Ischemia-reperfusion (IR) tissue injury is the resultant pathology from a combination of factors, including tissue hypoxia, followed by tissue damage associated with re-oxygenation. IR injury contributes to disease and mortality in a variety of pathologies, including myocardial infarction, ischemic stroke, acute kidney injury, trauma, circulatory arrest, sickle cell disease and sleep apnea. Whether resulting from traumatic vessel disruption, tourniquet application, or shock, the extremity is exposed to an enormous flux in vascular perfusion during a critical period of tissue repair and regeneration. The contribution of this ischemia and subsequent reperfusion on post-traumatic musculoskeletal tissues is unknown; however, it is likely that similar to cardiac and kidney tissue, IR significantly contributes to tissue fibrosis.

Serum lactate level is a proxy measure of tissue oxygenation. When tissues do not have adequate oxygen delivery (i.e., are ischemic), they revert to less efficient metabolic processes, producing lactic acid.

Myoglobin is released from damaged muscle, as in the case of ischemia.

Serum creatinine and BUN may be elevated in the setting of Acute Kidney Injury.

Reperfusion injury or reperfusion insult, sometimes called ischemia-reperfusion injury (IRI) or reoxygenation injury, is the tissue damage caused when blood supply returns to tissue ("" + "perfusion") after a period of ischemia or lack of oxygen (anoxia or hypoxia). The absence of oxygen and nutrients from blood during the ischemic period creates a condition in which the restoration of circulation results in inflammation and oxidative damage through the induction of oxidative stress rather than (or along with) restoration of normal function.

Early symptoms of an arterial embolism in the arms or legs appear as soon as there is ischemia of the tissue, even before any frank infarction has begun. Such symptoms may include:

A major presentation of diabetic "skeletal muscle infarction" is painful thigh or leg swelling.

Since oxygen is carried to tissues in the blood, insufficient blood supply causes tissue to become starved of oxygen. In the highly aerobic tissues of the heart and brain, irreversible damage to tissues can occur in as little as 3–4 minutes at body temperature. The kidneys are also quickly damaged by loss of blood flow (renal ischemia). Tissues with slower metabolic rates may undergo irreversible damage after 20 minutes.

Clinical manifestations of acute limb ischemia (which can be summarized as the "six P's") include pain, pallor, pulseless, paresthesia, paralysis, and poikilothermia.

Without immediate intervention, ischemia may progress quickly to tissue necrosis and gangrene within a few hours. Paralysis is a very late sign of acute arterial ischemia and signals the death of nerves supplying the extremity. Foot drop may occur as a result of nerve damage. Because nerves are extremely sensitive to hypoxia, limb paralysis or ischemic neuropathy may persist after revascularization and may be permanent.

Cardiac ischemia may be asymptomatic or may cause chest pain, known as angina pectoris. It occurs when the heart muscle, or myocardium, receives insufficient blood flow. This most frequently results from atherosclerosis, which is the long-term accumulation of cholesterol-rich plaques in the coronary arteries. Ischemic heart disease is the most common cause of death in most Western countries and a major cause of hospital admissions.

The first symptom of compartment syndrome is pain. Loss of function and decreased pulses or pulselessness, however, are late signs. According to Shears, paresthesia in the distribution of the nerves transversing the affected compartment has also been described as relatively early sign of compartment syndrome, and later is followed by anesthesia (Shears, 2006).

- Pain is often reported early and almost universally. The description is usually of deep, constant, and poorly localized pain out of proportion with the findings on physical examination (often incorrectly described as pain out of proportion to the injury). The pain is aggravated by passively stretching the muscle group within the compartment or actively flexing it (though this finding is not specific to compartment syndrome alone) and is not relieved by analgesia up to and including morphine.

- Paresthesia (altered sensation e.g., "pins & needles") in the cutaneous nerves of the affected compartment is another typical sign.

- Paralysis of the limb is usually a late finding. The compartment may also feel very tense and firm (pressure). Some find that their feet and even legs fall asleep. This is because compartment syndrome prevents adequate blood flow to the rest of the leg.

- A lack of pulse rarely occurs in patients, as pressures that cause compartment syndrome are often well below arterial pressures and pulse is only affected if the relevant artery is contained within the affected compartment.

- Tense and swollen shiny skin, sometimes with obvious bruising of the skin.

- Congestion of the digits with prolonged capillary refill time.

A limb infarction is an area of tissue death of an arm or leg. It may cause "skeletal muscle infarction", avascular necrosis of bones, or necrosis of a part of or an entire limb.

Compartment syndrome is a condition in which increased pressure within one of the body's compartments results in insufficient blood supply to tissue within that space. There are two main types: acute and chronic. The leg or arm are most commonly involved.

Symptoms of acute compartment syndrome may include severe pain, poor pulses, decreased ability to move, numbness, or a pale color of the affected limb. It is most commonly due to physical trauma such as a bone fracture or crush injury. It can also occur after blood flow returns following a period of poor blood flow. Diagnosis is generally based upon a person's symptoms. Treatment is by surgery to open the compartment performed in a timely manner. If not treated within six hours, permanent muscle or nerve damage can result.

In chronic compartment syndrome there is generally pain with exercise. Other symptoms may include numbness. Symptoms typically resolve with rest. Common activities that trigger it include running and biking. It does not generally result in permanent damage. Other conditions that may present similarly include stress fractures and tendinitis. Treatment may include physical therapy or if that is not effective surgery.

Acute compartment syndrome occurs in about 3% of those who have a midshaft fracture of the forearm. Rates in other areas and for chronic cases is unknown. The condition more often occurs in those under the age of 35 and in males. Compartment syndrome was first described in 1881 by Richard von Volkmann. Untreated, acute compartment syndrome can result in Volkmann's contracture.

Blue toe syndrome is a situation that may reflect atherothrombotic microembolism, causing transient focal ischaemia, occasionally with minor apparent tissue loss, but without diffuse forefoot ischemia. The development of blue or violaceous toes can also occur with trauma, cold-induced injury, disorders producing generalized cyanosis, decreased arterial flow, impaired venous outflow, and abnormal circulating blood.

The terms "blue toe syndrome", "grey toe syndrome" and "purple toe syndrome" are sometimes used interchangeably.

Studies may include echocardiography, thoracic and abdominal CT or MRI, peripheral arterial run off imaging studies, hypercoagulopathy labs, and interrogation of syndromes that lead to peripheral vascular pathology.

Crush syndrome (also traumatic rhabdomyolysis or Bywaters' syndrome) is a medical condition characterized by major shock and renal failure after a injury to skeletal muscle. Crush "injury" is compression of extremities or other parts of the body that causes muscle swelling and/or neurological disturbances in the affected areas of the body, while crush "syndrome" is localized crush injury with systemic manifestations. Cases occur commonly in catastrophes such as earthquakes, to victims that have been trapped under fallen or moving masonry.

Victims of crushing damage present some of the greatest challenges in field medicine, and may be among the few situations where a physician is needed in the field. The most drastic response to crushing under massive objects may be field amputation. Even if it is possible to extricate the patient without amputation, appropriate physiological preparation is mandatory: where permissive hypotension is the standard for prehospital care, fluid loading is the requirement in crush syndrome.

Phlegmasia alba dolens (also colloquially known as milk leg or white leg) is part of a spectrum of diseases related to deep vein thrombosis. Historically, it was commonly seen during pregnancy and in mothers who have just given birth. In cases of pregnancy, it is most often seen during the third trimester, resulting from a compression of the left common iliac vein against the pelvic rim by the enlarged uterus. Today, this disease is most commonly (40% of the time) related to some form of underlying malignancy. Hypercoagulability (a propensity to clot formation) is a well-known state that occurs in many cancer states. The incidence of this disease is not well reported.

Certain changes in morphology are associated with cerebral edema: the brain becomes soft and smooth and overfills the cranial vault, gyri (ridges) become flattened, sulci (grooves) become narrowed, and ventricular cavities become compressed.

Symptoms include nausea, vomiting, blurred vision, faintness, and in severe cases, seizures and coma. If brain herniation occurs, respiratory symptoms or respiratory arrest can also occur due to compression of the respiratory centers in the pons and medulla oblongata.

Three progressive phases of mesenteric ischemia have been described:

- A "hyper active" stage occurs first, in which the primary symptoms are severe abdominal pain and the passage of bloody stools. Many patients get better and do not progress beyond this phase.

- A "paralytic" phase can follow if ischemia continues; in this phase, the abdominal pain becomes more widespread, the belly becomes more tender to the touch, and bowel motility decreases, resulting in abdominal bloating, no further bloody stools, and absent bowel sounds on exam.

- Finally, a "shock" phase can develop as fluids start to leak through the damaged colon lining. This can result in shock and metabolic acidosis with dehydration, low blood pressure, rapid heart rate, and confusion. Patients who progress to this phase are often critically ill and require intensive care.

Cerebral edema is excess accumulation of fluid in the intracellular or extracellular spaces of the brain.

Distributive shock is a medical condition in which abnormal distribution of blood flow in the smallest blood vessels results in inadequate supply of blood to the body's tissues and organs. It is one of four categories of shock, a condition where there is not enough oxygen-carrying blood to meet the metabolic needs of the cells which make up the body's tissues and organs. Distributive shock is different from the other three categories of shock in that it occurs even though the output of the heart is at or above a normal level. The most common cause is sepsis leading to type of distributive shock called septic shock, a condition that can be fatal.

Symptoms of mesenteric ischemia vary and can be acute (especially if embolic), subacute, or chronic.

Case series report prevalence of clinical findings and provide the best available, yet biased, estimate of the sensitivity of clinical findings. In a series of 58 patients with mesenteric ischemia due to mixed causes:

- abdominal pain was present in 95% (median of 24 hours duration). The other three patients presented with shock and metabolic acidosis.

- nausea in 44%

- vomiting in 35%

- diarrhea in 35%

- heart rate > 100 in 33%

- 'blood per rectum' in 16% (not stated if this number also included occult blood – presumably not)

- constipation in 7%

The symptoms of brain ischemia reflect the anatomical region undergoing blood and oxygen deprivation. Ischemia within the arteries branching from the internal carotid artery may result in symptoms such as blindness in one eye, weakness in one arm or leg, or weakness in one entire side of the body. Ischemia within the arteries branching from the vertebral arteries in the back of the brain may result in symptoms such as dizziness, vertigo, double vision, or weakness on both sides of the body . Other symptoms include difficulty speaking, slurred speech, and the loss of coordination. The symptoms of brain ischemia range from mild to severe. Further, symptoms can last from a few seconds to a few minutes or extended periods of time. If the brain becomes damaged irreversibly and infarction occurs, the symptoms may be permanent.

Similar to cerebral hypoxia, severe or prolonged brain ischemia will result in unconsciousness, brain damage or death, mediated by the ischemic cascade.

Multiple cerebral ischemic events may lead to subcortical ischemic depression, also known as vascular depression. This condition is most commonly seen in elderly depressed patients. Late onset depression is increasingly seen as a distinct sub-type of depression, and can be detected with an MRI.

The disease presumably begins with a deep vein thrombosis that progresses to total occlusion of the deep venous system. It is at this stage that it is called phlegmasia alba dolens. It is a sudden (acute) process. The leg, then, must rely on the superficial venous system for drainage. The superficial system is not adequate to handle the large volume of blood being delivered to the leg via the arterial system. The result is edema, pain and a white appearance ("alba") of the leg.

The next step in the disease progression is occlusion of the superficial venous system, thereby preventing all venous outflow from the extremity. At this stage it is called phlegmasia cerulea dolens. The leg becomes more swollen and increasingly more painful. Additionally, the edema and loss of venous outflow impedes the arterial inflow. Ischemia with progression to gangrene are potential consequences. Phlegmasia alba dolens is distinguished, clinically, from phlegmasia cerulea dolens in that there is no ischemia.

The ischemic (ischaemic) cascade is a series of biochemical reactions that are initiated in the brain and other aerobic tissues after seconds to minutes of ischemia (inadequate blood supply). This is typically secondary to stroke, injury, or cardiac arrest due to heart attack. Most ischemic neurons that die do so due to the activation of chemicals produced during and after ischemia. The ischemic cascade usually goes on for two to three hours but can last for days, even after normal blood flow returns.

A cascade is a series of events in which one event triggers the next, in a linear fashion. Thus "ischemic cascade" is actually a misnomer, since the events are not always linear: in some cases they are circular, and sometimes one event can cause or be caused by multiple events. In addition, cells receiving different amounts of blood may go through different chemical processes. Despite these facts, the ischemic cascade can be generally characterized as follows:

1. Lack of oxygen causes the neuron's normal process for making ATP for energy to fail.

2. The cell switches to anaerobic metabolism, producing lactic acid.

3. ATP-reliant ion transport pumps fail, causing the cell to become depolarized, allowing ions, including calcium (Ca), to flow into the cell.

4. The ion pumps can no longer transport calcium out of the cell, and intracellular calcium levels get too high.

5. The presence of calcium triggers the release of the excitatory amino acid neurotransmitter glutamate.

6. Glutamate stimulates AMPA receptors and Ca-permeable NMDA receptors, which open to allow more calcium into cells.

7. Excess calcium entry overexcites cells and causes the generation of harmful chemicals like free radicals, reactive oxygen species and calcium-dependent enzymes such as calpain, endonucleases, ATPases, and phospholipases in a process called excitotoxicity. Calcium can also cause the release of more glutamate.

8. As the cell's membrane is broken down by phospholipases, it becomes more permeable, and more ions and harmful chemicals flow into the cell.

9. Mitochondria break down, releasing toxins and apoptotic factors into the cell.

10. The caspase-dependent apoptosis cascade is initiated, causing cells to "commit suicide."

11. If the cell dies through necrosis, it releases glutamate and toxic chemicals into the environment around it. Toxins poison nearby neurons, and glutamate can overexcite them.

12. If and when the brain is reperfused, a number of factors lead to reperfusion injury.

13. An inflammatory response is mounted, and phagocytic cells engulf damaged but still viable tissue.

14. Harmful chemicals damage the blood–brain barrier.

15. Cerebral edema (swelling of the brain) occurs due to leakage of large molecules like albumins from blood vessels through the damaged blood brain barrier. These large molecules pull water into the brain tissue after them by osmosis. This "vasogenic edema" causes compression of and damage to brain tissue (Freye 2011; Acquired Mitochondropathy-A New Paradigm in Western Medicine Explaining Chronic Diseases).

The broad term, "stroke" can be divided into three categories: brain ischemia, subarachnoid hemorrhage and intracerebral hemorrhage. Brain ischemia can be further subdivided, by cause, into thrombotic, embolic, and hypoperfusion. Thrombotic and embolic are generally focal or multifocal in nature while hypoperfusion affects the brain globally.

Seigo Minami, a Japanese physician, first reported the crush syndrome in 1923. He studied the pathology of three soldiers who died in World War I from insufficiency of the kidney. The renal changes were due to methemoglobin infarction, resulting from the destruction of muscles, which is also seen in persons who are buried alive. The progressive acute renal failure is because of acute tubular necrosis.

The syndrome was later described by British physician Eric Bywaters in patients during the 1941 London Blitz. It is a reperfusion injury that appears after the release of the crushing pressure. The mechanism is believed to be the release into the bloodstream of muscle breakdown products—notably myoglobin, potassium and phosphorus—that are the products of rhabdomyolysis (the breakdown of skeletal muscle damaged by ischemic conditions).

The specific action on the kidneys is not understood completely, but may be due partly to nephrotoxic metabolites of myoglobin.

The most devastating systemic effects can occur when the crushing pressure is suddenly released, without proper preparation of the patient, causing reperfusion syndrome. In addition to tissue directly suffering the crush mechanism, down stream tissue is subject to Ischemia-reperfusion injuries of the appendicular musculoskeletal system. Without proper preparation, the patient, with pain control, may be cheerful before extrication, but die shortly thereafter. This sudden decompensation is called the "smiling death."

These systemic effects are caused by a traumatic rhabdomyolysis. As muscle cells die, they absorb sodium, water and calcium; the rhabdomyolysis releases potassium, myoglobin, phosphate, thromboplastin, creatine and creatine kinase.

Compartment syndrome can be secondary to crush syndrome. Monitor for the classic 5 Ps: pain, pallor, parasthesias, pain with passive movement, and pulselessness.

Musculoskeletal injury (MI, not to be confused with myocardial infarction) refers to damage of muscular or skeletal systems, which is usually due to a strenuous activity. In one study, roughly 25% of approximately 6300 adults received a musculoskeletal injury of some sort within 12 months—of which 83% were activity-related. MI spans into a large variety of medical specialties including orthopedic surgery (with diseases such as arthritis requiring surgery), sports medicine, emergency medicine (acute presentations of joint and muscular pain) and rheumatology (in rheumatological diseases that affect joints such as rheumatoid arthritis). In many cases, during the healing period after a musculoskeletal injury, a period in which the healing area will be completely immobile, a cast-induced muscle atrophy can occur. Routine sessions of physiotherapy after the cast is removed can help return strength in limp muscles or tendons. Alternately, there exist different methods of electrical stimulation of the immobile muscles which can be induced by a device placed underneath a cast, helping prevent atrophies

A study of aortic cross-clamping, a common procedure in cardiac surgery, demonstrated a strong potential benefit with further research ongoing.

Clinical manifestations of intraparenchymal hemorrhage are determined by the size and location of hemorrhage, but may include the following:

- Hypertension, fever, or cardiac arrhythmias

- Nuchal rigidity

- Subhyaloid retinal hemorrhages

- Altered level of consciousness

- Anisocoria, Nystagmus

- Focal neurological deficits

- Putamen - Contralateral hemiparesis, contralateral sensory loss, contralateral conjugate gaze paresis, homonymous hemianopsia, aphasia, neglect, or apraxia

- Thalamus - Contralateral sensory loss, contralateral hemiparesis, gaze paresis, homonymous hemianopia, miosis, aphasia, or confusion

- Lobar - Contralateral hemiparesis or sensory loss, contralateral conjugate gaze paresis, homonymous hemianopia, abulia, aphasia, neglect, or apraxia

- Caudate nucleus - Contralateral hemiparesis, contralateral conjugate gaze paresis, or confusion

- Brain stem - Tetraparesis, facial weakness, decreased level of consciousness, gaze paresis, ocular bobbing, miosis, or autonomic instability

- Cerebellum - Ataxia, usually beginning in the trunk, ipsilateral facial weakness, ipsilateral sensory loss, gaze paresis, skew deviation, miosis, or decreased level of consciousness