To better facilitate research on appropriately determining prognosis after cardiac arrest and to establish better treatments for recovering from brain injury, a working group composed of a Johns Hopkins Medicine physician and American Heart Association (AHA) experts have released a scientific statement that provides best practices on how to predict recovery in comatose survivors.
The statement was released in the July 11 issue of Circulation.
At this time, there aren’t any rules or set criteria for how to carry out a study to predict recovery.
Because of low quality, flawed research, decisions related to current policies may result in prediction errors that may forecast a poor outcome for patients who may have a good outcome, or vice versa.
Moreover, the lack of standards for predicting outcomes has made it all but impossible to properly study therapies that could potentially heal the brain and the rest of the body after being resuscitated from cardiac arrest.
To develop this scientific statement, the AHA Emergency Cardiovascular Care Science Subcommittee formed an international panel of experts in the adult and pediatric specialties of neurology, cardiology, emergency medicine, intensive care medicine and nursing.
The group’s goal is for the clinical research community to develop an accurate, precise clinical test for most patients after resuscitation from a cardiac arrest to determine likely prognosis.
“We owe it to patients and families to ensure we are doing the best to both not prolong unnecessary suffering while balancing that with not withdrawing care too soon if the person has the potential to recover with a reasonably good quality of life,” says Romergryko Geocadin, M.D., the chair of the expert panel and professor of neurology, neurosurgery, and anesthesiology and critical care medicine at the Johns Hopkins University School of Medicine.
“At the current state of affairs, we have to acknowledge the limitations in our practices in this area because we don’t have high-quality science to back our decision-making.”
According to the statement, about 8% of the more than 320,000 people who have cardiac arrest outside of a health care setting in the U.S. are released from the hospital with a good outcome, whereas the vast majority of resuscitated patients end up in a coma or another state of consciousness due to brain injury.
Most of the deaths are reported as brain injury, yet only 10% of these patients show clinical signs of brain death.
Most die from being removed from life support because it’s predicted that they will have little brain function and will most likely not recover.
Currently, many physicians wait 48 hours after a cardiac arrest for a patient to awaken from a coma, and some even opt to wait 72 hours.
But due to testing limitations and other confounding factors, such as therapeutic hypothermia, predicting an outcome may be biased and premature.
During a cardiac arrest, there are two stages of brain injury: One is due to lack of oxygen and the other happens, ironically, after blood returns.
Healing may not begin until after the patient has cleared this hurdle, which may take at least a week after the cardiac arrest.
This further muddies the decision for how long to wait for a patient to awaken.
Sedatives may also influence some of the diagnostics that determine brain function, so the authors generally recommend waiting seven days or until after the patient comes off sedatives, whichever happens later.
“One possible reason that every single drug that has been tested in clinical trials to heal brain injury after cardiac arrest may have failed is because the studies are designed to look for these drug effects at 30 or 90 days after successful resuscitation from cardiac arrest, but we don’t allow most of the patients time to recover for that period.
Instead, early predictions on recovery (within 72 hours) are made based on low quality studies,” says Geocadin.
“By providing this statement, health care providers can use this as a guide to develop better, more rigorous studies that can inform how to undertake better clinical studies that will lead to better practice medicine and develop helpful treatments for our patients.”
The authors reviewed the current diagnostics available and their limitations to test brain function, such as assessing reflexes, stimulating sensory nerves in the arm, measuring pupil dilation after shining a penlight in the eye, using electroencephalogram to evaluate for seizures, applying MRI and computerized tomography brain imaging, and more.
By using existing or yet to be developed tools properly in better designed studies, they hope researchers can adopt these procedures or enhance them to create better diagnostics for predicting long-term brain function.
The statement offers clinician researchers parameters for setting up their studies, such as how many people they need to enroll, what statistical methods to use, when to reassess function in those that do recover, ways to avoid bias and applying protocols consistently.
The statement’s final section addresses ethical issues like respecting patient or family wishes for being on life support and do-not-resuscitate orders.
The authors address that quality of life is an important factor, and stress that currently there is limited data regarding long term outcomes after awakening and more work needs to be done.
Out-of-hospital cardiac arrest (OHCA) is a common initial disease in developed countries. According to the latest report, of the 123,987 patients with OHCA in Japan brought to the hospital, 75,397 patients were suffering from a cardiogenic cause.
The survival rate of the patients with bystander at 1 month was 11.9 % and the survival rate to hospital discharge was only 7.9 % (http://www.fdma.go.jp/neuter/topics/kyukyukyujo_genkyo/h26/01_kyukyu.pdf).
Patients who achieve return of spontaneous circulation (ROSC) after OHCA show significant morbidity and mortality due to the cerebral and cardiac dysfunction that leads to prolonged whole-body ischemia.
This syndrome, called the post-cardiac arrest syndrome (PCAS), comprises anoxic brain injury, post-cardiac arrest myocardial dysfunction, systemic ischemia/reperfusion response, and persistent precipitating pathology.
Cardiac arrest is often associated with neurological deterioration. Although many years of laboratory and clinical research have been spent, post-cardiac arrest brain injury (PBI), a key factor of PCAS that involves complex molecular mechanisms, remains a common cause of morbidity and mortality.
The four key components of PCAS were identified as (1) PBI, (2) post-cardiac arrest myocardial dysfunction, (3) systemic ischemia/reperfusion response, and (4) persistent precipitating pathology [1].
Many studies have examined the mechanisms involved in ischemic brain injury.
However, no effective pharmacological treatment directed at tissues of the central nervous system (CNS) has been established to prevent the pathological conditions that occur as a consequence.
Therefore, all aspects of the basic mechanisms responsible for brain damage require urgent elucidation.
Recently, our research has aimed towards understanding the involvement and importance of calcium and the calcineurin/immunophilin signal transduction pathway in brain damage.
We previously demonstrated that immunosuppressants interacting with the calcineurin/immunophilin signal transduction pathway show potent neuroprotective effects in several animal models of ischemic brain damage, and these effects are considered to be separate from their action on immunocompetent cells [2–6].
In clinical anesthesiology, the pathological conditions that involve neuronal degeneration can be broadly divided into several categories as follows: (i) global ischemia due to an extended period of cardiac arrest [7, 8]; (ii) cerebral infarction (focal ischemia) that occurs after the occlusion of cerebral arteries; (iii) direct injuries due to head trauma and cerebral compression associated with hematoma or cerebral edema; (iv) increased intracranial pressure and secondary hypoxic brain damage due to cerebrovascular spasm; (v) encephalitis or meningitis caused by viruses, bacteria, parasites, fungi, and spirochetes; and (vi) seizures caused by head trauma, cerebral tumors, cerebrovascular disorders, intracranial infections, and abnormal metabolism.
This condition is likely to share many aspects of the pathological mechanisms resulting in brain damage and neurological impairment.
Although the most crucial mechanisms responsible for the induction of brain damage remain unclear, it has been suggested that mitochondrial dysfunction is significantly involved.
The elucidation of the basic pathophysiology for each of these pathological conditions that involve neuronal degeneration is of great importance for the development of effective neuroprotective pharmaceutical agents.
In this review, we outline the role of major pathophysiological disturbances leading to PBI and PCAS due to cardiac arrest that involve increased intracellular calcium, reactive oxygen species (ROS), and inflammation in ischemic neuronal cell death, with special emphasis on the mitochondrial permeability transition (MPT), which is a pathological state of the inner mitochondrial membrane leading to bioenergetic failure [9–12].
Post-cardiac arrest myocardial dysfunction
Post-cardiac arrest myocardial dysfunction also contributes to the low survival rate [37]; however, this phenomenon is both responsive to therapy and reversible [13, 38].
Heart rate and blood pressure are extremely variable due to the transient increase in local and circulating catecholamine concentrations after ROSC [39].
In one series of 148 patients who underwent coronary angiography after cardiac arrest, 49 % of the subjects had myocardial dysfunction manifested by tachycardia and elevated left ventricular end-diastolic pressure, followed approximately 6 h later by hypotension (MAP < 75 mmHg) and low cardiac output (cardiac index <2.2 L min−1 m−2) [13].
Several case series have described transient myocardial dysfunction after human cardiac arrest. Cardiac index values reached their nadir at 8 h after resuscitation, improved substantially by 24 h, and almost uniformly returned to normal by 72 h in patients who survived OHCA [13].
The responsiveness of post-cardiac arrest global myocardial dysfunction to inotropic drugs is well documented in animal studies [38, 40].
Reperfusion injury and reactive oxygen species (ROS)
It is well known that reperfusion following brain ischemia induces the production of a large amount of ROS ubiquitously throughout a cell.
Cardiac arrest represents the most severe shock state, during which delivery of oxygen and metabolic substrates is abruptly halted and metabolites are no longer removed. CPR only partially reverses this process, achieving cardiac output and systemic oxygen delivery (DO2) that is much less than normal.
During CPR, a compensatory increase in systemic oxygen extraction occurs, leading to significantly decreased central (ScvO2) or mixed venous oxygen saturation [22].
The whole-body ischemia/reperfusion of cardiac arrest with associated oxygen debt causes generalized activation of immunological and coagulation pathways, increasing the risk of multiple organ failure and infection [23, 41, 42].
Activation of blood coagulation without adequate activation of endogenous fibrinolysis is an important pathophysiological mechanism that may contribute to microcirculatory reperfusion disorders [43, 44].
The stress of total body ischemia/reperfusion affects adrenal function. Although an increased plasma cortisol level occurs in many patients after OHCA, relative adrenal insufficiency, defined as failure to respond to corticotrophin (i.e., <9 μg mL−1 increase in cortisol), is common [45, 46].
Clinical manifestations of a systemic ischemic-reperfusion response include intravascular volume depletion, impaired vasoregulation, impaired oxygen delivery and utilization, and increased susceptibility to infection.
A potentially devastating sequence of reperfusion events is one in which resumption of oxygen supply leads to grossly enhanced production of ROS and, thereby, leads to free radical-mediated damage.
The restoration of cerebral blood flow, which is known as “reperfusion,” elicits multiple cellular and physiologic events.
Reperfusion reverses the disruption of cellular functions that was induced by ischemia.
In adults, ischemic insults to the brain typically result from stroke (caused by either thrombotic occlusion or rupture of a blood vessel) [47] or cardiac arrest [48], whereas in infants, cerebral ischemia can be initiated by complications during delivery, resulting in neonatal hypoxic-ischemic encephalopathy [49].
Spontaneous reperfusion or reperfusion created by an intervention can cause additional and substantial brain damage, which is referred to as “reperfusion injury.”
Reperfusion induces pathological events such as lipid peroxidation due to the elevation of ROS, inflammation, and calcium overload (calcium dysregulation) that leads to MPT associated with mitochondrial dysfunction [27, 28, 50, 51] (further discussed below).
There are a number of possible cellular sources of these free radicals, including xanthine oxidase, cyclooxygenase, lipoxygenase, cytochrome p450, endothelial nitric oxide synthase, and NADPH oxidase. Mitochondria also produce ROS in the form of a superoxide anion (O2−), H2O2, and hydroxyl radical (OH−) which have been suggested to play important roles in the regulation of signal transduction and cellular metabolism [52].
Alterations of phosphorylating (state 3) and basal (state 4) respiration and respiratory control indicate a normalization of the electron transport system after reperfusion. However, secondary mitochondrial dysfunction is a prominent consequence of transient cerebral ischemia [53] resulting in a reduction of mitochondrial ATP synthesis.
The other major target of ROS is lipids, and the peroxidative action of ROS promotes the inactivation of key metabolic enzymes that regulate glucose metabolism. ROS are inactivated by endogenous mitochondrial and cytoplasmic scavenging systems.
However, ischemic reperfusion can sometimes overwhelm these scavenging systems, resulting in the production of ROS originating primarily from mitochondrial complexes I and III of the electron transport chain, causing oxidative damage to the mitochondria and consequently the cell [54].
Other highly reactive free radicals are produced by protein nitrosylation due to the reaction of NO and superoxide anions, which can also lead to the dysregulation of cellular homeostasis.
Persistent precipitating pathology
Diagnosis and management of persistent precipitating pathologies such as acute coronary syndrome (ACS), pulmonary diseases, hemorrhage, sepsis, and various toxic syndromes can complicate and be complicated by the simultaneous pathophysiology of PCAS. Consecutive patients had no obvious non-cardiac etiology but had undergone coronary angiography after resuscitation from OHCA [55].
Nine of the patients with acute coronary occlusion did not have chest pain or ST segment elevation.
Elevations in troponin T measured during treatment of cardiac arrest suggest that ACS precedes OHCA in 40 % of the patients [56].
Another thromboembolic disease to consider after cardiac arrest is pulmonary embolism. Pulmonary emboli have been reported in 2–10 % of sudden deaths [57, 58].
Primary pulmonary diseases such as chronic obstructive pulmonary disease, asthma, or pneumonia can lead to respiratory failure and cardiac arrest.
When cardiac arrest is caused by respiratory failure, pulmonary physiology may be worse after restoration of circulation. Redistribution of blood into pulmonary vasculature can lead to frank pulmonary edema or at least increased alveolar-arterial oxygen gradients after cardiac arrest [59].
Acute brain edema is more common after cardiac arrest caused by asphyxia [60]. It is possible that perfusion with hypoxemic blood during asphyxia preceding complete circulatory collapse is harmful.
Sepsis is a cause of cardiac arrest, acute respiratory distress syndrome, and multiple organ failure. Thus, there is a predisposition for exacerbation of PCAS when cardiac arrest occurs in the setting of sepsis.
Other precipitating causes of cardiac arrest may require specific treatment during the post-cardiac arrest period. For example, drug overdose and intoxication may be treated with specific antidotes, and environmental causes such as hypothermia may require active temperature control.
Journal information: Circulation
Provided by Johns Hopkins University School of Medicine
