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Oxygen therapy and toxicity
Vet Clin Small Anim 32 (2002) 1005–1020
Oxygen therapy and toxicity Ann Marie Manning, DVM Emergency and Critical Care, The Angell Memorial Animal Hospital, 350 South Huntington Street, Boston, MA 02130, USA
Oxygen (O2) supplementation increases the O2 content of blood, increases the partial pressure of oxygen (PO2) in the capillary blood, and improves tissue delivery of O2. In addition to improving tissue oxygenation, the administration of O2 may improve the function of O2-dependent cellular systems, such as the cytochrome P450 system, which is important to drug and toxin metabolism; nitric oxide synthase, which regulates vasodilation; and host defense systems. Improved tissue oxygenation is also beneficial for wound healing. Given the important contributions that supplemental O2 can make, it is no wonder that O2 is one of the most common drugs administered in the emergency and intensive care settings. The physiology of oxygenation The important steps of oxygenation are O2 uptake, diffusion, delivery, and consumption (metabolism). Because not all diseases that cause O2 deprivation are responsive to O2 therapy, the clinician must possess a basic understanding of O2 physiology, the mechanisms that control O2 delivery to the tissues, and the various circumstances that produce hypoxia. This understanding enables the clinician to determine which patients are deprived of O2 and how best to correct the situation. The following section is a brief review of O2 physiology followed by the various causes of hypoxia and their responsiveness to O2 supplementation. Oxygen uptake and diffusion O2 uptake begins with the extraction of O2 from the environment during respiration followed by the movement of O2 into the lungs, which serve as part of the O2 delivery system. With inhalation of atmospheric air (room air), the fraction of inspired O2 (FIO2) is equal to 21%. The PO2 of inhaled E-mail address: [email protected] (A.M. Manning). 0195-5616/02/$ - see front matter 2002, Elsevier Science (USA). All rights reserved. PII: S 0 1 9 5 - 5 6 1 6 ( 0 2 ) 0 0 0 4 3 - 8
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O2 at sea level is equal to 159 mm Hg. The PO2 decreases progressively as it traverses the lung, blood, and tissues, and this process is known as the O2 cascade [1]. The PO2 initially decreases from 159 mm Hg to 149 mm Hg when inspired air is warmed and humidified by the mucous membranes in the nasal passages and upper airways. As air passes into terminal bronchioles and alveoli, O2 is diluted by carbon dioxide (CO2) and the PO2 decreases to 99 mm Hg. From the alveoli, O2 must diffuse across surfactant, alveolar epithelium (pneumocytes I and II), basement membrane, capillary basement membrane, and endothelial membrane of pulmonary capillaries before reaching the erythrocyte [2]. The PO2 in the alveoli is equal to 99 mm Hg compared with a PO2 of 40 mm Hg in pulmonary venous blood [3]. The difference of 59 mm Hg between alveolar air and venous blood provides the driving pressure that enables O2 diffusion to occur. Oxygen delivery O2 diffuses into the plasma of pulmonary capillaries and then into red blood cells, where it combines reversibly with the iron atom of hemoglobin (Hb) and converts deoxyhemoglobin to oxyhemoglobin. Each Hb binds four O2 molecules, and each gram of Hb can transport 1.36 mL of O2 when fully saturated. With this information, it is possible for the clinician to calculate the arterial oxygen content (CaO2), which is the sum of O2 dissolved in plasma and O2 chemically bound to Hb. CaO2 can be calculated using the following equation: Cao2 ¼ Bound O2 þ Dissolved O2 ¼ ðHb 1:36 Sao2 Þ þ ðPao2 0:0031Þ where SaO2 is arterial blood oxygen saturation, PaO2 is the partial pressure of arterial oxygen, and 0.0031 is the Bunsen coefficient. Under optimal conditions, arterial blood with a PaO2 of 100 mm Hg and complete saturation of Hb at a concentration of 15 g/dL would contain 200 mL of O2 per liter of blood [1]: Cao2 ¼ ð15 1:36 10Þ þ ð100 0:0031Þ Cao2 ¼ 200 mL From this equation, it is clear that the O2 dissolved in plasma (PaO2 · 0.0031) contributes little to O2 content unless there is increased cardiac output in the presence of severe anemia or unless hyperbaric O2 therapy is used, in which case, the PaO2 can be raised substantially. Total O2 content is thus mainly dependent on Hb concentration and SaO2. Hemoglobin and the oxyhemoglobin dissociation curve Hb is the primary O2 carrier in the circulating blood, and myoglobin is the primary O2 reservoir in muscle tissue. Hb has a high affinity for O2 at
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high O2 tension in the lungs and is able to release O2 at low O2 tension in the tissues. The oxyhemoglobin dissociation curve (Fig. 1) illustrates the relation between O2 and Hb at varying O2 tensions or, more accurately, describes the saturation of Hb with O2 as determined by the concentration of O2. The shape of the curve is sigmoidal and results from the conformational changes in the Hb molecules that occur during uptake and release of O2 [3,4]. The flat portion of the curve is an area of high PO2 (greater than 100 mm Hg). The steep portion of the curve is the physiologic range of PO2 (30–100 mm Hg). The affinity of O2 for Hb is influenced by many physiologic changes. Decreased affinity of Hb for O2 (a right shift in the curve) facilitates the release of O2 to the tissues. A right shift is seen with acidosis, hyperthermia, exercise, increased partial pressure of CO2 (PCO2), and increased 2,3-diphosphoglycerate (2,3-DPG) concentrations in the red cells, as occurs when there is insufficient O2 delivery to the tissues (e.g. anemia, altitude) lasting longer than 3 to 4 hours. Increased affinity of Hb for O2 (left shift) facilitates O2 loading into the blood in the alveoli. A left shift is seen with alkalosis, hypothermia, decreased 2,3-DPG levels, carbon monoxide (CO) poisoning, and hypocarbia [3,4]. Under normal physiologic conditions, near maximum Hb saturation is achieved at a PO2 of 75 to 80 mm Hg.
Total oxygen delivery Total O2 delivery (DO2) may also be calculated as the product of cardiac output and CaO2 [5]: Do2 ¼ Cao2 Cardiac Output ¼ 200 mL=L 5 L=min ¼ 1000 mL
Fig. 1. The oxyhemoglobin dissociation curve. Point a represents the flat portion of the curve, where hemoglobin is maximally bound with oxygen. Point b represents the physiologic range of the partial pressure of oxygen.
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Approximately 1000 mL of O2 leaves the left ventricle each minute and is distributed to regional vascular beds. When supply is adequate, O2 consumption is a function of metabolic rate and there is a wide margin between supply and demand. Normal systemic O2 consumption is 250 mL/min (25% of O2 transport), and the remaining 750 mL of O2 returns to the right heart in venous blood [3]. Only a small fraction of O2 is extracted from the capillary blood under normal conditions. In situations of low blood flow, the tissues have the ability to compensate by increasing O2 extraction. Oxygen consumption Once O2 enters the cell, it diffuses down a gradient into the mitochondria. The main location for O2 unloading is in the tissue capillaries, and O2 delivery maintains an interstitial PO2 of 20 to 40 mm Hg [3]. The mitochondria consume 80% to 90% of the O2, and 10% to 20% is consumed by subcellular organs. The mitochondria use O2 to produce energy through oxidative phosphorylation. Oxygen deprivation There are four physiologic situations that cause cells to convert from aerobic to anaerobic metabolism with the production of lactic acid: 1. Increased metabolic demand or O2 consumption generated by fever, shivering, seizures, or strenuous exercise may produce acidosis if the O2 supply is unable to meet demand. 2. Hypoxia, cardiac pump failure, and severe anemia create a deficient supply of O2, resulting in conversion from aerobic to anaerobic metabolism. 3. Uncoupling of oxidative phosphorylation, as occurs with cyanide poisoning, blocks cellular metabolism and stops O2 utilization. 4. Loss of microcirculatory autoregulation, as occurs in sepsis, leaves tissues with inadequate O2 to meet metabolic demands. Central and local mechanisms protect tissue oxygenation via shifts in the O2 dissociation curve and regulation of local blood flow. Hypoxia results if these mechanisms fail. Tissue hypoxia occurs if the intracellular PO2 is less than10 mm Hg or if the mitochondrial PO2 is less than 6 to 7mm Hg [6]. Insufficient O2 delivery is secondary to hypoxemia or inadequate blood flow. Indications for oxygen therapy Clinical signs of oxygen deprivation The decision to administer supplemental O2 is often based on several factors, including clinical signs, results of diagnostic tests (e.g. arterial blood
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gas and pulse oximeter measurements), and the patient’s clinical disease. Clinical signs of hypoxia include cyanosis, dyspnea, tachypnea, tachycardia, anxiety, postural changes, and central nervous system (CNS) depression [7– 9]. Greater than 5 g/dL of deoxygenated Hb must be present in the circulating blood before cyanosis can be detected [7,9,10]. Therefore, a patient may be hypoxic without obvious cyanosis. Tachycardia is a common finding as cardiac output is increased through stimulation of carotid body chemoreceptors and activation of the sympathetic nervous system in an attempt to circulate the available pool of Hb more quickly. Postural changes include abduction of the elbows (orthopneic stance), extension of the head and neck, recruitment of abdominal muscles, and open-mouth breathing. Patients with severe hypoxia may experience collapse or mental confusion or may become comatose. There are many disease conditions that can produce hypoxia, and recognition of these conditions should prompt the clinician to consider the need for supplemental O2 therapy. The response to O2 therapy is variable or nonexistent depending on the cause of hypoxia, however. The following is a discussion of the types of hypoxia, associated disease conditions, and their responsiveness to O2 supplementation. Categories of hypoxia Anoxic hypoxia Anoxic hypoxia is the inadequate delivery of O2 from the lungs to the blood, resulting in reduced arterial O2 content. This form of hypoxia may result from five different pathophysiologic causes, which include a low FIO2, hypoventilation, diffusion impairment, ventilation/perfusion (V/Q) mismatch, and pulmonary shunt. A PO2 in inspired gas/air (low FIO2) causes diminished arterial O2 content and may be caused by inadequate O2 delivery to patients receiving anesthesia or mechanical ventilation, excessive rebreathing of dead space gas, or high-altitude sickness [1]. This form of hypoxia can be corrected easily with administration of supplemental O2. Alveolar hypoventilation occurs when chest wall excursions are insufficient to achieve adequate lung inflation and gas exchange. CO2 replaces O2 in poorly ventilated alveoli, and the PaO2 decreases. Alveolar hypoventilation may result from peripheral neuromuscular disease, CNS disorders, cervical spinal cord lesions, oversedation, thoracic wall defects, rib fractures, or pleural space disease [8,11]. Supplemental O2 administration helps temporarily in this situation, but if the underlying problem cannot be remedied in a timely fashion, many of these patients require mechanical ventilation to reduce severe hypoventilation. Diffusion impairment occurs when the alveolar-capillary membrane interface thickens or the surface area available for diffusion decreases, as may occur with interstitial pulmonary edema, pulmonary interstitial fibrosis, chronic emphysema, and adult respiratory distress syndrome (ARDS) [2].
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This form of hypoxia is responsive to supplemental O2 administration, because O2 administration increases the driving pressure for O2. V/Q mismatch occurs when alveolar ventilation and pulmonary blood flow are not uniform. The degree of V/Q mismatch is dependent on whether ventilation or perfusion predominates. Pulmonary thromboembolism is an example of high V/Q mismatch, where regions of the lung are ventilated but are not perfused, increasing physiologic dead space. This form of V/Q mismatch responds well to supplemental O2 administration. Low V/Q mismatch is an inadequate supply of O2 to alveoli in the presence of normal perfusion [12]. This type of V/Q mismatch is seen commonly with pulmonary edema, pulmonary contusions, pneumonia, asthma, and pulmonary neoplasia. Response to O2 supplementation is generally poor to fair in cases of low V/Q mismatch. An extreme form of low V/Q mismatch exists with shunts in which perfusion occurs in the absence of ventilation. This type of V/Q mismatch occurs in several disease states, such as severe cardiogenic or noncardiogenic pulmonary edema, severe pneumonia, lung atelectasis, lung lobe torsion, and right-to-left cardiac shunts. Because the shunted blood makes no contact with ventilated lung units, supplemental O2 administration provides no benefit. In both types of low V/Q mismatch, however, if mechanical ventilation with positive end-expiratory pressure (PEEP) is provided, loss of alveolar gas volume may be relieved and supplemental O2 may be efficacious. Anemic hypoxia and dyshemoglobinemias Anemic hypoxia results when an inadequate quantity of Hb (<7 g/dL) is available to transport a sufficient supply of O2 for metabolism, Hb is present but rendered nonfunctional by conformational changes in the Hb molecule, or O2 binding to the Hb molecule is blocked. Anemic patients can generally tolerate Hb concentrations as low as 7 g/dL by increasing cardiac output to maintain O2 delivery. If myocardial function is limited or if O2 consumption exceeds a patient’s ability to increase cardiac output, hypoxemia develops. Because of limited cardiac reserves, patients with myocardial disease generally cannot tolerate an Hb concentration below 10 to 11 g/dL. Patients with anemic hypoxia benefit minimally from supplemental O2 therapy, because their Hb is already fully saturated, and any increase from O2 dissolved in plasma (PaO2 · 0.0031) is minor. Methemoglobinemia (metHb), such as that occurring with acetaminophen toxicity, is an example of a conformational change that renders Hb nonfunctional. Methemoglobin causes the iron component of the heme molecule to be oxidized from its normal ferrous state (Fe2+) to the ferric state (Fe3+), rendering it incapable of O2 binding. Patients can generally tolerate methemoglobin levels up to 15% to 20%, but levels greater than 30% produce signs of cyanosis, dyspnea, and discoloration of the blood [6]. Methemoglobin levels greater than 80% are often associated with death.
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A methemoglobin level of 1.5 g/dL creates the same effect as decreasing Hb by 5 g/dL. O2 administration in cases of metHb is generally ineffective because O2 binding to Hb is blocked, but some improvement may be seen as a result of the slight increase in the fraction of O2 dissolved in the plasma. CO poisoning demonstrates how access to the heme molecule may be blocked. CO has 218 times the affinity for Hb that O2 has, and once bound, carboxyhemoglobin (HbCO) is quite stable [3,4]. The presence of HbCO shifts the O2 Hb dissociation curve to the left, which increases the affinity of O2 for Hb in the lungs but decreases its ability to be released to the tissues, and tissue hypoxia results [4]. Clinical symptoms appear when HbCO levels exceed 20% and become severe when levels reach 30% to 40% [6]. Increasing the concentration of inspired O2 adds little O2 to Hb but increases the amount of O2 dissolved in plasma. Recommendations in human patients with CO poisoning include provision of 100% oxygen for 20 to 30 minutes and/or hyperbaric O2 therapy to increase the PO2, and thus the driving pressure for O2, which displaces CO from the heme molecule. Stagnant hypoxia Stagnant hypoxia results from inadequate O2 delivery to tissue because of low blood flow. Common causes of stagnant hypoxia include pump failure (cardiogenic shock) and loss of circulating volume as seen with hemorrhage or significant intravascular dehydration. Although O2 therapy may be slightly beneficial in these patients, this form of hypoxia is best corrected by intravascular fluid resuscitation or improved cardiac function rather than by O2 administration alone [13]. Histiocytic hypoxia Histiocytic hypoxia results from the cell’s inability to use O2. Prolonged use of nitroprusside, a balanced vasodilator used in the intensive care setting, may lead to formation of cyanide as a byproduct of its metabolism. Cyanide poisons the electron transport system so that cells are unable to utilize O2, and metabolic acidosis results. O2 administration is of no benefit in this situation. Rather, therapy should be directed at cyanide removal to correct the problem.
Modes and techniques for oxygen delivery A number of devices are available for O2 delivery, and the method chosen should be based on the desired FIO2, equipment availability, and anticipated treatment duration as well as the patient’s clinical condition, size, and temperament. Any O2 delivery system that causes patient resistance may create the undesirable side effect of increasing O2 demand and consumption. Table 1 summarizes the various O2 delivery systems, the FIO2 that may be achieved with each system, and the O2 flow rate required to reach the target
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Table 1 Fraction of inspired oxygen (FIO2) achieved with various oxygen delivery systems Target FIO2
Device
0.24–0.45 0.30–0.50 0.35–0.55 0.40–0.50 0.50–0.90 0.21–1.00
Flow-by Nasal catheter Face mask Oxygen cage Reservoir mask Continuous positive airway pressure
Oxygen flow (liters/minute) 6–8 1–6 6–10 5–15 10–15
FIO2. Each of these systems is discussed in further detail in the following section. Flow-by oxygen This method of O2 supplementation is perhaps the easiest in an emergency situation while attempts are being made to stabilize the patient. The O2 line is placed within 1 to 3 cm of the patient’s nose and mouth, creating a small area of increased FIO2. An FIO2 of approximately 0.25 to 0.45 may be achieved in this way with little stress to the patient. The drawbacks to this method are that it requires a care provider to be present to hold the delivery system and to ensure that the patient does not move away from the O2 source, it requires a high O2 flow rate that is potentially wasteful, and it creates rapid airflow that disturbs some patients so that they avoid the O2 source. Face mask O2 delivery by face mask is a useful short-term method for O2 supplementation in emergency situations. With a well-fitted mask and the O2 flow rate set at 6 to 10 L/min, an FIO2 of 0.35 to 0.55 may be achieved [1,10]. The presence of a reservoir bag increases the amount of O2 available for inhalation and may raise the FIO2 as high as 0.5 to 0.8 at an O2 flow rate of 8 to 10 L/ min [1,5,10]. The disadvantages of this method include gas leakage from poorly fitted masks (particularly in cats and brachycephalic breeds), poor elimination of CO2, and lack of patient cooperation. Nasal catheter The use of a nasal catheter allows for more prolonged O2 delivery and permits access to the patient for examination and treatment purposes without loss of the O2-rich environment as can occur with use of an O2 cage. A potential drawback to this method of supplementation is that the FIO2 cannot always be determined accurately [11]. O2 delivery through a nasal catheter can achieve an FIO2 of 0.3 to 0.5 with an O2 flow rate of 100 to
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150 mL/kg/min (1–6 L/min) [14]. Use of bilateral nasal catheters may increase the target FIO2 to 0.7. The appropriate O2 flow rate is based on patient size, respiratory rate, respiratory pattern, and degree of open-mouth breathing. In general, a higher FIO2 is achieved in patients with tachypnea and low tidal volumes than in those patients with a normal respiratory rate at the same flow rate. Additionally, each liter per minute increase in O2 flow raises the FIO2 by 3% to 4% [1–5,8,11,13–18]. Placement of the nasal O2 catheter is relatively easy. The clinician should premeasure the catheter the distance from the nostril to the medial canthus of the eye and clearly mark this point. A small amount of topical anesthetic (2% lidocaine jelly [Proparacaine]) is introduced into one nostril, and a welllubricated, soft, rubber catheter (5–10 French) is passed ventromedially into the nostril and into the ventral meatus. The catheter is advanced to the predetermined level of the medial canthus and secured to the skin at the nares with adhesive glue, suture, or a single staple. A second site on the forehead or ventral to the ear is chosen to secure the length of the catheter [14,19]. An adaptor allows connection of the nasal catheter to the tubing from a humidified O2 source. Placement of an Elizabethan collar is often necessary to prevent the patient from removing the nasal catheter. Problems with this method of O2 delivery include poor patient tolerance, jet damage to the nasal mucosa, desiccation of the nasal mucosa, and gastric dilatation [14]. When a unilateral nasal catheter is used, the catheter should be replaced with a new catheter in the opposite nares every 48 hours so as to reduce damage to the airway. Oxygen cage An O2 cage provides a sealed environment, where the FIO2, humidity, and ambient temperature can be manipulated in a predictable manner and CO2 can be removed efficiently [9]. Most commercially available cages are capable of providing a maximal FIO2 of 0.4 to 0.5 and allow the ambient temperature to be maintained optimally at 22C (70F) with a relative humidity of 40% to 50% [7,9,10]. Desirable O2 cages would have a Plexiglas front to allow complete visualization of the patient and access ports for entry and exit of intravenous lines and monitoring leads. Cages that have doors within doors or plastic sleeves allow manipulation of the patient without creating enormous O2 loss from the cage. The major advantage of the O2 cage is that it is a noninvasive means of providing O2 support to a critically ill animal. The disadvantage of the O2 cage is isolation of the patient from the clinician, which precludes frequent hands-on evaluation. Each time the cage door is opened to access the patient, loss of the O2-rich environment occurs and the patient may decompensate [14]. The amount of O2 required to fill the cage and the amount of O2 lost with each entry into the cage make this form of O2 supplementation relatively wasteful and expensive.
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Elizabethan collar canopy Utilization of an Elizabethan collar covered with plastic wrap may create a miniature O2-enriched environment. The Elizabethan collar is secured around the patient’s neck, and the end of an O2 line is fed into the collar and secured. A small hole in the top corner of the plastic facing is created to allow elimination of CO2 and to help modulate the temperature within. This is a temporary method of O2 delivery that can achieve an FIO2 of 0.3 to 0.4 with an O2 flow rate of 0.2 to 0.5 L/min [7,8]. Although this method of O2 delivery is easy to use in an emergency situation, disadvantages, such as O2 leakage, high humidity, hyperthermia, and patient intolerance, preclude its use in the long term. Intratracheal catheter Intratracheal or transtracheal catheters improve O2 delivery by bypassing anatomical dead space and allow for continuous O2 delivery at low O2 flow rates [18,20]. This form of O2 supplementation can achieve an FIO2 of 0.4 to 0.6 at an O2 flow rate of 50 mL/kg/min [7,9,10,18]. Placement of an intratracheal catheter is similar to performing a transtracheal wash. The selected insertion site is clipped and surgically prepared, and a small bleb of local anesthetic (2% lidocaine) is instilled at the site. A long, large-gauge, flexible catheter is used, the end of which is fenestrated before insertion to reduce jet damage to the trachea. The needle of the catheter is introduced percutaneously through the cricothyroid ligament in cats and small dogs or between two tracheal rings in larger dogs, and the catheter tip is fed to the level of the fifth intercostal rib space (just cranial to the carina) [19]. The needle is withdrawn, covered with a needle guard, and secured in place with a neck wrap, taking care to avoid kinking of the catheter. The end of the catheter is then attached to a humidified O2 source. Use of an intratracheal catheter for O2 supplementation is inexpensive, generally well tolerated by the patient, and allows easy access to the patient. Potential disadvantages include catheter kinking at the insertion site, subcutaneous emphysema, jet damage to airway mucosa, tracheitis, bronchospasm, infection at the insertion site, and airway obstruction as a result of excessive mucus accumulation. This is also a more invasive procedure than placement of a nasal catheter and may require sedation of the patient to allow placement. Mechanical ventilation Mechanical ventilation becomes necessary when a patient is unable to sustain a PaO2 greater than 60 mm Hg through its own efforts, despite conventional O2 supplementation [9]. Patient failure may result from respiratory fatigue, respiratory arrest, intracranial disease, or hypoventilation of any cause [8]. Likewise, any patient that is struggling to maintain a PaO2
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between 60 and 65 mm Hg and cannot rest because of respiratory effort would benefit from mechanical ventilation. Additionally, patients that require O2 supplementation at an FIO2 greater than 0.6 for more than 24 hours are at risk for O2 toxicity. Mechanical ventilation with application of PEEP may allow the FIO2 to be reduced to a safer level, thereby decreasing the risk for toxicity.
Monitoring oxygen therapy Improvement in the clinical condition of the patient is a sufficient means of determining response to O2 therapy in lieu of other diagnostics. Patients that respond favorably to O2 supplementation generally show improved mucous membrane color, decreased respiratory rate and effort, and reduced anxiety. Diagnostic tests like arterial blood gas measurements and pulse oximetry provide more objective means to monitor the efficacy of O2 supplementation. An arterial blood gas measures the amount of oxygen (PaO2) and carbon dioxide (PaCO2) in the arterial blood. This information allows the clinician to determine the effectiveness of gas exchange and efficacy of supplemental O2 therapy. A PaO2 less than 70 mm Hg and/or a PaCO2 greater than 45 mm Hg signals the need for supplemental O2, whereas a PaO2 less than 60 mm Hg and/or a PaCO2 greater than 50 mm Hg indicates respiratory failure and the need for ventilatory support. During O2 supplementation, the expected PaO2 should be five times the FIO2 (eg, at an FIO2 ¼ 40%, the expected PaO2 ¼ 40 · 5 ¼ 200 mm Hg). Any value lower than the expected value indicates a problem with gas exchange. An arterial blood gas may be obtained from the femoral artery, the dorsal metatarsal artery, or, in the anesthetized patient, the lingual artery. The major drawback to this method of assessment is that arterial blood gases can be difficult to obtain and may be stressful to critically ill patients. Determination of the alveolar-arterial gradient (A-a gradient) is another useful calculation that can be made with the information provided by the arterial blood gas. Calculation of the A-a gradient assesses the severity of V/Q mismatch. The A-a gradient may be calculated using the following formula: A-a Gradient ¼ Pao2 Pao2 ¼ ðFio2 ½PB PH2 O 1:2 Paco2 Þ Pao2 where FIO2 is the fraction of inspired oxygen, PB is the barometric pressure, PH2O is the vapor pressure of water, PaO2 is the alveolar partial pressure of oxygen, PaO2 is the arterial partial pressure of oxygen, and PaCO2 is the arterial partial pressure of carbon dioxide [7,21]. In the normal patient, where ventilation and perfusion are matched, the A-a gradient is less than 10 mm Hg.
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Pulse oximetry is a simple noninvasive method for continuous or intermittent monitoring of oxygen saturation (SaO2) or the percentage of oxyhemoglobin in the blood. An SaO2 less than or equal to 93% indicates the need for O2 supplementation. Measurements are obtained by attaching a transducer to the lip, ear, and digit or, in the anesthetized patient, via a rectal or esophageal probe. The accuracy of pulse oximetry may be limited in many instances, and its use is discussed in further detail elsewhere in this issue. Complications of oxygen therapy Denitrogenation (absorption) atelectasis In areas of poor oxygenation (with adequate perfusion), alveoli are held open primarily by nitrogen rather than by O2. Because the body is saturated with nitrogen, there is no effective nitrogen gradient between mixed venous (pulmonary arterial) blood and the alveolus. Therefore, nitrogen remains in the alveolus, preventing its collapse. As O2 is administered to the patient, it displaces nitrogen in the alveolus so that O2 volume becomes the main factor holding the alveolus open. Now, as mixed venous blood flows past the same alveolus, O2 rapidly diffuses down its concentration gradient and enters the blood, leaving behind inadequate amounts of gas to hold the alveolus open, and the alveolus collapses. Thus, an adequately perfused but poorly ventilated lung unit becomes both poorly ventilated and poorly perfused after O2 administration [5,6]. This event is known as denitrogenation (absorption) atelectasis. Miscellaneous complications In patients with chronic respiratory disease and chronic CO2 retention, hypoxemia becomes the main stimulus for ventilation, because the sensitivity of central chemoreceptors is lost [12]. Supplemental O2 administration in these patients may cause acute deterioration because of suppression of their respiratory drive. These patients require positive-pressure ventilation rather than O2 supplementation alone. Other potentially deleterious effects of O2 supplementation include decreased erythropoiesis, reduced cardiac output, pulmonary vasodilation, and systemic arteriolar vasoconstriction [16,17,22]. O2 toxicity represents the most serious complication associated with supplemental O2 therapy. Oxygen toxicity When the administration of O2 occurs at levels that exceed biotransformation and clearance, toxicity occurs. O2 is a potent drug because it serves as an efficient electron acceptor in respiration and has a powerful oxidizing effect. When the mitochondrial and nonmitochondrial metabolism of O2 is
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saturated, clearance is limited and there is excessive accumulation of toxic O2 intermediates. Toxic O2 metabolites include superoxide (O2), hydrogen peroxide (HOOH), hydroperoxide (ROOH), and hydroxyl radical (HO) [15,23]. O2 radicals are produced at a low level during normal metabolism. These radicals are removed by the normal defense mechanisms, including superoxide dismutase, which acts to converts O2 to H2O2, and catalase and glutathione peroxidase, which clear H2O2 by sequential degradation to water. Glutathione peroxidase is also able to remove products of lipid peroxidation [6,23]. Other nonenzymatic antioxidants include vitamin A, vitamin C, alpha-tocopherol (vitamin E), N-acetylcysteine, b-carotene, urate, bilirubin, and hemoglobin [1,15,23]. During hyperoxia, the normal defense mechanisms are overwhelmed and O2 intermediates accumulate. The consequences of O2 toxicity include lipid peroxidation of cell membranes with loss of cell integrity, oxidation of sulfhydryl groups, alteration of enzyme function, protein structural damage, and impairment of transcription and replication of RNA resulting in defects of DNA cross-linking and nucleic acid damage [5,23]. The lungs are particularly sensitive to the effects of lipid peroxidation, and signs of pulmonary damage predominate in O2 toxicity. Pathophysiology of pulmonary oxygen toxicity Initially, hyperoxia causes endothelial cell damage and destruction of alveolar lining cells, increasing microvascular permeability [5]. Damage to the endothelium allows inflammatory precursors to enter the pulmonary interstitium, leading to alveolar edema, hemorrhage, and congestion. Polymorphonuclear cells adhere to the endothelial cells and generate chemotactic factors to attract more inflammatory cells. These early changes represent an exudative phase of pulmonary O2 toxicity. The early stages of pulmonary damage are characterized by proliferation of alveolar type I epithelial cells, a fibrin exudate, and a prominent alveolar membrane [17]. Blood is shunted away from areas of the lung where oxygenation is inadequate, and V/Q mismatch develops. In the late stages of O2 toxicity, alveolar type I epithelial cells are lost, alveolar type II epithelial cells and fibroblasts proliferate, the basement membrane is denuded, and fibrosis results. These changes represent a proliferative phase of pulmonary O2 toxicity [5,17]. Absorption atelectasis occurs secondary to inactivation of surfactant when O2 is rapidly taken into the pulmonary blood, thus worsening V/Q mismatch. Diagnosis of oxygen toxicity Clinical signs of O2 toxicity include tachypnea, dyspnea, nasal congestion, and a cough resulting from tracheobronchitis. Human patients experience chest pain, paresthesias, and anorexia in the early stages of O2 toxicity [17]. Diagnosis of O2 toxicity is difficult and is based on findings of edema or
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an infiltrative lung pattern on radiographs, a worsening gas exchange manifested as a progressively decreasing PaO2, and evidence of V/Q mismatch. Treatment of oxygen toxicity There is no effective treatment for O2 toxicity; therefore, prevention is most important. To decrease the risk for O2 toxicity, the clinician should adhere to the following guidelines: 1. 2. 3. 4.
Use a PaO2 of 70 as an endpoint for O2 therapy. Use the lowest FIO2 possible to achieve a PaO2 of 70. Do not use an FIO2 greater than 0.6 for longer than 24 hours. Use PEEP to help decrease the FIO2 as necessary. The use of PEEP maximizes the PaO2 at lower FIO2 levels.
Most injury is sustained with exposure to 24 to 48 hours of an FIO2 at 0.6 to 1.0 [5,19]. ARDS patients are more susceptible to O2 toxicity, because toxicity accelerates lung fibrosis; however, any patient with underlying lung injury is at higher risk for O2 toxicity than is a patient with normal lungs. In these patients, O2 toxicity may manifest at an FIO2 less than 0.6 and/or when supplemental O2 therapy has been provided for less than 12 to 24 hours [5]. Certain drugs may offer protection against O2 toxicity, such as vitamin E, vitamin C, b-carotene, mannitol, and N-acetylcysteine, all of which act as antioxidants [15]. Deferoxamine, an iron chelator, inhibits production of hydroxyl radicals by preventing activation of the Haber-Weiss reaction. Conversely, certain drugs have been shown to enhance O2 toxicity through their ability to increase tissue O2 consumption, cause increased production of free radicals through their metabolism, or decrease protective antioxidant systems. Such drugs include epinephrine, norepinephrine, steroids, cyclophosphamide, thyroid hormone, and nitrofurantoin. The effect of steroids on the development of O2 toxicity and their use in the treatment of O2 toxicity is controversial. Some reports indicate that steroids like dexamethasone decrease the levels of antioxidant enzymes and therefore potentiate injury, whereas other reports suggest that high doses of steroids are therapeutic in the late stages of O2 toxicity [6]. Based on this limited information, steroids should be avoided except in the late stages of toxicity. Future directions Future directions for O2 therapy include the use of O2-carrying Hb solutions. Hb-based O2 carriers administered intravascularly bind O2 in the lungs and deliver O2 to the tissues in exchange for CO2. Hb solutions have been shown to improve tissue O2 tension in cases of anemic hypoxia and stagnant hypoxia at room air (FIO2 ¼ 0.21). The use of Hb-based O2 carriers may reduce or completely eliminate the need for supplemental O2 at high FIO2 during conditions of anemic and stagnant hypoxemia, thus reducing the risk of O2 toxicity.
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Partial liquid ventilation with the use of perfluorocarbons is also an area of intensive ongoing investigation. Perfluorocarbons are inert liquids that are used to fill the pulmonary airspace and are employed in conjunction with mechanical ventilation or tracheal gas insufflation to improve oxygenation [24,25]. The advantages of perfluorocarbons are numerous and include facilitated opening of collapsed and noncompliant lung segments, reduced oxidative damage in acute lung injury, and diminished shear forces acting on lung parenchyma [24–26]. Perfluorocarbons may also function as ‘‘liquid PEEP’’ by preventing complete collapse of unstable alveoli at low airway pressures [24]. Use of partial liquid ventilation would also allow for lower FIO2 in patients at risk for O2 toxicity. Although partial liquid ventilation is still under investigation, it represents an exciting new direction for O2 therapy.
References [1] Ermakov S, Hoyt JW. Oxygen therapy and pharmacologic modulation of respiratory drive. In: Chernow B, editor. The pharmacologic approach to the critically ill patient. 3rd edition. Baltimore: Williams & Wilkins; 1994. p. 579–604. [2] Guyton AC, Hall JE. Physical principles of gas exchanges; diffusion of oxygen and carbon dioxide through the respiratory membrane. In: Textbook of medical physiology. 10th edition. Philadelphia: WB Saunders; 2000. p. 452–62. [3] Guyton AC, Hall JE. Transport of oxygen and carbon dioxide in the blood and body fluids. In: Textbook of medical physiology. 10th edition. Philadelphia: WB Saunders; 2000. p. 463–73. [4] Hsia C. Respiratory function of hemoglobin. N Engl J Med 1998;38:239–47. [5] O’Connor BS, Vender JS. Oxygen therapy. Crit Care Clin 1995;11:67–78. [6] Silverman HJ. Pharmacologic approach in patients with pulmonary failure. In: Chernow B, editor. The pharmacologic approach to the critically ill patient. 3rd edition. Baltimore: Williams & Wilkins; 1994. p. 114–38. [7] Camps-Palau AM, Marks SL, Cornick JL. Small animal oxygen therapy. Compend Contin Educ Pract Vet 1999;21:587–98. [8] Murtaugh RJ. Acute respiratory distress. Vet Clin North Am Small Anim Pract 1994; 24:1041–55. [9] Pascoe PJ. Oxygen and ventilatory support for the critical patient. Semin Vet Med Surg Small Anim 1998;3:202–9. [10] Drobatz KJ, Hackner S, Powell S. Oxygen supplementation. In: Bonagura JD, editor. Kirk’s current veterinary therapy XII. Philadelphia: WB Saunders; 1995. p. 175–9. [11] March PA. Neural regulation of respiration physiology and pathophysiology. Probl Vet Med 1992;4:387–404. [12] West JB, editor. Ventilation-perfusion relationships. In: Respiratory physiology: the essentials. 4th edition. Baltimore: Williams & Wilkins; 1995. p. 51–68. [13] Hayes MA, Timmins AC, Yau EHS, et al. Elevation of systemic oxygen delivery in the treatment of critically ill patients. N Engl J Med 1994;330:1717–22. [14] Fitzpatrick RK, Crowe DT. Nasal oxygen administration in dogs and cats: experimental and clinical investigations. J Am Anim Hosp Assoc 1986;22:293–300. [15] Halliwell B, Gutteridge JM. Oxygen toxicity, oxygen radicals, transition metals and disease. J Biochem 1984;219:1–14. [16] Haque WA, Boehmer J, Clemson BS, et al. Hemodynamic effects of supplemental oxygen administration in congestive heart failure. J Am Coll Cardiol 1996;27:353–7.
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[17] Jackson RM. Oxygen therapy and toxicity. In: Shoemaker WC, Ayres SM, Grenvik A, et al., editors. Textbook of critical care. 3rd edition. Philadelphia: WB Saunders; 1995. p. 784–9. [18] Mann FA, Wagner-Mann C, Allert JA, et al. Comparison of intranasal and intratracheal oxygen administration in healthy awake dogs. Am J Vet Res 1992;53:856–60. [19] Court MH. Respiratory support of the critically ill small animal patient. In: Murtaugh RJ, Kaplan PM, editors. Veterinary emergency and critical care medicine. St. Louis: Mosby Year Book; 1992. p. 575–92. [20] Tarpy SP, Celli BR. Long term oxygen therapy. N Engl J Med 1995;333:710–4. [21] West JB. Gas exchange. In: Pulmonary pathophysiology: the essentials. 4th edition. Baltimore: Williams & Wilkins; 1995. p. 18–40. [22] Rubanyi GM, Vanhoutte PM. Superoxide anions and hyperoxia inactivate endothelium derived relaxing factor. Am J Physiol 1986;250:H22–7. [23] Otto CM. Oxidative stress: too much oxygen. Proceedings of International Veterinary Emergency Critical Care 1998;6:523–8. [24] Blanch L, Van der Kloot TE, Youngblood AM, et al. Selective tracheal gas insufflation during partial liquid ventilation improves lung function in an animal model of unilateral acute lung injury. Crit Care Med 2001;29:2251–7. [25] Steinhorn DM, Papo MC, Rotta AT, et al. Liquid ventilation attenuates pulmonary oxidative damage. J Crit Care 1999;14:20–8. [26] Overbeck MC, Pranikoff T, Hirschl RB. Partial liquid ventilation provides effective gas exchange in a large animal model. J Crit Care 1996;11:37–42.
Oxygen therapy and toxicity Ann Marie Manning, DVM Emergency and Critical Care, The Angell Memorial Animal Hospital, 350 South Huntington Street, Boston, MA 02130, USA
Oxygen (O2) supplementation increases the O2 content of blood, increases the partial pressure of oxygen (PO2) in the capillary blood, and improves tissue delivery of O2. In addition to improving tissue oxygenation, the administration of O2 may improve the function of O2-dependent cellular systems, such as the cytochrome P450 system, which is important to drug and toxin metabolism; nitric oxide synthase, which regulates vasodilation; and host defense systems. Improved tissue oxygenation is also beneficial for wound healing. Given the important contributions that supplemental O2 can make, it is no wonder that O2 is one of the most common drugs administered in the emergency and intensive care settings. The physiology of oxygenation The important steps of oxygenation are O2 uptake, diffusion, delivery, and consumption (metabolism). Because not all diseases that cause O2 deprivation are responsive to O2 therapy, the clinician must possess a basic understanding of O2 physiology, the mechanisms that control O2 delivery to the tissues, and the various circumstances that produce hypoxia. This understanding enables the clinician to determine which patients are deprived of O2 and how best to correct the situation. The following section is a brief review of O2 physiology followed by the various causes of hypoxia and their responsiveness to O2 supplementation. Oxygen uptake and diffusion O2 uptake begins with the extraction of O2 from the environment during respiration followed by the movement of O2 into the lungs, which serve as part of the O2 delivery system. With inhalation of atmospheric air (room air), the fraction of inspired O2 (FIO2) is equal to 21%. The PO2 of inhaled E-mail address: [email protected] (A.M. Manning). 0195-5616/02/$ - see front matter 2002, Elsevier Science (USA). All rights reserved. PII: S 0 1 9 5 - 5 6 1 6 ( 0 2 ) 0 0 0 4 3 - 8
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O2 at sea level is equal to 159 mm Hg. The PO2 decreases progressively as it traverses the lung, blood, and tissues, and this process is known as the O2 cascade [1]. The PO2 initially decreases from 159 mm Hg to 149 mm Hg when inspired air is warmed and humidified by the mucous membranes in the nasal passages and upper airways. As air passes into terminal bronchioles and alveoli, O2 is diluted by carbon dioxide (CO2) and the PO2 decreases to 99 mm Hg. From the alveoli, O2 must diffuse across surfactant, alveolar epithelium (pneumocytes I and II), basement membrane, capillary basement membrane, and endothelial membrane of pulmonary capillaries before reaching the erythrocyte [2]. The PO2 in the alveoli is equal to 99 mm Hg compared with a PO2 of 40 mm Hg in pulmonary venous blood [3]. The difference of 59 mm Hg between alveolar air and venous blood provides the driving pressure that enables O2 diffusion to occur. Oxygen delivery O2 diffuses into the plasma of pulmonary capillaries and then into red blood cells, where it combines reversibly with the iron atom of hemoglobin (Hb) and converts deoxyhemoglobin to oxyhemoglobin. Each Hb binds four O2 molecules, and each gram of Hb can transport 1.36 mL of O2 when fully saturated. With this information, it is possible for the clinician to calculate the arterial oxygen content (CaO2), which is the sum of O2 dissolved in plasma and O2 chemically bound to Hb. CaO2 can be calculated using the following equation: Cao2 ¼ Bound O2 þ Dissolved O2 ¼ ðHb 1:36 Sao2 Þ þ ðPao2 0:0031Þ where SaO2 is arterial blood oxygen saturation, PaO2 is the partial pressure of arterial oxygen, and 0.0031 is the Bunsen coefficient. Under optimal conditions, arterial blood with a PaO2 of 100 mm Hg and complete saturation of Hb at a concentration of 15 g/dL would contain 200 mL of O2 per liter of blood [1]: Cao2 ¼ ð15 1:36 10Þ þ ð100 0:0031Þ Cao2 ¼ 200 mL From this equation, it is clear that the O2 dissolved in plasma (PaO2 · 0.0031) contributes little to O2 content unless there is increased cardiac output in the presence of severe anemia or unless hyperbaric O2 therapy is used, in which case, the PaO2 can be raised substantially. Total O2 content is thus mainly dependent on Hb concentration and SaO2. Hemoglobin and the oxyhemoglobin dissociation curve Hb is the primary O2 carrier in the circulating blood, and myoglobin is the primary O2 reservoir in muscle tissue. Hb has a high affinity for O2 at
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high O2 tension in the lungs and is able to release O2 at low O2 tension in the tissues. The oxyhemoglobin dissociation curve (Fig. 1) illustrates the relation between O2 and Hb at varying O2 tensions or, more accurately, describes the saturation of Hb with O2 as determined by the concentration of O2. The shape of the curve is sigmoidal and results from the conformational changes in the Hb molecules that occur during uptake and release of O2 [3,4]. The flat portion of the curve is an area of high PO2 (greater than 100 mm Hg). The steep portion of the curve is the physiologic range of PO2 (30–100 mm Hg). The affinity of O2 for Hb is influenced by many physiologic changes. Decreased affinity of Hb for O2 (a right shift in the curve) facilitates the release of O2 to the tissues. A right shift is seen with acidosis, hyperthermia, exercise, increased partial pressure of CO2 (PCO2), and increased 2,3-diphosphoglycerate (2,3-DPG) concentrations in the red cells, as occurs when there is insufficient O2 delivery to the tissues (e.g. anemia, altitude) lasting longer than 3 to 4 hours. Increased affinity of Hb for O2 (left shift) facilitates O2 loading into the blood in the alveoli. A left shift is seen with alkalosis, hypothermia, decreased 2,3-DPG levels, carbon monoxide (CO) poisoning, and hypocarbia [3,4]. Under normal physiologic conditions, near maximum Hb saturation is achieved at a PO2 of 75 to 80 mm Hg.
Total oxygen delivery Total O2 delivery (DO2) may also be calculated as the product of cardiac output and CaO2 [5]: Do2 ¼ Cao2 Cardiac Output ¼ 200 mL=L 5 L=min ¼ 1000 mL
Fig. 1. The oxyhemoglobin dissociation curve. Point a represents the flat portion of the curve, where hemoglobin is maximally bound with oxygen. Point b represents the physiologic range of the partial pressure of oxygen.
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Approximately 1000 mL of O2 leaves the left ventricle each minute and is distributed to regional vascular beds. When supply is adequate, O2 consumption is a function of metabolic rate and there is a wide margin between supply and demand. Normal systemic O2 consumption is 250 mL/min (25% of O2 transport), and the remaining 750 mL of O2 returns to the right heart in venous blood [3]. Only a small fraction of O2 is extracted from the capillary blood under normal conditions. In situations of low blood flow, the tissues have the ability to compensate by increasing O2 extraction. Oxygen consumption Once O2 enters the cell, it diffuses down a gradient into the mitochondria. The main location for O2 unloading is in the tissue capillaries, and O2 delivery maintains an interstitial PO2 of 20 to 40 mm Hg [3]. The mitochondria consume 80% to 90% of the O2, and 10% to 20% is consumed by subcellular organs. The mitochondria use O2 to produce energy through oxidative phosphorylation. Oxygen deprivation There are four physiologic situations that cause cells to convert from aerobic to anaerobic metabolism with the production of lactic acid: 1. Increased metabolic demand or O2 consumption generated by fever, shivering, seizures, or strenuous exercise may produce acidosis if the O2 supply is unable to meet demand. 2. Hypoxia, cardiac pump failure, and severe anemia create a deficient supply of O2, resulting in conversion from aerobic to anaerobic metabolism. 3. Uncoupling of oxidative phosphorylation, as occurs with cyanide poisoning, blocks cellular metabolism and stops O2 utilization. 4. Loss of microcirculatory autoregulation, as occurs in sepsis, leaves tissues with inadequate O2 to meet metabolic demands. Central and local mechanisms protect tissue oxygenation via shifts in the O2 dissociation curve and regulation of local blood flow. Hypoxia results if these mechanisms fail. Tissue hypoxia occurs if the intracellular PO2 is less than10 mm Hg or if the mitochondrial PO2 is less than 6 to 7mm Hg [6]. Insufficient O2 delivery is secondary to hypoxemia or inadequate blood flow. Indications for oxygen therapy Clinical signs of oxygen deprivation The decision to administer supplemental O2 is often based on several factors, including clinical signs, results of diagnostic tests (e.g. arterial blood
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gas and pulse oximeter measurements), and the patient’s clinical disease. Clinical signs of hypoxia include cyanosis, dyspnea, tachypnea, tachycardia, anxiety, postural changes, and central nervous system (CNS) depression [7– 9]. Greater than 5 g/dL of deoxygenated Hb must be present in the circulating blood before cyanosis can be detected [7,9,10]. Therefore, a patient may be hypoxic without obvious cyanosis. Tachycardia is a common finding as cardiac output is increased through stimulation of carotid body chemoreceptors and activation of the sympathetic nervous system in an attempt to circulate the available pool of Hb more quickly. Postural changes include abduction of the elbows (orthopneic stance), extension of the head and neck, recruitment of abdominal muscles, and open-mouth breathing. Patients with severe hypoxia may experience collapse or mental confusion or may become comatose. There are many disease conditions that can produce hypoxia, and recognition of these conditions should prompt the clinician to consider the need for supplemental O2 therapy. The response to O2 therapy is variable or nonexistent depending on the cause of hypoxia, however. The following is a discussion of the types of hypoxia, associated disease conditions, and their responsiveness to O2 supplementation. Categories of hypoxia Anoxic hypoxia Anoxic hypoxia is the inadequate delivery of O2 from the lungs to the blood, resulting in reduced arterial O2 content. This form of hypoxia may result from five different pathophysiologic causes, which include a low FIO2, hypoventilation, diffusion impairment, ventilation/perfusion (V/Q) mismatch, and pulmonary shunt. A PO2 in inspired gas/air (low FIO2) causes diminished arterial O2 content and may be caused by inadequate O2 delivery to patients receiving anesthesia or mechanical ventilation, excessive rebreathing of dead space gas, or high-altitude sickness [1]. This form of hypoxia can be corrected easily with administration of supplemental O2. Alveolar hypoventilation occurs when chest wall excursions are insufficient to achieve adequate lung inflation and gas exchange. CO2 replaces O2 in poorly ventilated alveoli, and the PaO2 decreases. Alveolar hypoventilation may result from peripheral neuromuscular disease, CNS disorders, cervical spinal cord lesions, oversedation, thoracic wall defects, rib fractures, or pleural space disease [8,11]. Supplemental O2 administration helps temporarily in this situation, but if the underlying problem cannot be remedied in a timely fashion, many of these patients require mechanical ventilation to reduce severe hypoventilation. Diffusion impairment occurs when the alveolar-capillary membrane interface thickens or the surface area available for diffusion decreases, as may occur with interstitial pulmonary edema, pulmonary interstitial fibrosis, chronic emphysema, and adult respiratory distress syndrome (ARDS) [2].
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This form of hypoxia is responsive to supplemental O2 administration, because O2 administration increases the driving pressure for O2. V/Q mismatch occurs when alveolar ventilation and pulmonary blood flow are not uniform. The degree of V/Q mismatch is dependent on whether ventilation or perfusion predominates. Pulmonary thromboembolism is an example of high V/Q mismatch, where regions of the lung are ventilated but are not perfused, increasing physiologic dead space. This form of V/Q mismatch responds well to supplemental O2 administration. Low V/Q mismatch is an inadequate supply of O2 to alveoli in the presence of normal perfusion [12]. This type of V/Q mismatch is seen commonly with pulmonary edema, pulmonary contusions, pneumonia, asthma, and pulmonary neoplasia. Response to O2 supplementation is generally poor to fair in cases of low V/Q mismatch. An extreme form of low V/Q mismatch exists with shunts in which perfusion occurs in the absence of ventilation. This type of V/Q mismatch occurs in several disease states, such as severe cardiogenic or noncardiogenic pulmonary edema, severe pneumonia, lung atelectasis, lung lobe torsion, and right-to-left cardiac shunts. Because the shunted blood makes no contact with ventilated lung units, supplemental O2 administration provides no benefit. In both types of low V/Q mismatch, however, if mechanical ventilation with positive end-expiratory pressure (PEEP) is provided, loss of alveolar gas volume may be relieved and supplemental O2 may be efficacious. Anemic hypoxia and dyshemoglobinemias Anemic hypoxia results when an inadequate quantity of Hb (<7 g/dL) is available to transport a sufficient supply of O2 for metabolism, Hb is present but rendered nonfunctional by conformational changes in the Hb molecule, or O2 binding to the Hb molecule is blocked. Anemic patients can generally tolerate Hb concentrations as low as 7 g/dL by increasing cardiac output to maintain O2 delivery. If myocardial function is limited or if O2 consumption exceeds a patient’s ability to increase cardiac output, hypoxemia develops. Because of limited cardiac reserves, patients with myocardial disease generally cannot tolerate an Hb concentration below 10 to 11 g/dL. Patients with anemic hypoxia benefit minimally from supplemental O2 therapy, because their Hb is already fully saturated, and any increase from O2 dissolved in plasma (PaO2 · 0.0031) is minor. Methemoglobinemia (metHb), such as that occurring with acetaminophen toxicity, is an example of a conformational change that renders Hb nonfunctional. Methemoglobin causes the iron component of the heme molecule to be oxidized from its normal ferrous state (Fe2+) to the ferric state (Fe3+), rendering it incapable of O2 binding. Patients can generally tolerate methemoglobin levels up to 15% to 20%, but levels greater than 30% produce signs of cyanosis, dyspnea, and discoloration of the blood [6]. Methemoglobin levels greater than 80% are often associated with death.
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A methemoglobin level of 1.5 g/dL creates the same effect as decreasing Hb by 5 g/dL. O2 administration in cases of metHb is generally ineffective because O2 binding to Hb is blocked, but some improvement may be seen as a result of the slight increase in the fraction of O2 dissolved in the plasma. CO poisoning demonstrates how access to the heme molecule may be blocked. CO has 218 times the affinity for Hb that O2 has, and once bound, carboxyhemoglobin (HbCO) is quite stable [3,4]. The presence of HbCO shifts the O2 Hb dissociation curve to the left, which increases the affinity of O2 for Hb in the lungs but decreases its ability to be released to the tissues, and tissue hypoxia results [4]. Clinical symptoms appear when HbCO levels exceed 20% and become severe when levels reach 30% to 40% [6]. Increasing the concentration of inspired O2 adds little O2 to Hb but increases the amount of O2 dissolved in plasma. Recommendations in human patients with CO poisoning include provision of 100% oxygen for 20 to 30 minutes and/or hyperbaric O2 therapy to increase the PO2, and thus the driving pressure for O2, which displaces CO from the heme molecule. Stagnant hypoxia Stagnant hypoxia results from inadequate O2 delivery to tissue because of low blood flow. Common causes of stagnant hypoxia include pump failure (cardiogenic shock) and loss of circulating volume as seen with hemorrhage or significant intravascular dehydration. Although O2 therapy may be slightly beneficial in these patients, this form of hypoxia is best corrected by intravascular fluid resuscitation or improved cardiac function rather than by O2 administration alone [13]. Histiocytic hypoxia Histiocytic hypoxia results from the cell’s inability to use O2. Prolonged use of nitroprusside, a balanced vasodilator used in the intensive care setting, may lead to formation of cyanide as a byproduct of its metabolism. Cyanide poisons the electron transport system so that cells are unable to utilize O2, and metabolic acidosis results. O2 administration is of no benefit in this situation. Rather, therapy should be directed at cyanide removal to correct the problem.
Modes and techniques for oxygen delivery A number of devices are available for O2 delivery, and the method chosen should be based on the desired FIO2, equipment availability, and anticipated treatment duration as well as the patient’s clinical condition, size, and temperament. Any O2 delivery system that causes patient resistance may create the undesirable side effect of increasing O2 demand and consumption. Table 1 summarizes the various O2 delivery systems, the FIO2 that may be achieved with each system, and the O2 flow rate required to reach the target
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Table 1 Fraction of inspired oxygen (FIO2) achieved with various oxygen delivery systems Target FIO2
Device
0.24–0.45 0.30–0.50 0.35–0.55 0.40–0.50 0.50–0.90 0.21–1.00
Flow-by Nasal catheter Face mask Oxygen cage Reservoir mask Continuous positive airway pressure
Oxygen flow (liters/minute) 6–8 1–6 6–10 5–15 10–15
FIO2. Each of these systems is discussed in further detail in the following section. Flow-by oxygen This method of O2 supplementation is perhaps the easiest in an emergency situation while attempts are being made to stabilize the patient. The O2 line is placed within 1 to 3 cm of the patient’s nose and mouth, creating a small area of increased FIO2. An FIO2 of approximately 0.25 to 0.45 may be achieved in this way with little stress to the patient. The drawbacks to this method are that it requires a care provider to be present to hold the delivery system and to ensure that the patient does not move away from the O2 source, it requires a high O2 flow rate that is potentially wasteful, and it creates rapid airflow that disturbs some patients so that they avoid the O2 source. Face mask O2 delivery by face mask is a useful short-term method for O2 supplementation in emergency situations. With a well-fitted mask and the O2 flow rate set at 6 to 10 L/min, an FIO2 of 0.35 to 0.55 may be achieved [1,10]. The presence of a reservoir bag increases the amount of O2 available for inhalation and may raise the FIO2 as high as 0.5 to 0.8 at an O2 flow rate of 8 to 10 L/ min [1,5,10]. The disadvantages of this method include gas leakage from poorly fitted masks (particularly in cats and brachycephalic breeds), poor elimination of CO2, and lack of patient cooperation. Nasal catheter The use of a nasal catheter allows for more prolonged O2 delivery and permits access to the patient for examination and treatment purposes without loss of the O2-rich environment as can occur with use of an O2 cage. A potential drawback to this method of supplementation is that the FIO2 cannot always be determined accurately [11]. O2 delivery through a nasal catheter can achieve an FIO2 of 0.3 to 0.5 with an O2 flow rate of 100 to
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150 mL/kg/min (1–6 L/min) [14]. Use of bilateral nasal catheters may increase the target FIO2 to 0.7. The appropriate O2 flow rate is based on patient size, respiratory rate, respiratory pattern, and degree of open-mouth breathing. In general, a higher FIO2 is achieved in patients with tachypnea and low tidal volumes than in those patients with a normal respiratory rate at the same flow rate. Additionally, each liter per minute increase in O2 flow raises the FIO2 by 3% to 4% [1–5,8,11,13–18]. Placement of the nasal O2 catheter is relatively easy. The clinician should premeasure the catheter the distance from the nostril to the medial canthus of the eye and clearly mark this point. A small amount of topical anesthetic (2% lidocaine jelly [Proparacaine]) is introduced into one nostril, and a welllubricated, soft, rubber catheter (5–10 French) is passed ventromedially into the nostril and into the ventral meatus. The catheter is advanced to the predetermined level of the medial canthus and secured to the skin at the nares with adhesive glue, suture, or a single staple. A second site on the forehead or ventral to the ear is chosen to secure the length of the catheter [14,19]. An adaptor allows connection of the nasal catheter to the tubing from a humidified O2 source. Placement of an Elizabethan collar is often necessary to prevent the patient from removing the nasal catheter. Problems with this method of O2 delivery include poor patient tolerance, jet damage to the nasal mucosa, desiccation of the nasal mucosa, and gastric dilatation [14]. When a unilateral nasal catheter is used, the catheter should be replaced with a new catheter in the opposite nares every 48 hours so as to reduce damage to the airway. Oxygen cage An O2 cage provides a sealed environment, where the FIO2, humidity, and ambient temperature can be manipulated in a predictable manner and CO2 can be removed efficiently [9]. Most commercially available cages are capable of providing a maximal FIO2 of 0.4 to 0.5 and allow the ambient temperature to be maintained optimally at 22C (70F) with a relative humidity of 40% to 50% [7,9,10]. Desirable O2 cages would have a Plexiglas front to allow complete visualization of the patient and access ports for entry and exit of intravenous lines and monitoring leads. Cages that have doors within doors or plastic sleeves allow manipulation of the patient without creating enormous O2 loss from the cage. The major advantage of the O2 cage is that it is a noninvasive means of providing O2 support to a critically ill animal. The disadvantage of the O2 cage is isolation of the patient from the clinician, which precludes frequent hands-on evaluation. Each time the cage door is opened to access the patient, loss of the O2-rich environment occurs and the patient may decompensate [14]. The amount of O2 required to fill the cage and the amount of O2 lost with each entry into the cage make this form of O2 supplementation relatively wasteful and expensive.
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Elizabethan collar canopy Utilization of an Elizabethan collar covered with plastic wrap may create a miniature O2-enriched environment. The Elizabethan collar is secured around the patient’s neck, and the end of an O2 line is fed into the collar and secured. A small hole in the top corner of the plastic facing is created to allow elimination of CO2 and to help modulate the temperature within. This is a temporary method of O2 delivery that can achieve an FIO2 of 0.3 to 0.4 with an O2 flow rate of 0.2 to 0.5 L/min [7,8]. Although this method of O2 delivery is easy to use in an emergency situation, disadvantages, such as O2 leakage, high humidity, hyperthermia, and patient intolerance, preclude its use in the long term. Intratracheal catheter Intratracheal or transtracheal catheters improve O2 delivery by bypassing anatomical dead space and allow for continuous O2 delivery at low O2 flow rates [18,20]. This form of O2 supplementation can achieve an FIO2 of 0.4 to 0.6 at an O2 flow rate of 50 mL/kg/min [7,9,10,18]. Placement of an intratracheal catheter is similar to performing a transtracheal wash. The selected insertion site is clipped and surgically prepared, and a small bleb of local anesthetic (2% lidocaine) is instilled at the site. A long, large-gauge, flexible catheter is used, the end of which is fenestrated before insertion to reduce jet damage to the trachea. The needle of the catheter is introduced percutaneously through the cricothyroid ligament in cats and small dogs or between two tracheal rings in larger dogs, and the catheter tip is fed to the level of the fifth intercostal rib space (just cranial to the carina) [19]. The needle is withdrawn, covered with a needle guard, and secured in place with a neck wrap, taking care to avoid kinking of the catheter. The end of the catheter is then attached to a humidified O2 source. Use of an intratracheal catheter for O2 supplementation is inexpensive, generally well tolerated by the patient, and allows easy access to the patient. Potential disadvantages include catheter kinking at the insertion site, subcutaneous emphysema, jet damage to airway mucosa, tracheitis, bronchospasm, infection at the insertion site, and airway obstruction as a result of excessive mucus accumulation. This is also a more invasive procedure than placement of a nasal catheter and may require sedation of the patient to allow placement. Mechanical ventilation Mechanical ventilation becomes necessary when a patient is unable to sustain a PaO2 greater than 60 mm Hg through its own efforts, despite conventional O2 supplementation [9]. Patient failure may result from respiratory fatigue, respiratory arrest, intracranial disease, or hypoventilation of any cause [8]. Likewise, any patient that is struggling to maintain a PaO2
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between 60 and 65 mm Hg and cannot rest because of respiratory effort would benefit from mechanical ventilation. Additionally, patients that require O2 supplementation at an FIO2 greater than 0.6 for more than 24 hours are at risk for O2 toxicity. Mechanical ventilation with application of PEEP may allow the FIO2 to be reduced to a safer level, thereby decreasing the risk for toxicity.
Monitoring oxygen therapy Improvement in the clinical condition of the patient is a sufficient means of determining response to O2 therapy in lieu of other diagnostics. Patients that respond favorably to O2 supplementation generally show improved mucous membrane color, decreased respiratory rate and effort, and reduced anxiety. Diagnostic tests like arterial blood gas measurements and pulse oximetry provide more objective means to monitor the efficacy of O2 supplementation. An arterial blood gas measures the amount of oxygen (PaO2) and carbon dioxide (PaCO2) in the arterial blood. This information allows the clinician to determine the effectiveness of gas exchange and efficacy of supplemental O2 therapy. A PaO2 less than 70 mm Hg and/or a PaCO2 greater than 45 mm Hg signals the need for supplemental O2, whereas a PaO2 less than 60 mm Hg and/or a PaCO2 greater than 50 mm Hg indicates respiratory failure and the need for ventilatory support. During O2 supplementation, the expected PaO2 should be five times the FIO2 (eg, at an FIO2 ¼ 40%, the expected PaO2 ¼ 40 · 5 ¼ 200 mm Hg). Any value lower than the expected value indicates a problem with gas exchange. An arterial blood gas may be obtained from the femoral artery, the dorsal metatarsal artery, or, in the anesthetized patient, the lingual artery. The major drawback to this method of assessment is that arterial blood gases can be difficult to obtain and may be stressful to critically ill patients. Determination of the alveolar-arterial gradient (A-a gradient) is another useful calculation that can be made with the information provided by the arterial blood gas. Calculation of the A-a gradient assesses the severity of V/Q mismatch. The A-a gradient may be calculated using the following formula: A-a Gradient ¼ Pao2 Pao2 ¼ ðFio2 ½PB PH2 O 1:2 Paco2 Þ Pao2 where FIO2 is the fraction of inspired oxygen, PB is the barometric pressure, PH2O is the vapor pressure of water, PaO2 is the alveolar partial pressure of oxygen, PaO2 is the arterial partial pressure of oxygen, and PaCO2 is the arterial partial pressure of carbon dioxide [7,21]. In the normal patient, where ventilation and perfusion are matched, the A-a gradient is less than 10 mm Hg.
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Pulse oximetry is a simple noninvasive method for continuous or intermittent monitoring of oxygen saturation (SaO2) or the percentage of oxyhemoglobin in the blood. An SaO2 less than or equal to 93% indicates the need for O2 supplementation. Measurements are obtained by attaching a transducer to the lip, ear, and digit or, in the anesthetized patient, via a rectal or esophageal probe. The accuracy of pulse oximetry may be limited in many instances, and its use is discussed in further detail elsewhere in this issue. Complications of oxygen therapy Denitrogenation (absorption) atelectasis In areas of poor oxygenation (with adequate perfusion), alveoli are held open primarily by nitrogen rather than by O2. Because the body is saturated with nitrogen, there is no effective nitrogen gradient between mixed venous (pulmonary arterial) blood and the alveolus. Therefore, nitrogen remains in the alveolus, preventing its collapse. As O2 is administered to the patient, it displaces nitrogen in the alveolus so that O2 volume becomes the main factor holding the alveolus open. Now, as mixed venous blood flows past the same alveolus, O2 rapidly diffuses down its concentration gradient and enters the blood, leaving behind inadequate amounts of gas to hold the alveolus open, and the alveolus collapses. Thus, an adequately perfused but poorly ventilated lung unit becomes both poorly ventilated and poorly perfused after O2 administration [5,6]. This event is known as denitrogenation (absorption) atelectasis. Miscellaneous complications In patients with chronic respiratory disease and chronic CO2 retention, hypoxemia becomes the main stimulus for ventilation, because the sensitivity of central chemoreceptors is lost [12]. Supplemental O2 administration in these patients may cause acute deterioration because of suppression of their respiratory drive. These patients require positive-pressure ventilation rather than O2 supplementation alone. Other potentially deleterious effects of O2 supplementation include decreased erythropoiesis, reduced cardiac output, pulmonary vasodilation, and systemic arteriolar vasoconstriction [16,17,22]. O2 toxicity represents the most serious complication associated with supplemental O2 therapy. Oxygen toxicity When the administration of O2 occurs at levels that exceed biotransformation and clearance, toxicity occurs. O2 is a potent drug because it serves as an efficient electron acceptor in respiration and has a powerful oxidizing effect. When the mitochondrial and nonmitochondrial metabolism of O2 is
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saturated, clearance is limited and there is excessive accumulation of toxic O2 intermediates. Toxic O2 metabolites include superoxide (O2), hydrogen peroxide (HOOH), hydroperoxide (ROOH), and hydroxyl radical (HO) [15,23]. O2 radicals are produced at a low level during normal metabolism. These radicals are removed by the normal defense mechanisms, including superoxide dismutase, which acts to converts O2 to H2O2, and catalase and glutathione peroxidase, which clear H2O2 by sequential degradation to water. Glutathione peroxidase is also able to remove products of lipid peroxidation [6,23]. Other nonenzymatic antioxidants include vitamin A, vitamin C, alpha-tocopherol (vitamin E), N-acetylcysteine, b-carotene, urate, bilirubin, and hemoglobin [1,15,23]. During hyperoxia, the normal defense mechanisms are overwhelmed and O2 intermediates accumulate. The consequences of O2 toxicity include lipid peroxidation of cell membranes with loss of cell integrity, oxidation of sulfhydryl groups, alteration of enzyme function, protein structural damage, and impairment of transcription and replication of RNA resulting in defects of DNA cross-linking and nucleic acid damage [5,23]. The lungs are particularly sensitive to the effects of lipid peroxidation, and signs of pulmonary damage predominate in O2 toxicity. Pathophysiology of pulmonary oxygen toxicity Initially, hyperoxia causes endothelial cell damage and destruction of alveolar lining cells, increasing microvascular permeability [5]. Damage to the endothelium allows inflammatory precursors to enter the pulmonary interstitium, leading to alveolar edema, hemorrhage, and congestion. Polymorphonuclear cells adhere to the endothelial cells and generate chemotactic factors to attract more inflammatory cells. These early changes represent an exudative phase of pulmonary O2 toxicity. The early stages of pulmonary damage are characterized by proliferation of alveolar type I epithelial cells, a fibrin exudate, and a prominent alveolar membrane [17]. Blood is shunted away from areas of the lung where oxygenation is inadequate, and V/Q mismatch develops. In the late stages of O2 toxicity, alveolar type I epithelial cells are lost, alveolar type II epithelial cells and fibroblasts proliferate, the basement membrane is denuded, and fibrosis results. These changes represent a proliferative phase of pulmonary O2 toxicity [5,17]. Absorption atelectasis occurs secondary to inactivation of surfactant when O2 is rapidly taken into the pulmonary blood, thus worsening V/Q mismatch. Diagnosis of oxygen toxicity Clinical signs of O2 toxicity include tachypnea, dyspnea, nasal congestion, and a cough resulting from tracheobronchitis. Human patients experience chest pain, paresthesias, and anorexia in the early stages of O2 toxicity [17]. Diagnosis of O2 toxicity is difficult and is based on findings of edema or
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an infiltrative lung pattern on radiographs, a worsening gas exchange manifested as a progressively decreasing PaO2, and evidence of V/Q mismatch. Treatment of oxygen toxicity There is no effective treatment for O2 toxicity; therefore, prevention is most important. To decrease the risk for O2 toxicity, the clinician should adhere to the following guidelines: 1. 2. 3. 4.
Use a PaO2 of 70 as an endpoint for O2 therapy. Use the lowest FIO2 possible to achieve a PaO2 of 70. Do not use an FIO2 greater than 0.6 for longer than 24 hours. Use PEEP to help decrease the FIO2 as necessary. The use of PEEP maximizes the PaO2 at lower FIO2 levels.
Most injury is sustained with exposure to 24 to 48 hours of an FIO2 at 0.6 to 1.0 [5,19]. ARDS patients are more susceptible to O2 toxicity, because toxicity accelerates lung fibrosis; however, any patient with underlying lung injury is at higher risk for O2 toxicity than is a patient with normal lungs. In these patients, O2 toxicity may manifest at an FIO2 less than 0.6 and/or when supplemental O2 therapy has been provided for less than 12 to 24 hours [5]. Certain drugs may offer protection against O2 toxicity, such as vitamin E, vitamin C, b-carotene, mannitol, and N-acetylcysteine, all of which act as antioxidants [15]. Deferoxamine, an iron chelator, inhibits production of hydroxyl radicals by preventing activation of the Haber-Weiss reaction. Conversely, certain drugs have been shown to enhance O2 toxicity through their ability to increase tissue O2 consumption, cause increased production of free radicals through their metabolism, or decrease protective antioxidant systems. Such drugs include epinephrine, norepinephrine, steroids, cyclophosphamide, thyroid hormone, and nitrofurantoin. The effect of steroids on the development of O2 toxicity and their use in the treatment of O2 toxicity is controversial. Some reports indicate that steroids like dexamethasone decrease the levels of antioxidant enzymes and therefore potentiate injury, whereas other reports suggest that high doses of steroids are therapeutic in the late stages of O2 toxicity [6]. Based on this limited information, steroids should be avoided except in the late stages of toxicity. Future directions Future directions for O2 therapy include the use of O2-carrying Hb solutions. Hb-based O2 carriers administered intravascularly bind O2 in the lungs and deliver O2 to the tissues in exchange for CO2. Hb solutions have been shown to improve tissue O2 tension in cases of anemic hypoxia and stagnant hypoxia at room air (FIO2 ¼ 0.21). The use of Hb-based O2 carriers may reduce or completely eliminate the need for supplemental O2 at high FIO2 during conditions of anemic and stagnant hypoxemia, thus reducing the risk of O2 toxicity.
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Partial liquid ventilation with the use of perfluorocarbons is also an area of intensive ongoing investigation. Perfluorocarbons are inert liquids that are used to fill the pulmonary airspace and are employed in conjunction with mechanical ventilation or tracheal gas insufflation to improve oxygenation [24,25]. The advantages of perfluorocarbons are numerous and include facilitated opening of collapsed and noncompliant lung segments, reduced oxidative damage in acute lung injury, and diminished shear forces acting on lung parenchyma [24–26]. Perfluorocarbons may also function as ‘‘liquid PEEP’’ by preventing complete collapse of unstable alveoli at low airway pressures [24]. Use of partial liquid ventilation would also allow for lower FIO2 in patients at risk for O2 toxicity. Although partial liquid ventilation is still under investigation, it represents an exciting new direction for O2 therapy.
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[17] Jackson RM. Oxygen therapy and toxicity. In: Shoemaker WC, Ayres SM, Grenvik A, et al., editors. Textbook of critical care. 3rd edition. Philadelphia: WB Saunders; 1995. p. 784–9. [18] Mann FA, Wagner-Mann C, Allert JA, et al. Comparison of intranasal and intratracheal oxygen administration in healthy awake dogs. Am J Vet Res 1992;53:856–60. [19] Court MH. Respiratory support of the critically ill small animal patient. In: Murtaugh RJ, Kaplan PM, editors. Veterinary emergency and critical care medicine. St. Louis: Mosby Year Book; 1992. p. 575–92. [20] Tarpy SP, Celli BR. Long term oxygen therapy. N Engl J Med 1995;333:710–4. [21] West JB. Gas exchange. In: Pulmonary pathophysiology: the essentials. 4th edition. Baltimore: Williams & Wilkins; 1995. p. 18–40. [22] Rubanyi GM, Vanhoutte PM. Superoxide anions and hyperoxia inactivate endothelium derived relaxing factor. Am J Physiol 1986;250:H22–7. [23] Otto CM. Oxidative stress: too much oxygen. Proceedings of International Veterinary Emergency Critical Care 1998;6:523–8. [24] Blanch L, Van der Kloot TE, Youngblood AM, et al. Selective tracheal gas insufflation during partial liquid ventilation improves lung function in an animal model of unilateral acute lung injury. Crit Care Med 2001;29:2251–7. [25] Steinhorn DM, Papo MC, Rotta AT, et al. Liquid ventilation attenuates pulmonary oxidative damage. J Crit Care 1999;14:20–8. [26] Overbeck MC, Pranikoff T, Hirschl RB. Partial liquid ventilation provides effective gas exchange in a large animal model. J Crit Care 1996;11:37–42.