Physiology of Gas Exchange

In the lung, gas exchange occurs at the capillary-alveolar interface. Close examination of septal capillaries reveals that they are significantly thinner on the side that bulges into the air space. This conformation enhances the diffusion of oxygen from the air space into the blood and the elimination of carbon dioxide from the blood into the air space. Equilibration of partial pressures of gases between the two compartments occurs rapidly. Oxygen in the blood is carried by hemoglobin. Only a small percentage is transported as dissolved gas. The following equation describes the arterial oxygen content (CaO₂):

where CaO₂ is the oxygen content of arterial blood in milliliters of O₂ per deciliter of blood; Hgb is the hemoglobin concentration in grams per deciliter of blood; SaO₂ is the fraction of hemoglobin sites bound by oxygen; and PaO₂ is the arterial partial pressure of oxygen.

Because the amount of dissolved oxygen is small in comparison to the amount transported by hemoglobin, in most clinical situations, CaO₂ depends primarily on the hemoglobin concentration and the oxygen saturation of the arterial blood, not on PaO₂. Even in severe anemia, the contribution of dissolved oxygen in the overall CaO₂ is negligible despite very high PaO₂. This principle is important clinically in patients with ARF for whom increasing CaO₂ can be accomplished by increasing hemoglobin concentration and SaO₂, but not necessarily by increasing PaO₂. This follows from the sigmoid shape of the oxygen-hemoglobin dissociation curve, in which significantly higher PaO₂ is needed to increase the SaO₂ beyond 90% as the curve plateaus.

Carbon dioxide is transported in the blood mostly in the form of carbonic acid. Only approximately 5% is transported by binding with hemoglobin. Ten percent is transported as dissolved gas.¹ As the tissues extract more and more oxygen from the blood, the deoxygenated hemoglobin increases its ability to carry carbon dioxide (Haldane effect). Similarly, as more and more oxygen becomes available in the arterial and venous blood, less carbon dioxide may be carried by the oxidized hemoglobin. This effect has been implicated in the pathogenesis of worsening hypercapnia after oxygen supplementation in patients with baseline hypercapnia.

To achieve optimal gas exchange, local matching of ventilation and perfusion has to occur. The interrelationships between ventilation and blood flow are shown schematically in Figure 31-1 where imbalance (B) is typified by bronchospasm, shunt (C) is typified by dense pneumonia or severe acute respiratory distress syndrome (ARDS), and dead space (D) is typified by digestion of the capillaries in emphysema.

Figure 31-1 Schematic representation of various patterns of ventilation () and perfusion (). A, Normal ratio in which the P = 40 mm Hg and PCO₂ = 46 mm Hg. After equilibration, the capillary PO₂ = 101 mm Hg, PCO₂ = 40 mm Hg, and P(A − a)O₂ = 0 mm Hg. B, imbalance caused by airway obstruction would decrease the PO₂. This could be corrected with supplemental oxygen. C, A shunt allows mixed venous blood to traverse the capillary without any gas transfer. D, Dead space, the ventilated area of the lung that does not participate in gas exchange.

(From Greene KE, Peters JI: Pathophysiology of acute respiratory failure. Clin Chest Med 1994;15:1-11.)

Normally, both ventilation and perfusion exhibit a gradient from the top to the bottom of the lung. However, the gradient is more pronounced in blood flow than in ventilation, such that in the upper portions of the lung there are predominantly high areas and in the lower portions of the lung, low areas. The overall ratio of the normal lung is 0.8.²

The overall efficiency of gas exchange can be assessed in terms of maintenance of normal PaO₂ and PaCO₂. The assessment can be performed by calculating the alveolar-arterial partial pressure oxygen difference (PAO₂-PaO₂), which is also known as the A-a gradient. The mean alveolar oxygen tension (PAO₂) is calculated by using the alveolar gas equation as follows:

where Pb is the barometric pressure of the atmosphere, which changes with altitude; FIO₂ is the fraction of inspired oxygen (approximately 0.21 in room air); PaCO₂ is the partial pressure of arterial carbon dioxide; and R is the respiratory quotient.

This equation gives an estimation of PAO₂, which changes with altitude (Pb), with inspired oxygen concentration, and with PaCO₂. PaO₂ not only changes with changes in PAO₂ but also decreases with age in normal individuals. Therefore PAO₂-PaO₂ increases with age and can be estimated in most adults breathing room air to be approximately 4 mm Hg for each decade of life until the maximum of the seventh decade. This estimation is not valid for patients receiving oxygen supplementation. For these patients, assessment of efficiency of gas exchange can be obtained using the ratio of PaO₂ to FIO₂ (PaO₂/FIO₂ ratio normally is above 400 mm Hg). Although it is not as accurate as the PAO₂-PaO₂ difference, it is useful clinically because most patients with ARF receive supplemental oxygen at the time blood gas analysis is performed. This ratio also forms one of the newer basic criteria for the diagnosis of acute lung injury or ARDS. By consensus acute lung injury is defined as noncardiogenic pulmonary edema with a PaO₂/FIO₂ ratio of less than or equal to 300 mm Hg; ARDS is diagnosed in the presence of a ratio of less than or equal to 200 mm Hg.³ This ratio is most helpful when used serially or when the ratio changes significantly with a therapeutic maneuver.

Pathophysiology of Acute Respiratory Failure

The three most important pathophysiologic mechanisms that cause ARF are hypoventilation, mismatch, and shunt. Diffusion abnormalities, which occur with mild pulmonary edema or early interstitial lung disease, may cause exercise-induced hypoxemia but rarely cause clinically significant hypoxemia. Reduction of inspired PO₂ and venous admixture are other potential but less common causes of hypoxemia.

Hypoventilation can be defined as the inadequate movement of fresh alveolar gas necessary for maintaining a normal PaCO_2. Pure hypoventilation is a relatively uncommon clinical event. In most cases, hypoventilation occurs along with other causes of hypoxemia.

When pure hypoventilation does occur, it is usually caused by depression of the respiratory center by sedative-hypnotic drugs or by neuromuscular diseases that affect the respiratory muscles.

The increase in PaCO₂ that accompanies pure alveolar hypoventilation invariably affects PAO₂ as predicted in the alveolar gas equation, causing a decrease in PaO_2. This results in hypoxemia with a normal PAO₂-PaO₂ gradient. In patients on room air, the PaO₂ will fall 5 mm Hg for every 3 mm Hg rise in PaCO₂. If the PAO₂-PaO₂ gradient is abnormally increased, then other mechanisms may also be involved in the pathogenesis of hypoxemia. Hypoxemia resulting from pure alveolar hypoventilation usually responds adequately to increasing FIO₂.

By far the most common cause of clinically important hypoxemia is mismatching. mismatching is present as a continuum from pure shunt without to pure dead space ventilation without , with unlimited patterns of mismatching in between. In young normal individuals, ratios range from 0.6 to 3.0 and usually center around 1.0.⁴ Low lung units can result from compromised ventilation such as obstructed airways or from partial alveolar filling with pneumonia or pulmonary edema. High lung units most often occur with obstruction of blood flow due to pulmonary vascular disease or from a lack of capillaries due to lung parenchymal destruction such as that seen in emphysema.

mismatching causes hypoxemia and hypercapnia. However, in most cases, an increase in minute ventilation stimulated by hypercapnia results in normalization of PaCO₂ with persistent hypoxemia. This is possible because the CO₂ dissociation curve is linear, allowing well-ventilated areas to compensate. The O₂ dissociation curve is sigmoid-shaped; therefore the increase in minute ventilation, despite producing higher end-capillary PO₂, results in very modest changes in oxygen saturation, which in most cases is inadequate to reverse the hypoxemia (Figure 31-2). Hypoxemia due to mismatching is usually correctable with increasing the FIO₂. Local hypoxia in low areas triggers reflex hypoxic pulmonary vasoconstriction in an attempt to correct the imbalance. This reflex vasoconstriction can be abolished by a number of vasodilators, including nitroprusside, nitroglycerin, calcium channel blockers, and inhalational anesthetics. When compensatory mechanisms fail in a patient with severe lung disease, the body may set a new steady state PaCO₂ and pH as an adaptive response to conserve the work of breathing.

Figure 31-2 Variations in PO₂, PCO₂, and O₂ content in a gas exchange lung unit as its ventilation-perfusion ratio is progressively increased. This lung is assumed to be breathing air, and the mixed venous blood PO₂ and PCO₂ are 40 mm Hg and 45 mm Hg.

(From West JB: Ventilation-perfusion relationships. Am Rev Respir Dis 1977;116:919-943.)

Right-to-left shunt occurs when there is no ventilation into a lung unit while perfusion is preserved. It is one of the extreme ends in the spectrum of mismatches. In a normal lung, the amount of shunt present is less than 5%. Shunt in the lung results from atelectasis, severe pulmonary edema, and air space consolidation such as pneumonia. In addition, right-to-left shunt can also occur as a consequence of arteriovenous malformation and intracardiac shunts from a patent foramen ovale, patent ductus arteriosus, or ventricular septal defect. Shunt causes significant hypoxemia due to the mixture of oxygenated blood with shunted, poorly oxygenated venous blood. Hypercapnia is usually not present until the shunt is greater than 50%. In contrast to other mechanisms of respiratory failure, hypoxemia due to shunting is not responsive to increases in FIO₂. This feature of shunt can be conveniently used to separate it from other causes of hypoxemia. Calculation of shunt () is easily done by administering 100% oxygen for 15 minutes and then analyzing arterial blood gases. Percent shunt can be estimated using a nomogram or by using the following formula:

In this equation, C denotes content, and the lower case letters c, a, and denote end-capillary, arterial, and venous blood, respectively. A simplified shunt equation assumes that the is normal and that the shunt is less than 25%. This simplified shunt equation states

When the FIO₂ used is less than 1.0, the resulting calculation is called venous admixture instead of shunt. This reflects the contribution of severe mismatching, including very low ratios that approach zero, which may act like shunts when alveoli are not ventilated with 100% oxygen.

The hypoxemia of shunt is remarkably resistant to correction by increasing the FIO₂. Patients with significant shunts may have the same arterial oxygen saturation when maintained on a relatively toxic FIO₂ (near 1.0) or when titrated down to relatively safe FIO₂ (0.6 to 0.7).

Clinical Assessment

Patients with ARF commonly have dyspnea. For those with underlying lung disease, dyspnea may be present chronically. Therefore mild changes in the degree of dyspnea may or may not be perceived. In the presence of significant hypoxemia and acidosis, patients may have symptoms of central nervous system depression ranging from irritability to coma. Patients may also have evidence of the effects of hypoxemia or acidosis on the cardiovascular system, such as arrhythmias, angina, or infarction. Depending on the underlying disease, other symptoms may also be present. Although they may be important and helpful in evaluating the underlying process causing the respiratory failure, they are not that helpful in evaluating the degree of respiratory dysfunction. For example, the additional symptoms of cough, sputum production, and fever may suggest pneumonia, whereas pleuritic chest pain with certain characteristics may suggest pneumothorax or pulmonary embolism as the cause of the respiratory distress.

Initial physical examination of patients with ARF should focus on overall appearance, vital signs, and the ABCs (airway, breathing, circulation). In general, patients with ARF have tachypnea, tachycardia, and variable mental status. Assessment of mental status may help by anticipating the cooperation the patient will give in the process of evaluation and management. The degree of alteration of mental status may reflect the severity of the respiratory failure. Confusion or disorientation in the presence of dyspnea and tachypnea may reflect profound hypoxemia or hypercapnia with its attendant respiratory acidosis. Pulsus paradoxus, a decrease in arterial systolic pressure of greater than 10 mm Hg with inspiration, also suggests severe airway obstruction associated with significant negative intrathoracic pressures. Patients with severe respiratory distress are usually unable to speak in full sentences. Likewise, the presence or absence of adventitious breath sounds may assist the clinician in evaluating the degree and acuity of the respiratory distress. Crackles suggest alveolar flooding or early bronchopneumonia, whereas rhonchi often herald an increase in mucus production or an inability to clear secretions. Wheezing suggests airway obstruction, whereas wheezes located over the neck suggest upper airway stridor that may be associated with respiratory collapse. Decrease in breath sounds may be seen in patients with chronic obstructive pulmonary disease (COPD) or those with severe airway obstruction. The absence of wheezing and breath sounds in a patient with underlying obstructive lung disease and respiratory distress may suggest impending respiratory collapse as a result of very limited air movement. Absence of breath sounds may also be associated with pneumothorax. Subcutaneous emphysema usually indicates pneumomediastinum with or without accompanying pneumothorax.

Despite advances in noninvasive technologies in oxygenation assessment, arterial blood gas analysis remains the best and most accurate test in the initial assessment of patients with ARF. Pulse oximetry is acceptable as a method for following oxygenation once it has been calibrated to true blood gas co-oximetry saturation and the arterial PAO₂ is known. Pulse oximetry (SpO₂) carries ± 4% error in measuring oxygen saturation. In patients with carbon monoxide poisoning, SpO₂ does not reflect true PaO₂, and profound hypoxemia may be missed. With methemoglobinemia, the SpO₂ may falsely read the oxygen saturation at around 85%, irrespective of the true saturation. Furthermore, pulse oximetry does not give information on PaCO₂ and pH, which may be crucial in the differential diagnosis and management of the patient with ARF. The presence of hypercapnia is a marker of the severity of disease. Hypercapnia is more likely to complicate hypoxemic failure when the disease is superimposed on significant underlying lung or neuromuscular disease.

The presence of hypoxemia, hypercapnia, and respiratory acidosis can be used to define ARF, but it is difficult to set specific levels of PaO₂ or PaCO₂ because patients with underlying lung disease may have markedly abnormal baselines. Given these qualifications, generally patients with ARF have a PaO₂ less than 55 mm Hg or a PaCO₂ more than 50 mm Hg. The pH is very helpful in assessing the acuity of the hypoventilation. In cases of subacute or chronic hypoventilation, the patient usually has an elevated serum bicarbonate level and a mild depression of the pH. In acute respiratory acidosis without renal compensation, the pH drops by 0.08 for each 10-mm Hg rise in PaCO₂. Compensatory bicarbonate retention or wasting by the kidneys to buffer the pH changes usually takes 2 to 3 days to occur. After renal compensation, a change of 10 mm Hg of PaCO₂ will produce 0.03 change in pH in the opposite direction.

The chest radiograph is useful in sorting out the differential diagnosis of ARF during the initial presentation. The causes of hypoxemia can be classified based on radiographic appearance. Table 31-1 shows examples of diseases associated with “white” chest radiographs showing diffuse or patchy infiltrates and diseases associated with “black” chest radiographs showing normal or clear lung fields.

Table 31–1 Radiographic Approach to Acute Respiratory Failure

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Jun 4, 2016 | Posted by admin in CRITICAL CARE | Comments Off on Acute Respiratory Failure

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Radiograph	Clinical Characteristics	Responses to Oxygen∗
“White” Chest Radiograph
Pneumonia	Fever, leukocytosis, sputum production	+ to + + +
Adult respiratory distress syndrome	Predisposing risk factors, wedge ≤ 18 mm Hg	+ to + +
Cardiogenic edema	Paroxysmal nocturnal dyspnea, orthopnea, edema	+ + + to + + + +
Interstitial lung disease	Prior chest radiographic abnormalities	+ + + to + + + +
“Black” Chest Radiograph
Chronic obstructive pulmonarydisease/asthma	Reduced flow on bedside spirometry	+ + to + + + +
Pulmonary emboli	Acute dyspnea, pleuritic pain	+ + + to + + + +
Right-to-left shunt	History and physical examination consistent withpulmonary hypertension	+