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Mechanism
Rather than in hypoxia, a more general term denoting a shortage of oxygen (usually a result of lack of oxygen in the air being breathed), ischemia is an absolute or relative shortage of the blood supply to an organ. Relative shortage means the mismatch of blood supply (oxygen delivery) and blood request for adequate oxygenation of tissue. Ischemia results in tissue damage because of a lack of oxygen and nutrients. Ultimately, this causes great damage because of a buildup of metabolic wastes.
Ischemia can also be described as an inadequate flow of blood to a part of the body, caused by constriction or blockage of the blood vessels supplying it. Ischemia of heart muscle produces angina pectoris.
This can be due to:
- Tachycardia (abnormally rapid beating of the heart)
- Atherosclerosis (lipid-laden plaques obstructing the lumen of arteries)
- Hypotension (low blood pressure, e.g. in septic shock, heart failure)
- Thromboembolism (blood clots)
- Outside compression of a blood vessel, e.g. by a tumor
- Foreign bodies in the circulation (e.g. amniotic fluid in amniotic fluid embolism)
- Sickle cell disease (abnormally shaped hemoglobin)
- Induced g-forces which restrict the blood flow and force the blood to the extremities of the body, as in aerobatics and military flying
Consequences
Since oxygen is mainly bound to hemoglobin in red blood cells, insufficient blood supply causes tissue to become hypoxic, or, if no oxygen is supplied at all, anoxic. This can cause necrosis (i.e. cell death). In very aerobic tissues such as heart and brain, at body temperature necrosis due to ischemia usually takes about 3-4 hours before becoming irreversible. This and typically some collateral circulation to the ischemic area accounts for the efficacy of "clot-buster" drugs such as Alteplase, given for stroke and heart-attack within this time period. However, complete cessation of oxygenation of such organs for more than 20 minutes typically results in irreversible damage.
Ischemia is a feature of heart diseases, transient ischemic attacks, cerebrovascular accidents, ruptured arteriovenous malformations, and peripheral artery occlusive disease. The heart, the kidneys, and the brain are among the organs that are the most sensitive to inadequate blood supply. Ischemia in brain tissue, for example due to stroke or head injury, causes a process called the ischemic cascade to be unleashed, in which proteolytic enzymes, reactive oxygen species, and other harmful chemicals damage and may ultimately kill brain tissue.
Restoration of blood flow after a period of ischemia can actually be more damaging than the ischemia. Reintroduction of oxygen causes a greater production of damaging free radicals, resulting in reperfusion injury. With reperfusion injury, necrosis can be greatly accelerated.
Variations
The mechanism of ischemia depends on the type. One important type is cardiac ischemia, another is bowel ischemia.
Cardiac ischemia
Cardiac ischemia may cause chest pain, known as angina pectoris
Detection
Initial evaluation of chest-pain patients involves a 12 lead electrocardiogram (ECG) and cardiac markers such as troponins. These tests are highly specific but very insensitive and often leave the requirement for further testing to achieve an accurate diagnosis. Magnetocardiography (MCG) imaging utilises superconducting quantum interference devices (SQUIDs) to detect the weak magnetic fields generated by the heart's electrical fields. There is a direct correlation between abnormal cardiac depolarisation or repolarisation and abnormality in the magnetic field map. In July 2004, the Food and Drug Administration (FDA) approved the CardioMag Imaging MCG as a safe device for the non-invasive detection of ischemia.
Bowel ischemia
An ischemia in the large bowel caused by an inflammation results in ischemic colitis. An ischemia in the small bowel, on the other hand, caused by an inflammation results in mesenteric ischemia.
Cutaneous ischemia
Reduced blood flow to the skin layers may result in mottling or uneven, patchy discoloration of the skin.
Treatment
A dietary supplement based on superoxide dismutase and wheat gliadin (also known as glisodin) has shown promise in the protection against ischemia-reperfusion injury by inhibiting oxidative DNA damage.
References
Notes
- Oxford Reference: Concise Medical Dictionary (1990, 3rd ed.). Oxford University Press: Market House Books.
See also
Reperfusion injury refers to damage to tissue caused when blood supply returns to the tissue after a period of ischemia. The absence of oxygen and nutrients from blood creates a condition in which the restoration of circulation results in inflammation and oxidative damage through the induction of oxidative stress rather than restoration of normal function.
Mechanisms of reperfusion injury
The damage of reperfusion injury is due in part to the inflammatory response of damaged tissues. White blood cells carried to the area by the newly returning blood release a host of inflammatory factors such as interleukins as well as free radicals in response to tissue damage [1].The restored blood flow reintroduces oxygen within cells that damages cellular proteins, DNA, and the plasma membrane. Damage to the cell's membrane may in turn cause the release of more free radicals. Such reactive species may also act indirectly in redox signaling to turn on apoptosis. Leukocytes may also build up in small capillaries, obstructing them and leading to more ischemia[1].
Reperfusion injury plays a part in the brain's ischemic cascade, which is involved in stroke and brain trauma. Repeated bouts of ischemia and reperfusion injury also are thought to be a factor leading to the formation and failure to heal of chronic wounds such as pressure sores and diabetic foot ulcers[2]. Continuous pressure limits blood supply and causes ischemia, and the inflammation occurs during reperfusion. As this process is repeated, it eventually damages tissue enough to cause a wound[2].
In prolonged ischemia (60 minutes or more), hypoxanthine is formed as breakdown product of ATP metabolism. The enzyme xanthine dehydrogenase acts in reverse, that is as a xanthine oxidase as a result of the higher availability of oxygen. This oxidation results in molecular oxygen being converted into highly reactive superoxide and hydroxyl radicals. Xanthine oxidase also produces uric acid, which may act as both a prooxidant and as a scavenger of reactive species such as peroxinitrite. Excessive nitric oxide produced during reperfusion reacts with superoxide to produce the potent reactive species peroxynitrite. Such radicals and reactive oxygen species attack cell membrane lipids, proteins, and glycosaminoglycans, causing further damage. They may also initiate specific biological processes by redox signaling.
Treatment
Glisodin, a dietary supplement derived from superoxide dismutase (SOD) and wheat gliadin, has been studied for its ability to mitigate ischemia-reperfusion injury. A study of aortic cross-clamping (a common procedure in cardiac surgery), demonstrated a strong potential benefit with further research ongoing.
See also
References
- ^ a b Clark, Wayne M. (January 5, 2005). Reperfusion Injury in Stroke. eMedicine. WebMD. Retrieved on 2006-08-09.
- ^ a b Mustoe T. (2004). "Understanding chronic wounds: a unifying hypothesis on their pathogenesis and implications for therapy". AMERICAN JOURNAL OF SURGERY 187 (5A): 65S-70S. doi:10.1016/S0002-9610(03)00306-4 . PMID 15147994.
External links
To Treat the Dead
Consider someone who has just died of a heart attack. His organs are intact, he hasn't lost blood. All that's happened is his heart has stopped beating—the definition of "clinical death"—and his brain has shut down to conserve oxygen. But what has actually died?
As recently as 1993, when Dr. Sherwin Nuland wrote the best seller "How We Die," the conventional answer was that it was his cells that had died. The patient couldn't be revived because the tissues of his brain and heart had suffered irreversible damage from lack of oxygen. This process was understood to begin after just four or five minutes. If the patient doesn't receive cardiopulmonary resuscitation within that time, and if his heart can't be restarted soon thereafter, he is unlikely to recover. That dogma went unquestioned until researchers actually looked at oxygen-starved heart cells under a microscope. What they saw amazed them, according to Dr. Lance Becker, an authority on emergency medicine at the University of Pennsylvania. "After one hour," he says, "we couldn't see evidence the cells had died. We thought we'd done something wrong." In fact, cells cut off from their blood supply died only hours later.
But if the cells are still alive, why can't doctors revive someone who has been dead for an hour? Because once the cells have been without oxygen for more than five minutes, they die when their oxygen supply is resumed. It was that "astounding" discovery, Becker says, that led him to his post as the director of Penn's Center for Resuscitation Science, a newly created research institute operating on one of medicine's newest frontiers: treating the dead.
Biologists are still grappling with the implications of this new view of cell death—not passive extinguishment, like a candle flickering out when you cover it with a glass, but an active biochemical event triggered by "reperfusion," the resumption of oxygen supply. The research takes them deep into the machinery of the cell, to the tiny membrane-enclosed structures known as mitochondria where cellular fuel is oxidized to provide energy. Mitochondria control the process known as apoptosis, the programmed death of abnormal cells that is the body's primary defense against cancer. "It looks to us," says Becker, "as if the cellular surveillance mechanism cannot tell the difference between a cancer cell and a cell being reperfused with oxygen. Something throws the switch that makes the cell die."
With this realization came another: that standard emergency-room procedure has it exactly backward. When someone collapses on the street of cardiac arrest, if he's lucky he will receive immediate CPR, maintaining circulation until he can be revived in the hospital. But the rest will have gone 10 or 15 minutes or more without a heartbeat by the time they reach the emergency department. And then what happens? "We give them oxygen," Becker says. "We jolt the heart with the paddles, we pump in epinephrine to force it to beat, so it's taking up more oxygen." Blood-starved heart muscle is suddenly flooded with oxygen, precisely the situation that leads to cell death. Instead, Becker says, we should aim to reduce oxygen uptake, slow metabolism and adjust the blood chemistry for gradual and safe reperfusion.
Researchers are still working out how best to do this. A study at four hospitals, published last year by the University of California, showed a remarkable rate of success in treating sudden cardiac arrest with an approach that involved, among other things, a "cardioplegic" blood infusion to keep the heart in a state of suspended animation. Patients were put on a heart-lung bypass machine to maintain circulation to the brain until the heart could be safely restarted. The study involved just 34 patients, but 80 percent of them were discharged from the hospital alive. In one study of traditional methods, the figure was about 15 percent.
Becker also endorses hypothermia—lowering body temperature from 37 to 33 degrees Celsius—which appears to slow the chemical reactions touched off by reperfusion. He has developed an injectable slurry of salt and ice to cool the blood quickly that he hopes to make part of the standard emergency-response kit. "In an emergency department, you work like mad for half an hour on someone whose heart stopped, and finally someone says, 'I don't think we're going to get this guy back,' and then you just stop," Becker says. The body on the cart is dead, but its trillions of cells are all still alive. Becker wants to resolve that paradox in favor of life.Syncope is a prevalent disorder, accounting for 1-3% of emergency department (ED) visits and as many as 6% of hospital admissions each year in the United States. As much as 50% of the population may experience a syncopal event during their lifetime. Although many etiologies for syncope are recognized, studies suggest categorization into cardiac, noncardiac, and unknown groups for the purposes of future risk stratification may be helpful in the initial evaluation. Cardiac syncope is associated with increased mortality, whereas noncardiac syncope is not. In addition, significant morbidity may result from falls or accidents that result from syncope.
Syncope is usually benign; however, in a subset of patients, this symptom presages a life-threatening event. As a result of this risk, hospital admission is frequent because of the difficulties encountered in promptly addressing causes of syncope, the lack of a diagnostic criterion standard, and concern about potentially dangerous arrhythmias.
Once a diagnostic category is identified, limited therapies are available. Little is known regarding the effects of therapies on longevity. Those with initially unknown causes may require further costly testing. Most individual tests have low diagnostic yield and provide limited insight into guiding future clinical management.
Pathophysiology
Syncope occurs due to global cerebral hypoperfusion. Brain parenchyma depends on adequate blood flow to provide a constant supply of glucose, the primary metabolic substrate. Brain tissue cannot store energy in the form of high-energy phosphates found elsewhere in the body; therefore, a cessation of cerebral perfusion lasting only 3-5 seconds results in syncope. Cerebral perfusion is maintained relatively constant by an intricate and complex feedback system involving cardiac output, systemic vascular resistance, arterial pressure, intravascular volume status, cerebrovascular resistance with intrinsic autoregulation, and metabolic regulation. A clinically significant defect in any one of these or subclinical defects in several of these systems may cause syncope.
Cardiac output can be diminished secondary to mechanical outflow obstruction, pump failure, hemodynamically significant arrhythmias, or conduction defects. Systemic vascular resistance can drop secondary to vasomotor instability, autonomic failure, or vasodepressor/vasovagal response. Arterial pressure decreases with all causes of hypovolemia.
A CNS event, such as a hemorrhage or an unwitnessed seizure, can also present as syncope.
Syncope can occur without reduction in cerebral blood flow in patients who have severe metabolic derangements (eg, HYPOglycemia, hyponatremia, hypoxemia).
Frequency
United States
Framingham data demonstrate a first occurrence rate of 6.2 cases per 1000 patient-years.1, 2 Syncope reoccurs in 3% of affected individuals, and approximately 10% of affected individuals have a cardiac etiology.
A glucose level, checked by rapid fingerstick (eg, Accu-Chek), should be evaluated in any patient with syncope. HYPOglycemia can produce a clinical picture identical to syncope, including the prodromal symptoms, absence of memory for the event, and spontaneous resolution.
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