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Post-cardiac arrest syndrome (PCAS) is an inflammatory state of
pathophysiology Pathophysiology ( physiopathology) – a convergence of pathology with physiology – is the study of the disordered physiological processes that cause, result from, or are otherwise associated with a disease or injury. Pathology is the ...
that can occur after a patient is resuscitated from a
cardiac arrest Cardiac arrest is when the heart suddenly and unexpectedly stops beating. It is a medical emergency that, without immediate medical intervention, will result in sudden cardiac death within minutes. Cardiopulmonary resuscitation (CPR) and possib ...
. While in a state of cardiac arrest, the body experiences a unique state of global
ischemia Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems wi ...
. This ischemia results in the accumulation of
metabolic waste Metabolic wastes or excrements are substances left over from metabolic processes (such as cellular respiration) which cannot be used by the organism (they are surplus or toxic), and must therefore be excreted. This includes nitrogen compounds, ...
which instigate the production of
inflammatory mediators Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molecu ...
. If
return of spontaneous circulation Return of spontaneous circulation (ROSC) is the resumption of a sustained heart rhythm that perfuses the body after cardiac arrest. It is commonly associated with significant respiratory effort. Signs of return of spontaneous circulation include bre ...
(ROSC) is achieved after CPR, then circulation resumes, resulting in global reperfusion and the subsequent distribution of the ischemia products throughout the body. While PCAS has a unique cause and consequences, it can ultimately be thought of as type of global
ischemia-reperfusion injury Reperfusion injury, sometimes called ischemia-reperfusion injury (IRI) or reoxygenation injury, is the tissue damage caused when blood supply returns to tissue ('' re-'' + ''perfusion'') after a period of ischemia or lack of oxygen (anoxia or hy ...
. The damage, and therefore prognosis, of PCAS generally depends on the length of the patient's ischemic period; therefore the severity of PCAS is not uniform across different patients.


Causes and mechanisms

Before cardiac arrest, the body is in a state of
homeostasis In biology, homeostasis (British English, British also homoeostasis) Help:IPA/English, (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physics, physical, and chemistry, chemical conditions maintained by organism, living systems. Thi ...
. Arterial blood circulates appropriately through the body, supplying oxygen to tissues while the venous blood collects metabolic waste products to be utilized elsewhere and/or eliminated from the body. However, during cardiac arrest, the body is in circulatory and pulmonary arrest. Oxygen is no longer being ventilated by the lungs, and blood ceases to circulate throughout the body. As a result, all tissues in the body start to enter a state of ischemia. In this state, metabolic waste products, such as lactic acid and carbon dioxide, begin to accumulate as there is no circulation to move these products to the appropriate organs. This state of ischemia will continue until ROSC is achieved through CPR, at which time, blood starts to be reperfused throughout the body. This reperfusion results in inflammatory injury through three overlapping mechanisms. Some complimentary combination of, first, mitochondrial damage and, second,
endothelial activation Endothelial activation is a proinflammatory and procoagulant state of the endothelial cells lining the lumen of blood vessel The blood vessels are the components of the circulatory system that transport blood throughout the human body. Th ...
, causes a release of reactive oxygen species (ROS), which initiates and/or exacerbates a pathophysiological inflammatory response. Third, reperfusion initiates an immune, inflammatory response resulting in the circulation of pro-inflammatory cytokines such as
TNFα Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...
, IL-6 and IL-8 as well as complement activation (such as TCC and C3bc). Unlike other causes of ischemia-reperfusion injury, such as organ transplants, PCAS results from global ischemia-reperfusion and subsequently has global organ damage.


Signs and symptoms

The severity of PCAS is highly dependent on many variables including: the underlying cause of the arrest, the length of the ischemic period, the quality of CPR received, and a patient's physiologic reserve. However, organs generally respond to an ischemic period in predictable ways and therefore PCAS has an average presentation. The symptoms of PCAS are related to the effect of ischemia-reperfusion injury on individual systems, though there is significant co-morbidity between all organs' responses.


Brain

Being highly metabolic with low blood reserves, the brain is the most sensitive organ to ischemia. As a result, any amount of brain ischemia, especially when it is prolonged in cases of cardiac arrest, typically results in brain injury. Increasingly severe injury can lead to long term consequences such as cognitive dysfunction, persistent vegetative state and finally
brain death Brain death is the permanent, irreversible, and complete loss of brain function which may include cessation of involuntary activity necessary to sustain life. It differs from persistent vegetative state, in which the person is alive and some aut ...
. The brain sustains irreversible injury after about 20 minutes of ischemia. Even after blood flow is restored to the brain, patients can experience hours-days of hypotension, hypoxemia, impaired cerebrovascular autoregulation, brain edema, fever, hyperglycemia and/or seizures which further insult brain tissue. Diagnosis of brain injury involves neurological examination, EEG, brain imaging and/or biomarker evaluation (such as S100B and NSE). For out-of-hospital cardiac arrest, brain injury is the cause of death in most patients who undergo ROSC but ultimately die.


Heart

After the brain, the heart is the second most sensitive organ to ischemia. If the cause of the cardiac arrest was fundamentally a coronary pathology, then the consequences to the heart may include myocardial infarction complications. However, if the fundamental cause was non-coronary, then the heart becomes ischemic as a consequence, not a cause, of the arrest. In this case, PCAS very frequently presents with myocardial dysfunction in the first minute-hours post-ROSC. This myocardial dysfunction may present as prolonged
cardiogenic shock Cardiogenic shock (CS) is a medical emergency resulting from inadequate blood flow due to the dysfunction of the ventricles of the heart.Textbooks of Internal MedicinHarrison's Principles of Internal Medicine 16th Edition, The McGraw-Hill Compan ...
, highly variable blood pressures, reduced cardiac output and/or dysrhythmias. PCAS myocardial dysfunction seems to start almost immediately after ROSC. Unlike brain tissue, evidence suggests that the myocardial injury is generally transient and can mostly recover within 72 hours, though full recovery may take months.


Lungs

While the lungs are generally oxygenated during the ischemic period of arrest, they are still susceptible to ischemic damage. While ischemia is not the mechanism of injury, evidence suggests that the lack of perfusion through the pulmonary vasculature during an arrest reduces the
alveolar–arterial gradient The Alveolar–arterial gradient (A-, or A–a gradient), is a measure of the difference between the alveolar concentration (A) of oxygen and the arterial (a) concentration of oxygen. It is a useful parameter for narrowing the differential diagno ...
which creates
dead space ''Dead Space'' is a science fiction/horror fiction, horror media franchise created by Glen Schofield and Michael Condrey, developed by Visceral Games, and published and owned by Electronic Arts. The franchise's chronology is not presented in a lin ...
. The oxygen accumulation in the alveoli encourages ROS production which then leads to pulmonary damage. This pulmonary-specific damage, together with the systemic inflammation, causes
acute respiratory distress syndrome Acute respiratory distress syndrome (ARDS) is a type of respiratory failure characterized by rapid onset of widespread inflammation in the lungs. Symptoms include shortness of breath (dyspnea), rapid breathing (tachypnea), and bluish skin colo ...
in about 50% of ROSC patients who survive for at least 48 hours. Lung complications, such as
pulmonary contusion A pulmonary contusion, also known as lung contusion, is a bruise of the lung, caused by chest trauma. As a result of damage to capillaries, blood and other fluids accumulate in the lung tissue. The excess fluid interferes with gas exchange, pot ...
and
pulmonary edema Pulmonary edema, also known as pulmonary congestion, is excessive edema, liquid accumulation in the parenchyma, tissue and pulmonary alveolus, air spaces (usually alveoli) of the lungs. It leads to impaired gas exchange and may cause hypoxemia an ...
, may result from other aspects of PCAS such as CPR and left ventricular dysfunction, respectively. Finally,
pneumonia Pneumonia is an inflammatory condition of the lung primarily affecting the small air sacs known as alveoli. Symptoms typically include some combination of productive or dry cough, chest pain, fever, and difficulty breathing. The severity ...
is a common pulmonary complication due to multifactoral mechanisms including: loss of airway protection, aspiration, emergency intubation, and mechanical ventilation.


Kidneys

The kidneys are the third most sensitive organ to ischemia. Prolonged renal ischemia from cardiac arrest leads to acute kidney injury (AKI) in about 40% of patients. While PCAS may independently present with AKI, the development of AKI can be exacerbated by the administration of intravenous contrast if the patient undergoes angiography. It is unclear if the development of AKI worsens PCAS overall prognosis, but it does not seem to be a major contributor to death or poor neurological outcome at this time. PCAS patients, both as a cause and a consequence of the arrest, present with acid-base and electrolyte imbalances. Accumulation of lactate and carbon dioxide during the ischemic period largely accounts for the
metabolic acidosis Metabolic acidosis is a serious electrolyte disorder characterized by an imbalance in the body's acid-base balance. Metabolic acidosis has three main root causes: increased acid production, loss of bicarbonate, and a reduced ability of the kidneys ...
seen in PCAS patients, though strong ion gaps and phosphate also plays a role. Worse acidosis is generally predictive of worse outcomes. Finally, though electrolytes can present variably, PCAS patients most often demonstrate hypokalemia, hypocalcemia and hypomagnesaemia Acute kidney injury is not the leading cause of death after cardiac arrest. However, evidence suggests that the kidney damage after a cardiac arrest should be highly considered in the prognosis of the patients' health outcome.


Liver

PCAS patients, especially those with longer ischemic times, can present with liver complications. About 50% of PCAS patients present with acute liver failure (ALF), while about 10% may present with the more severe hypoxic hepatitis. Development of hypoxic hepatitis predicts poor PCAS outcomes, however ALF-similar to AKI- is not necessarily associated with poor outcomes.


Coagulation

PCAS is associated with pro-thrombotic
coagulopathy Coagulopathy (also called a bleeding disorder) is a condition in which the blood's ability to coagulate (form clots) is impaired. This condition can cause a tendency toward prolonged or excessive bleeding (bleeding diathesis), which may occur spo ...
. The coagulopathy is, itself, pathophysiological, but
thrombi A thrombus (plural thrombi), colloquially called a blood clot, is the final product of the blood coagulation step in hemostasis. There are two components to a thrombus: aggregated platelets and red blood cells that form a plug, and a mesh of c ...
can additionally contribute to co-morbidiities in the aforementioned organ systems. The ischemia-reperfusion injury promotes
damage-associated molecular pattern Damage-associated molecular patterns (DAMPs) are molecules within cells that are a component of the innate immune response released from damaged or dying cells due to trauma or an infection by a pathogen. They are also known as danger-associated m ...
s (DAMPs) which encourage pro-inflammatory cytokine circulation, which then induces a pro-coagulopathic state. Major mechanisms of pro-coagulation in PCAS include: multiimodal activation of factors V, VII, VIII and IX leading to a thrombin burst, decreased activity of proteins C and S, and decreased anti-thrombin and tissue factor pathway inhibitor levels. Early PCAS (first 24 hours) is generally defined by
hyperfibrinolysis The fibrinolysis system is responsible for removing blood clots. Hyperfibrinolysis describes a situation with markedly enhanced fibrinolytic activity, resulting in increased, sometimes catastrophic bleeding. Hyperfibrinolysis can be caused by acquir ...
, due to increased tissue plasminogen activator activity, resulting in a risk of
disseminated intravascular coagulation Disseminated intravascular coagulation (DIC) is a condition in which blood clots form throughout the body, blocking small blood vessels. Symptoms may include chest pain, shortness of breath, leg pain, problems speaking, or problems moving parts o ...
. However late PCAS generally presents with hypofibrinolysis, due to increased PAI-1 levels, resulting in a risk of multiorgan dysfunction. PCAS patients also generally show some degree of thrombocytopenia within the first 48 hours.


Endocrine

The endocrine functions most clinically relevant to PCAS are glycemic control and the hypothalamic–pituitary–adrenal axis (HPA axis). Regarding blood glucose levels, it is very common for PCAS to present with hyperglycemia; the hyperglycemia is usually higher in diabetic patients than non-diabetic patients. Mechanisms for hyperglycemia in PCAS are mostly similar as those in stress-induced hyperglycemia and therefore include elevated cortisol levels, catchecholamine surges and elevated cytokine levels. Blood glucose levels are associated with poor outcomes in a U-shaped distribution, meaning that both very high and very low levels of glucose are associated with poor outcomes. Regarding the HPA axis, PCAS can present with elevated cortisol levels from the stress of the arrest, but relative adrenal insufficiency is not uncommon in PCAS. Lower cortisol levels have been associated with poor PCAS outcomes. Newer research suggests that cardiac arrest may damage the pituitary gland, thus explaining some of the HPA dysregulation.


Management

PCAS consist of five phases: the immediate phase (20 minutes after ROSC), early phase (from 20 minutes to 6–12 hours after ROSC), intermediate phase (from 6–12 to 72 hours after ROSC), recovery phase (3 days after ROSC), and the rehabilitation phase. Management of PCAS is inherently variable, as it depends on the phase, organ systems affected and overall patient presentation. With the exception of targeted temperature management, there is no treatment that is unique to the pathophysiology of PCAS; therefore PCAS treatment is largely system-dependent, supportive treatment.


Targeted temperature management

Targeted temperature management (TTM) is the use of various cooling methods to reduce a patient's internal temperature. The main methods of cooling include using either cold intravenous solutions or by circulating cool fluids through an external, surface blanket/pad. While most commonly applied as a post-ROSC intervention, there are some studies and EMS systems that start the cooling process in the initial intra-arrest stage. Patients are generally cooled to a range of 32-36 °C. As of January 2021, there is active debate about the ideal cooling temperature but there is generally agreement that PCAS patients benefit by not being hyperthermic. TTM is an important therapy in PCAS because it directly targets the systemic nature of the pathophysiological inflammatory and metabolic processes. TTM works through three major mechanisms. First, it decreases metabolism 6% to 7% per 1 °C decrease in temperature. Second, it decreases cell
apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
which reduces tissue damage. Third, TTM directly reduces inflammation and ROS production.


System-based treatment

PCAS can present variably depending on intra-arrest dynamics and patient-specific variables. Therefore, there is no universally applicable treatments for PCAS other than TTM. However, because there are generally predictable problems, the table below presents some of the more common treatments; supporting one organ system generally has mutual benefits for the healing of other body systems. These treatments, while common, may not be applicable to every patient.


Prognosis

Survival from PCAS is convoluted with survival from cardiac arrest generally. There are two common metrics used to define "survival" from cardiac arrest and subsequent PCAS. First is survival-to-hospital-discharge which binarily describes whether one survived long enough to leave the hospital. The second metric is neurological outcome which describes the cognitive function of a patient who survives arrest. Neurological outcome is frequently measured with a CPC score or mRS score. Cardiac arrest and PCAS outcomes are influenced by many complicated patient and treatment variables which allows for a wide array of outcomes ranging from full physical and neurological recovery to death. PCAS outcomes are generally better under certain conditions including: fewer patient comorbidities, initial shockable rhythms, rapid CPR responses, and treatment at a high-volume cardiac arrest center. Cardiac arrest survival-to-hospital-discharge, , is around 10%. Common long term complications of cardiac arrest and subsequent PCAS include: anxiety, depression, PTSD, fatigue, post–intensive care syndrome, muscle weakness, persistent chest pain, myoclonus, seizures, movement disorders and risk of re-arrest.


Research

Research on PCAS benefits from disease-specific work as well as general improvements in critical care treatments. As of 2022, research on PCAS includes, non-exclusively, work on early resolution of ischemia through pre-hospital
extracorporeal membrane oxygenation Extracorporeal membrane oxygenation (ECMO), also known as extracorporeal life support (ECLS), is an extracorporeal technique of providing prolonged cardiac and respiratory support to persons whose heart and lungs are unable to provide an adequat ...
, and wide distribution of defibrillators and CPR-trained bystanders, continued investigation of TTM, use of immunosuppressive drugs such as steroids and tocilizumab, the use of cytoprotective perfusates, and the use cerebral tissue oxygen extraction fraction.


See also

*
Cardiac arrest Cardiac arrest is when the heart suddenly and unexpectedly stops beating. It is a medical emergency that, without immediate medical intervention, will result in sudden cardiac death within minutes. Cardiopulmonary resuscitation (CPR) and possib ...
* Cardiac Arrest Registry to Enhance Survival * Advanced cardiac life support


References

{{reflist Ischemia Syndromes affecting the heart