Despite our recognition of the brain’s dominant role in determining quality of life, the ability to intervene and reverse neuronal injury remains limited. Consequently, modern brain resuscitation techniques are focused on restoring cerebral homeostasis and mitigating the effects of secondary brain injuries. Hypoxic-ischemic injury following cardiac arrest can be seen as a model of global ischemic disease, and recent advances in understanding its pathophysiologic mechanisms have led to improvements in neurologic outcomes. Although hypoxic-ischemic injury represents a so-called pure form of brain ischemia, its underlying pathology has significant overlap with other cerebral injuries, such as stroke and traumatic brain injury (TBI). Thus, many of the physiologic principles of brain resuscitation following cardiac arrest apply to these conditions. Therefore, this chapter reviews the pathophysiology of ischemic brain injury and discusses therapies for improving neurologic recovery following cardiac arrest and other critical neurologic illnesses in which cerebral ischemia may occur.

The human brain consists of 10 billion neurons, each with multiple connections to other cells, totaling an estimated 500 trillion synapses. Although the brain constitutes only 2% of body weight, it receives 15% of the body’s cardiac output and accounts for 20% of its overall oxygen use. When the brain is deprived of adequate blood flow, the resulting ischemia is characterized by a bewildering array of interrelated physiologic and cellular responses that ultimately result in neuronal cell death ( Fig. 4.1 ). Although this complex cascade of events can be triggered by periods of ischemia lasting only a few minutes, the resulting neuronal death is usually delayed by hours or days. Furthermore, the biology of cerebral cell death after global cerebral ischemia follows the pattern of delayed cerebral cell death after stroke, TBI, and other forms of hypoxic or toxic brain injury, with slight variations. Increased understanding of the brain’s response to injury during the period between insult and neuronal cell death will eventually allow more specific brain resuscitation therapies.

Synopsis of Events Contributing to Neuron Cell Death Cascade After Ischemia. (A) Decreased cerebral flow (CBF) and arterial oxygen content during ischemia cause decreased adenosine triphosphate (ATP) production, failure of ATP-driven ion pump efflux of potassium ions (K ⁺ ), and influx of sodium ions (Na ⁺ ) and calcium ions (Ca ²⁺ ) through voltage-gated channels. ADP, Adenosine diphosphate. (B) Na ⁺ influx causes depolarization and glutamate (Glu) release, opening Glu receptor α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and kainate (KA) channels and exacerbating intracellular Na ⁺ overload. Increased Na ⁺ concentration ([Na ⁺ ]i) leads to cytotoxic edema. Glu-mediated N -methyl- d -aspartate (NMDA) channels allow intracellular Ca ²⁺ overload. Insufficient ATP causes failure of energy-dependent Ca ²⁺ pumps, and high [Na ⁺ ]i prevents removal of Ca ²⁺ by Na ⁺ /Ca ²⁺ exchange pumps. γ-Aminobutyric acid (GABA) release can attenuate excitatory changes by opening a receptor-gated Cl ⁻ . (C) Increased [Ca ²⁺ ]i is amplified by calcium-induced release of Ca ²⁺ from the endoplasmic reticulum (ER) . Mitochondria may be injured attempting to buffer increasing [Ca ²⁺ ]i, resulting in further metabolic failure and diminished ATP. Ca ²⁺ activates nitric oxide synthase (NOS) , transforming it to nitric oxide (NO) , which is amplified by NO activation of NOS. NO contributes to the formation of damaging oxygen free radicals and inhibits mitochondrial cytochrome oxidase function. ATP degradation to xanthine and then uric acid by xanthine oxidase (XO) yields hydrogen peroxide (H ₂ O ₂ ), which reacts with iron to form dangerous oxygen radicals. Oxygen free radicals react with lipids in the cell membrane, which leads to membrane degradation and more free radicals. Oxygen free radicals also can damage proteins. (D) Ca ²⁺ also activates kinase transcription factors, such as mitogen-activated protein kinase (MAPK) . Oxygen radicals trigger nuclear factor κB (NFκB) , another transcription factor. Many genes, including immediate early genes (IEGs) , heat shock protein (HSP) genes, genes for caspases, and the Bax/Bcl-2 systems, are activated. IEG products include AP-1, another transcription factor. Mitochondrial release of cytochrome c, existing and newly formed caspases, and other factors trigger apoptosis. DNA is damaged by oxygen free radicals and by endonucleases formed in apoptosis. DNA damage activates poly(ADP-ribose) polymerase (PARP) , which further depletes ATP stores. (E) Ca ²⁺ and apoptosis activate calpains, proteases that degrade a variety of structural elements (e.g., cytoskeletal and membrane proteins), signaling elements (e.g., G proteins, kinases), and PARP. (F) Transcription and NO contribute to the neuronal expression of cytokines, chemokines, and growth factors. These intercellular signals activate complement, epithelial cells, leukocytes, and microglia. Complement can amplify chemotactic signals, activate microglia directly, or cause cellular damage by creation of the membrane attack complex (MAC) . Leukocyte integrins, epithelial cell selectins, and intercellular adhesion molecules (ICAMs) allow demargination. Activated leukocytes cause neuronal injury by releasing potent oxidants and protease. Cerebrovascular resistance may be affected by the epithelial release of NO and endothelin and by leukocyte clumping. ADP, Adenosine diphosphate; [Ca ²⁺ ]i, Ca ²⁺ concentration; cAMP, cyclic adenosine monophosphate; eNOS, endothelial nitric oxide synthase; E.T., enzyme trafficking; mGluR, metabotropic glutamate receptor; PKC, protein kinase C.

Elevated Intracranial Pressure

Intracranial pressure (ICP) is an essential consideration in ischemic brain injury because cerebral ischemia can directly result in ICP elevation. Failure of oxidative phosphorylation depletes adenosine triphosphate (ATP) stores, resulting in an inability to actively maintain osmotic gradients. Increased intracellular osmolarity leads to water influx and the development of cytotoxic edema, which usually peaks 48 to 72 hours after injury. By decreasing cerebral perfusion pressure (CPP), elevated ICP is also an important contributor to secondary brain injury. This relationship is discussed in further detail as follows; additional information on ICP management is contained in subsequent sections.

To understand the pathophysiology of elevated ICP, note that the skull is a rigid container whose relatively non-compressible contents include the brain (∼80%), blood (∼10%), and cerebrospinal fluid (CSF; ∼10%). According to the Monro-Kellie doctrine, any addition to the volume of one of these components—for example, increased brain volume due to cerebral edema—must be offset by reducing the volume of the other contents or the ICP will rise.

Typically, adaptation to increased intracranial volume is initially accomplished by shifting CSF from the intracranial to spinal subarachnoid compartment. Approximately two-thirds of cerebral blood volume is contained in the cerebral veins and dural sinuses, and this venous capacitance can be reduced to accommodate increased intracranial volume further. Unfortunately, these mechanisms can become quickly exhausted, resulting in decreased compliance and a rapid increase in ICP ( Fig. 4.2 ). This may occur rapidly with acute cerebral injury or slowly with mass lesions such as tumors.

Favorable Neurological Outcomes Across Cardiac Arrest Randomized Trials.

Studies of neurologic outcome after out-of-hospital cardiac arrest (OHCA) generally demonstrate better outcomes with 33°C and longer duration of targeted temperature management (TTM). TTM48 demonstrated numerically better outcomes with 48 hours versus 24 hours of cooling but was not powered to detect the difference observed. The 2002 Hypothermia After Cardiac Arrest (HACA) and Bernard trials compared cooling to no temperature management with large treatment effects. The 2013 TTM trial did not demonstrate the superiority of a target of 33°C versus 36°C, although with a median time to bystander CPR of 0 minutes likely enrolled a relatively mildly affected population. The Therapeutic Hypothermia After Pediatric Cardiac Arrest (THAPCA) trial in children with OHCA also demonstrated numerically better outcomes with 33°C. The 2019 HYPERION trial included only non-shockable rhythm patients (and some patients in HYPERION were inpatient arrests), but demonstrated significantly better outcomes with TTM to 33°C.

In its final stages, uncontrolled intracranial hypertension results in downward herniation of the cerebellar tonsils through the foramen magnum, thereby compressing critical cardiorespiratory centers in the medulla. Prior to or concurrently with this, elevated ICP can exacerbate ischemic injury by reducing cerebral blood flow (CBF). CPP is equal to the mean arterial pressure (MAP) minus ICP. As ICP increases, CPP decreases, which is compensated for by cerebral arteriolar vasodilation. Unfortunately, this vasodilation may increase cerebral blood volume, which can additionally increase ICP and further reduce CPP. This vicious cycle is one of the primary inciting factors for the prolonged periods of refractory ICP elevation that can occur after global ischemic injury.

Standard medical management of ischemic brain damage involves restoring CBF and preventing secondary insult. Many standard treatments have not been studied in prospective, randomized, controlled trials, but have been supported by clinical experience and limited experimental data. Although proposed and experimental neuroprotectant therapies are generally aimed at specific molecular interventions in the pathophysiology of ischemic brain injuries, as yet none of these have proven effective in clinical trials. In the case of ischemic and other secondary brain injuries following cardiac arrest, the American Heart Association (AHA), the European Resuscitation Council (ERC), and European Society of Intensive Care Medicine (ESICM) published guidelines for post-cardiac arrest care based on the International Consensus on CPR and Emergency Cardiovascular Care Science with Treatment Recommendations (CoSTR) from the International Liaison Committee on Resuscitation (ILCOR). Improvements in post–cardiac arrest care, through an inclusive multisystem approach, can increase the likelihood of meaningful recovery in these patients. However, tremendous disparities in outcomes following cardiac arrest exist, which appear to be driven by substantial variation in processes of care.

In the United States, overall survival to hospital discharge following out-of-hospital cardiac arrest is 12% with three-fourth of those survivors having a favorable neurological outcome, while for in-hospital cardiac arrest, 25% survive to discharge. However, some single-center registries suggest that nearly 50% of patients who are successfully resuscitated from cardiac arrest and receive TTM may achieve a favorable neurological outcome. The majority of patients with primary cardiac arrest enrolled in a recent TTM trial achieved a favorable neurological outcome. ^, Implementation of standardized protocols for post-resuscitation care including many or all of the following components have demonstrated increases in survival in patients following cardiac arrest, as well as other conditions where early resuscitation may avoid additional secondary ischemic brain injury.

While families will be most focused on whether their loved one will awaken intact, emergency clinicians must be firm that no historical, exam, imaging, or lab tests available in the emergency department can exclude the possibility of a full recovery. In fact, guidelines recommend waiting at least 72 hours to perform neurological prognostication. Despite this, many cardiac arrest patients have withdrawal of life-sustaining treatment before 72 hours. While families may not want to engage in prolonged intensive care if it is not within the patient’s goals of care, the emergency department represents an opportunity to educate families. While there may be appropriate reasons to limit care, such as pre-existing terminal illness or the development of refractory multiple organ failure, families should not immediately limit care due to an assumption that a patient will not wake up. It is important for emergency physicians to temper expectations. Given the inability to predict neurologic prognosis in the first hours to days, it is important that families understand that it takes some time to determine if the brain will recover. Apart from restoring circulation, setting expectations for allowing adequate time and the uncertainty regarding prognosis is where emergency physicians can have the largest impact on increasing survival in this disease.

As with other topics discussed in this chapter, successful management of elevated ICP requires a combination of pharmacological and non-pharmacological interventions deployed in an organized, stepwise fashion. Initial management for all patients with brain injuries at risk of developing elevated ICP should focus on avoiding pain, agitation, and fever. We recommend titrated doses of a hemodynamically stable opioid medication, such as fentanyl 25 to 50 mcg every 5 minutes, as needed. Avoid coughing or ventilator dyssynchrony. This is best accomplished by achieving adequate sedation and analgesia to permit mechanical ventilation, as described in Chapters 2 , 151 , and 154 . Propofol is our sedative agent of choice for this purpose because it decreases cerebral metabolic activity, oxygen demand, and blood flow, and rapidly clears for neurologic assessment. Propofol can cause or contribute to hypotension, which may be avoided by dosage adjustment, but can necessitate starting vasopressors.

Alternatively, dexmedetomidine can also control agitation and promote endotracheal tube tolerance while facilitating frequent neurological examinations. However, dexmedetomidine does not suppress respiratory drive, and therefore, patients may have ventilator dyssynchrony in controlled ventilation. Some patients will not tolerate this agent due to hypotension and bradycardia, and tolerance does develop with long-term use. In refractory cases of intracranial hypertension, induced coma with a barbiturate will further decrease CBF and lower ICP. Pentobarbital is started with a 10 mg/kg loading dose over 30 minutes, followed by a continuous infusion of 1 to 4 mg/kg/h, titrated to achieve electroencephalographic burst suppression. Barbiturate administration is frequently accompanied by hypotension, which often requires vasopressors to maintain adequate CPP, and causes a variety of systemic side effects that should be carefully weighed when initiating treatment. Consideration of barbiturate infusion for severe TBI should simultaneously trigger consideration of a decompressive hemicraniectomy.

Acute spikes in ICP or cerebral herniation syndromes can sometimes be rapidly reversed via osmolar therapy with mannitol or hypertonic saline. Both work by drawing water across an intact blood-brain barrier, thereby lowering ICP. However, the extremely rapid onset of both agents is facilitated by changes in blood viscosity and reductions in cerebral blood volume. Mannitol, 0.25 to 1 g/kg is given every 6 hours, up to a serum osmolality of 320 mOsm/kg. Treating with 30 mL of 23.4% sodium chloride appears to be at least as effective as mannitol at rapidly lowering ICP and reversing herniation, and 30 to 60 mL can be given every 6 hours, up to a maximum serum sodium level of 160 mEq/L. A central line is preferred for safe administration. Hypertonic saline at 3% concentration can also be administered at an initial rate of 30 to 50 mL/hr as a continuous infusion. At present, there are insufficient data to recommend one agent over another, or to determine if continuous infusion or bolus dosing of hypertonic saline is preferred. Because it is a potent diuretic, mannitol is preferred in cases of fluid overload, whereas hypertonic saline can be used as a resuscitative fluid.