Oxygen & Wound Healing: Going Beyond Hyperbaric Therapy

Wounded skin and body tissue are dependent on the supply of oxygen delivered by blood hemoglobin and the pulmonary gas exchange. For chronic wound patients who are living with comorbid chronic obstructive pulmonary disease (COPD) and/or sleep apnea, a restricted flow of oxygen can substantially impact healing, especially among patients who are also compromised by a diabetes diagnosis. Interventions such as hyperbaric oxygen therapy (HBOT) can be beneficial for wounded tissue (and other health conditions) to improve oxygenation levels, but its use is limited by insurance restrictions and clinical protocol. This can place a significant burden on the outpatient clinician to heal wounds. This article will focus on how providers can identify conditions that can affect blood oxygenation levels, how to assess patients for symptoms, and appropriate treatment measures.

OXYGEN OVERVIEW
Oxygen is an abundant element that makes up 65% of our body mass.¹ Normal blood oxygen level is categorized in the 94-98% range, while levels below 90% are considered dangerous and require intervention. Hypoxia, defined as the presence of lower than normal oxygen content in the cells, can be caused by hypoxemia (low blood oxygen content and pressure), impaired oxygen delivery, and impaired cellular oxygen uptake/utilization.¹ Symptoms of low oxygen levels that may be present at the time of assessment include confusion; sense of euphoria; restlessness; headache; shortness of breath; rapid breathing; dizziness, lightheadedness, and/or fainting spells; lack of coordination; rapid heart rate; elevated blood pressure; visual disturbances; and bluish tint to the lips, earlobes, and/or nail beds (cyanosis). Elevated red blood cell count or polycythemia (if a long-term problem) may also be a factor.² The brain requires oxygen to process information, the body uses oxygen to energize its cells, oxygen helps repair injured tissue, and our immune system fights bacteria with the help of oxygen. When hypoxia is experienced in medical conditions such as stroke, carbon monoxide (CO) poisoning, and heart irregularities, cells begin to die — and this can occur in mild or severe forms, resulting in cognitive and behavioral changes, fainting, and, eventually, death.³ In a hypoxic state, the heart will increase its rate in an attempt to deliver more oxygen to the needed cells, tissues, and organs. If this deficit or demand is too much, it may cause myocardial infarction. Cardiac output, perfusion rate, the number of capillaries around a chronic wound, and the consumption rate of cells help to determine oxygen levels.⁴ Patients who develop hypoxia due to low oxygenation levels see an increase in cardiac output as the body attempts to maintain oxygen delivery to tissues. In a chronic state, pulmonary artery pressure increases, leading to pulmonary hypertension that eventually yields to heart failure, shortness of breath, decreased mobility, and respiratory failure.⁵ Oxygen and nutrients travel to needed cells in the capillaries, where they are converted into usable energy through a process called cellular respiration. It is within the capillary system that the exchange of oxygen and waste products occurs. The arterial circulatory system is responsible for delivering oxygen and nutrients to cells while the venous arterial system removes waste products along with the lymphatic system. In a healthy individual, at the capillary level one can also find lymphatic vessels that help remove larger molecules, such as proteins and long fatty acid chains, along with a small percentage of water that cannot be reabsorbed by the venous side of the capillary. If the diffusion distance is disturbed, the delivery of oxygen to tissues will lead to consequences that may impede wound healing. Hemoglobin’s ability to carry oxygen can be affected by certain diseases, environmental factors, body temperature, carbon dioxide (CO₂) levels, and blood acidity levels (pH). When in the blood, CO₂ reacts with water to create bicarbonate (HCO₃) and hydrogen ions. When CO₂ in the blood increases, the pH decreases, thus reducing the ability for oxygen to bind to hemoglobin. The higher the blood acidity, the lower the ability to absorb or retain oxygen. A slight change in pH can result in severe injury or death. Near the lungs, CO₂ decreases, causing pH to increase and allowing hemoglobin to pick up oxygen entering the blood from the lungs to be carried out to the tissues. On the other hand, CO has a greater affinity for hemoglobin than does oxygen. When CO is present, oxygen will not be able to bind to hemoglobin, therefore limiting oxygen to be transported throughout the body. For example, oxygenation saturation rates fall below 80% when there is 20% CO in the body. At the capillary level, homeostasis is achieved by having a balanced filtration and reabsorption process. Filtration occurs on the capillary arterial side, which is controlled by the precapillary sphincter, and hydrostatic pressure pushes fluid out of the capillary. When this sphincter vasodilates, it allows blood to enter the capillary, therefore increasing the blood capillary pressure. When this sphincter constricts, it decreases the volume entered, therefore decreasing the blood capillary pressure. On the venous side of the capillary, the process is called reabsorption, in which 80-90% of the water is returned to the vascular system. This process occurs because of osmotic pressure. The often-misunderstood lymphatic system will remove proteins and large molecules (eg, large-chain fatty acids, fragmented cells) that cannot be absorbed through the venous system, along with 20% of water that remains in the space. If overworked over time, the lymphatic system may fatigue and become damaged, creating havoc as seen among patients who are diagnosed with progressive chronic venous insufficiency (CVI). In the event that reabsorption is disrupted, more volume will backflow to the space, which will ultimately increase pressure. When there is no homeostasis at the capillary level, the patient may encounter progressive swelling stemming from active hyperemia (arterial-side insult) or passive hyperemia (venous-side insult). Prolonged active or passive hyperemia, lymphatic insufficiency, or systemic insult will lead to an increased diffusion distance in which oxygen travels longer distances, and thus oxygen level delivery to needed cells decreases. This applies to a large number of patients seen in outpatient wound clinics, where the presentation of CVI, lymphedema, lipedema, phlebolymphedema, and traumatic edema are quite common. Due to an imbalance of the capillary filtration/reabsorption process, there may be an abnormal accumulation of fluid in certain tissues. Prolonged edema may tax and fatigue the lymphatic system, causing protein-rich fluid to accumulate and affect the diffusion distance while limiting interventions for good outcomes. Normal diffusion distance is approximately 50 μm or 0.005 cm. To compare this distance, fingernail thickness is < 1 mm (or 0.1 cm). For patients living with CVI, in which venous return back to the heart is damaged due to valvular incompetence and/or poor muscle pump mechanism, there is an increase in blood volume and pressure at the capillary level as the valves in the venous system are damaged. With decreased reabsorption response, edema will continue to accumulate. CVI patients will encounter the typical hemosiderin staining as red blood cells remain in the interstitial space, encounter frequent skin infections, and, if wounds are present, healing potential is diminished due to this increase in diffusion distance.   

MAINTAINING OXYGEN LEVELS
An adequate amount of oxygen is crucial for various cellular processes. Oxygen keeps cells nourished, oxidizes food during cellular respiration, and is overall an essential element of healing. Oxygen is involved in the production of adenosine triphosphate (ATP), which provides energy to our cells to keep them alive and functioning. ATP is “the fuel” that powers the cells. Often, wound care clinicians concentrate on achieving good oxygenation or perfusion to local injured tissue by establishing adequate arterial supply to the wounded area. Outpatient clinics may perform typical noninvasive tests such as an ankle-brachial index, toe-brachial index, transcutaneous oxygen measurement, and skin perfusion pressure. If abnormal values are attained and/or clinical assessment leads to arterial inadequacy, further invasive testing with the likelihood of a vascular referral is imminent. The need for adequate perfusion is of upmost importance as blood delivers oxygen and removes waste products necessary for healing. Maintaining adequate oxygen levels to the injured tissue has prognostic value. If poor oxygenation due to inadequate perfusion is not addressed, the likelihood of tissue repair is nil.  When arterial vessels are damaged, have various amounts of calcification, or have occluded segments, the delivery of oxygen is disrupted and not supplied to cells or injured tissue. A vascular referral is recommended when there’s vascular inadequacy; the level of urgency is determined by the objective measurable test results. In addition to arterial insufficiency, prolonged inflammatory response, infection, and/or edema will impair oxygen delivery and removal of waste. The lymphatic system (and with it, lymphedema) is poorly understood. A full discussion on lymphedema is beyond the scope of this article, but education for both wound clinic providers and patients is available.^6,7 Related to oxygen delivery in lymphedema (when lymphatic involvement is present), the diffusion distance will also increase, but the edema fluid becomes a protein-rich fluid. At the capillary level, proteins are typically removed by the lymphatic system because they are too large to be removed by the venous capillary system. When the lymphatic system is damaged, the proteins continue to collect at the capillary level, attracting more water to leave this system while decreasing its return to the venous side of the capillary, therefore increasing diffusion distance. As patients progress through lymphedema stages, skin will become fibrotic; healing will be significantly delayed; and papillomas, hyperkeratosis, dermatitis, chronic inflammation, and cellulitis will be eminent due to the poor delivery of oxygen and nutrients to the cells caused by the progressive increase in diffusion distance.

OXYGEN & THE PHASES OF HEALING
Oxygen is needed for energy metabolism, as it produces high-energy phosphates needed for cellular functions and is involved in the hydroxylation of proline and lysine into procollagen used for maturation of collagen. In angiogenesis, oxygen sustains growth of tissue and has an antimicrobial action to kill bacteria.⁸ The phases of healing are a dynamic cascade of events that follow a timeline and an overlapping process. While tissue is being repaired, any number of external and internal factors can impede healing progression. The inflammatory phase will typically last 4-6 days, the proliferative phase may extend to 3 weeks, and the maturation phase may last 1-2 years. Each phase takes on its own important role, and sufficient oxygen is needed throughout this healing cascade⁹ because wounded tissue requires an increased energy demand. Acute hypoxia is reported to stimulate wound healing, but re-oxygenation of tissue is required.  During the inflammatory phase, oxygen is needed for the production of ATP. Hypoxia also activates platelets and growth factors. Oxygen also possesses a preventative factor against wound infections, which has been proven in studies that found higher concentrations of oxygen resulted in lower rates of infection.¹⁰ Hypoxia can induce inflammation. For example, one study involving participants experiencing mountain sickness were found to have an increase in proinflammatory cytokines and a leakage of fluid causing pulmonary or cerebral edema.¹¹ Also, vascular leakage, accumulation of inflammatory cells in multiple organs, and elevated serum levels of cytokines have occurred in mice after short-term exposure to low oxygen concentrations.^12-16 Just as hypoxia can induce inflammation, inflamed lesions often become severely hypoxic.¹⁷ Contributors to tissue hypoxia during inflammation include increased metabolic demands of cells. Multiplication of intracellular pathogens can deprive infected cells of oxygen.¹⁸ Other conditions commonly seen among patients in the outpatient center that may impair the quantity and quality of oxygen delivery include chronic lung diseases and sleep apnea. 

BREATHING, SLEEPING & WOUND HEALING

An understanding of COPD and sleep apnea is important for wound care providers because they affect the quantity and quality of oxygenation in the body.

COPD
COPD is a progressive disease that is the third leading cause of death in the United States, currently affects more than 11 million people, and includes emphysema and chronic bronchitis. There are four stages of severity characterized by the restriction of airflow into and out of the lungs. (See Table 1 for a listing of COPD stages and symptoms.) Physicians use the GOLD (Global Initiative for Chronic Obstructive Lung Disease) guidelines to categorize COPD stages and to better understand symptom severity. Emphysema often accompanies a COPD diagnosis and gradually destroys the alveoli of the lungs. Emphysema also damages the elasticity of the airways that lead to the alveoli. Chronic bronchitis is an inflammation of the airways leading to the lungs. When the lungs become inflamed, they produce excess mucus, causing painful coughing and sputum. Stage I COPD often goes undiagnosed and is often written off as a side effect of smoking, allergies, and/or the common cold. Treatment for stages I and II are similar, with lifestyle changes being more important as the disease progresses. Pulmonary rehab with a combination of a short-acting bronchodilator and a corticosteroid would help manage symptoms, and oxygen is probably not needed at this point. As the disease progresses, severity changes. Stage III COPD is severe and causes significant changes in symptoms, lung health, and overall health. Symptoms are increasingly more prominent and harder to manage. A pulmonary function test will show how fast the disease is progressing. As COPD becomes more severe and lung function deteriorates, supplemental oxygen therapy may be needed. Patients living with COPD may have lower “normal” oxygen saturation levels (88-92%). The end stage of COPD is extremely severe, exacerbations are more frequent and more difficult to overcome, and hospitalization may be needed. Treatment of COPD becomes more intense as lung function declines. Oxygen therapy, bronchodilators, corticosteroids, and pulmonary rehabilitation are needed to manage symptoms. Patients who present to the wound clinic with supplemental oxygen as part of their care plans must have their oxygen intake and peripheral capillary oxygen saturation levels monitored closely, as therapy can cause increased levels of CO₂ in the blood. This is known as hypercapnia (carbon dioxide intoxication or poisoning) and is closely associated with hypoxemia, which causes breathing difficulty. Other conditions that cause hypercapnia include hyperventilation, drug overdose, repeated seizures, formation of lesions or bumps in the brain, obstructive sleep apnea (OSA), and skeletal muscle weakness. Symptoms include drowsiness, loss of consciousness, headaches, and decrease in respiration. Hypercapnia is an emergency medical condition that requires the patient to be hospitalized immediately. Depending on the condition of the patient and severity of hypercapnia, noninvasive ventilation therapy such as continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BiPAP) has been shown to be effective in patients with acute respiratory failure. Patients who fail to improve with positive airway pressure and/or are unable to tolerate the mask may need more invasive methods, such as mechanical ventilation, which requires endotracheal intubation. Collaboration with a respiratory therapist will be necessary. 

Sleep Apnea
Poor oxygen levels can affect sleep — from feeling tired the next morning to putting people at higher risk of heart failure, stroke, obesity, and diabetes. Likewise, the presence of any of these conditions can lead to decreased delivery of oxygen to tissues, and thus negatively impact sleep quality. When the human body does not breathe for 30 seconds or more while sleeping, oxygen levels may drop to 80% or lower. Wound care clinicians should consider the effect of patients not getting enough oxygen to the brain and cells during their sleep as potential culprits to delayed wound healing. Common sleep disorders include OSA and central sleep apnea (CSA). OSA is a serious disorder in which breathing stops repeatedly (for as little as 10 seconds and up to 1 minute or longer). If left untreated, OSA can affect blood pressure and contribute to the development of type 2 diabetes, heart conditions, strokes, and depression. It is estimated that 50-70 million Americans live with chronic sleep disorders, and there is plenty of evidence that indicates sleep deprivation can be responsible for car accidents, falls, and broken bones. (In addition, sleep deficiency plays a role in human errors, which can be especially scary in the healthcare setting.) CSA occurs when the brain does not send the signals needed to breathe. The National Sleep Foundation’s sleep-duration recommendations for adults 26-64 years of age is 7-9 hours per night. (The guidelines also recommend not getting any less than six hours or more than 10 hours.) Sleeping is needed at the cellular level because our bodies begin restorative functions such as cell renewal and tissue repair while we sleep. An adequate oxygen supply is needed for these processes to occur. While we sleep, our breathing and heartbeat slow down and growth hormone is produced to help repair tissue. During the sleep cycle, extra oxygen is supplied to our muscles as well. For the wound care patient, healthy sleep is just as important as nutrition and exercise to maintain physical, cognitive, and emotional health. When we think of the “whole” patient, sleep disorders should be a factor.  Sleeping will produce a predictable cycle that includes two parts:  non-rapid eye movement (NREM) and rapid eye movement (REM). During NREM sleep, the body repairs and regrows tissue, builds bone and muscle, and strengthens the immune system.¹⁹ If the body is deprived of sleep, there will be a decreased time spent within these important cycles, or certain sleep disorders may continuously disturb sleep cycles even if the patient believes he or she is getting the recommended number of sleep hours. (Table 2 provides some insight into the different sleep cycles.²⁰) OSA and other chronic conditions can affect the amount of oxygen taken in during sleep. On the opposite side, CO₂ can build up if breathing becomes disrupted. Sleep disorders can also increase the risk for obesity, affect how the body responds to insulin, and contribute to cognitive impairment and memory loss.²¹ Also, patients who receive less than optimal oxygen as they sleep have higher levels of microinfarcts (small areas of brain damage²²). Lack of sleep also decreases levels of the fat-regulating hormone leptin (an appetite suppressant) while increasing the hunger hormone ghrelin. Research has also demonstrated that women who slept five hours or fewer every night were 34% more likely to develop diabetes symptoms²³ and that when people cut sleep from 7.5 to 6.5 hours per night there is increased expression of genes associated with inflammation, immune excitability, diabetes, cancer risk, and stress. In another trial, 87% of depressed patients who resolved their insomnia had major improvements to their depression, with symptoms disappearing after eight weeks.²⁴ Adequate sleep releases a hormone that promotes normal growth, boosts muscle mass, helps repair cells and tissue, helps keep the immune system healthy, and decreases levels of cortisol (the “stress hormone”). Prolonged high levels of cortisol in the bloodstream have been shown to impair cognitive performance, cause blood sugar imbalances, decrease bone density, decrease muscle tissue, raise blood pressure, lower immunity and inflammatory response, slow wound healing, increase abdominal fat that is associated with heart attacks and strokes, and increase cholesterol levels.²⁵ Tracey J. Smith, PhD, a nutrition scientist at the U.S. Army Research Institute of Environmental Medicine in Natick, MA, studied three groups of patients to determine if sleep deprivation affected wound healing. All groups received a blister on their forearms with the roof removed. One group received the recommended number of sleep (control); the other two groups were sleep deprived. The sleep-deprived groups only slept two hours for three consecutive nights (sleep- restricted placebo), but one of the groups received nutritional drinks (sleep-restricted nutrition). The results showed that people who slept the normal recommended hours healed in approximately 4.2 days, whereas the sleep-deprived groups took approximately five days to heal.  The nutrition offered did not have a clear benefit on healing time, but those volunteers had a stronger immune response at the wound site (but did not have quicker healing).²⁶

OXYGEN & SLEEP STUDIES
A polysomnography (sleep) study is a diagnostic test used to determine the presence of sleep apnea and other disorders. These studies record brain waves, oxygen level, heart rate, breathing, and eye and leg movement. Sleep studies also record the number of episodes of slow or stopped breathing (OSA events) and the number of CSA events detected in an hour. They also determine whether oxygen levels in the blood are lower during these events. In OSA, the throat muscles intermittently relax and block the airway during sleep. The brain senses impaired breathing and briefly arouses the patient from sleep so that the airway can be reopened, though most people will not realize they have stopped breathing. Signs and symptoms of OSA include excessive daytime sleepiness, loud snoring, witnessed apnea, abrupt awakenings by gasping or choking, morning headaches, difficulty concentrating during the day, high blood pressure, and mood changes such as depression or irritability. Anyone can develop sleep apnea at any time. However, certain factors can increase risk, including morbid obesity, narrowed airway, hypertension, chronic nasal congestion, smoking, diabetes, asthma, COPD, and family history. Complications of untreated sleep apnea include coronary artery disease, heart attack, heart failure, atrial fibrillation, and sudden death. Common signs and symptoms of CSA are similar to OSA in addition to abnormal breathing patterns during sleep, waking up with shortness of breath, difficulty staying asleep, and chest pain at night. Causes of CSA include Cheyne-Stokes breathing (common in patients living with congestive heart failure or stroke), drug-induced apnea (opioids, morphine sulfate, oxycodone, codeine sulfate), and high-altitude periodic breathing (change in oxygen at a higher altitude causes alternating, rapid breathing - ie, hyperventilation). Treatment for OSA and CSA requires lifestyle changes, such as losing weight and/or the use of CPAP. As with COPD treatments, patients may be unable to tolerate the high pressures of CPAP, which could result in the use of BiPAP therapy because it provides a higher pressure during inhale and a lower pressure during exhale. More commonly today, insurance companies are requiring sleep studies to be conducted by patients in their homes as a convenient and less expensive method of diagnosis. These tests utilize a nasal cannula that monitors oxygen flow in and out of the nose, a chest belt that monitors rise and fall of the lungs, and a finger probe (pulse oximetry) that monitors oxygen levels and heart rate. Test scores will determine if the patient qualifies for an in-lab CPAP titration.

CONCLUSION
Oxygen transport is dependent on the exchange of gases in the lungs, blood, and circulation. When adequate levels of oxygen decrease, various processes are affected, including the ability for damaged tissue to be repaired. Oxygen is essential for the synthesis of ATP; a decrease in this compound will lead to a reduction in energy and cell damage. Poor perfusion, edema, lymphedema, COPD, sleep disorders, and CO₂ buildup/poisoning will decrease the quantity and quality of oxygen delivered throughout the body, ultimately affecting health and wound healing. n

Frank Aviles Jr. is wound care service line director at Natchitoches (LA) Regional Medical Center (NRMC); wound care and lymphedema instructor at the Academy of Lymphatic Studies, Sebastian, FL; physical therapy (PT)/wound care consultant at Louisiana Extended Care Hospital, Natchitoches; and PT/wound care consultant at Cane River Therapy Services LLC, Natchitoches. Debbi Whitten-Byles is the business development and clinical manager of the Sleep Center at NRMC.

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