, one may expect to see damage to vascular watershed areas.

MRI findings demonstrate distinct characteristics that delineate four discrete phases of HIBI [17]. These are summarized in the following adapted table.

DISTINCTIVE MRI FINDINGS BY PHASE IN HIBI

SELECTED UNIQUE SYNDROMES SEEN IN HIBI

• Movement disorders: These are more prevalent in HIBI because the subcortical structures of the basal ganglia associated with motor control (caudate, putamen, globus pallidus, and substantia nigra) are particularly vulnerable to hypoxia [10].

• Seizure disorders: Reports describe a risk of 11% for late seizures in HIBI (higher than the 3%–7% risk seen in TBI) [18]. Overall incidence of seizures (immediate, early, and late) in HIBI ranges from 15% to 36% [19,20].

Subtle generalized convulsive state (also referred to as “myoclonic status epilepticus”): Typically occurs in the first 12 hours after injury in 30% to 40% patients who sustain a severe HIBI and are in the comatose state [21]. This condition is defined as at least 30 minutes of sustained generalized myoclonic twitches of the facial and/or axial muscles. This does not respond well to antiepileptic drugs, often requiring propofol or neuromuscular blockade, and is frequently noted to precede death due to the severity of the underlying HIBI [22]. This condition has a poor prognosis, with death or persistent vegetative state predicted in over 90% of survivors [22].

• Posthypoxic action myoclonus: Also known as “Lance-Adams Syndrome.” This condition typically appears days to weeks after severe HIBI, most often in survivors of cardiac arrest, and is thought to be secondary to hypoxic damage to Purkinje cells in the cerebellar cortex [23]. It is a relatively rare movement disorder, with less than 200 reported cases in the literature [24]. However, with improving survival following cardiac arrest, the incidence can be expected to increase, and with its characteristically delayed onset, initial manifestation will likely occur in the rehabilitation setting. Myoclonic twitches are provoked by voluntary action or movement attempts, particularly actions that are complex and require significant dexterity and cortically based intentional focus. This myoclonus characteristically worsens as the complexity and requirement for precisely timed intentional control of movement increases, as would be expected with cerebellar damage. It can also have triggers, such as sudden sound or stimulation (such as tracheal suctioning or testing of deep tendon reflexes) [25]. This is sometimes called “startle myoclonus.” Myoclonic twitches are thought to arise either when an action or intention triggers hyperexcitability of the contralateral cortex (“cortical reflex myoclonus”), or from activity in the rostral brainstem (“subcortical” or “reticular” myoclonus) [26]. If the primary treatment goal is control of myoclonus, treatment should be instituted early and aggressively, and often requires combinations of medications; first-line agents include valproate and clonazepam [22]. Levetiracetam has also been reported to have efficacy as a second-line agent [27]. Often, competing cognitive treatment goals will complicate management; consequently, treatment must be carefully titrated to avoid unacceptable side effects including cognitive suppression, retardation of cognitive recovery, and/or agitation. Regardless of medication used, the response is characteristically incomplete. Despite this incomplete treatment response, and in contrast to the acute posthypoxic myoclonus associated with subtle generalized convulsive disorder, posthypoxic action myoclonus is not uniformly associated with a poor prognosis [21].

UNIQUE SYNDROMES OF PURE IBI

• Watershed infarct/ischemia: hypoperfusion can result in watershed infarcts (ischemia in border-zones between major cerebrovascular territories), leading to classic presentations.

Anterior cerebral arteries–middle cerebral arteries watershed ischemia: “Man-in-a-Barrel” syndrome: This is seen when infarction occurs in the border zones between the anterior cerebral arteries (ACAs) and the middle cerebral arteries (MCAs), causing disproportionate ischemia to the territory supplying motor control to the upper extremities. This results in preserved lower extremity strength with paresis of the bilateral upper extremities. In one small study of 34 subjects who had sustained severe systemic hypotension, 32% exhibited symptoms of this syndrome [28].

MCA–PCA watershed ischemia: Cortical blindness. With bilateral posterior watershed ischemia, one can also see disturbance not only of vision, but also of eye movement. This condition is characterized by simultagnosia, optic ataxia, and oculomotor apraxia. It has been termed “Balint–Holmes Syndrome” [29].

UNIQUE SYNDROME OF PURE HBI

• Delayed postanoxic leukencephalopathy (PAL): Also known as “delayed posthypoxic demyelination.”

Extremely rare, characterized by apparent complete recovery, subsequently followed in the ensuing 1 to 4 weeks by deterioration, following HBI. Due to the timing of the presentation of this syndrome, diagnosis is often made in the rehabilitation setting.

Often seen in the setting of exposure to carbon monoxide.

Symptoms include cognitive impairment, urinary incontinence, and gait disturbance [30].

Pathophysiology is unclear, and no effective neuroprotective agents or treatments have been described to address PAL. Nevertheless, between 50% and 75% of those affected have a good prognosis (mild or no disability) [31].

TREATMENT

Acute Setting

A great deal of neurocritical care focus addresses the mitigation of cerebral hypoxia. For more specific information, please see the dedicated Chapters 19, 20, 22, 23, respectively on Field, Emergency, Neurosurgical, and Neurocritical care of individuals with TBI regarding monitoring for and prevention of HIBI in the context of acute TBI.

Rehabilitation Setting

• Acute inpatient rehabilitation: The handful of studies that compare pure TBI with HIBI patients describe the practice that exists across many rehabilitation centers: HIBI and TBI patients are frequently treated by the same rehabilitation team on the same rehabilitation unit. This allows for direct comparison of the relative progress of both groups of patients using a case-control design. A theme among the majority of the case-control studies comparing HIBI and TBI is the observation of a slower rate of recovery and poorer overall outcome in the HIBI groups compared to TBI groups. Despite this finding, patients with HIBI have been shown to benefit significantly from acute inpatient rehabilitation [6,8–10]. In contrast to these reports, two studies by the same group of investigators have demonstrated similar functional outcomes between HIBI and TBI in the acute inpatient rehabilitation setting [9,13]. It is important to note that all of the studies comparing HIBI and TBI suffer from significant methodological challenges, not the least of which include very small sample sizes. Selected specific results of these studies are presented in the table in the “Prognosis” section.

• Pharmacotherapy: The evidence for use of pharmacotherapeutics for the treatment of the cognitive sequelae in HIBI is limited, and is comprised primarily of retrospective studies, case series, and case reports:

Methylphenidate and amantadine: A retrospective study of 588 patients who sustained HBI and disorders of consciousness following cardiac arrest compared the group to 16 patients who were treated with either amantadine (n = 8), methylphenidate (n = 6), or both (n = 2), and demonstrated improved rates of emergence of consciousness with treatment with either amantadine, methylphenidate, or both [32].

Levodopa +/-bromocriptine: One case series describes the beneficial effects of levodopa and/or bromocriptine for the treatment of the cognitive impairments seen in five individuals who sustained HBI, noting significant improvements in agitation, apathy, and involuntary movements, and mild improvements in memory [33].

Zolpidem: a single case report describes a patient with HBI and decreased arousal refractory to amantadine and methylphenidate, who demonstrated improved arousal with the administration of twice-daily zolpidem, and worsening with withdrawal of the medication [34].

PROGNOSIS

Of great importance to the patient, his or her family, and the rehabilitation physician, is prognostication. It is prudent to note that HIBI generally carries a poorer prognosis than TBI, and in the setting of a patient who sustains O/HIBI+TBI, recovery is expected to progress more slowly and to ultimately achieve a lower level of functional independence than an otherwise matched individual who sustained a pure TBI [10].

Of the handful of studies that compare patients with HIBI and TBI, the focus is frequently centered on comparison of prognosis between these two groups of patients. For more information about prognosis after TBI, please see Chapter 40. For the purposes of this chapter, we will focus on prognosis after HIBI, and direct comparisons that have been described between TBI and HIBI outcomes.

Outcomes in HIBI and Comparison of Outcomes in HIBI Versus TBI

Although HIBI patients tend to have lower admission and discharge Functional Independence Measure (FIM) scores, and lower FIM efficiency than TBI patients, they do demonstrate meaningful improvements in function with acute inpatient rehabilitation [12,35]. The following table describes outcomes described in HIBI, and when indicated, comparison of specific outcomes in HIBI to those of TBI, based on the available literature to date.

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