<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Rotator cuff tear and explain in detail? [/INST] A rotator cuff tear is an injury where one or more of the tendons or muscles of the rotator cuff of the shoulder get torn. Symptoms may include shoulder pain, which is often worse with movement, limited range of motion, or weakness. This may limit peoples ability to brush their hair or put on clothing. Clicking may also occur with movement of the arm.Tears may occur as the result of a sudden force or gradually over time. Risk factors include certain repetitive activities, smoking, and a family history of the condition. Diagnosis is based on symptoms, examination, and medical imaging. The rotator cuff is made up of the supraspinatus, infraspinatus, teres minor, and subscapularis. The supraspinatus is the most commonly affected.Treatment may include pain medication such as NSAIDs and specific exercises. It is recommended that people who are unable to raise their arm above 90 degrees after 2 weeks should be further assessed. In severe cases surgery may be tried, however benefits of surgery are unclear as of 2019. Rotator cuff tears are common. Those over the age of 40 are most often affected. The condition has been described since at least the early 1800s.

Signs and symptoms
Many rotator cuff tears have no symptoms. Both partial and full thickness tears have been found on post mortem and MRI studies in those without any history of shoulder pain or symptoms. However, the most common presentation is shoulder pain or discomfort. This may occur with activity, particularly shoulder activity above the horizontal position, but may also be present at rest in bed. Pain-restricted movement above the horizontal position may be present, as well as weakness with shoulder flexion and abduction.Abnormal mobility or function of the scapula (scapular dyskinesia) may be present and is related to lower functional scores; it unclear whether scapular dyskinesia is a cause, effect or compensation for rotator cuff pathology.

Risk factors
Epidemiological studies strongly support a relationship between age and cuff tear prevalence, with the most common cause being age-related degeneration and, less frequently, sports injuries or trauma.Those most prone to failed rotator cuff syndrome are people 65 years of age or older; and those with large, sustained tears. Smokers, people with diabetes, individuals with muscle atrophy or fatty infiltration, and those who do not follow postoperative-care recommendations also are at greater risk. In a 2008 study the frequency of such tears increased from 13% in the youngest group (aged 50–59 y) to 20% (aged 60–69 y), 31% (aged 70–79 y), and 51% in the oldest group (aged 80–89 y).Some risk factors such as increased age and height cannot be changed. Increased body mass index is also associated with tearing. Recurrent lifting and overhead motions are at risk for rotator cuff injury as well. This includes jobs that involve repetitive overhead work, such as carpenters, painters, custodians, and servers. People who play sports that involve overhead motions, such as swimming, water polo, volleyball, baseball, tennis, and American football quarterbacks, are at a greater risk of experiencing a rotator cuff tear. Striking-based combat sports, such as boxing, also account for severe rotator cuff injuries of competitors, typically when their punches miss the target, or overusing the shoulder by throwing excessively large amounts of punches. Certain track-and-field activities, such as shot put, javelin throw are also of considerable risk, especially when performing outdoors under cold weather conditions or neglecting warming-up procedures, for proper warm-up of the throwing and/or swinging arm can help reduce the stress on the musculature of the shoulder girdle. Corticosteroid injections around the tendons increases the risk of tendon tear and delay tendon healing.

Mechanisms of injury
The shoulder is a complex mechanism involving bones, ligaments, joints, muscles, and tendons.
The two main causes are acute injury or chronic and cumulative degeneration of the shoulder joint. Mechanisms can be extrinsic, intrinsic or a combination of both.The cuff is responsible for stabilizing the glenohumeral joint to allow abduction and rotation of the humerus. When trauma occurs, these functions can be compromised. Because individuals are dependent on the shoulder for many activities, overuse can lead to tears, with the vast majority being in the supraspinatus tendon.The role of the supraspinatus is to resist downward motion, both while the shoulder is relaxed and carrying weight. Supraspinatus tears usually occurs at its insertion on the humeral head at the greater tubercle. Though the supraspinatus is the most commonly injured tendon in the rotator cuff, the other three can also be injured at the same time.

Acute tears
The amount of stress needed to acutely tear a rotator cuff tendon will depend on the underlying condition of the tendon. If healthy, the stress needed will be high, such as with a fall on the outstretched arm. This stress may occur coincidentally with other injuries such as a dislocation of the shoulder or separation of the acromioclavicular joint. In the case of a tendon with pre-existing degeneration, the force may be more modest, such as with a sudden lift, particularly with the arm above the horizontal position.  The type of loading involved with injury is usually eccentric, such as when two people are carrying a load and one lets go, forcing the other to maintain force while the muscle elongates.

Chronic tears
Chronic tears are indicative of extended use in conjunction with other factors such as poor biomechanics or muscular imbalance.  Ultimately, most are the result of wear that occurs slowly over time as a natural part of aging. They are more common in the dominant arm, but a tear in one shoulder signals an increased risk of a tear in the opposing shoulder.Several factors contribute to degenerative, or chronic, rotator cuff tears of which repetitive stress is the most significant. This stress consists of repeating the same shoulder motions frequently, such as overhead throwing, rowing, and weightlifting.  Many jobs that require frequent shoulder movement such as lifting and overhead movements also contribute. In older populations impairment of blood supply can also be an issue.  With age, circulation to the rotator cuff tendons decreases, impairing natural ability to repair, increasing risk for tear. Another potential contributing cause is impingement syndrome, the most common non-sports related injury and which occurs when the tendons of the rotator cuff muscles become irritated and inflamed while passing through the subacromial space beneath the acromion. This relatively small space becomes even smaller when the arm is raised in a forward or upward position. Repetitive impingement can inflame the tendons and bursa, resulting in the syndrome.

Extrinsic factors
Well-documented anatomic factors include the morphologic characteristics of the acromion, a bony projection from the scapula that curves over the shoulder joint.  Hooked, curved, and laterally sloping acromia are strongly associated with cuff tears and may cause damage through direct traction on the tendon. Conversely, flat acromia may have an insignificant involvement in cuff disease and consequently may be best treated conservatively. The development of these different acromial shapes is likely both genetic and acquired. In the latter case, there can be a progression from flat to curved or hooked with increasing age.  Repetitive mechanical activities such as sports and exercise may contribute to flattening and hooking of the acromion. Cricket bowling, swimming, tennis, baseball, and kayaking are often implicated.  Progression to a hooked acromion could be an adaptation to an already damaged, poorly balanced rotator cuff with resultant stress on the coracoacromial arch. Other anatomical factors include an os acromiale and acromial spurs. Environmental factors include age, shoulder overuse, smoking, and medical conditions that affect circulation or impair the inflammatory and healing response, such as diabetes mellitus.

Intrinsic factors
Intrinsic factors refer to injury mechanisms that occur within the rotator cuff itself. The principal is a degenerative-microtrauma model, which supposes that age-related tendon damage compounded by chronic microtrauma results in partial tendon tears that then develop into full rotator cuff tears. As a result of repetitive microtrauma in the setting of a degenerative rotator cuff tendon, inflammatory mediators alter the local environment, and oxidative stress induces tenocyte apoptosis causing further rotator cuff tendon degeneration. A neural theory also exists that suggests neural overstimulation leads to the recruitment of inflammatory cells and may also contribute to tendon degeneration.

Surgical considerations
Depending upon the diagnosis, several treatment alternatives are available. They include revision repair, non-anatomic repair, tendon transfer and arthroplasty. When possible, surgeons make tension-free repairs in which they use grafted tissues rather than stitching to reconnect tendon segments. This can result in a complete repair. Other options are a partial repair, and reconstruction involving a bridge of biologic or synthetic substances. Partial repairs typically are performed on retracted cuff tears.Tendon transfers are prescribed for young, active cuff-tear individual who experience weakness and decreased range of motion, but little pain. The technique is not considered appropriate for older people, or those with pre-operative stiffness or nerve injuries. People diagnosed with glenohumeral arthritis and rotator cuff anthropathy have the alternative of total shoulder arthroplasty, if the cuff is largely intact or repairable. If the cuff is incompetent then a reverse shoulder arthroplasty is available and, although not as robust a prosthesis, does not require an intact cuff to maintain a stable joint.

Diagnosis
Diagnosis is based upon physical assessment and history, including description of previous activities and acute or chronic symptoms.  A systematic, physical examination of the shoulder comprises inspection, palpation, range of motion,  provocative tests to reproduce the symptoms, neurological examination, and strength testing.  The shoulder should also be examined for tenderness and deformity.  Since pain arising from the neck is frequently referred to the shoulder, the examination should include an assessment of the cervical spine looking for evidence suggestive of a pinched nerve, osteoarthritis, or rheumatoid arthritis.
Neer promoted the concept of three stages of rotator cuff disease. Stage I, according to Neer, occurred in those younger than 25 years and involved edema and hemorrhage of the tendon and bursa. Stage II involved tendinitis and fibrosis of the rotator cuff in 25- to 40-year-olds. Stage III involved tearing of the rotator cuff (partial or full thickness) and occurred in those older than 40 years.  For surgical purposes, tears are also described by location, size or area, and depth. Further subclasses include the acromiohumeral distance, acromial shape, fatty infiltration or degeneration of muscles, muscle atrophy, tendon retraction, vascular proliferation, chondroid metaplasia, and calcification.  Again, in surgical planning, age-related degeneration of thinning and disorientation of the collagen fibers, myxoid degeneration, and hyaline degeneration are considered.Diagnostic modalities, dependent on circumstances, include X-ray, MRI, MR arthrography, double-contrast arthrography, and ultrasound. Although MR arthrography is currently considered the gold standard, ultrasound may be most cost-effective.  Usually, a tear will be undetected by X-ray, although bone spurs, which can impinge upon the rotator cuff tendons, may be visible.  Such spurs suggest chronic severe rotator cuff disease.  Double-contrast arthrography involves injecting contrast dye into the shoulder joint to detect leakage out of the injured rotator cuff  and its value is influenced by the experience of the operator. The most common diagnostic tool is magnetic resonance imaging (MRI), which can sometimes indicate the size of the tear, as well as its location within the tendon.  Furthermore, MRI enables the detection or exclusion of complete rotator cuff tears with reasonable accuracy and is also suitable to diagnose other pathologies of the shoulder joint.The logical use of diagnostic tests is an important component of effective clinical practice.Clinical judgement, rather than over reliance on MRI or any other modality, is strongly advised in determining the cause of shoulder pain, or planning its treatment, since rotator cuff tears are also found in some without pain or symptoms. The role of X-ray, MRI, and ultrasound, is adjunctive to clinical assessment and serves to confirm a diagnosis provisionally made by a thorough history and physical examination. Over-reliance on imaging may lead to overtreatment or distract from the true dysfunction causing symptoms.

Symptoms
Symptoms may occur immediately after trauma (acute) or develop over time (chronic).
Acute injury is less frequent than chronic disease, but may follow bouts of forcefully raising the arm against resistance, as occurs in weightlifting, for example.  In addition, falling forcefully on the shoulder can cause acute symptoms.  These traumatic tears predominantly affect the supraspinatus tendon or the rotator interval and symptoms include severe pain that radiates through the arm, and limited range of motion, specifically during abduction of the shoulder.
Chronic tears occur among individuals who constantly participate in overhead activities, such as pitching or swimming, but can also develop from shoulder tendinitis or rotator cuff disease. Symptoms arising from chronic tears include sporadic worsening of pain, debilitation, and atrophy of the muscles, noticeable pain during rest, crackling sensations (crepitus) when moving the shoulder, and inability to move or lift the arm sufficiently, especially during abduction and flexion motions.Pain in the anterolateral aspect of the shoulder is not specific to the shoulder, and may arise from, and be referred from, the neck, heart or gut.
Symptoms will often include pain or ache over the front and outer aspect of the shoulder, pain aggravated by leaning on the elbow and pushing upwards on the shoulder (such as leaning on the armrest of a reclining chair), intolerance of overhead activity, pain at night when lying directly on the affected shoulder, pain when reaching forward (e.g. unable to lift a gallon of milk from the refrigerator). Weakness may be reported, but is often masked by pain and is usually found only through examination. With longer-standing pain, the shoulder is favored and gradually loss of motion and weakness may develop, which, due to pain and guarding, are often unrecognized and only brought to attention during the physical exam.Primary shoulder problems may cause pain over the deltoid muscle intensified by abduction against resistance – the impingement sign. This signifies pain arising from the rotator cuff, but cannot distinguish between inflammation, strain, or tear. Individuals may report that they are unable to reach upwards to brush their hair or to lift a food can from an overhead shelf.

Signs
No single physical examination test distinguishes reliably between bursitis, partial-thickness, and full-thickness tears. The most useful single test for infraspinatous tendon tears is the drop sign (the examiner lifts the arm straight out from the body with the palm up, the person then needs to hold it there for 10 seconds) and the external rotation lag sign (with the arm by the side and the elbow bent to 90 degrees the person tries to rotate outwards against resistance).A combination of tests seems to provide the most accurate diagnosis. For impingement, these tests include the Hawkins-Kennedy impingement sign in which an examiner medially rotates the injured individuals flexed arm, forcing the supraspinatus tendon against the coracoacromial ligament and so producing pain if the test is positive a positive painful arc sign, and weakness in external rotation with the arm at the side.
For the diagnosis of full-thickness rotator cuff tear, the best combination appears to include once more the painful arc and weakness in external rotation, and in addition, the drop arm sign. This test is also known as Codmans test. The arm is raised to the side to 90° by the examiner.  The injured individual then attempts to look to lower the arm back to neutral, palm down. If the arm drops suddenly or pain is experienced, the test is considered positive.

MRI
Magnetic resonance imaging (MRI) and ultrasound are comparable in efficacy and helpful in diagnosis although both have a false positive rate of 15–20%.  MRI can reliably detect most full-thickness tears although very small pinpoint tears may be missed. In such situations, an MRI combined with an injection of contrast material, an MR-arthrogram, may help to confirm the diagnosis.  It should be realized that a normal MRI cannot fully rule out a small tear (a false negative) while partial-thickness tears are not as reliably detected. While MRI is sensitive in identifying tendon degeneration (tendinopathy), it may not reliably distinguish between a degenerative tendon and a partially torn tendon. Again, magnetic resonance arthrography can improve the differentiation. An overall sensitivity of 91% (9% false negative rate) has been reported indicating that magnetic resonance arthrography is reliable in the detection of partial-thickness rotator cuff tears. However, its routine use is not advised, since it involves entering the joint with a needle with potential risk of infection. Consequently, the test is reserved for cases in which the diagnosis remains unclear.

Ultrasound
Musculoskeletal ultrasound has been advocated by experienced practitioners, avoiding the radiation of X-ray and the expense of MRI while demonstrating comparable accuracy to MRI for identifying and measuring the size of full-thickness and partial-thickness rotator cuff tears. This modality can also reveal the presence of other conditions that may mimic rotator cuff tear at clinical examination, including tendinosis, calcific tendinitis, subacromial subdeltoid bursitis, greater tuberosity fracture, and adhesive capsulitis. However, MRI provides more information about adjacent structures in the shoulder such as the capsule, glenoid labrum muscles and bone and these factors should be considered in each case when selecting the appropriate study.

Xray
X-ray projectional radiography cannot directly reveal tears of the rotator cuff, a soft tissue, and consequently, normal X-rays cannot exclude a damaged cuff. However, indirect evidence of pathology may be seen in instances where one or more of the tendons have undergone degenerative calcification (calcific tendinitis). The humeral head may migrate upwards (high-riding humeral head) secondary to tears of the infraspinatus, or combined tears of the supraspinatus and infraspinatus. The migration can be measured by the distance between:

A line crossing the center of a line between the superior and inferior rims of the glenoid articular surface (blue in image).
The center of a "best-fit" circle positioned over the humeral articular surface (green in image)Normally, the former is positioned inferiorly to the latter, and a reversal is therefore indicating a rotator cuff tear. Prolonged contact between a high-riding humeral head and the acromion above it, may lead to X-rays findings of wear on the humeral head and acromion and secondary degenerative arthritis of the glenohumeral joint (the ball and socket joint of the shoulder), called cuff arthropathy, may follow. Incidental X-ray findings of bone spurs at the adjacent acromioclavicular joint may show a bone spur growing from the outer edge of the clavicle downwards towards the rotator cuff. Spurs may also be seen on the underside of the acromion, once thought to cause direct fraying of the rotator cuff from contact friction, a concept currently regarded as controversial.

In-office testing
As part of clinical decision-making, a simple, minimally invasive, in-office procedure may be performed, the rotator cuff impingement test. A small amount of a local anesthetic and an injectable corticosteroid are injected into the subacromial space to block pain and to provide anti-inflammatory relief. If pain disappears and shoulder function remains good, no further testing is pursued. The test helps to confirm that the pain arises from the shoulder primarily rather than referred from the neck, heart, or gut.
If pain is relieved, the test is considered positive for rotator-cuff impingement, of which tendinitis and bursitis are major causes. However, partial rotator-cuff tears may also demonstrate good pain relief, so a positive response cannot rule out a partial rotator-cuff tear. However, with demonstration of good, pain-free function, treatment will not change, so the test is useful in helping to avoid overtesting or unnecessary surgery.

Classification
Tears of the rotator cuff tendon are described as partial or full thickness, and full thickness with complete detachment of the tendons from bone.

Partial-thickness tears often appear as fraying of an intact tendon.
Full-thickness tears are "through-and-through". These tears can be small pinpoint, larger buttonhole, or involve the majority of the tendon where it still remains substantially attached to the humeral head and thus maintains function.
Full-thickness tears may also involve complete detachment of the tendon(s) from the humeral head and may result in significantly impaired shoulder motion and function.Shoulder pain is variable and may not be proportional to the size of the tear.
Tears are also sometimes classified based on the trauma that caused the injury:

Acute, as a result of a sudden, powerful movement which might include falling onto an outstretched hand at speed, making a sudden thrust with a paddle in kayaking, or following a powerful pitch/throw
Subacute, arising in similar situations but occurring in one of the five layers of the shoulder anatomy
Chronic, developing over time, and usually occurring at or near the tendon (as a result of the tendon rubbing against the overlying bone), and usually associated with an impingement syndrome

Prevention
Long-term overuse/abuse of the shoulder joint is generally thought to limit range of motion and productivity due to daily wear and tear of the muscles, and many public web sites offer preventive advice. (See external links)
The recommendations usually include:

regular shoulder exercises to maintain strength and flexibility
using proper form when lifting or moving heavy weights
resting the shoulder when experiencing pain
application of cold packs and heat pads to a painful, inflamed shoulder
strengthening program to include the back and shoulder girdle muscles as well as the chest, shoulder and upper arm
adequate rest periods in occupations that require repetitive lifting and reaching

Size
According to a study which measured tendon length against the size of the injured rotator cuff, researchers learned that as rotator cuff tendons decrease in length, the average rotator cuff tear severity is proportionally decreased, as well.  This shows that larger individuals are more likely to develop a severe rotator cuff tear if they do not "tighten the shoulder muscles around the joint".

Position
Another study observed 12 different positions of movements and their relative correlation with injuries occurred during those movements.  The evidence shows that putting the arm in a neutral position relieves tension on all ligaments and tendons.

Stretching
One article observed the influence of stretching techniques on preventive methods of shoulder injuries.  Increased velocity of exercise increases injury, but beginning a fast-movement exercise with a slow stretch may cause muscle/tendon attachment to become more resistant to tearing.

Muscle groups
When exercising, exercising the shoulder as a whole and not one or two muscle groups is also found to be imperative.  When the shoulder muscle is exercised in all directions, such as external rotation, flexion, and extension, or vertical abduction, it is less likely to develop a tear of the tendon.

Treatment
A rotator cuff tear can be treated operatively or non-operatively. No benefit is seen from early rather than delayed surgery, and many with partial tears and some with complete tears will respond to nonoperative management. Consequently, an individual may begin with nonsurgical management. However, early surgical treatment may be considered in significant (>1 cm – 1.5 cm) acute tears, or in young individuals with full-thickness tears who have a significant risk for the development of irreparable rotator cuff damage.Rotator-cuff surgery appears to result in similar benefits as nonoperative management. As a conservative approach has less complications and is less expensive it is recommended as initial treatment.

Non-operative treatment
Those with pain but reasonably maintained function are suitable for nonoperative management. This includes medications that provide pain relief such as anti-inflammatory agents, topical pain relievers such as cold packs, and if warranted, subacromial corticosteroid or local anesthetic injection. Topical glyceryl trinitrate appears effective at relieving acute symptoms however, headaches were reported as a side effect. A sling may be offered for short-term comfort, with the understanding that undesirable shoulder stiffness can develop with prolonged immobilization. Early physical therapy may afford pain relief with modalities (e.g. iontophoresis) and help to maintain motion. Ultrasound treatment is not efficacious. As pain decreases, strength deficiencies and biomechanical errors can be corrected.Shock wave therapy has seen widespread use since the 1990s to treat various musculoskeletal disorders including rotator cuff disease, but evidence of its efficacy remains dubious. In a review of 2020, the benefits and harms of shock wave therapy for rotator cuff disease, with or without calcificationcurrently, were investigated. They found low to moderate certainty evidence, that there were very few clinically important benefits of shock wave therapy, and uncertainty regarding its safety.A conservative physical therapy program begins with preliminary rest and restriction from engaging in activities which gave rise to symptoms. Normally, inflammation can usually be controlled within one to two weeks, using a nonsteroidal anti-inflammatory drug and subacromial steroid injections to decrease inflammation, to the point that pain has been significantly decreased to make stretching tolerable. After this short period, rapid stiffening and an increase in pain can result if sufficient stretching has not been implemented.
A gentle, passive range-of-motion program should be started to help prevent stiffness and maintain range of motion during this resting period. Stiffness negatively affects the tendon-bone healing process, a critical part of recovery. Stiffness during rehabilitation is related to worse clinical outcomes, so it is important for the patient to understand the importance of a proactive regimen. Strain induced tendon remodeling, which is part of an accelerated rehabilitation protocol, has been shown to speed up the time to return to daily activities. Exercises, for the anterior, inferior, and posterior shoulder, should be part of this program. Codman exercises (giant, pudding-stirring), to "permit the patient to abduct the arm by gravity, the supraspinatus remains relaxed, and no fulcrum is required" are widely used. The use of NSAIDs, hot and cold packs, and physical therapy modalities, such as ultrasound, phonophoresis, or iontophoresis, can be instituted during this stretching period, if effective.  Corticosteroid injections are recommended two to three months apart with a maximum of three injections. Multiple injections (four or more) have been shown to compromise the results of rotator cuff surgery which result in weakening of the tendon. Kinesio taping was compared to sham taping and other conservative treatment for the approach of the rotator cuff disease and has uncertain effects in terms of self‐reported pain, function, pain on motion and active range of motion.Rockwood coined the term orthotherapy to describe the program which is aimed at creating an exercise regimen that initially gently improves motion, then gradually improves strength in the shoulder girdle. This program involves a home therapy kit which includes elastic bands of six different colors and strengths, a pulley set, and a three-piece, one-meter-long stick. The program is individually customized. Participants are asked to use their exercise program whether at home, work, or traveling.

Surgery
Benefits of surgery are unclear as of 2019. Several instances when surgery may be recommended include:

20 to 30-year-old active person with an acute tear and severe functional deficit from a specific event
30 to 50-year-old person with an acute rotator cuff tear secondary to a specific event
a highly competitive athlete who is primarily involved in overhead or throwing sportsThese individuals more often benefit from operative treatment because they are willing to tolerate the risks of surgery to return to their preoperative level of function, and have higher likelihood of a successful outcome. Those who do not respond to, or are unsatisfied with, conservative treatment can seek a surgical opinion.The three general surgical approaches are arthroscopic, mini open, and open-surgical repair.
In the past, small tears were treated arthroscopically, while larger tears would usually require an open procedure.  Advances in arthroscopy now allow arthroscopic repair of even the largest tears, and arthroscopic techniques are now required to mobilize many retracted tears. The results match open surgical techniques, while permitting a more thorough evaluation of the shoulder at time of surgery, increasing the diagnostic value of the procedure, as other conditions may simultaneously cause shoulder pain. Arthroscopic surgery also allows for shorter recovery time although differences in postoperative pain or pain medication use are not seen between arthroscopic- and open-surgery. A 2019 review found that the evidence does not support decompression surgery in those with more than 3 months of shoulder pain without a history of trauma.Even for full-thickness rotator cuff tears, conservative care (i.e., nonsurgical treatment) outcomes are usually reasonably good.If a significant bone spur is present, any of the approaches may include an acromioplasty, a subacromial decompression, as part of the procedure.  Subacromial decompression, removal of a small portion of the acromion that overlies the rotator cuff, aims to relieve pressure on the rotator cuff in certain conditions and promote healing and recovery.  Although subacromial decompression may be beneficial in the management of partial and full-thickness tear repair, it does not repair the tear itself and arthroscopic decompression has more recently been combined with "mini-open" repair of the rotator cuff, allowing for the repair of the cuff without disruption of the deltoid origin.  The results of decompression alone tend to degrade with time, but the combination of repair and decompression appears to be more enduring. Subacromial decompression may not improve pain, function, or quality of life.Repair of a complete, full-thickness tear involves tissue suture. The method currently in favor is to place an anchor in the bone at the natural attachment site, with resuture of torn tendon to the anchor. If tissue quality is poor, mesh (collagen, Artelon, or other degradable material) may be used to reinforce the repair. Repair can be performed through an open incision, again requiring detachment of a portion of the deltoid, while a mini-open technique approaches the tear through a deltoid-splitting approach. The latter may cause less injury to muscle and produce better results.  Contemporary techniques now use an all arthroscopic approach.
Recovery can take as long as three–six months, with a sling being worn for the first one–six weeks. In the case of partial thickness tears, if surgery is undertaken, tear completion (converting the partial tear to a full tear) and then repair, is associated with better early outcomes than transtendinous repairs (where the intact fibres are preserved) and no difference in failure rates.Biceps tenotomy and tenodesis are often performed concomitantly with rotator cuff repair or as separate procedures, and can also cause shoulder pain. Tenodesis, which may be performed as an arthroscopic or open procedure, generally restores pain free motion it the biceps tendon, or attached portion of the labrum, but can cause pain. Tenotomy is a shorter surgery requiring less rehabilitation, that is more often performed in older patients, though after surgery there can be a cosmetic popeye sign visible in thin arms.In a small minority of cases where extensive arthritis has developed, an option is shoulder joint replacement (arthroplasty). Specifically, this is a reverse shoulder replacement, a more constrained form of shoulder arthroplasty that allows the shoulder to function well even in the presence of large full thickness rotator cuff tears.

Shoulder Replacement
The latest systematic reviews suggests (with low quality evidence) that total shoulder arthroplasty does not provide important benefits over hemiarthroplasty for glenohumeral osteoarthritis and rotator cuff tears. It highlighted the current lack of high-quality evidence and need for randomized controlled trials.

Biologics
The main goal in biological augmentation is to enhance healing. There are a number of potential options. These include injecting an individuals own stem cells, growth factors or platelet rich plasma (PRP) into the repair site, and installing scaffolds as biological or synthetic supports to maintain tissue contour. A 2014 Cochrane review evaluated PRP and found insufficient evidence to make recommendations. Mesenchymal stem cells have no convincing evidence for their use overall, with quality human trials lacking. The greater tuberosity can also be microfractured to create a small blood clot just lateral to the repair site.

Rehabilitation
Rehabilitation after surgery consists of three stages. First, the arm is immobilized so that the muscle can heal. Second, when appropriate, a therapist assists with passive exercises to regain range of motion. Third, the arm is gradually exercised actively, with a goal of regaining and enhancing strength. The empty can and full can exercises are amongst the most effective at isolating and strengthening the supraspinatus.Following arthroscopic rotator-cuff repair surgery, individuals need rehabilitation and physical therapy. Exercise decreases shoulder pain, strengthens the joint, and improves range of motion. Therapists, in conjunction with the surgeon, design exercise regimens specific to the individual and their injury.Traditionally, after injury the shoulder is immobilized for six weeks before rehabilitation. However, the appropriate timing and intensity of therapy are subject to debate. Most surgeons advocate using the sling for at least six weeks, though others advocate early, aggressive rehabilitation. The latter group favors the use of passive motion, which allows an individual to move the shoulder without physical effort. Alternatively, some authorities argue that therapy should be started later and carried out more cautiously. Theoretically, that gives tissues time to heal; though there is conflicting data regarding the benefits of early immobilization. A study of rats suggested that it improved the strength of surgical repairs, while research on rabbits produced contrary evidence. Individuals with a history of rotator cuff injury, particularly those recovering from tears, are prone to reinjury. Rehabbing too soon or too strenuously might increase the risk of retear or failure to heal. However, no research has proven a link between early therapy and the incidence of re-tears.  In some studies, those who received earlier and more aggressive therapy reported reduced shoulder pain, less stiffness and better range of motion. Other research has shown that accelerated rehab results in better shoulder function.
There is consensus amongst orthopaedic surgeons and physical therapists regarding rotator cuff repair rehabilitation protocols. The timing and duration of treatments and exercises are based on biologic and biomedical factors involving the rotator cuff. For approximately two to three weeks following surgery, an individual experiences shoulder pain and swelling; no major therapeutic measures are instituted in this window other than oral pain medicine and ice. Those at risk of failure should usually be more conservative with rehabilitations.That is followed by the "proliferative" and "maturation and remodeling" phases of healing, which ensues for the following six to ten weeks. The effect of active or passive motion during any of the phases is unclear, due to conflicting information and a shortage of clinical evidence.  Gentle physical therapy guided motion is instituted at this phase, only to prevent stiffness of the shoulder; the rotator cuff remains fragile. At three months after surgery, physical therapy intervention changes substantially to focus on scapular mobilization and stretching of the glenohumeral joint.  Once full passive motion is regained (at usually about four to four and a half months after surgery) strengthening exercises are the focus.  The strengthening focuses on the rotator cuff and the upper back/scapular stabilizers.  Typically at about six months after surgery, most have made a majority of their expected gains.The objective in repairing a rotator cuff is to enable an individual to regain full function. Surgeons and therapists analyze outcomes in several ways. Based on examinations, they compile scores on tests; some examples are those created by the University of California at Los Angeles and the American Shoulder and Elbow Surgeons. Other outcome measures include the Constant score; the Simple Shoulder Test; and the Disabilities of the Arm, Shoulder and Hand score. The tests assess range of motion and the degree of shoulder function.Due to the conflicting information about the relative benefits of rehab conducted early or later, an individualized approach is necessary. The timing and nature of therapeutic activities are adjusted according to age and tissue integrity of the repair. Management is more complex in those who have had multiple tears.

Prognosis
While people with rotator cuff tears may not have any noticeable symptoms, studies have shown that, those with age related tears,  over time 40% will have enlargement of the tear over a five-year period. Of those whose tears enlarge, 20% have no symptoms while 80% eventually develop symptoms.Most usually regain function and experience less pain following surgery. For some, however, the joint continues to hurt. Weakness and a limited range of motion also may persist. Those who report such symptoms frequently are diagnosed with failed rotator cuff syndrome. There is no irrefutable evidence that rotator cuff surgery benefits more than non-surgical management and a percentage of individuals never regain full range of motion after surgery.Arthroscopic procedures produce "satisfactory results" more than 90 percent of the time. However, 6-8 percent of patients have "incompetent" rotator cuffs because their repaired tendons either fail to heal or develop additional tears. In some cases, persistent rotator cuff type pain after surgery can be due to disease elsewhere. For example, cervical spine disease and can involve neck pain radiating into the shoulder. Suprascapular neuropathy, shoulder impingement, superior labral anterior-posterior (SLAP) tears and arthritis can all mimic rotator cuff disease and cause persistent pain that does not respond to rotator cuff surgery.

Epidemiology
Rotator cuff tears are among the most common conditions affecting the shoulder.A rotator cuff tear can be caused by the weakening of the rotator cuff tendons. This weakening can be caused by age or how often the rotator cuff is used. Adults over the age of 60 are more susceptible to a rotator cuff tear, with the overall frequency of tears increasing with age. By the age of 50 10% of people with normal shoulders have a rotator cuff tear.In an autopsy study of rotator cuff tears, the incidence of partial tears was 28%, and of complete rupture 30%. Frequently, tears occurred on both sides and occurred more often with females and with increasing age. Other cadaver studies have noted intratendinous tears to be more frequent (7.2%) than bursal-sided (2.4%) or articular-sided tears (3.6%). However, clinically, articular-sided tears are found to be 2 to 3 times more common than bursal-sided tears and among a population of young athletes, articular-sided tears constituted 91% of all partial-thickness tears. Rotator cuff tears may be more common in men between the ages of 50–60, though between 70 and 80 there is minimal difference across genders.In terms of the size of tears, a study compared the ages of patient to the size of tears. It was emphasized the older you are, the more massive of a tear you will have </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Aortic regurgitation and explain in detail? [/INST] Aortic regurgitation (AR), also known as aortic insufficiency (AI), is the leaking of the aortic valve of the heart that causes blood to flow in the reverse direction during ventricular diastole, from the aorta into the left ventricle. As a consequence, the cardiac muscle is forced to work harder than normal.

Signs and symptoms
Symptoms of aortic regurgitation are similar to those of heart failure and include the following:
Dyspnea on exertion
Orthopnea
Paroxysmal nocturnal dyspnea
Palpitations
Angina pectoris
Cyanosis (in acute cases)

Causes
In terms of the cause of aortic regurgitation, is often due to the aortic root dilation (annuloaortic ectasia), which is idiopathic in over 80% of cases, but otherwise may result from aging, syphilitic aortitis, osteogenesis imperfecta, aortic dissection, Behçets disease, reactive arthritis and systemic hypertension. Aortic root dilation is the most common cause of aortic regurgitation in developed countries. Additionally, aortic regurgitation has been linked to the use of some medications, specifically medications containing fenfluramine or dexfenfluramine isomers and dopamine agonists. Other potential causes that affect the valve directly include Marfan syndrome, Ehlers–Danlos syndrome, ankylosing spondylitis, and systemic lupus erythematosus. In acute cases of aortic regurgitation, the main causes are infective endocarditis, aortic dissection or trauma.

Pathophysiology
The mechanism of aortic regurgitation, comprises the pressure in the left ventricle falling below the pressure in the aorta, the aortic valve is not able to completely close. This causes a leaking of blood from the aorta into the left ventricle. This means that some of the blood that was already ejected from the heart is regurgitating back into the heart. The percentage of blood that regurgitates back through the aortic valve due to AR is known as the regurgitant fraction. This regurgitant flow causes a decrease in the diastolic blood pressure in the aorta, and therefore an increase in the pulse pressure. Since some of the blood that is ejected during systole regurgitates back into the left ventricle during diastole, there is decreased effective forward flow in AR.While diastolic blood pressure is diminished and the pulse pressure widens, systolic blood pressure generally remains normal or can even be slightly elevated, this is because sympathetic nervous system and the renin-angiotensin-aldosterone axis of the kidneys compensate for the decreased cardiac output. Catecholamines will increase the heart rate and increase the strength of ventricular contraction, directly increasing cardiac output. Catecholamines will also cause peripheral vasoconstriction, which causes increased systemic vascular resistance and ensures that organs are adequately perfused. Renin, a proteolytic enzyme, cleaves angiotensinogen to angiotensin I, which is converted to angiotensin II. In the case of chronic aortic  with resultant cardiac remodeling, heart failure will develop, and it is possible to see systolic pressures diminish. Aortic regurgitation causes both volume overload (elevated preload) and pressure overload (elevated afterload) of the heart.The volume overload, due to elevated pulse pressure and the systemic effects of neuroendocrine hormones causes left ventricular hypertrophy (LVH).  There is both concentric hypertrophy and eccentric hypertrophy in AI. The concentric hypertrophy is due to the increased left ventricular pressure overload associated with AI, while the eccentric hypertrophy is due to volume overload caused by the regurgitant fraction.Physiologically, in individuals with a normally functioning aortic valve, the valve is only open when the pressure in the left ventricle is higher than the pressure in the aorta. This allows the blood to be ejected from the left ventricle into the aorta during ventricular systole. The amount of blood that is ejected by the heart is known as the stroke volume. Under normal conditions,  >50% of the blood in a filled left ventricle is ejected into the aorta to be used by the body. After ventricular systole, the pressure in the left ventricle decreases as it relaxes and begins to fill up with blood from the left atrium.  This relaxation of the left ventricle (early ventricular diastole) causes a fall in its pressure. When the pressure in the left ventricle falls below the pressure in the aorta, the aortic valve will close, preventing blood in the aorta from going back into the left ventricle.

Diagnosis
In terms of the diagnosis of aortic regurgitation a common test for the evaluation of the severity is transthoracic echocardiography, which can provide two-dimensional views of the regurgitant jet, allow measurement of velocity, and estimate jet volume. The findings in severe aortic regurgitation, based on the 2012 American College of Cardiology/American Heart Association guidelines include:

Chest X-ray can assist in making the diagnosis, showing left ventricular hypertrophy and dilated aorta. ECG typically indicates left ventricular hypertrophy. Cardiac chamber catheterization assists in assessing the severity of regurgitation and any left ventricular dysfunction.

Physical examination
The physical examination of an individual with aortic regurgitation involves auscultation of the heart to listen for the murmur of aortic regurgitation and the S3 heart sound (S3 gallop correlates with development of LV dysfunction). The murmur of chronic aortic regurgitation is typically described as early diastolic and decrescendo, which is best heard in the third left intercostal space and may radiate along the left sternal border.

If there is increased stroke volume of the left ventricle due to volume overload, an ejection systolic flow murmur may also be present when auscultating the same aortic area. Unless there is concomitant aortic valve stenosis, the murmur should not start with an ejection click. There may also be an Austin Flint murmur, a soft mid-diastolic rumble heard at the apical area; it appears when a regurgitant jet of blood from severe aortic regurgitation partially closes the anterior mitral leaflet. Peripheral physical signs of aortic regurgitation are related to the high pulse pressure and the rapid decrease in blood pressure during diastole due to blood returning to the heart from the aorta through the incompetent aortic valve, although the usefulness of some of the eponymous signs has been questioned: Phonocardiograms detect AI by having electric voltage mimic the sounds the heart makes.Characteristics- indicative of aortic regurgitation are as follow:

Classification
The hemodynamic sequelae of AI are dependent on the rate of onset of AI. Therefore, can be acute or chronic as follows:

Acute aortic regurgitation In acute AR, as may be seen with acute perforation of the aortic valve due to endocarditis, there will be a sudden increase in the volume of blood in the left ventricle. The ventricle is unable to deal with the sudden change in volume. The filling pressure of the left ventricle will increase. This causes pressure in the left atrium to rise, and the individual will develop pulmonary edema. Severe acute aortic regurgitation is considered a medical emergency. There is a high mortality rate if the individual does not undergo immediate surgery for aortic valve replacement.Acute AR usually presents as florid congestive heart failure, and will not have any of the signs associated with chronic AR since the left ventricle had not yet developed the eccentric hypertrophy and dilatation that allow an increased stroke volume, which in turn cause bounding peripheral pulses.  On auscultation, there may be a short diastolic murmur and a soft S1.  S1 is soft because the elevated filling pressures close the mitral valve in diastole.Chronic aortic regurgitation If the individual survives the initial hemodynamic derailment that acute AR presents, the left ventricle adapts by its eccentric hypertrophy and dilatation with a subsequent compensated volume overload. The left ventricular filling pressures will revert to normal and the individual will no longer have overt heart failure. In this compensated phase, the individual may be totally asymptomatic and may have normal exercise tolerance. Eventually (typically after a latency period) the left ventricle will become decompensated, and filling pressures will increase. Some individuals enter this decompensated phase asymptomatically, treatment for AR involves aortic valve replacement prior to this decompensation phase.

Treatment
Aortic regurgitation can be treated either medically or surgically, depending on the acuteness of presentation, the symptoms and signs associated with the disease process, and the degree of left ventricular dysfunction. Surgical treatment in asymptomatic patients has been recommended if the ejection fraction falls to 50% or below, in the face of progressive and severe left ventricular dilatation, or with symptoms or abnormal response to exercise testing. For both groups of patients, surgery before the development of worsening ejection fraction/LV dilatation is expected to reduce the risk of sudden death, and is associated with lower peri-operative mortality. Also, surgery is optimally performed immediately in acute cases.

Medical treatment
Medical therapy of chronic aortic regurgitation that is stable and asymptomatic involves the use of vasodilators. Trials have shown a short-term benefit in the use of ACE inhibitors or angiotensin II receptor antagonists, nifedipine, and hydralazine in improving left ventricular wall stress, ejection fraction, and mass. The goal in using these pharmacologic agents is to decrease the afterload so that the left ventricle is somewhat spared. The regurgitant fraction may not change significantly, since the gradient between the aortic and left ventricular pressures is usually fairly low at the initiation of treatment. Other rather conservative medical treatments for stable and asymptomatic cases include low sodium diet, diuretics, digoxin, calcium blockers and avoiding very strenuous activity.As of 2007, the American Heart Association no longer recommends antibiotics for endocarditis prophylaxis before certain procedures in patients with aortic regurgitation. Antibiotic prophylaxis to prevent endocarditis before gastrointestinal or genitourinary procedures is no longer recommended for any patient with valvular disease. Cardiac stress test is useful in identifying individuals that may be best suited for surgical intervention. Radionuclide angiography is recommended and useful when the systolic wall stress is calculated and combined to the results.

Surgery
A surgical treatment for AR is aortic valve replacement;  this is currently an open-heart procedure. In the case of severe acute aortic regurgitation, all individuals should undergo surgery, if there are no absolute contraindications (for surgery).  Individuals with bacteremia with aortic valve endocarditis should not wait for treatment with antibiotics to take effect, given the high mortality associated with the acute AI. Replacement with an aortic valve homograft should be performed if feasible.

Prognosis
The risk of death in individuals with aortic regurgitation, dilated ventricle, normal ejection fraction who are asymptomatic is about 0.2 percent per year.  Risk increases if the ejection fraction decreases or if the individual develops symptoms.Individuals with  chronic (severe) aortic regurgitation follow a course that once symptoms appear, surgical intervention is needed. AI is fatal in 10 to 20% of individuals who do not undergo surgery for this condition. Left ventricle dysfunction determines to an extent the outlook for severity of aortic regurgitation cases.

References
Further reading
Hamirani, Yasmin S.; Dietl, Charles A.; Voyles, Wyatt; Peralta, Mel; Begay, Darlene; Raizada, Veena (2012-08-28). "Acute Aortic Regurgitation". Circulation. 126 (9): 1121–1126 </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Carbon monoxide poisoning and explain in detail? [/INST] Carbon monoxide poisoning typically occurs from breathing in carbon monoxide (CO) at excessive levels. Symptoms are often described as "flu-like" and commonly include headache, dizziness, weakness, vomiting, chest pain, and confusion. Large exposures can result in loss of consciousness, arrhythmias, seizures, or death. The classically described "cherry red skin" rarely occurs. Long-term complications may include chronic fatigue, trouble with memory, and movement problems.CO is a colorless and odorless gas which is initially non-irritating. It is produced during incomplete burning of organic matter. This can occur from motor vehicles, heaters, or cooking equipment that run on carbon-based fuels. Carbon monoxide primarily causes adverse effects by combining with hemoglobin to form carboxyhemoglobin (HbCO) preventing the blood from carrying oxygen and expelling carbon dioxide as carbaminohemoglobin. Additionally, many other hemoproteins such as myoglobin, Cytochrome P450, and mitochondrial cytochrome oxidase are affected, along with other metallic and non-metallic cellular targets.Diagnosis is typically based on a HbCO level of more than 3% among nonsmokers and more than 10% among smokers. The biological threshold for carboxyhemoglobin tolerance is typically accepted to be 15% COHb, meaning toxicity is consistently observed at levels in excess of this concentration. The FDA has previously set a threshold of 14% COHb in certain clinical trials evaluating the therapeutic potential of carbon monoxide. In general, 30% COHb is considered severe carbon monoxide poisoning. The highest reported non-fatal carboxyhemoglobin level was 73% COHb.Efforts to prevent poisoning include carbon monoxide detectors, proper venting of gas appliances, keeping chimneys clean, and keeping exhaust systems of vehicles in good repair. Treatment of poisoning generally consists of giving 100% oxygen along with supportive care. This should generally be carried out until symptoms are no longer present and the HbCO level is less than 3%/10%.Carbon monoxide poisoning is relatively common, resulting in more than 20,000 emergency room visits a year in the United States. It is the most common type of fatal poisoning in many countries. In the United States, non-fire related cases result in more than 400 deaths a year. Poisonings occur more often in the winter, particularly from the use of portable generators during power outages. The toxic effects of CO have been known since ancient history. The discovery that hemoglobin is affected by CO emerged with an investigation by James Watt and Thomas Beddoes into the therapeutic potential of hydrocarbonate in 1793, and later confirmed by Claude Bernard between 1846 and 1857.

Background
Carbon monoxide is not toxic to all forms of life, and the toxicity is a classical dose-dependent example of hormesis. Small amounts of carbon monoxide are naturally produced through many enzymatic and non-enzymatic reactions across phylogenetic kingdoms where it can serve as an important neurotransmitter (subcategorized as a gasotransmitter) and a potential therapeutic agent. In the case of prokaryotes, some bacteria produce, consume and respond to carbon monoxide whereas certain other microbes are susceptible to its toxicity. Currently, there are no known adverse effects on photosynthesizing plants.The harmful effects of carbon monoxide are generally considered to be due to tightly binding with the prosthetic heme moiety of hemoproteins that results in interference with cellular operations, for example: carbon monoxide binds with hemoglobin to form carboxyhemoglobin which affects gas exchange and cellular respiration. Inhaling excessive concentrations of the gas can lead to hypoxic injury, nervous system damage, and even death.
As pioneered by Esther Killick, different species and different people across diverse demographics may have different carbon monoxide tolerance levels. The carbon monoxide tolerance level for any person is altered by several factors, including genetics (hemoglobin mutations), behavior such as activity level, rate of ventilation, a pre-existing cerebral or cardiovascular disease, cardiac output, anemia, sickle cell disease and other hematological disorders, geography and barometric pressure, and metabolic rate.

History
Humans have maintained a complex relationship with carbon monoxide since first learning to control fire circa 800,000 BC. Primitive caveman probably discovered the toxicity of carbon monoxide upon introducing fire into their dwellings. The early development of metallurgy and smelting technologies emerging circa 6,000 BC through the Bronze Age likewise plagued humankind with carbon monoxide exposure. Apart from the toxicity of carbon monoxide, indigenous Native Americans may have experienced the neuroactive properties of carbon monoxide through shamanistic fireside rituals.Early civilizations developed mythological tales to explain the origin of fire, such as Vulcan, Pkharmat, and Prometheus from Greek mythology who shared fire with humans. Aristotle (384–322 BC) first recorded that burning coals produced toxic fumes. Greek physician Galen (129–199 AD) speculated that there was a change in the composition of the air that caused harm when inhaled, and symptoms of CO poisoning appeared in Cassius Iatrosophistas Quaestiones Medicae et Problemata Naturalia circa 130 AD. Julian the Apostate, Caelius Aurelianus, and several others similarly documented early knowledge of the toxicity symptoms of carbon monoxide poisoning as caused by coal fumes in the ancient era.Documented cases by Livy and Cicero allude to carbon monoxide being used as a method of suicide in ancient Rome. Emperor Lucius Verus used smoke to execute prisoners. Many deaths have been linked to carbon monoxide poisoning including Emperor Jovian, Empress Fausta, and Seneca. The most high-profile death by carbon monoxide poisoning may possibly have been Cleopatra or Edgar Allan Poe.In the fifteenth century, coal miners believed sudden death was caused by evil spirits; carbon monoxide poisoning has been linked to supernatural and paranormal experiences, witchcraft, etc. throughout the following centuries including in the modern present day exemplified by Carrie Poppys investigations.Georg Ernst Stahl mentioned carbonarii halitus in 1697 in reference to toxic vapors thought to be carbon monoxide. Friedrich Hoffmann conducted the first modern scientific investigation into carbon monoxide poisoning from coal in 1716, notably rejecting villagers attributing death to demonic superstition. Herman Boerhaave conducted the first scientific experiments on the effect of carbon monoxide (coal fumes) on animals in the 1730s. Joseph Priestley is credited with first synthesizing carbon monoxide in 1772 which he had called heavy inflammable air, and Carl Wilhelm Scheele isolated carbon monoxide from coal in 1773 suggesting it to be the toxic entity.The dose-dependent risk of carbon monoxide poisoning as hydrocarbonate was investigated in the late 1790s by Thomas Beddoes, James Watt, Tiberius Cavallo, James Lind, Humphry Davy, and many others in the context of inhalation of factitious airs, much of which occurred at the Pneumatic Institution.William Cruickshank discovered carbon monoxide as a molecule containing one carbon and one oxygen atom in 1800, thereby initiating the modern era of research exclusively focused on carbon monoxide. The mechanism for toxicity was first suggested by James Watt in 1793, followed by Adrien Chenot in 1854 and finally demonstrated by Claude Bernard after 1846 as published in 1857 and also independently published by Felix Hoppe-Seyler in the same year.The first controlled clinical trial studying the toxicity of carbon monoxide occurred in 1973.

Historical detection
Carbon monoxide poisoning has plagued coal miners for many centuries. In the context of mining, carbon monoxide is widely known as whitedamp. John Scott Haldane identified carbon monoxide as the lethal constituent of afterdamp, the gas created by combustion, after examining many bodies of miners killed in pit explosions. By 1911, Haldane introduced the use of small animals for miners to detect dangerous levels of carbon monoxide underground, either white mice or canaries which have little tolerance for carbon monoxide thereby offering an early warning, i.e. Canary in a coal mine. The canary in British pits was replaced in 1986 by the electronic gas detector.
The first qualitative analytical method to detect carboxyhemoglobin emerged in 1858 with a colorimetric method developed by Felix Hoppe-Seyler, and the first quantitative analysis method emerged in 1880 with Josef von Fodor.

Historical treatment
The use of oxygen emerged with anecdotal reports such as Humphry Davy having been treated with oxygen in 1799 upon inhaling three quarts of hydrocarbonate (water gas). Samuel Witter developed an oxygen inhalation protocol in response to carbon monoxide poisoning in 1814. Similarly, an oxygen inhalation protocol was recommend for malaria (literally translated to "bad air") in 1830 based on malaria symptoms aligning with carbon monoxide poisoning. Other oxygen protocols emerged in the late 1800s. The use of hyperbaric oxygen in rats following poisoning was studied by Haldane in 1895 while its use in humans began in the 1960s.

Incidents
The worst accidental mass poisoning from carbon monoxide was the Balvano train disaster which occurred on 3 March 1944 in Italy, when a freight train with many illegal passengers stalled in a tunnel, leading to the death of over 500 people.Over 50 people are suspected to have died from smoke inhalation as a result of the Branch Davidian Massacre during the Siege of Waco in 1993.

Weaponization
In ancient history, Hannibal executed Roman prisoners with coal fumes during the Second Punic War.The extermination of stray dogs by a carbon monoxide gas chamber was described in 1874. In 1884, an article appeared in Scientific American describing the use of a carbon monoxide gas chamber for slaughterhouse operations as well as euthanizing a variety of animals.As part of the Holocaust during World War II, the Nazis used gas vans at Chelmno extermination camp and elsewhere to murder an estimated over 700,000 people by carbon monoxide poisoning. This method was also used in the gas chambers of several death camps such as Treblinka, Sobibor, and Belzec. Gassing with carbon monoxide started in Action T4. The gas was supplied by IG Farben in pressurized cylinders and fed by tubes into the gas chambers built at various mental hospitals, such as Hartheim Euthanasia Centre. Exhaust fumes from tank engines, for example, were used to supply the gas to the chambers.Recently, carbon monoxide gas chambers have been used to facilitate capital punishment exemplified by execution practices at the San Quentin State Prison.

Physiology
Carbon monoxide is produced naturally by many physiologically relevant enzymatic and non-enzymatic reactions best exemplified by heme oxygenase catalyzing the biotransformation of heme (an iron protoporphyrin) into biliverdin and eventually bilirubin. Aside from physiological signaling, most carbon monoxide is stored as carboxyhemoglobin at non-toxic levels below 3% HbCO.

Therapeutics
Small amounts of CO are beneficial and enzymes exist that produce it at times of oxidative stress. A variety of drugs are being developed to introduce small amounts of CO, these drugs are commonly called carbon monoxide-releasing molecules. Historically, the therapeutic potential of factitious airs, notably carbon monoxide as hydrocarbonate, was investigated by Thomas Beddoes, James Watt, Tiberius Cavallo, James Lind, Humphry Davy, and others in many labs such as the Pneumatic Institution.

Signs and symptoms
On average, exposures at 100 ppm or greater is dangerous to human health. In the United States, the OSHA limits long-term workplace exposure levels to less than 50 ppm averaged over an 8-hour period; in addition, employees are to be removed from any confined space if an upper limit ("ceiling") of 100 ppm is reached.

Acute poisoning
The main manifestations of carbon monoxide poisoning develop in the organ systems most dependent on oxygen use, the central nervous system and the heart. The initial symptoms of acute carbon monoxide poisoning include headache, nausea, malaise, and fatigue. These symptoms are often mistaken for a virus such as influenza or other illnesses such as food poisoning or gastroenteritis. Headache is the most common symptom of acute carbon monoxide poisoning; it is often described as dull, frontal, and continuous. Increasing exposure produces cardiac abnormalities including fast heart rate, low blood pressure, and cardiac arrhythmia; central nervous system symptoms include delirium, hallucinations, dizziness, unsteady gait, confusion, seizures, central nervous system depression, unconsciousness, respiratory arrest, and death. Less common symptoms of acute carbon monoxide poisoning include myocardial ischemia, atrial fibrillation, pneumonia, pulmonary edema, high blood sugar, lactic acidosis, muscle necrosis, acute kidney failure, skin lesions, and visual and auditory problems. Carbon monoxide exposure may lead to a significantly shorter life span due to heart damage.One of the major concerns following acute carbon monoxide poisoning is the severe delayed neurological manifestations that may occur. Problems may include difficulty with higher intellectual functions, short-term memory loss, dementia, amnesia, psychosis, irritability, a strange gait, speech disturbances, Parkinsons disease-like syndromes, cortical blindness, and a depressed mood. Depression may occur in those who did not have pre-existing depression. These delayed neurological sequelae may occur in up to 50% of poisoned people after 2 to 40 days. It is difficult to predict who will develop delayed sequelae; however, advanced age, loss of consciousness while poisoned, and initial neurological abnormalities may increase the chance of developing delayed symptoms.

Chronic poisoning
Chronic exposure to relatively low levels of carbon monoxide may cause persistent headaches, lightheadedness, depression, confusion, memory loss, nausea, hearing disorders and vomiting. It is unknown whether low-level chronic exposure may cause permanent neurological damage. Typically, upon removal from exposure to carbon monoxide, symptoms usually resolve themselves, unless there has been an episode of severe acute poisoning. However, one case noted permanent memory loss and learning problems after a three-year exposure to relatively low levels of carbon monoxide from a faulty furnace.Chronic exposure may worsen cardiovascular symptoms in some people. Chronic carbon monoxide exposure might increase the risk of developing atherosclerosis. Long-term exposures to carbon monoxide present the greatest risk to persons with coronary heart disease and in females who are pregnant.In experimental animals, carbon monoxide appears to worsen noise-induced hearing loss at noise exposure conditions that would have limited effects on hearing otherwise. In humans, hearing loss has been reported following carbon monoxide poisoning. Unlike the findings in animal studies, noise exposure was not a necessary factor for the auditory problems to occur.

Fatal poisoning
One classic sign of carbon monoxide poisoning is more often seen in the dead rather than the living – people have been described as looking red-cheeked and healthy (see below). However, since this "cherry-red" appearance is more common in the dead, it is not considered a useful diagnostic sign in clinical medicine. In autopsy examinations, the appearance of carbon monoxide poisoning is notable because unembalmed dead persons are normally bluish and pale, whereas dead carbon-monoxide poisoned people may appear unusually lifelike in coloration. The colorant effect of carbon monoxide in such postmortem circumstances is thus analogous to its use as a red colorant in the commercial meat-packing industry.

Epidemiology
The true number of cases of carbon monoxide poisoning is unknown, since many non-lethal exposures go undetected. From the available data, carbon monoxide poisoning is the most common cause of injury and death due to poisoning worldwide. Poisoning is typically more common during the winter months. This is due to increased domestic use of gas furnaces, gas or kerosene space heaters, and kitchen stoves during the winter months, which if faulty and/or used without adequate ventilation, may produce excessive carbon monoxide. Carbon monoxide detection and poisoning also increases during power outages, when electric heating and cooking appliances become inoperative and residents may temporarily resort to fuel-burning space heaters, stoves, and grills (some of which are safe only for outdoor use but nonetheless are errantly burned indoors).It has been estimated that more than 40,000 people per year seek medical attention for carbon monoxide poisoning in the United States. 95% of carbon monoxide poisoning deaths in the United States are due to gas space heaters. In many industrialized countries, carbon monoxide is the cause of more than 50% of fatal poisonings. In the United States, approximately 200 people die each year from carbon monoxide poisoning associated with home fuel-burning heating equipment. Carbon monoxide poisoning contributes to the approximately 5613 smoke inhalation deaths each year in the United States. The CDC reports, "Each year, more than 500 Americans die from unintentional carbon monoxide poisoning, and more than 2,000 commit suicide by intentionally poisoning themselves." For the 10-year period from 1979 to 1988, 56,133 deaths from carbon monoxide poisoning occurred in the United States, with 25,889 of those being suicides, leaving 30,244 unintentional deaths. A report from New Zealand showed that 206 people died from carbon monoxide poisoning in the years of 2001 and 2002. In total carbon monoxide poisoning was responsible for 43.9% of deaths by poisoning in that country. In South Korea, 1,950 people had been poisoned by carbon monoxide with 254 deaths from 2001 through 2003. A report from Jerusalem showed 3.53 per 100,000 people were poisoned annually from 2001 through 2006. In Hubei, China, 218 deaths from poisoning were reported over a 10-year period with 16.5% being from carbon monoxide exposure.

Causes
Carbon monoxide is a product of combustion of organic matter under conditions of restricted oxygen supply, which prevents complete oxidation to carbon dioxide (CO2). Sources of carbon monoxide include cigarette smoke, house fires, faulty furnaces, heaters, wood-burning stoves, internal combustion vehicle exhaust, electrical generators, propane-fueled equipment such as portable stoves, and gasoline-powered tools such as leaf blowers, lawn mowers, high-pressure washers, concrete cutting saws, power trowels, and welders. Exposure typically occurs when equipment is used in buildings or semi-enclosed spaces.Riding in the back of pickup trucks has led to poisoning in children. Idling automobiles with the exhaust pipe blocked by snow has led to the poisoning of car occupants. Any perforation between the exhaust manifold and shroud can result in exhaust gases reaching the cabin. Generators and propulsion engines on boats, especially houseboats, has resulted in fatal carbon monoxide exposures.Poisoning may also occur following the use of a self-contained underwater breathing apparatus (SCUBA) due to faulty diving air compressors.In caves carbon monoxide can build up in enclosed chambers due to the presence of decomposing organic matter. In coal mines incomplete combustion may occur during explosions resulting in the production of afterdamp. The gas is up to 3% CO and may be fatal after just a single breath. Following an explosion in a colliery, adjacent interconnected mines may become dangerous due to the afterdamp leaking from mine to mine. Such an incident followed the Trimdon Grange explosion which killed men in the Kelloe mine.Another source of poisoning is exposure to the organic solvent dichloromethane, also known as methylene chloride, found in some paint strippers, as the metabolism of dichloromethane produces carbon monoxide. In November 2019, an EPA ban on dichloromethane in paint strippers for consumer use took effect in the United States.

Prevention
Detectors
Prevention remains a vital public health issue, requiring public education on the safe operation of appliances, heaters, fireplaces, and internal-combustion engines, as well as increased emphasis on the installation of carbon monoxide detectors. Carbon monoxide is tasteless, odourless, and colourless, and therefore can not be detected by visual cues or smell.The United States Consumer Product Safety Commission has stated, "carbon monoxide detectors are as important to home safety as smoke detectors are," and recommends each home have at least one carbon monoxide detector, and preferably one on each level of the building. These devices, which are relatively inexpensive and widely available, are either battery- or AC-powered, with or without battery backup. In buildings, carbon monoxide detectors are usually installed around heaters and other equipment. If a relatively high level of carbon monoxide is detected, the device sounds an alarm, giving people the chance to evacuate and ventilate the building. Unlike smoke detectors, carbon monoxide detectors do not need to be placed near ceiling level.
The use of carbon monoxide detectors has been standardized in many areas. In the US, NFPA 720–2009, the carbon monoxide detector guidelines published by the National Fire Protection Association, mandates the placement of carbon monoxide detectors/alarms on every level of the residence, including the basement, in addition to outside sleeping areas. In new homes, AC-powered detectors must have battery backup and be interconnected to ensure early warning of occupants at all levels. NFPA 720-2009 is the first national carbon monoxide standard to address devices in non-residential buildings. These guidelines, which now pertain to schools, healthcare centers, nursing homes, and other non-residential buildings, include three main points:
1. A secondary power supply (battery backup) must operate all carbon monoxide notification appliances for at least 12 hours,
2. Detectors must be on the ceiling in the same room as permanently installed fuel-burning appliances, and
3. Detectors must be located on every habitable level and in every HVAC zone of the building.Gas organizations will often recommend getting gas appliances serviced at least once a year.

Legal requirements
The NFPA standard is not necessarily enforced by law. As of April 2006, the US state of Massachusetts requires detectors to be present in all residences with potential CO sources, regardless of building age and whether they are owner-occupied or rented. This is enforced by municipal inspectors and was inspired by the death of 7-year-old Nicole Garofalo in 2005 due to snow blocking a home heating vent. Other jurisdictions may have no requirement or only mandate detectors for new construction or at time of sale.
Despite similar deaths in vehicles with clogged exhaust pipes (for example in the Northeastern United States blizzard of 1978 and February 2013 noreaster) and the commercial availability of the equipment, there is no legal requirement for automotive CO detectors.

World Health Organization recommendations
The following guideline values (ppm values rounded) and periods of time-weighted average exposures have been determined in such a way that the carboxyhaemoglobin (COHb) level of 2.5% is not exceeded, even when a normal subject engages in light or moderate exercise:

100 mg/m3 (87 ppm) for 15 min
60 mg/m3 (52 ppm) for 30 min
30 mg/m3 (26 ppm) for 1 h
10 mg/m3 (9 ppm) for 8 h
7 mg/m3 (6 ppm) for 24 h (for indoor air quality, so as not to exceed 2% COHb for chronic exposure)

Diagnosis
As many symptoms of carbon monoxide poisoning also occur with many other types of poisonings and infections (such as the flu), the diagnosis is often difficult. A history of potential carbon monoxide exposure, such as being exposed to a residential fire, may suggest poisoning, but the diagnosis is confirmed by measuring the levels of carbon monoxide in the blood. This can be determined by measuring the amount of carboxyhemoglobin compared to the amount of hemoglobin in the blood.The ratio of carboxyhemoglobin to hemoglobin molecules in an average person may be up to 5%, although cigarette smokers who smoke two packs per day may have levels up to 9%. In symptomatic poisoned people they are often in the 10–30% range, while persons who die may have postmortem blood levels of 30–90%.As people may continue to experience significant symptoms of CO poisoning long after their blood carboxyhemoglobin concentration has returned to normal, presenting to examination with a normal carboxyhemoglobin level (which may happen in late states of poisoning) does not rule out poisoning.

Measuring
Carbon monoxide may be quantitated in blood using spectrophotometric methods or chromatographic techniques in order to confirm a diagnosis of poisoning in a person or to assist in the forensic investigation of a case of fatal exposure.
A CO-oximeter can be used to determine carboxyhemoglobin levels. Pulse CO-oximeters estimate carboxyhemoglobin with a non-invasive finger clip similar to a pulse oximeter. These devices function by passing various wavelengths of light through the fingertip and measuring the light absorption of the different types of hemoglobin in the capillaries. The use of a regular pulse oximeter is not effective in the diagnosis of carbon monoxide poisoning as these devices may be unable to distinguish carboxyhemoglobin from oxyhemoglobin.Breath CO monitoring offers an alternative to pulse CO-oximetry. Carboxyhemoglobin levels have been shown to have a strong correlation with breath CO concentration. However, many of these devices require the user to inhale deeply and hold their breath to allow the CO in the blood to escape into the lung before the measurement can be made. As this is not possible in people who are unresponsive, these devices may not appropriate for use in on-scene emergency care detection of CO poisoning.

Differential diagnosis
There are many conditions to be considered in the differential diagnosis of carbon monoxide poisoning. The earliest symptoms, especially from low level exposures, are often non-specific and readily confused with other illnesses, typically flu-like viral syndromes, depression, chronic fatigue syndrome, chest pain, and migraine or other headaches. Carbon monoxide has been called a "great mimicker" due to the presentation of poisoning being diverse and nonspecific. Other conditions included in the differential diagnosis include acute respiratory distress syndrome, altitude sickness, lactic acidosis, diabetic ketoacidosis, meningitis, methemoglobinemia, or opioid or toxic alcohol poisoning.

Treatment
Initial treatment for carbon monoxide poisoning is to immediately remove the person from the exposure without endangering further people. Those who are unconscious may require CPR on site. Administering oxygen via non-rebreather mask shortens the half-life of carbon monoxide from 320 minutes, when breathing normal air, to only 80 minutes. Oxygen hastens the dissociation of carbon monoxide from carboxyhemoglobin, thus turning it back into hemoglobin. Due to the possible severe effects in the baby, pregnant women are treated with oxygen for longer periods of time than non-pregnant people.

Hyperbaric oxygen
Hyperbaric oxygen is also used in the treatment of carbon monoxide poisoning, as it may hasten dissociation of CO from carboxyhemoglobin and cytochrome oxidase to a greater extent than normal oxygen. Hyperbaric oxygen at three times atmospheric pressure reduces the half life of carbon monoxide to 23 (~80/3 minutes) minutes, compared to 80 minutes for oxygen at regular atmospheric pressure. It may also enhance oxygen transport to the tissues by plasma, partially bypassing the normal transfer through hemoglobin. However, it is controversial whether hyperbaric oxygen actually offers any extra benefits over normal high flow oxygen, in terms of increased survival or improved long-term outcomes. There have been randomized controlled trials in which the two treatment options have been compared; of the six performed, four found hyperbaric oxygen improved outcome and two found no benefit for hyperbaric oxygen. Some of these trials have been criticized for apparent flaws in their implementation. A review of all the literature concluded that the role of hyperbaric oxygen is unclear and the available evidence neither confirms nor denies a medically meaningful benefit. The authors suggested a large, well designed, externally audited, multicentre trial to compare normal oxygen with hyperbaric oxygen. While hyperbaric oxygen therapy is used for severe poisonings, the benefit over standard oxygen delivery is unclear.

Other
Further treatment for other complications such as seizure, hypotension, cardiac abnormalities, pulmonary edema, and acidosis may be required. Increased muscle activity and seizures should be treated with dantrolene or diazepam; diazepam should only be given with appropriate respiratory support. Hypotension requires treatment with intravenous fluids; vasopressors may be required to treat myocardial depression. Cardiac dysrhythmias are treated with standard advanced cardiac life support protocols. If severe, metabolic acidosis is treated with sodium bicarbonate. Treatment with sodium bicarbonate is controversial as acidosis may increase tissue oxygen availability. Treatment of acidosis may only need to consist of oxygen therapy. The delayed development of neuropsychiatric impairment is one of the most serious complications of carbon monoxide poisoning. Brain damage is confirmed following MRI or CAT scans. Extensive follow up and supportive treatment is often required for delayed neurological damage. Outcomes are often difficult to predict following poisoning, especially people who have symptoms of cardiac arrest, coma, metabolic acidosis, or have high carboxyhemoglobin levels. One study reported that approximately 30% of people with severe carbon monoxide poisoning will have a fatal outcome. It has been reported that electroconvulsive therapy (ECT) may increase the likelihood of delayed neuropsychiatric sequelae (DNS) after carbon monoxide (CO) poisoning. A device that also provides some carbon dioxide to stimulate faster breathing (sold under the brand name ClearMate) may also be used.

Pathophysiology
The precise mechanisms by which the effects of carbon monoxide are induced upon bodily systems are complex and not yet fully understood. Known mechanisms include carbon monoxide binding to hemoglobin, myoglobin and mitochondrial cytochrome c oxidase and restricting oxygen supply, and carbon monoxide causing brain lipid peroxidation.

Hemoglobin
Carbon monoxide has a higher diffusion coefficient compared to oxygen, and the main enzyme in the human body that produces carbon monoxide is heme oxygenase, which is located in nearly all cells and platelets. Most endogenously produced CO is stored bound to hemoglobin as carboxyhemoglobin. The simplistic understanding for the mechanism of carbon monoxide toxicity is based on excess carboxyhemoglobin decreasing the oxygen-delivery capacity of the blood to tissues throughout the body. In humans, the affinity between hemoglobin and carbon monoxide is approximately 240 times stronger than the affinity between hemoglobin and oxygen. However, certain mutations such as the Hb-Kirklareli mutation has a relative 80,000 times greater affinity for carbon monoxide than oxygen resulting in systemic carboxyhemoglobin reaching a sustained level of 16% COHb.Hemoglobin is a tetramer with four prosthetic heme groups to serve as oxygen binding sites. The average red blood cell contains 250 million hemoglobin molecules, therefore 1 billion heme sites capable of binding gas. The binding of carbon monoxide at any one of these sites increases the oxygen affinity of the remaining three sites, which causes the hemoglobin molecule to retain oxygen that would otherwise be delivered to the tissue; therefore carbon monoxide binding at any site may be as dangerous as carbon monoxide binding to all sites. Delivery of oxygen is largely driven by the Bohr effect and Haldane effect. To provide a simplified synopsis of the molecular mechanism of systemic gas exchange in laymans terms, upon inhalation of air it was widely thought oxygen binding to any of the heme sites triggers a conformational change in the globin/protein unit of hemoglobin which then enables the binding of additional oxygen to each of the other vacant heme sites. Upon arrival to the cell/tissues, oxygen release into the tissue is driven by "acidification" of the local pH (meaning a relatively higher concentration of acidic protons/hydrogen ions) caused by an increase in the biotransformation of carbon dioxide waste into carbonic acid via carbonic anhydrase. In other words, oxygenated arterial blood arrives at cells in the "hemoglobin R-state" which has deprotonated/unionized amino acid residues (regarding nitrogen/amines) due to the less-acidic arterial pH environment (arterial blood averages pH 7.407 whereas venous blood is slightly more acidic at pH 7.371). The "T-state" of hemoglobin is deoxygenated in venous blood partially due to protonation/ionization caused by the acidic environment hence causing a conformation unsuited for oxygen-binding (in other words, oxygen is ejected upon arrival to the cell because acid "attacks" the amines of hemoglobin causing ionization/protonation of the amine residues resulting in a conformation change unsuited for retaining oxygen). Furthermore, the mechanism for formation of carbaminohemoglobin generates additional acidic hydrogen ions that may further stabilize the protonated/ionized deoxygenated hemoglobin. Upon return of venous blood into the lung and subsequent exhalation of carbon dioxide, the blood is "de-acidified" (see also: hyperventilation) allowing for the deprotonation/unionization of hemoglobin to then re-enable oxygen-binding as part of the transition to arterial blood (note this process is complex due to involvement of chemoreceptors and other physiological functionalities). Carbon monoxide is not ejected due to acid, therefore carbon monoxide poisoning disturbs this physiological process hence the venous blood of poisoning patients is bright red akin to arterial blood since the carbonyl/carbon monoxide is retained. Hemoglobin is dark in deoxygenated venous blood, but it has a bright red color when carrying blood in oxygenated arterial blood and when converted into carboxyhemoglobin in both arterial and venous blood, so poisoned cadavers and even commercial meats treated with carbon monoxide acquire an unnatural lively reddish hue.At toxic concentrations, carbon monoxide as carboxyhemoglobin significantly interferes with respiration and gas exchange by simultaneously inhibiting acquisition and delivery of oxygen to cells and preventing formation of carbaminohemoglobin which accounts for approximately 30% of carbon dioxide exportation. Therefore, a patient with carbon monoxide poisoning may experience severe hypoxia and acidosis (potentially both respiratory acidosis and metabolic acidosis) in addition to the toxicities of excess carbon monoxide inhibiting numerous hemoproteins, metallic and non-metallic targets which affect cellular machinery.

Myoglobin
Carbon monoxide also binds to the hemeprotein myoglobin. It has a high affinity for myoglobin, about 60 times greater than that of oxygen. Carbon monoxide bound to myoglobin may impair its ability to utilize oxygen. This causes reduced cardiac output and hypotension, which may result in brain ischemia. A delayed return of symptoms have been reported. This results following a recurrence of increased carboxyhemoglobin levels; this effect may be due to a late release of carbon monoxide from myoglobin, which subsequently binds to hemoglobin.

Cytochrome oxidase
Another mechanism involves effects on the mitochondrial respiratory enzyme chain that is responsible for effective tissue utilization of oxygen. Carbon monoxide binds to cytochrome oxidase with less affinity than oxygen, so it is possible that it requires significant intracellular hypoxia before binding. This binding interferes with aerobic metabolism and efficient adenosine triphosphate synthesis. Cells respond by switching to anaerobic metabolism, causing anoxia, lactic acidosis, and eventual cell death. The rate of dissociation between carbon monoxide and cytochrome oxidase is slow, causing a relatively prolonged impairment of oxidative metabolism.

Central nervous system effects
The mechanism that is thought to have a significant influence on delayed effects involves formed blood cells and chemical mediators, which cause brain lipid peroxidation (degradation of unsaturated fatty acids). Carbon monoxide causes endothelial cell and platelet release of nitric oxide, and the formation of oxygen free radicals including peroxynitrite. In the brain this causes further mitochondrial dysfunction, capillary leakage, leukocyte sequestration, and apoptosis. The result of these effects is lipid peroxidation, which causes delayed reversible demyelination of white matter in the central nervous system known as Grinker myelinopathy, which can lead to edema and necrosis within the brain </s>