Pathophysiological (who rounds with me known is one of my fav words) processes triggered by the whole-body ischemia-reperfusion response that occurs during cardiac arrest and subsequent restoration of systemic circulation.
Immediate phase: first 20 min following ROSC
Early phase: 20 minutes and 6-12 hrs after ROSC: window where secondary injury prevention could be most effective.
Intermediate phase: 6 to 12 hours and 72 hours when injury pathways are still active, and aggressive treatment needs to be in place.
Recovery phase: After 3 days. Prognostication and neuro-recovery start.
Why it matters ? Hypoxic Ischemic Encephalopathy ( HIE) is the overall endpoint result of the post-cardiac arrest syndrome. This topic is particularly relevant to neurointsvisits because 1) they can influence it by managing the post-cardiorespiratory arrest syndrome, and 2) they lead neuroprognostication.
Pathophysiology of Brain damage during and after Cardiac Arrest
Evidence is obviously limited to animal data or post-mortem histologic descriptions. Different animal models have shown different results, especially in term of recovery of function after restoration of blood flow.
Main mechanisms include, free radical formation, disordered calcium homeostasis, activation of cell death signaling pathways, pathological protease cascades and excitotoxicity. Ultimately, cerebral edema forms and cerebral blood flow is compromised. More specifically:
CNS storage of glucose and ATP is consumed in 5 minutes after circulatory arrest and apoptosis unsure shorty after.
The cell membrane becomes dysfunctional, leaks K and , H+ and lactic acid and glutamate, increasing extracellular acidosis. Excess Ca++ enters the cell.
ROSC causes re-oxygenation injury with free radicals and NO formation .
Microcirculation impairment due to microthrombosis and stagnant flow can occur despite adequate measured CPP, causing failure to reperfusion to some parts of the brain ( no re-flow phenomenon).
Excitatory synapses are probably more vulnerable than inhibitory synapses, leading to disturbed excitation-inhibition ratio’s that are associated with characteristic EEG patterns. (Ask Dr. Mizrahi to teach you more about this :)
These processes can continue in the hours to days following ROSC and may be modifiable (that is why as neurointensivists we can’t help believing in Target temp management after cardiac arrest).
Which areas of the brain are most affected?
The most commonly affected regions are watershed vascular areas and locations at higher metabolic demand like CAA1 pyramidal neurons of the hippocampus, cerebellar purkinje cells, thalamic reticular neurons, and specific layers of the neocortex. Interestingly, patients with a prolonged period of hypoxia followed by a global ischemic event appear to be susceptible to preferential injury to the subcortical white matter, in what appears to be a primary myelinolytic process (see Neurological Deterioration after the anoxic insult).
Neuroimaging series based on DWI/ADC MRI studies have described characteristic patterns like the “bright hippocampus sign” or bilateral motor cortices involvements, trying to associate prognostic values to the burden and location of MRI lesion, which variable degree of accuracy. MRI changes over time follow a relatively characteristic pattern of initial changes involving the cortex, basal ganglia, and cerebellum within the first 3 to 5 days, followed by primarily white matter changes in the late subacute periods. However, MRI can initially appear normal and show florid changes only at later time-points, adding challenges to prognostication.
Different clinico-radiological forms of HIE are described in the literature based on mechanism of injury. Patients who suffer a purely hypoxic event without a concomitant cardiovascular collapse have different patterns of dysfunction and chances for recovery than those who suffer a cardiac arrest. Pathologically, other anoxic injuries can be classified as: hypoxic hypoxia, from decreased partial pressure of blood oxygen, as in patients with hanging or drowning; histotoxic hypoxia, from tissue inability to utilize oxygen, as in cases of mitochondrial encephalopathy or exposure to mitochondrial toxins like carbon monoxide and cyanide; anemic hypoxia, from decreased hemoglobin content or function, as in cases of severe anemia or carbon monoxide poisoning.
With a purely hypoxic event (think about our young OD patients) , the cerebral blood flow (CBF) initially increases, secondary to intact cerebral autoregulatory mechanisms in the setting of an elevated carbon dioxide level and falling pH, nutrients are still supplied and waste products are still washed away. Hypoxia likely induces changes in the function of the neuron, without necessarily causing death of the neuron. Patients who suffer a hypoxic event may also be unresponsive and even comatose but may have a much better chance for survival with good neurological recovery than those with cardiac arrest ( ..but most of the time we treat them the same way ?). The neuronal dysfunction induced by hypoxia appears to occur on the synaptic level, with a selective gamma-aminobutyric acid-ergic deficiency, leading to an increased frequency of myoclonus and seizures. The time course for recovery from a purely hypoxic event mirrors the time for synaptic regeneration is approximately 2 weeks. These patients are typically younger. The event is typically caused by airway obstruction or decreased respiratory drive, such as caused by epiglottitis, anaphylaxis, trauma, or drug intoxication. Therefore, with a comatose patient who has suffered a purely hypoxic event and who does not have additional ancillary data pointing to a likely poor outcome, it is reasonable to continue supportive care in anticipation of a good neurological outcome.
Pearls and Oysters
In Delayed Neurological Deterioration after anoxia Plum and Posner in 1962 described a delay or relapse in neurological deterioration days or weeks after anoxia, related to white matter rather than neuronal damage. They postulated that injury occurs preferentially in the subcortical matter in situations in which there is a significant period of alveolar hypoventilation (also described as DELAYED POSTHYPOXIC DEMYELINATION), progressive acidosis, and severe metabolic disturbances in the peri-arrest period and may occur because of cerebral edema, elevated venous or cerebrospinal fluid pressure, or disturbances to the regional vasculature, which lies in the watershed areas of the brain. More recently, MRI studies have noted a similar pattern of injury primarily involving the white matter in patients undergoing diffusion-weighted imaging following a primary respiratory arrest followed by a cardiac decompensation.
Sequelae of Hypoxic Ischemic Encephalopathy
Prognostication after cardiac arrest ( will this patient wake up ? How long should we wait ? ) is challenging and contaminated by self-fulling prophecy-driven outcomes. Broadly, we categorize these patients as poor outcome (comatose/vegetative), intermediate outcome (awake but impaired), and good outcome (awake with minimal no deficits). After the initial dichotomy regarding awakening and not awakening after cardiac arrest, more complex measures are needed to characterize the patient’s disability (see figure above). Extreme durations of cardiac arrest result in brain death, in which both the cerebrum and brain stem are totally destroyed. In forebrain failure or vegetative states, there is relative sparing of brain stem function, but individuals have varying degrees of damage to cerebral cortex. In contrast, patients with less prolonged injury to the cerebral cortex often have a shorter duration of coma (although we don’t know how long a “Short coma” is, and we have all heard of isolated cases of delayed recovery) and have moderate deficits that may interfere their return to independent living. In addition to memory and executive impairments, language and visuospatial functions are disturbed. This usually confirms that the injury likely involves cortex and the more vulnerable subcortical and hippocampal regions.
For cardiac arrest survivors, cognitive impairment has been detected in as many a half cases when assessed by detailed neuropsychological investigations, suggesting reduced quality of life and increased caregiver strain. Frontal impairment has been described as one of the most common findings. Executive functions such as planning, flexibility, and abstract thinking are important factors for the ability to learn strategies and to adjust to new circumstances, which may be crucial for the patient’s recovery and ability to return to work.
Post-cardiac arrest syndrome A. BINKS, J. P. NOLAN. Minerva Anestesiol. 2010 May;76(5):362-8. PMID: 20395899.
Mechanisms of Injury in Hypoxic-Ischemic Encephalopathy: Implications to Therapy. David M. Greer. Semin Neurol. 2006 Sep;26(4):373-9. DOI: 10.1055/s-2006-948317.
Brain imaging in comatose survivors of cardiac arrest: pathophysiological correlates and prognostic properties. H.M. Keijzer, C.W.E. Hoedemaekers, F.J.A. Meijer, B.A.R. Tonino, C.J.M. Klijn, J. Hofmeijer. Resuscitation. 2018 Sep 19;133:124-136. 10.1016/j.resuscitation.2018.09.012. [Epub ahead of print]
Neuroimaging in Cardiac Arrest Prognostication. David M. Greer. Ona Wu. Semin Neurol. 2017 Feb;37(1):66-74. doi: 10.1055/s-0036-1594253. Epub 2017 Feb 1.
Long-Term Neurological Complications after Hypoxic-Ischemic Encephalopathy. Sandeep Khot, M.D., M.P.H. and David L. Tirschwell, M.D. Semin Neurol. 2006 Sep;26(4):422-31. DOI: 10.1055/s-2006-948323.
How would you define the post cardiac arrest syndrome to your trainee or to the attending that consulted you?
How would you describe the mechanism of injury that occurs in cardiac arrest to the neurology residents?
What is the no-reflow phenomenon?
You are sitting down with a family of a 30 yo woman, s/p CA from OD. It is day 3 after TTM completion. MRI at day 4, has some BG changes . EEG shows severe slowing. She is intubated, off sedation, with some grimacing to deep pain. The question is not whether or not to withdraw care, but how things will look in one month, in six months, in one year. How would you frame your talk? Practice this conversation and decide which data you will use (or decide not to use) to guide them.
A nurse has an asthma attack at work, codes and receives all the usual UC post-CA care. Day 5 MRI shows intact cortex and diffuse WM flair changes. Teach us about POSTHYPOXIC demyelination.