016 Fishman's Pulmonary Diseases and Disorders, Se > Chapter 144: Oxygen Therapy and Toxicity Matthew Wempke; Joshua O. Benditt Introduction ‘Oxygen was discovered in the late 18th century simultaneously by several investigators. Joseph Priestley, a minister in England, made his discovery after attempting to melt mercury oxide using a magnifying glass and the sun's rays. The vapor that was produced by this mehing allowed a candle to bum brighter, and Priestley later discovered the vapor could be used in place of air to keep a mouse alive, He first published his findings in 1774. At about the same time, and ina similar way (ie., by burning mercury oxide), Carl Scheele, a pharmacist in Sweden, described a gas he called “fire air.” He may have done his experiments before Priestley, but he did not publish his findings until 1777. Finally, after being told about this new vapor during a 1774 visit by Joseph Priestley, the chemist, Antoine Lavoisier, devised quantitative experiments which he used to prove the existence of this element and its role in combustion. He named the element “oxygen” and published his research in 1777. Soon affer its discovery, oxygen was being utilized as a medicine and cure-all for many respiratory diseases, including “consumption” and asthma. However, suspicions about the safety of oxygen therapy were raised almost as soon as it was discovered and even before the element was named. In 1775, Joseph Priestley wrote of oxygen (Which, at that time, he called “dephlogisticated air”): “A moralist, at least, may say that the air which nature has provided for us is as good as we deserve." Rigorous scientific evaluation of the potential toxicities of oxygen did not occur until the work of James Lorrain Smith, an Edinburgh pathologist, who first published the pulmonary pathologic alterations associated with oxygen exposure in 1899. It was also recognized around this time that under ambient air, the arterial blood was already at near-maximal oxygen-cartying capacity, putting into doubt the utility of further increasing the fiaction of inspired oxygen, Following these observations, the use of therapeutic oxygen fll into some disrepute. Inthe early 1920s, supplemental oxygen therapy was reevaluated yet again. This was occurring as the detrimental effects of tissue hypoxia were being recognized, along with their reversibility with supplemental oxygen. Since the mid- 20th century, especially with the advent of improved oxygen delivery systems, mechanical ventilation, and the modem intensive care unit, the use of oxygen has become a standard prescribed therapy for a multitude of cardiac and respiratory diseases, Oxygen therapy is now common in the outpatient setting. As of 2005 in the United States, approximately 1 milion people receive long-term oxygen therapy (LTOT) from the Medicare Program, with total reimbursement costs related to LTOT exceeding 2 bilion dollars per year? In this chapter, the physiology of hypoxia atthe tissue level and mechanisms of arterial hypoxemia are discussed. In addition, various clinical assessments of hypoxemia, indications for acute and LTO, and available methods of noninvasive oxygen administration are considered. Finally, the pathophysiology and clinical manifestations of pulmonary oxygen toxicity are addressed, along with the potential for oxygen toxicity in other organ systems. 31016 Tissue Oxygenation Important to remember is that the primary goal of supplemental oxygen therapy is to ensure appropriate oxygen delivery to vital end-organ tissues. Therefore, one must understand the mechanisms of tissue hypoxia to understand the indications for using supplemental oxygen, Tissue hypoxia is governed by the balance between oxygen delivery and oxygen uliization. Generally, failures in oxygen delivery lead to most instances of tissue hypoxia. Oxygen delivery is determined by the cardiac output and the oxygen content of arterial blood, as described by the formula: Do, (oxygen delivery) = CO (cardiac output) x Cao, "(oxygen content of arterial blood) @ where Cag, is calculated by the formula: Cao, (mL O,/4L) = (1.34 x hemoglobin concentration x $ao,) + (0.0031 x Pag,} (2) where Sao, is the arterial hemoglobin oxygen saturation and Pag, isthe oxygen tension or partial pressure of arterial blood. From this formula, the causes of poor oxygen delivery can be narrowed to three categories: Low cardiac output states (e., various forms of shock), low hemoglobin concentration states (Le., anemia), and low Sag, states (ie., arterial hypoxemia or hemoglbinopathies). Note that a low oxygen tension, although offen leading to low arterial hemoglobin saturation, does not contribute appreciably to oxygen delivery. This can be seen numerically in the above formula for Cag,, where the Pap, is mulipfied by 0.0031 and, therefore, contributes litle to the final product. It is important to point out that supplemental oxygen therapy addresses only arterial hypoxemia, For other causes of tissue hypoxia, more specific therapies are generally required, such as vasoactive agents or intravenous fluid administration to reverse shock, and blood transfusions for anemia ‘Along with the primary basis of poor oxygen delivery, tissue hypoxia can akso be caused by inappropriate or excessive utilzation of oxygen, One cause of inappropriate oxygen utilzation is histotoxic hypoxia, which occurs when cells, for a variety of reasons, are unable to utilize oxygen for aerobic metabolic respiration, This is classically seen in cyanide poisoning, where the cyanide molecule inhibits the enzyme cytochrome ¢ oxidase, and the cell is subsequently unable to use oxygen to produce adenosine triphosphate (ATP) via the mitochondrial electron transport chain, ‘This leads to glycolysis, profound lactic acidosis, and cell and tissue death, Administration of oxygen is indicated in this condition, bbut it will not, by itself, reverse the toxicity of cyanide; other antidotes must be given (generally, sodium nitrite, amyl nitrite, and sodium thiosulfate) 2 Another cause of decreased oxygen utilization may occur in the setting of sepsis. In this case, oxygen isnot utilized by tissues due to both mitochondrial damage and abnormal shunting of blood from a variety of insults at the endothelial and microcirculatory levels. Finally, oxygen may be excessively utilzed by tissues relative to oxygen delivery, This may ‘occur in hypermetabolic states, such as thyrotoxicosis! and fever. Arterial Hypoxemia Important is the distinction between the terms hypoxia and hypoxemia, Hypoxia may be thought of as the functional equivalent of ischemia and refers to a lack or misuse of oxygen at the tissue level. Hypoxemia refers to the blood’s oxygen content and can be more formally defined as a validated deficiency of oxygen tension in the blood. In other words, when a patient's Pag, and, therefore, Sag, are low, the patient is hypoxemic. Since arterial hypoxemia is a 21svano1e major cause of tissue hypoxia, the cause of which is most likely to be reversed or improved with oxygen therapy, its major etiologies are discussed below. ‘The driving force of oxygen transport across the alveolar barrier into the blood depends on both the partial pressure of oxygen in the alveohis (Pao,) and overall respiratory fimetion. Thus, arterial hypoxemia results ffom either reduction of the inspired oxygen tension or dysfimetion of the respiratory system. Along with the reduction of inspired oxygen tension (such as at altitude), there are four other pathophysiologic causes of arterial hypoxemia (Fable 144-1), Table 144-1 Causes of Arterial Hypoxemia and Response to Oxygen Therapy Cause Clinical Examples Response to Oxygen Therapy Decreased oxygen intake Alitude (reduced Pig,) Rapid increase in Pag, a Increase in Pag,, may depress minute ventilation, Alveolar hypoventilation COPD, obesity hypoventilation however Diffusion defect Interstitial pneumonitis Moderately rapid increase in Pag, Ventilation-perfusion — Goypp Moderately rapid increase in Pag, mismatch ° Shunt Avil septal defect, with rght-to-let Variable increase in Pag, depending on size of shunting shunt Alveolar hypoventilation leads to a diminished Pao, and resultant decrease in Pag, and Sap,. It may constitute the final common pathophysiologic denominator for a variety of pulmonary and nonpulmonary disorders leading to hypercapnia and hypoxemia. Examples of nonpuimonary disorders leading to these derangements include narcotic overdose, which reduces the central drive to breath; abdominal compartment syndrome, which can mechanically reduce ventilation due to abdominal distension; and obstructive sleep apnea, which isthe result of transient loss of the upper airway patency. Another pathophysiologic cause of hypoxemia arises with defects in diffusion of oxygen across the alveolarcapillary membrane, as, for example, in fibrotic hing diseases and interstitial pneumonias. The increased barrier to oxygen 25) indicates severe hypoxemic respiratory failure Indications for Oxygen Therapy Supplemental oxygen is a drug with indications, contraindications, and a therapeutic window. Oxygen dosage should be titrated as precisely as possible and oxygen administration monitored closely with respect to clinical benefits and potential toxicities. Indications for oxygen therapy may be considered in both acute and chronic settings. In addition, special circumstances under which oxygen is used therapeutically warrant special discussion, including hyperbaric administration (oxygen delivered at>1 atmosphere) and oxygen therapy during air travel. ‘Acute Indications for Oxygen Therapy Indications for acute, short-term supplemental oxygen therapy, listed in Table 144-3, are based upon guidelines established by the American Association of Respiratory Care and other organizations.9—11. Table 144-3 Guidelines for Acute Oxygen Therapy Accepted Indications * Documented hypoxemia, defined as Pag, below the normal range. Usually Pag, <60 mm Hg or Sag, <90%. ‘+ Acute care situation in which hypoxemia is suspected, such as respiratory distress. Requires substantiation of hypoxemia (by Sag, or Pag,) ina reasonable time. * Severe trauma * Acute myocardial infarction with hypoxemia *+ Low cardiac output with metabolic acidosis ‘+ Hypotension (systolic blood pressure < 100 mm Hg) Questionable Indications + Acute myocardial infarction without hypoxemia + Dyspnea without hypoxemia (palliative) © Sickle cell pain crisis + Preumothorax Source: Data from Kallstrom TJ; American Association for Respiratory Care (AARC). AARC Clinical Practice Guideline: oxygen therapy for adults in the acute care facility 2002 revision & update. Respir Care. 0santa 2002;47(6):717-720; O'Driscoll BR, Howard LS, Davison AG; British Thoracic Society. BTS guideline for emergency oxygen use in adult patients. Thorax. 2008;63 Suppl 6.vil-vi68; Fulmer JD, Snider GL. American College of Chest Physicians (ACCP)-National Heart, Lung, and Blood Institute (NHLBI) Conference on oxygen therapy. Arch Intern Med. 1984;144(8):1645—1655. ‘Usually, when a patient presents with respiratory distress, supplemental oxygen is administered until an assessment of hypoxemia is made. The clearest indication for oxygen therapy is arterial hypoxemia, and supplemental oxygen is generally administered when the Pag, is <60 mm Hg, which normally corresponds to an Sag, or SP, of 89% to 90%. When the Pag, drops below 60 mm Hg, oxygen saturation may drop precipitously, leading to a much lower arterial oxygen content and resultant tissue hypoxia. ‘As noted previously, the most common pathophysiologic cause of hypoxemia is ventilation-perfusion mismatch, which responds readily to supplemental oxygen, Hypoxemia secondary to right-to-left shunt is less responsive to supplemental oxygen; when the shunt fraction exceeds 20% to 25%, hypoxemia persists, despite administration of inspired gas with an Fig, of 100%, In the case of hypoxemia due to alveolar hypoventiation, oxygen therapy offen improves Sao, and oxygen delivery, but it does not correct the underlying cause of respiratory dysfimetion; restoration of ventilation must be pursued. An oxygen saturation target of 94% to 98% is reasonable for patients at sea level who are hypoxemic and who have normal baseline lung function? In certain circumstances, such as shock states characterized by hypoperfusion, the target may be even higher in an attempt to maximize the oxygen content of arterial blood. Conversely, in patients who have abnormal control of respiration, such as those with chronic hypercapnia, a lower Pag, goal may be more appropriate (as discussed later inthis chapter) ‘Use of supplemental oxygen may be indicated in a few clinical scenarios other than arterial hypoxemia. As discussed earlier, patients in shock states may benefit from enhanced arterial oxygen content and delivery, as may patients in cardiac and respiratory arrest. Similarly, trauma victims and critically ill surgical patients benefit from carly oxygen therapy to improve tissue hypoxia. Use of short-term, postoperative supplemental oxygen has also been shown to reduce wound infection in surgical populations.!2 In patients with carbon monoxide poisoning, in whom pulse oximetry readings are unreliable, supplemental oxygen increases Pag,. More importantly, it shortens the half-life of carboxyhemogibin, thereby inereasing the percentage of oxyhemoglobin. With administration of pure oxygen, the half life of carboxyhemoglobin is 70 to 80 minutes,!3 compared with a half-life of 320 minutes when a patient is breathing room air.!4 Under hyperbaric conditions, when pure oxygen is delivered at higher atmospheric pressure, the halflife is shortened even further. Hyperbaric oxygen is generally employed when carboxyhemogiobin levels are high (25%) and there is an evidence of end-organ damage, such as cardiac ischemia or alterations in sensorium,!5 although use of hyperbaric oxygen in this setting is curently controversial. Several other disorders may benefit ftom administration of supplemental oxygen, although supportive data in these settings are lacking or equivocal. Oxygen therapy is offen used in cluster headaches, sickle cell pain erises (although this is falling out of favor)” palliative relief of dyspnea without hypoxemia,1® and pneumothorax in patients who do not have a chest tube (in an effort to facilitate resorption of pleural air).1222 Administration of supplemental oxygen has also been proposed to reduce postoperative nausea and vomiting and to alleviate nausea associated with medical transport in ambulances.! Use of supplemental oxygen in uncomplicated myocardial infarction is common but controversial; the topic is discussed in more detail below. Finally, hyperbaric oxygen is sometimes used in an effort to 2 disease. accelerate healing of complicated, chronic wounds arising inthe setting of peripheral or microvase Hyperbaric oxygen therapy is widely accepted as the therapy of choice in decompression sickness (see Chapter 93). ast016 Indications for Long-Term Oxygen Therapy The use of LTOT has been growing as our abilty to deliver oxygen in outpatient settings has improved. Criteria for administering LTOT have become well established, generally in the context of chronic obstructive pulmonary disease (COPD). Table 144-4 outlines the guidelines of the American Thoracic Society (ATS) for LTOT in COPD The guidelines are based on the data derived ffom two major tials. Table 144-4 Physiologic Indications for Long-Term Oxygen Therapy (LTOT) in COPD* Pao, Sao, LTOT Indication Qualifier <55 mmHg <88% Absolute None needed Presence of any of the following signs of cor pulmonake: ‘+ History of dependent edema 55-59 mm Hg 88-90% Relative with qualifier ph emia (ICT > 55%) + P pulmonale on EKG (P wave > 3 mmin leads Il, Ill, or aVF) Atleast one of the following + Exercise desaturation 260 mmHg 290% None unless qualifier, 1.25 desaturation not corrected by CPAP ‘+ Lung disease with dyspnea responding to O therapy Generally used in other conditions as well. Source: Data from Force ATSERST. Standards for the diagnosis and management of patients with COPD [internet]. American Thoracic Society [Guidelines]. 2004; htip:/svww.thoracic.org/eolcopd., Version 1.2; Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease: a clinical trial Nocturnal Oxygen Therapy Trial Group. Ann Intern Med. 1980;93(3):391-398; Long term domiciliary oxygen therapy in chronic hypoxic cor pulmonale complicating chronic bronchitis and emphysema. Report of the Medical Research Council Working Party. Lancet. 1981;1(8222):68 1-686. ‘The first tral, published in 1980, is the Nocturnal Oxygen Therapy Trial (NOTT)2$ In NOTT, 203 hypoxemic patients with COPD were randomized to the treatment with either nocturnal (at least 12 hours) or continuous oxygen. Patients who received noctumal oxygen therapy alone had a higher mortality at both 12 and 24 months (40.8% at 24 months) compared with those who received continuous oxygen therapy (22.4% at 24 months). ‘The second trial, published in 1981, is the British Medical Research Council Domiciliary (BMRCD) trial 2° In this trial, 87 patients with hypoxemia and COPD were randomized to receive cither no oxygen therapy or at east 15 hid of supplemental oxygen. Similar to the NOT trial, mortality was significantly higher in the no-oxygen group. From these two tral, in patients with COPD and hypoxemia, we can infer that supplemental oxygen for >15 hid is better than no oxygen at all, and that continuous supplemental oxygen is better than noctumal-only therapy. The entry criteria for these trials form the basis of the current Medicare criteria and ATS guidelines for LTOT. Based on the BMRCD trial, most prescriptions for oxygen are written for at least 15 Iv, The data from the two trials have been a1svano1e extrapolated to other conditions complicated by chronic hypoxemia for which data ffom large trials are lacking, including cystic fibrosis, restrictive lnmg diseases, and chronic cardiac diseases. In patients whose hypoxemia does not meet resting criteria for administration of LTOT, evaluation for exercise-related desaturation may be indicated. Some patients may require supplemental oxygen only with exertion; improved exercise performance may be noted,” unless cardiac and peripheral circulatory factors are performance-limiting. Finally, patients with significant desaturation while sleeping may warrant nocturnal supplemental oxygen. Important to note, however, is that in the absence of underlying lung disease, these patients offen have obstructive sleep apnea or obesity hypoventilation syndrome, for which noninvasive positive pressure ventilation constitutes primary therapy.2® ‘Table 144-5 lists the physiologic indications for oxygen therapy during sleep Table 144-5 Physiologic Indications for Nocturnal Oxygen Therapy Pao, <55 mm Hg with sleep or Sap, <88% with sleep Or Pao, decreases more than 10 mm Hg with sleep Or Sag, decreases more than 5% with sleep and signs of nocturnal hypoxemia including: + Pulmonary hypertension * Daytime somnolence * Cardiac anythmias Patient should be evaluated for a sleep disorder and need for positive pressure device Indications for Oxygen Therapy in Air Travel An important consideration for clinicians who manage patients with ling disease is determining the need for supplemental oxygen during air travel Most commercial aircraft fly at cruising altitudes between 25,000 and 45,000 ff, which would normally result in a very low inspired oxygen tension (Pio,). Airplane cabins, however, are generally pressurized to an akitude of 8000 ff, which results in an oxygen tension of approximately 108 mm He (the Pig, at sea level is 149 mm Hg). In patients with hg disease, this reduced Pio, may result in marked reductions in Pao, and Pao, placing the patient at risk for hypoxemia. Prior to travel, the patient should have a thorough medical evaluation, with consideration for reevaluating pulmonary fimetion tests, specifically spizometry and Digo, and obtaining an arterial blood gas. For patients whose Pag, 270 mm Hg (SPo, > 95%) at ground level, their in-flight Pag), will lkely exceed 50 mm Hg, which is generally considered adequate. For patients with a more marginal SPo, or Pag, and other risk factors, a 6-minute walk test or other evaluation may be considered.22 ‘The 6-minute walk fest may be a reliable and practical way of estimating the cardiopulmonary reserve that patients require to deal with the physiologic demands ofa reduced Pig, during fight. Although the entire medical evaluation 1031svano1e must be taken into account, if patient has an abnormally low 6-minute walk distance, has significant dyspnea during the test, or experiences a decline in SP, to <85%, the patient will likely need supplemental oxygen during air travel. Finally in anticipation of air travel, a hypoxia altitude simulation test (HAST) may be performed®2 (see Chapter 33). In this test, an arterial blood gas is drawn just prior to administration of a gas mixture with an Fig, of 15.1%. Another arterial blood gas is drawn 20 minutes later, while the patient breathes the hypoxic gas mixture, Ifthe Pao, is <50 mm He, administration of supplemental oxygen during flight is recommended. Ifthe Pao, is between 50 and 55 mm Hg, futher testing should be considered, inchuding a 6-minute walk test. Reviews on oxygen therapy and air travel address the testing options available =! Techniques of Oxygen Administration ‘When choosing an oxygen delivery device for a given patient, the clinician must consider the degree of hypoxemia, the specificity required with regard to setting the Fig, (which depends on the patient's respiratory control), and the patient's minute ventilation. The oxygen flow that the device can deliver, the adjustability and precision of that delivery, and the comfort and cost of the device are additional considerations. Oxygen delivery devices utilized in the acute setting may be divided into low-flow and high-flow delivery systems, The required flow depends on the patient's degree of hypoxemia and minute ventilation. Patients who exhibit a high minute ventilation or are profoundly hypoxemic require high-flow devices (i, ifthey do not require mechanical ventilation). Patients with more moderate degrees of hypoxemia may only need loweflow systems, which are generally more comfortable. Low-Flow and Variable Performance Oxygen Devices Loweflow systems deliver only a fraction of the patient's minute ventilation as pure oxygen. The maximum flow in these systems is 15 L/min, Since a patient's tidal volume usually varies from breath to breath, and the delivered flow of oxygen fiom the device is constant, the fraction of inspired oxygen for any given breath is impossible to predict. For example, when a patient takes very deep breaths, more room air is entrained, but the flow of pure oxygen is constant, thereby diluting the administered Fip,. Conversely, when a patient has a reduced minute ventilation or is taking very shallow breaths, the amount of entrained room air is minimal, and the Fig, inspired is greater than what might be expected. Table 144-6 illustrates this important principle mathematically. The variation in Fig, with minute ventilation ‘must be considered when administering oxygen to patients with chronic CO) retention who are at risk for worsening hypercapnia with excessive oxygen therapy. Because of the uncertainty of the Fig, delivered by low-flow devices, they are sometimes referred to as “variable performance devices.” Table 144-6 Effects of Minute Ventilation on Fig, in Low-Flow Systems Respiratory Distress Relief of Respiratory Distress Minute 30min 5 Umin ventilation (49 breaths/min x 750 mL/breath) (10 breaths/min x 500 mU/breath) Op flow rate 2 Limin 2 Limin Calculation of 11016 inspired 0, 2 Umin of 100% oxygen 2 Limin of 100% oxygen concentration + F o,) 28 Limin of 21% oxygen (room airdrawn into mask) 3 L/min of 21% oxygen (toom al drawn intomeask) ° = 20 L/min minute ventilation = 5 L/min minute volume +1021 x2 1.0% 2) + (0.21 3) , Thus Fi AB EUR 28. = 0.25 (26% Figg) Thus, Fi cw = 053 (53% Figs) Source: Adapted with permission from Bateman NT, Leach RM. ABC of oxygen: acute oxygen therapy. BMJ. 1998;317(7161):798-801 Naval Cannulie Nasal cannuke allow comfortable delivery of oxygen and unimpeded communication and access to oral intake. The ccamnula rests just below the nares (Fig_144-1) and entrains a constant flow of pure oxygen, generally ranging from 2 to 6 Limin, At 6 Limin or higher, the patient may experience discomfort, excessive mucosal dryness, and epistaxis. The continuous flow creates a reservoir of oxygen in the nasopharynx fiom which the patient draws during inspiration. Contrary to popular belief, even if' patient is a “mouth-breather,” the gas inhaled is oxygen enriched because of the effect of the nasopharyngeal reservoir. Ahough Fig, varies widely with nasal cannulae (as described above), an approximation of Fig, based on oxygen flow rate can be derived (Table 144-7). Typically, Fig, inereases by 3% to 4% with each 1 L increment in flow. Figure 144-1 Nasal oxygen delivery devices. A. Nasal cannulae, B. Pendant nasal cannulae. C. “Moustache” nasal cannule. 281Table 144-7 Approximate Fig, Using Various Oxygen Devices (Assumes Perfect Fil of Mask) 100% O Flow Rate (L/min) Fi, (°%) Nasal Cannula 1 24 2 28 3 32 4 36 5 40 6 44 Oxygen Mask016 3 40 67 50 18 60 Mask with Reservoir Bag 6 60 7 70 8 80 9 90 10 2909 Nonrebreathing Mask 410 60-100 Venturi Mask 3 (80) 24 6 (68) 28 9 (50) 35 1250) 40 15 (41) 50 Number in parentheses indicates total flow of entrained room air with Venturi mixture. Several variations in nasal cannulae design may reduce oxygen waste, ‘The moustache-style reservoir (Fig. 144-1C) contains a sof, inflatable reservoir with a volume of approximately 20 mL. During exhalation, the reservoir fils with oxygen. During inspiration, the patient initially draws from the reservoir and then, when the reservoir is depleted, from the continuous flow of the cannula, This acts to deliver a bos of oxygen carly in the course of the inspiration, while reducing wasted oxygen during expiration, Generally, patients can be maintained at a slightly lower flow rate using the ‘moustache-style cannula compared with a regular nasal cannula, Another modification is the pendant reservoir camnula (Fig, 144-1). This device consists of a reservoir wom on the chest like a pendant, The reservoir is attached to a nasal camila with tubing of slightly greater diameter than normal ‘The pendant reservoir cannula provides a similar fmction to the moustache-style cannula, Simple Oxygen Masks Oxygen masks can deliver higher oxygen flow rates than nasal cannulae; they entrain less room air and, therefore, can generate a higher Fig, . In addition, the configuration of simple masks (Fig. 144-2.) enables an enlarged reservoir of ‘oxygen for inhalation, With nasal cannulae, the reservoir comprises anatomic dead space in the airway, such as the nasopharynx. With a wellfiting oxygen mask, the reservoir is expanded to include the volume within the mask. Generally, flow rates for simple masks range ffom 5 to 12 L/min, which usually requires some room air to be entrained Via the side ports of the mask to meet the patient's minute ventilatory needs. Given the higher flow rates delivered using face masks, a humidifier is also often required. The flow rate ofa simple mask should never be <5 L/min; below this level, carbon dioxide rebreathing may occur, along with an increased resistance to inspiration. Figure 144-2 a1016 Mask oxygen delivery devices. A. Simple fice mask. B, Nonrebreather mask. C. High-flow nasal cannulae, D. ‘Venturi mask. SOR Bd ee ats As is the case with nasal cannulae, predicting the actual Fig, delivered by simple oxygen masks is difficult, since the Fig, varies with the size of the patients tidal volumes and total minute ventilation. Simple masks are also more uncomfortable, making cating and communicating challenging. Because they cover the mouth, aspiration isa risk with any mask, Reservoir Maske016 A reservoir mask is similar to a simple mask but has an attached reservoir of 600 to 800 mL, resting below the patient's chin, Generally, the mask provides flow between 8 and 15 L/min, which keeps the reservoir bag at least half fall. Reservoir masks include partial rebreather and nonrebreather types (Eig. 144-3). Figure 144-3 Mask reservoir bag systems, illustrating airflows with partial rebreathing (A) and nonrebreathing (B) masks. Arrows indicate direction of airflow. Partiatrebreating Noceebreathing Expired 02s Seed gas ‘one-way vaho Expired 035 Ered as ome ae Inspred 03s, nspied gas 100% Oxygen tied ons onenay valve 100% Onygen ° Reservoir bag ‘When using a partial rebreather mask, the patient exhales approximately the first one-third of the expired tidal volume into the reservoir, That volume is derived predominantly ffom anatomic dead space and, consequently, its © content is high and CO, content low. The reservoir bag is filed with the exhaled volume and continued oxygen inflow, while the remainder of the patient’ tidal volume is exhaled via the mask's side ports and edges. A patient with a high minute ventilation can sometimes deflate the reservoir. As with simple oxygen masks and nasal cannulae, the Fig, the patient is ceiving cannot be determined precisely at any point in time ‘The nonrebreathing reservoir mask (Fig. 144-28) is similar to the partial rebreather, with the exception ofa one-way valve at the exit ofthe reservoir bag. The valve ensures that no exhaled air enters the reservoir (ie., air can travel only in an inward direction), enabling delivery of 100% oxygen. The mask also incorporates one-way valves on its side ports to minimize the inhalation of room air. When using a nonrebreathing reservoir mask, oxygen flow should be set high enough to prevent deflation of the reservoir bag—usually about 15 Limin, Currently available masks do not fit securely enough to ensure a delivered Fig, of 100%. Typically, these masks provide a maximum Fig, of 80% to 90%; the Fig, may be even lower (60%-80%) in the setting of very high minute ventilation 22 High-Flow or Fixed Performance Oxygen Devices Higheflow oxygen devices deliver a constant Fig, and are, therefore, sometimes referred to as “fixed performance devices.” The devices allow for a fixed Fig, by providing very high flows of pure oxygen which exceed the patient's minute ventilation, sometimes by a factor of four. Along with very high flow rates, the devices incorporate oxygen reservoirs whose volumes exceed the patient's anatomical dead space. Since the Fio, is predictable, high-flow devices 1891santa are ideal for patients who have precise oxygen needs that should be neither exceeded nor unmet. Patients for whom high-flow devices are prescribed may be severely hypoxemic and must be monitored closely for the possible need for noninvasive mechanical ventilation or intubation. Air-batrainment Masks (Venturi Masks) ‘The Venturi mask consists of'a mask, a jet nozzle, and entrainment ports (Fig, 144-2D). Oxygen is delivered under pressure via the jet nozzle, which acts to dramatically increase the velocity of the gas. The high-velocity gas entrains ambient air via the entrainment ports. Depending upon the size of entrainment ports, size of the jet nozde, and flow rate of oxygen, a predictable Fig, can be delivered. Typically, the Venturi mask has interchangeable or adjustable valves that enable the clinician or respiratory therapist to better titrate the Fig, to the patient's needs. Humidifcation is sometimes difficult to ensure and requires the use ofan aerosol-entrainment collar over the jet orifice and entrainment port. Humidification increases the density of the entrained air, slows the speed of entrainment, and thereby reduces the amount of room air entrained, resulting in a higher Fio,. Although described as a high-flow device, air-entrainment masks generally can only ensure a high-flow rate when the Fig, is <30%.%2 As the Fig, increases above 30%, the devices are unable to deliver flow rates of 40 Limi (as less room air is entrained) and are considered variable performance devices. However, the ability of these masks to deliver an exact Fig, at lower levels of Fig, makes them ideal for patients with chronic imng disease who require a specific Fig, due to the risk of hypercapnia from hyperoxia. In fact, for treatment of patients with COPD in emergency departments, the British Thoracic Society recommends oxygen administration using a Venturi mask to censure an appropriate Fig, 1? High-Flow Generators High-flow generators are used to ensure noninvasive delivery of'a constant, high concentration of inspired oxygen. High-flow generators are capable of delivering gas in excess of 40 to 60 L/min. From the generator, gas is routed through a heated humidifir, similar to that used for mechanical ventilators. A large reservoir is often placed in line between the humidifier and aerosol fice mask. The face mask may incorporate valves which ensure that no rebreathing occurs. Given the high flows delivered, a constant Fig, is achieved, regardless of the patients minute ventilation and fit ofthe mask. When precise oxygen titration is required, aioxygen blenders are used. The blenders are metering devices which use compressed oxygen and air ftom a high-pressure wall source (50 psi) to generate a gas mixture which can be delivered at high flow (e.g., 100 Limin) and precise Fig,. The devices are noisy and require specialized personnel to set up and monitor, limiting their usage to intensive care settings.*3 High-Mtow Nasal Cannulae Recently, nasal cannulae (Fig. 144-2C) that can deliver much higher rates of flow than simple nasal cannulae have been developed (¢.g., Vapotherm®) that allow delivery of much higher flows (and therefore, higher Fig,) of humidified oxygen. The devices can deliver between I and 60 L/min and may be more comfortable than a facemask.4 However, particularly in infants, these devices may increase positive end-expiratory pressures (4 em HO or higher). Therefore, the devices’ clinical benefits must be weighed against the risk of barotrauma, especially in infants 2 Long-Term Oxygen Therapy 1031santa As noted previously, LTOT has a significant beneficial effect on survival in patients with chronic hypoxemia. However, initiation of chronic home oxygen therapy can be a substantial burden for patients. Like any therapy, LTOT is subject to patient noncompliance. Various studies have noted adherence to LTOT in only 45% to 70% of patients.*© The barriers to adherence are many and include patient concems of addiction and dependency, embarrassment from the igma” that an oxygen delivery device represents with respect to a smoking-related disease, and the associated limitations on physical activity arising from bulky ambulatory oxygen sources. Therefore, appropriate counseling about the benefits and demands of oxygen therapy is necessary before beginning treatment. Furthermore, the clinician should consider oxygen source portability, social and home support available (e.g., from fiends, family, or visiting nurses), and patient attitudes and belief when considering LTOT. Finally, the clinical needs to facilitate sufficiently close patient monitoring to ensure long-term benefit fiom therapy. In the United States, oxygen therapy requires a Cetiticate of Medical Necessity (CMN). Continued need for LTOT must be recertified annually Oaygen Concentrators Oxygen concentrators use specialized fiters to eliminate other gases ffom room air, thus “concentrating” oxygen for delivery to the patient. Concentrators accomplish this by (1) using a compressor to draw room air ito the system, (2) cooling the air (which has been heated up ftom the compression) using a heat exchanger, and (3) passing the air into mokeular sieve beds where oxygen is concentrated. Sieve beds contain granular zeolite crystal composed of an array of small particles which separate gases according to siz. Air cycles through two separate sieve beds; the cycling szadually removes nitrogen as waste and isolates oxygen which is diverted to a product tank. The oxygen in the product tank is pressurized at 10 psiand, prior to patient delivery, is passed through a bacteria fiter and flow meter. Concentrators usually can produce oxygen concentrations of 95% to 97% at 2 L/min flow; the concentration flls to 86% to 93% at 3 to 5 L/min flow (note that pure oxygen tanks provide 100% oxygen at any flow rate up to 6 Limin) 3 Oxygen concentrators include large devices (weighing about 35 Ib) intended for stationary use in the home and smaller portable devices, designed for use outside the home. The larger concentrators can produce high flows (up to 10 Limin) but are ofien tethered by power cords. High flow rates also demand humidification, which can also be provided by most large concentrators. Portable oxygen concentrators permit patient mobilty; their use is increasingly being approved for air travel2 They usually weigh between 5 and 10 Ib. Battery lit is variable, typically ofthe order of 2.5 hours. Liquid Oxygen Although compressed gas oxygen is stil utilized, offen as an emergency supply in the home environment, liquid oxygen (LOx) has become standard in domiciliary systems, LOx has advantages of being more compact, requiring fewer refils, and operating at lower pressures than gaseous oxygen. A home system of LOx typically consists of large stationary reservoir which can hold up to 100 Ib of LOx, and a smaller portable system for ambulation. The portable system can be refiled by the patient and may weigh as litle as S 1b. LOx is stored in tanks called dewars, which generally resemble a thermos bottl. The dewar consists of nner and ‘outer containers and interposed insulating material and vacuum to maintain low temperatures.23 Generally, LOx is more expensive than compressed gas and requires pressure-relief venting. However, LOx delivery systems consume less electricity and enable longer periods of high-flow oxygen administration. Oxygen-Conserving Devices LTOT és expensive, and oxygen-conserving devices have been designed to limit oxygen waste. Simple oxygen- conserving devices were discussed earlier. In addition to these simple devices, electronic oxygen-conserving devices 1st016 are available, Electronic oxygen-conserving devices are triggered by the onset of inspiration and deliver oxygen in boluses, the volume of which depends on device settings. For pulse-type devices, a fixed volume of oxygen is delivered (based on the flow setting) each time a breath is initiated. Some pulse-type devices deliver the volume with alternating breaths, rather than with every breath. For demand-type devices, the volume of oxygen is delivered throughout the whole inspiratory cycle; consequently, the volume varies according to the length of the cycle, For demand-type devices, as respiratory rate decreases, the amount of oxygen conserved also decreases. In fact, demand-type devices commonly deliver an equal or greater volume of oxygen than a continuous-flow device. In the event of an eleetronic-conserving device malfnction, the delivery system defaults to continuous flow, often without the patient being aware. ranstracheal Catheters ‘Transtracheal catheters, also considered oxygen-conserving devices, are considerably mote invasive than other forms of LTOT. Transtracheal catheters require insertion directly into the trachea. Usually, this is accomplished pereutancously, using a modified Seldinger technique (similar to that used for placement of a percutaneous tracheostomy), or surgically, using a Lipkin procedure or mini-tracheotomy = ‘The benefit ofa transtracheal catheter is that it delivers oxygen that bypasses much ofthe anatomical dead space and utiizes the natural oxygen reservoir of the upper airway. Oxygen usage may be reduced by 50% to 75% with the use ofa transtracheal catheter. In addition, nasal or facial irritation is minimal, Unfortunately, the catheter can be a nidus for infection and formation of “mucus balls,” which rarely are fatal. B® Pulmonary Oxygen Toxicity ‘The modem study of pulmonary oxygen toxicity essentially began with J. Lorrain Smith in 1899. Smith described pathologic changes of oxygen toxicity in small animals exposed to the gas at a fractional concentration of 0.4 at 4.5 atmospheres (hyperbaric oxygen). He noted that with high levels of oxygen exposure in mice, “the effet was uniformly fatal, and the immediate cause of death was inflammation of the himgs... and the mgs were found postmortem to be extremely congested ... the alveoli were to a great extent filed with an exudate, which was granular and fibrillated in appearance...” Further studies were conducted in animals to confirm Smith's findings. In the late 1930s, Becker-Freysang et a studied oxygen exposure in humans and found that with 65 hours of exposure to © at 730 mm Hg, paresthesia, nausea, and significant decreases in vital capacity occurted.“2 In the early 1960s, a healthy volunteer exposed to 110 hours of continuous high oxygen exposure experienced profound alterations in vital capacity, minute ventilation, pH, and Pag,.“! However, in general, the study of oxygen toxicity in humans has proved challenging. Based on animal models, information has been generated on the underlying cellular mechanisms. Biochemical Basis of Pulmonary Oxygen To In considering the biochemical basis of pulmonary oxygen toxicity, the roles of free radicals and cellular antioxidant defenses in the production of issue damage should be noted Free Radicals 1931santa Descriptions of the mechanisms of oxygen toxicity invariably begin with the concept of highly reactive oxygenederived fice radicals, specifically, superoxide (O”), hydrogen peroxide (H,0,) and the hydroxyl radical (OH). By definition, free radicals have an unpaired orbital electron which causes either oxidation or reduction ofa surrounding molecule. Free radicals are ubiquitously produced during cellular respiration; however, cells normally have the capability of neutralizing them quickly. Invariably, in hyperoxic conditions, generation of free radicals overcomes the cell's natural defenses.2 Once formed in excess, free radicals are responsible for a cascade of effects, including lipid damage, leading to membrane dysfunction; disruption of enzymatic protein fimction; and nucleic acids damage.“ Ukimately, these effects may result in cell death. In the case of nucleic acid damage, mutagenesis may occur. Cellular Antioxidant Defenses Various enzymes and cofactors in cells neutralize free radicals produced normally as a by-product of metabolism. ‘These neutralizing enzymes are ubiquitous in eukaryotes.“ The prototype is the metalloprotein, superoxide dismutase, which converts superoxide to hydrogen peroxide. Hydrogen peroxide so-generated is converted intracellularly to HO and O» through the actions of catalase (found in peroxisomes) and glutathione peroxidase (found in the cytoplasm). Glutathione peroxidase also repairs damaged lipids. Glutathione reductase and ghicose-6-phosphate dehydrogenase regenerate glutathione enabling its recycling as an antioxidant, Nonenzymatic antioxidants, which are present within cell, include the vitamins, a-tocopherol (vitamin E) and ascorbate (vitamin C). Other antioxidants, such as ceruloplasmnin and cysteine, are also normally present in cells and the extracellular fd. In fact, human lung tissue contains a high concentration of extracellular antioxidants and superoxide dismutase enzymes, which allow exposure to higher-concentration oxygen without development of toxicity S47 ‘Tiesue Damage ‘The cascade of reactions leading to hyperoxia-induced puknonary tissue damage can be described in two phases. ‘Thee to four days following hyperoxic exposure and generation of ffee radicals, an exudative phase commences, characterized by death of alveolar type I and endothelial cells. Interstitial edema is seen along with exudative alveolar filing. Neutrophil recruitment into the capillaries and interstitum is present. Alveolar epithelial damage then occurs, as neutrophils enter the alveoli, as seen in BAL specimens. A second, proliferative phase follows, characterized by proliferation of endothelial cells and type 2 pneumocytes. The pneumocytes cover the previously exposed basement membrane. Fibroblast proliferation also occurs in this phase. Recovery from oxygen injury is characterized by interstitial scarring and fuily normal-appearing capillary endothelium and alveolar epithelium. Clinical Manifestations of Pulmonary Oxygen Toxicity ‘The exposure level at which oxygen toxicity occurs has not been clearly identified, although a higher Fig, experienced for a longer period of time is associated with an increased risk. Clinical oxygen toxicity is manifest in several ways. Normal subjects experience a decrease in vital capacity and fallin Dico- Lung compliance is diminished.“? Tracheobronchitis, which produces substernal chest pain, may also occur 52 Clinical toxicity is generally absent when the Fig, is <50%, Most clinically relevant concems over oxygen toxicity center around (1) absorption atelectasis; (2) hypereapnic respiratory fislure in at-risk individuals; (3) acute respiratory distress syndrome (ARDS); and (4) hyaline membrane aot016 disease, leading to bronchopulmonary dysplasia (BPD) in newborns. 2-33 Absorption Atelectasis Absorption atelectasis begins with complete or partial collapse of an alveolar unit's proximal airway. With airway closure, previously inhaled gas is trapped in the distal alveoli, Oxygen passes freely from the alveoli into the capillaries and is bound to hemoglobin or dissolved in plasma, Nitrogen, however, does not diffuse into the blood at nearly the same as oxygen. Hence, alveolar nitrogen “stents” open the alveoli, maintaining patency. For a patient breathing pure oxygen, the absence of nitrogen promotes alveolar collapse. Ina study based on mathematical modeling of alveolar collapse, the time from airway occlusion to alveolar collapse ‘was 37 minutes using 3 minutes of preoxygenation with ambient ar, compared with 8.7 minutes using preoxygenation with 100% oxygen (taking into account hypoxic vasoconstriction). In a clinical context, patients who received 40% ‘oxygen just prior to extubation were shown to have less atelectasis on CT imaging compared with those who received. 100% oxygen.*> Finally, absorption atelectasis is commonly seen with induction of anesthesia. Preoxygenation and resulting nitrogen washout, along with a decrease in FRC from chest wall and diaphragmatic paralysis that occurs with the use of neuromuscular blockade, lead to small airway collapse. Hypercapnia in the Setting of Chronic CO Retention and Hyperoxia Patients with chronic CO, retention, usually in the setting of COPD, are at risk of worsening hypercapnia when exposed to high levels of oxygen. Classically, this worsening of hypercapnia during excessive supplemental oxygen administration has been attributed to the suppression of hypoxic drive to breathe in the setting ofa blunted hypercapnic drive. This formulation was first proposed in a case report published in the middle of the 20th century 2 However, three other mechanisms have been proposed,” as discussed below. ‘Ventilation-perfusion mismatch is an important cause of hypoxemia in patients with COPD. As discussed previously, hypoxic vasoconstriction (HPV) minimizes the adverse effects of'a low Pap, on Pago,. When Pag, is increased through administration of supplemental oxygen, HPV is partially reversed, increasing perfision to alveolar units which are still underventilated and now, oxygen enriched. Alveolar oxygen diffuses across the alveolar-capillary membrane, but because ventilation is still reduced, Pago, remains high, reducing the diffision gradient for CO, diffision out ofthe blood. As a result, Paco, increases. An additional consideration is the Haldane effect—the increased capacity of deoxygenated blood over oxygenated blood for CO3 binding. As hemoglobin molecules become deoxygenated (ie., reduced), they more readily accept protons (H7), Removal of dissolved protons from plasma drives formation of bicarbonate, which, in tum, is catalyzed by carbonic anhydrase: CO, + H,0 + H,CO, + HCO, + Ht (3) Bicarbonate is the primary form in which CO, is transported and eliminated from the body. Furthermore, deoxygenated hemoglobin binds CO, directly, forming carbaminohemoglobin. As Pao, and, consequently, Pag, increase with oxygen therapy, the concentration of oxyhemoglobin increases while that of deoxyhemoglobin decreas Asa resul, buffering capacity is depleted, diminishing venous blood's transport capacity for tissue-generated CO; Pago, rises. aitsanta Finally, since pure oxygen is of higher viscosity than air, the increased viscosity of oxygen-enriched mixtures may contribute to increased work of breathing in an already compromised patient.55 Regardless of the underlying mechanism(s), clinicians must be vigilant when administering supplemental oxygen to those with chronic CO3 retention. Unfortunately, the worsening of hypercapnia with oxygen administration is unpredictable; some patients with COPD do not develop hypercapnia with hyperoxia, while others may develop frank respiratory failure. Use ofa high-performance oxygen delivery device (e.g., Venturi mask), and titration of Fig, to achieve a goal Sap, of 88% to 90% in selected populations is the preferred management strategy. Acute Respiratory Distress Syndrome and Bronchopulmonary Dysplasia Oxygen toxicity has been implicated in the pathophysiology ofthe ARDS, although this subject is controversial. In alnost all nonhuman mammals, prolonged exposure to 100% oxygen leads to diffuse alveolar damage and, eventually, death, In humans, replicating these findings has been challenging. Conducting human studies on oxygen toxicity presents ethical considerations of testing healthy human subjects. In addition, when oxygen toxicity is studied in the setting of pulmonary disease, differentiation between damage caused by the underlying lung disease and that caused by excessive oxygen exposure may be impossible. Many human studies have failed to show an association between excessive oxygen exposure and development of acute lg injury or ARDS. Ina study of brain-dead patients whose normal lings were exposed for 24 hours to 100% oxygen delivered via a mechanical ventilator, only mid increases in alveolar capillary permeability were demonstrated; several more days of oxygen exposure failed to produce pathologic evidence of img injury.®2 Similarly, another tral in postoperative cardiac patients failed to show any clinical differences between those ventilated with 100% oxygen and those ventilated with the minimal amount of oxygen needed (mean Fip, of 32%). Notably, an acute hung injury pattern due to oxygen toxicity may be seen in humans with prior drug exposure, as discussed below. Premature newboms offen requite high levels of oxygen therapy in the setting of hyaline membrane disease—a disorder caused by surfictant deficiency and characterized by alveolar collapse and inflammation.*! In survivors, chronic hung disease in the form of BPD és often seen. ‘Oxygen toxicity is considered a major factor in the pathogenesis of BPD. BPD has been described in infants administered a high concentration of oxygen but not mechanically ventiated.5! Newboms are particularly prone to damage by hyperoxia, as their cellular antioxidant defenses are not filly developed. ‘The initial pathologic lesions of BPD resemble diffuse alveolar damage. As BPD evolves, pathologie findings include alternating areas of collapse and emphysema, hyaline eosinophilic material ning distended terminal aways, marked epithelial hyperplasia or metaplasia, peribronchial fibrosis, and elastic fibers around air sacs and lobules. Clinically, the condition presents as a persistent requirement for supplemental oxygen or mechanical ventilation following hyaline membrane disease, along with poor kng compliance and pulmonary hypertension, Most infants gradually improve after 2.10 4 months. In more severe cases, infants require prolonged mechanical ventilation and may develop cor pulmonale fom severe pulmonary hypertension. Potent n of Pulmonary Oxygen Toxicity Several drugs have well-known pulmonary toxicity and may potentiate the pulmonary toxicity of oxygen. Bleomycin, an antibiotic agent first isolated from the fimgus Streptomyces verticillus in the late 1960s, has been. maosvano1e used as a chemotherapeutic agent in the treatment of lymphomas, germ cell tumors, Kaposi sarcoma, cervical cancer, and squamous cell carcinomas of the head and neck. One mechanism by which bleomycin exerts is antitumor effect is through induction of cytotoxicity via generation of free radicals. Bleomycin forms a complex with Fe’, which is oxidized to Fe*, resuting in reduction of oxygen to free radicals. Bleomycin is also thought to exert direct effects on DNA. Along with its elimination by the kidneys, bleomycin can be deactivated by the enzyme bleomycin hydrolase, which is found in most tissues (especially the liver), However, two notable organs lack the enzyme: Lung and skin. In the lungs, bleomycin toxicity is manifest in three ways: Organizing pneumonia, eosinophilic hypersensitivity, and interstitial pneumonitis, which may progress to fibrosis. An experiment in the hamster demonstrated that high doses of ‘oxygen may work synergistically with bleomycin to cause worsening lung injury. In humans, several case reports describe ARDS in patients previously treated with bleomycin who have exposure to a high Fig, perioperatively. 5 However, one prospective tral failed to show an association between high levels of oxygen exposure, past bleomycin ‘exposure, and significant postoperative pulmonary dysfimetion. Another well-known potentiator of pulmonary oxygen toxicity is paraquat. Paraquat is a commercial herbicide commonly used in the United States. It is associated with considerable toxicity and mortality when ingested orally, often in suicide attempts. Like bleomycin, paraquat-induced pulmonary toxicity is the result of oxidative stress arising from the generation of free radicals, leading to pneumonitis and pulmonary fibrosis. Similar to models of bleomycin toxicity, animal studies suggest worsening toxicity in the setting of higher levels of inspired oxygen. Therefore, in ‘managing patients with paraquat poisoning, Fig, shoukl be minimized as much as clinically possible. Use of paraquat is banned in the European Union and in several other countries, but the herbicide is still available for agricultural use in the United States. Fulminant poisonings carry a mortality that well exceeds 50%.2 Other drugs studied with regard to potentiation of oxygen toxicity include disulliram and nitrofurantoin, Disulfiram is converted in vivo to diethyklthiocarbamate, which inhibits cytosolic superoxide dismutase 2! Metabolism of, nitrofurantoin results in the production of superoxide in a similar way to paraquat. The final pathway in both cases is an accumulation of oxygen-fiee radicals.22 Finally, elements of dietary intake are also associated with potentiation of oxygen toxicity, at least in animal models. Protein deficiency leads to hyperoxic damage, possibly through a lack of sulfiur-containing amino acids, which are crucial to glutathione synthesis. Deficiencies in the antioxidants vitamin A and vitamin E have also been implicated in the potentiation of oxygen toxicity. 425 Oxygen Toxicity in Other Organ Systems Hyperoxia has the potential for producing toxicity in other organ systems. For example, an association between increased mortality and hyperoxia in the setting of retum of spontaneous circulation (ROSC) following cardiac arrest has been reported. In this large, muicenter, retrospective cohort study, patients who had a Pag, >300 mm Hg following ROSC had an odds ratio for in-hospital death of 1.8 (95% CI, 1.8-2.2), based on a model controlling for potential confounders. The increased mortality secn in this study was attributed to hyperoxic reperfusion injury eading to oxidative stress—specifically worsening postarrestfimctioning of the central nervous system, Based on the results of this study, the American Heart Association has adjusted its postarrest guidelines to emphasize titration of Fi, to maintain an oxygen saturation 94%, Prospective data are not currently available to prove causation. Ina retrospective study conducted at a single trauma center, higher mortality was noted in patients with traumatic brain 2301svano1e injuries exposed to hyperoxia (Pag, > 200 mm Hg) compared to normoxia.” Patients with hyperoxic exposure were more likely to have low Glasgow coma scores (3-8) on discharge than those who were normoxic. In the same study, patients with hypoxemia also had worse outcomes compared to those who were normoxic, emphasizing the importance of close and continued monitoring using puke oximetry. Finally, in the case of acute myocardial infarction (AMD), controversy exists regarding oxygen therapy. When treating patients with myocardial ischemia who ate hypoxemic, oxygen is absolutely indicated, as it can be life-saving However, when a patient with AMI is not hypoxemic, whether supplemental oxygen is beneficial is unclear. A double-blind randomized trial conducted in the late 1970s compared oxygen therapy (6 L/min) with no oxygen therapy in 157 patients with uncomplicated AMIS In patients who received oxygen, higher rates of sinus tachycardia and a greater rise in myocardial enzymes were noted, along with no difference in mortality (actually, a trend toward improved mortality was seen in the no-oxygen arm). Several reasons for the potential deleterious effects of hyperoxia in an AMI have been proposed. In healthy humans, hyperoxia has been shown to induce coronary vasoconstriction. Furthermore, in critically ill patients, high-flow oxygen therapy may lead to maldistribution of microcirculatory blood flow, increased functional 0 shunting, and a reduction in total body oxygen consumption. Although data supporting the use of supplemental oxygen in uncomplicated AMI remain unclear, the practice remains nearly universal. Conclusion Since its discovery, oxygen has been successfilly tized in medicine, revolutionizing the field in the early half of the 20th century. Supplemental oxygen remains among the most common therapies provided in the inpatient setting. Oxygen therapy may improve oxygen delivery and reverse tissue ischemia, The role of supplemental oxygen in ‘management of outpatients with chronic, severe, pulmonary and cardiac diseases is broad. In the outpatient setting, supplemental oxygen may considerably improve quality of lit in those patients willing to adapt to its use. Despite the widespread availability of supplemental oxygen and is relative ease of use, oxygen must be considered a drug with a therapeutic window, above which the potential for significant toxicity exists, Acknowledgment The authors would like to acknowledge the previous version of this chapter, authored by Dr. Michael F. Beers. References 1 Priestley J. Experiments And Observations On Different Kinds Of Air. London: J Johnson; 1775. 2. Croxton TL, Bailey WC. Long-term oxygen treatment in chronic obstructive pulmonary disease: recommendations for fiture research: an NHLBI workshop report. Am J Respir Crit Care Med. 2006;174(4)373-378. PubMed: 166143491 3. Gracia R, Shepherd G. Cyanide poisoning and its treatment. Pharmacotherapy. 2004;24(10):1358-1365. (PubMed: 15628833 4. Robin ED. Special report: dysoxia. Abnormal tissue oxygen utilizati PubMed: 879930 n. Arch Inte Med. 1977;137(7):905-910. astsvano1e 5. Manthous CA, Hall JB, Olson D, et al Effect of cooling on oxygen consumption in febrile critically ill patients. Am Respir Crit Care Med. 1995;151(1):10-14, (PubMed: 7812538] 6. Holland AE, Exercise limitation in interstitial hmg disease — mechanisms, significance and therapeutic options. Chron Respir Dis. 2010;7(2):101-111. (PubMed: 20056733. 7. Schnapp LM, Cohen NH. Puke oximetry. Uses and abuses, Chest. 1990;98(5):1244-1250, PubMed: 2225973 8 Trachsel D, MeCrindle BW, Nakagawa S, Bohn D, Oxygenation index predicts outcome in chikiren with acute hypoxemie respiratory future. Am J Respir Crit Care Med, 2005;172(2)206-211. PubMed: 15817802] 9% Kallstrom TJ; American Association for Respiratory Care (AARC). AARC CI therapy for adults in the acute care Baclty-2002 revision & update. Respir C: (PubMed: 12078655: 10. O'Driscoll BR, Howard LS, Davison AG; British Thoracic Society. BTS guideline for emergeney oxygen use in adult patients. Thorax. 2008;63 Suppl 6:vil—vi6s. PubMed: 18838559) ul. Fulmer JD, Snider GL, American College of Chest Physicians (ACCP)-Nationsl Heart, Lag, and Blood Institute (NHLBI) Conierence on oxygen therapy. Arch Intern Med. 1984;144(8):1645-1655, (PubMed: 6466020] 12. Qadan M, Akca O, Mahid SS, Homung CA, Polk HC Jr, Perioperative supplemental oxygen therapy and surgical site infection: a meta-analysis of randomized controlled trials, Arch Surg. 2009;144(4)359-366; discussion 366-367. (PubMed: 1938065! 13, Weaver LK, Howe S, Hopkins R, Chan KJ. Carboxyhemogiobin balf ie in carbon monoxide-poisoned patients treated with 100% oxygen at atmospheric pressure, Chest, 2000;117(3):801-808. (PubMed: 10713010) 14. Peterson JE, Stewart RD. Absorption and elimination of carbon monoxide by inactive young men. Arch Environ Health, 1970;21(2):165-171. PubMed: 5430002 15. Hampson NB, Piantadosi CA, Thom SR, Weaver LK. Practice recommendations in the diagnosis, management, and prevention of carbon monoxide poisoning. Am J Respir Crit Care Med. 2012;186(1 1):1095—1 101 (PubMed: 23087025. 16. Cohen AS, Bums B, Goadsby PJ. High-flow oxygen for treatment of cluster headache: a randomized trial. JAMA. 2009;302(22):245 12457. (PubMed: 19996400) al Practice Guideline: oxygen . 2002;47(6):717-720. 2501svano1e 17. Miller ST, Kim HY, Weiner D, ot ak Investigators of the Sickle Cell Dis (SCDCRN). Inpatient management of sickle cell pain: a ‘snapshot’ of current practi 2012;87(3)333-336. PubMed: 22231150) 18 Abemethy AP, Curow DC, Frith P, Fazekas B. Prescribing palliative oxygen: a clinician survey of expected benefit and patterns of use. Palliat Med, 2005;19(2):168-170. (PubMed: 15810762 19. Chadha ‘TS, Cohn MA. Noninvasive treatment of pneumothorax with oxygen inhalation. Respiration. 1983;44(2):147-152, PubMed: 6836190) 20. Hill RC, DeCarlo DP Jr, Hill JF, Beamer KC, Hill ML, Timberlake GA. Resolution of experimental pneumothorax in rabbits by oxygen therapy. Ann Thorac Surg. 1995;59(4):825~827; discussion 827-828, (PubMed: 7695404) 21, Kober A, Fleischackl R, Scheck ‘I, et al A randomized controlled trial of oxygen for reducing nausea and vomiting during emergency transport of patients older than 60 years with minor trauma, Mayo Clin Proc. 2002;77(1)35-38. (PubMed: 11794455] 2 Kranke P, Bennett M, RoecktWiedmam 1, Debus S. Hyperbaric oxygen therapy for chronic wounds, Cochrane Database Syst Rev. 2004(2):CD004123. Tibbles PM, Edelsberg JS. Hyperbaric-oxygen therapy. N Engl J Med, 1996;334(25):1642—1648, (PubMed: 8628361 24 Force ATSERST. Standards for the diagnosis and management of patients with COPD [intemet], American Thoracie Society [Guidelines]. 2004; hitp:/www.thoracic.org/go/copd., Version 1.2. 28, Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive hing disease: a clinical trial. Nocturnal Oxygen Therapy Trial Group. Ann Inter Med, 1980;93(3)391-398, PubMed: 6776858 26. Long term domiciliary oxygen therapy in chronic hypoxic cor pulmonale complicating chronic bronchitis and emphysema, Report of the Medical Research Council Working Party. Lancet, 1981;1(8222):681-686, (PubMed: 6110912) 27. Fujimoto K, Matsuzawa Y, Yamaguchi S, Koizumi T, Kubo K. Benefits of oxygen on exercise performance and pulmonary hemodynamics in patients with COPD with mild hypoxemia, Chest, 2002;122(2)457-463. PubMed: 12171817) 28. Kushida CA, Littner MR, Hirshkowitz M, et al, American Academy of Sleep Medicine. Practice parameters for the use of continuous and bilevel positive airway pressure devices to treat adult patients with sleep-related breathing disorders. Sleep. 2006;29(3)375-380. (PubMed: 16553024] 29, 251svano1e Chetta A, Castagnetti C, Aiello M, et al Walking capacity and fimess to ly inpatients with chronic respiratory disease, Aviat Space Environ Med, 2007;78(8):789-792, (PubMed: 17760287) 30. Gong H Jr, Tashkin DP, Lee EY, Simmons MS. Hypoxiz-altitude simulation test. Evaluation of patients with chronic airway obstruction. Am Rev Respir Dis. 1984;130(6):980-986. (PubMed: 6508019) 31, Mobr LC. Hypoxia during air travel in adults with pulmonary disease. Am J Med Sei, 2008;335(1):71-79, (PubMed: 18195588 32. Wagstaff TA, Soni N. Performance of six types of oxygen delivery devices at varying respiratory rates. Anaesthesia, 2007;62(5):492-503. (PubMed: 17448063. 33. Branson RD, Hess DR, Chatbum RL. Respiratory Care Equipment. Philadelphia, PA: Lippincott; 1995. 34, Roca ©, Riera J, Torres F, Masclans JR. High-flow oxygen therapy in acute respiratory failure, Respir Care. 2010;55(4):408-413. (PubMed: 20406507) 35. Lee JH, Rehder KJ, Williford L, Cheifetz IM, Tumer DA. Use of high flow nasal cannula in critically il infants, children, and adults: critical review of the literature. Intensive Care Med, 2013;39(2)247-257. PubMed: 23143331 36. Cullen DL, Long term oxygen therapy adherence and COPD: what we don’t know, Chron Respir Dis. 2006;3(4)217-222. (PubMed: 17190126) 37. Siverman D, Gendreau M. Medical issues asso (PubMed: 19232708 38, Christopher KL, Schwartz MD. Transtracheal oxygen therapy. Chest, 201 1;139(2)435-440. PubMed: 21285058: 39. Burton GG, Wagshul FA, Henderson D, Kime SW. Fatal airway obstruction caused by a mucous ball froma transtracheal oxygen catheter. Chest, 1991;99(6):1520-1523. [PubMed: 2036843] 40 Becker-Freysang H (1950) Physiological and pathophysiological effects of increased oxygen tension. In German Aviation Medicine in World War II, Volume 1 (pp. 493-514). Washington, DC: Department of the Air Force. 41. Dokzal_V. The effet of longlasting oxygen inhalation upon respiratory parameters in man. Physiol Bohemoslov. ted with commercial fights, Lancet, 2009;373(9680):2067-2077, Frank L, Bucher JR, Roberts RJ. Oxygen toxicity in neonatal and adult animals of various spe Respir Environ Exere Physiol. 1978;45(5):699-704. J Appl Physiol aptsvano1e (PubMed: 730565, 4B. Freeman BA, Crapo JD. Biology of disease: five radicals and tissue injury. Lab Invest. 1982:47(5):412-426. (PubMed: 6290784) 44. Fridovich I. Superoxide dismutases. Adv Enzymol Relat Areas Mol Biol. 1986;58:61-97. (PubMed: 35212181 45. Cantin AM, North SL, Hubbard RC, Crystal RG, Normal alveolar epithelial lining fd contains high levels of glutathione, J Appl Physiol (1985). 1987;63(1):152-157. (PubMed: 3040659) 46. Ouy TD, Chang LY, Marklund SL, Day BJ, Crapo JD. Immumocytochemical localization of extracellular superoxide dismutase in human ling. Lab Invest, 1994;70(6):889-898, PubMed: 8015293 47. Carlsson LM, Jonsson J, Edlund T, Markhmd SL. Mice lacking extracellular superoxide dismutase are more sensitive to hyperoxia, Proc Natl Acad Sci U $ A. 1995;92(14):6264~6268, PubMed: 7603981 48 Matute-Bello G, Frevert CW, Martin TR. Animal models of acute hung injury. Am J Physiol Lung Cell Mol Physiol. 2008;295(3)1379-1399. (PubMed: 18621912) 49. Caldwell PR, Lee WL Jr, Schildkraut HS, Archibaki ER. Changes in hing volume, diffusing capacity, and blood gases in men breathing oxygen. J Appl Physiol. 1966;21(5):1477—1483 (PubMed: 5923218] 50. Sackner MA, Landa J, Hirsch J, Zapata A. Pulmonary effects of oxygen breathing, A 6-hour study in normal men, ‘Amn Intem Med, 1975;82(1)40-43, PubMed: 1235760) SL, Carvalho CR, de Paula Pinto Schettino G, Maranhio B, Bethlem EP. Hyperoxia and lung disease. Curr Opin Pulm Med. 1998;4(5)300-304 [PubMed: 10813206] 52. Hayes D Jr, Feo DJ, Murphy BS, Shook LA, Ballard HO, Pathogenesis of bronchopulmonary dysplasia Respiration, 2010;79(5)425-436. (PubMed: 19786727) 53. Downs JB, Has oxygen administration delayed appropriate respiratory care? Fallacies regarding oxygen therapy. Respir Care. 2003;48(6):611~620. (PubMed: 12780949) 34, Joyce CJ, Williams AB. Kinetics of absorption atelectasis during anesthesia: a mathematical model. J Appl Physiol (1985), 1999;86(4):1 116-1125. (PubMed: 10194192 38. 28081svano1e Benoit Z, Wicky S, Fischer JF, ef al The efféct of'increased FIO(2) before tracheal extubation on postoperative atelectasis. Anesth Analg, 2002:95(6):1777-1781, table of contents. PubMed: 12456458 56. Hedenstiema G, Edmark L. Mechanisms of atelectasis inthe perioperative period. Best Pract Res Clin Anaesthesiol. 2010;24(2):157-169. (PubMed: 20608554] 57. Donald KW. Neurological effects of oxygen. Lancet. 1949;2:1056-1057, 58. Johnson JE, Peacock MD, Hayes JA, Morris MJ, Anders GT, Blanton HM. Forced expiratory flow is reduced by 100% oxygen in patients with chronic obstructive pulmonary disease. South Med J. 1995;88(4)443-449, PubMed: 7716598] 59. Barber RE, Hamilton WK. Oxygen toxicity in man, A A/Barber RE, Lee J, Hamilton WK: Oxygen toxicity in man, A prospective study in patients with irreversible brain damage. N Engl J Med. 1970;283(27):1478-1484. PubMed: 4921729} 60. Singer MM, Wright F, Stanley LK, Roe BB, Hamilton WK. Oxygen toxicity in man, A prospective study in patients afler open-heart surgery. N Engl J Med, 1970;283(27):1473—1478, (PubMed: 4921728] 61. Clark RH, Gerstmann DR, Jobe AH, Moffitt ST, Slutsky AS, Yoder BA. Lung injury in neonates: causes, strategies for prevention, and long-term consequences. J Pediatr, 2001;139(4)478-486. (PubMed: 11598592] 62. Meadors M, Fhyd J, Perry MC. Pulmonary toxicity of chemotherapy. Semin Oncol, 2006;33(1)98-105. PubMed: 16473648 6 Tryka AF, Skomik WA, Godleski JJ, Brain JD, Potentiation of bleomycin-induced hing injury by exposure to 70% oxygen. Morphologic assessment, Am Rev Respir Dis, 1982;126(6):1074-1079. PubMed: 6185024) 64, Nygaard K, Smith-Erichsen N, Hatkvoll R, Refum SB. Pulmonary complications after bleomycin, radiation and surgery for esophageal cancer. Cancer. 1978;41(1):17-22. (PubMed: 75052] 65, Gilson AJ, Sahn SA. Reactivation of bleomycin lng toxicity following oxygen administration, A second response to corticosteroids. Chest. 1985;88(2):304—306. (PubMed: 2410201 66. Donat SM, Levy DA. Bleomycin associated pulmonary toxicity: is perioperative oxygen restriction necessary? J Urol. 1998;160(4):1347-1352. (PubMed: 9751352) 67. Gawarammana IB, Buckley NA. Medi 757. PubMed: 21615775: | management of paraquat ingestion. Br J Clin Pharmacol. 2011;72(5):745— 2981santa 68. Pratt IS, Keeling PL, Smith LL. The effect of high concentrations of oxygen on paraquat and diquat toxicity in rats. Arch Toxicol Suppl. 1980;4:415-418, PubMed: 6933951 69. Hoet PH, Demedts M, Nemery B. Efigcts of oxygen pressure and medium volume on the toxicity of paraquat in rat and human type II pneumocytes. Hum Exp Toxicol, 1997;16(6)305—310. PubMed: 9219025 70. Huang NC, Lin SL, Hmg YM, Hung SY, Chung HM. Severity assessment in acute paraquat poisoning by analysis of APACHE Il score. J Formos Med Assoc. 2003;102(11):782—787. (PubMed: 147247241 1. Forman HJ, York JL, Fisher AB. Mechanism for the potentiation of oxygen toxicity by disulfiram, J Pharmacol Exp ‘Ther. 1980:212(3):452-455. PubMed: 6244385 2. Boyd MR, Catignani GL, Sasame HA, Mitchell JR, Stiko AW. Acute pulmonary injury in rats by nitrofirantoin and modification by vitamin E, dietary fat, and oxygen. Am Rev Respir Dis. 1979;120(1):93-99. (PubMed: 464388) 2B. Deneke SM, Gershoff SN, Fanburg BL. Potentiation of oxygen toxicity in rats by dietary protein or amino acid deficiency. J App! Physiol Respir Environ Exere Physiol. 1983;54(1):147-151. (PubMed: 6826398 74, Cohen-Addad N, Bollinger R, Chou J, Poland R. Vitamin A deficiency and pulmonary oxygen toxicity morphometric studies in the murine lung. Pediatr Res. 1988;23(1):76-80. PubMed: 3340450 15. Yamaoka S, Kim HS, Oghara T, et al Severe Vitamin E deficiency exacerbates acute hyperoxic lung injury associated with increased oxidative stress and inflammation, Free Radic Res. 2008;42(6):602-612. (PubMed: 18569018 16. Kilgannon JH, Jones AE, Shapiro NI, et al; Emergency Medicine Shock Research Network (EMShockNet) Investigators. Association between arterial hyperoxia following resuscitation from cardiac arrest and in-hospital mortality. JAMA. 2010;303(21)2165-2171. (PubMed: 205164171 71 Bremer M, Stein D, Hu P, Kuftra J, Wooford M, Scalea T. Association between early hyperoxia and worse outcomes after traumatic brain injury. Arch Surg, 2012;147(11):1042-1046. (PubMed: 228019941 8. Rawles JM, Kenmure AC, Controlled trial of oxygen in uncomplicated myocardial infarction. Br Med J. 1976;1(6018):1121-1123 (PubMed: 773507] 79. Reinhart K, Bloos F, Konig F, Bredle D, Hannemann L. Reversible decrease of oxygen consumption by hyperoxia. Chest. 1991;99(3):690-694sazoi6 (PubMed: 1995227) undefined MeGraw Hill Copyright © McGraw-Hill Global Education Holdings, LLC. Allrights reserved, ‘Your IP address is 172.22.1.124 Access Provided by: Universidad del Norte ‘Silverchair sist