Degree of swelling

New concepts in the treatment of pulmonary edema

Steven J. Allen, M.D.

The University of Texas Medical School, Houston, Texas 77030

Lung edema is a pathological condition, withthe water content in the pulmonary interstitium is greater than normal (1). We have become much better understand the factors that affect the movement of fluid from the pulmonary microcirculation system into the pulmonary interstitium, below will be laid down the fundamental principles of this process. New research focuses on the study of biochemical mediators that are responsible for increasing permeability in the pulmonary microcirculation system, mechanisms for removing excess interstitial fluid (edema of the edema) (2), assessing the function of the lymphatic system and mechanical stress-related factors (excessive overexpansion of pulmonary tissue and pulmonary vascular hypertension ) (3). Recent clinical data suggest a more favorable outcome in those critically ill patients whose accumulation of water in the lungs is minimized (4-6). This renewed interest in more advanced methods for estimating the amount of extravascular water in the lungs that can be carried out "at the patient's bedside" (7).

A small excess accumulation of liquid inpulmonary interstitium, most likely, is well tolerated. However, a significant accumulation of fluid in the interstitium of the lungs leads to impairment of pulmonary functions, the mechanism of this phenomenon is multicomponent. At the earliest stages, the accumulation of excess fluid in the pulmonary interstitium leads to a decrease in the elasticity of the lungs and they become more rigid (8). The study of lung function at this stage reveals the presence of restrictive disorders. Tachypnea is an early indication of an increase in the amount of fluid in the lungs and is particularly typical for patients with reduced elasticity of the lungs. Nevertheless, in the lungs, stretch receptors or receptors that react to volume changes may be present, stimulation of which during swelling of the lungs leads to the development of tachypnea, even in cases where the elasticity of the lungs is not reduced. However, the question of whether such "J-receptors" exist in humans is still open.

The second problem occurs when swollen fluidsweats into the alveoli. Liquid-filled alveoli do not have the ability to participate in gas exchange, which leads to the appearance in the lungs of sites with a reduced rate of ventilation / perfusion (ratio V / Q). In the left atrium, the blood that passed through the unventilated alveoli (shunt) is mixed with completely oxygenated blood, which leads to a decrease in the total arterial partial pressure of oxygen. When the fraction of desaturated blood reaches a significant level, the state of hypoxemia develops. The study of the distribution in the lungs of the "ventilation / perfusion" ratio in acute respiratory distress syndrome (ARDS) indicated the effect of the "all or nothing" law. According to him, the perfused areas of the lungs are either ventilated quite satisfactorily, or are not ventilated (9).

Anatomic features of accumulation of edematousFluids in the lungs themselves can also cause problems. Initially, edematous fluid accumulates in the surrounding tissues of the alveoli and then spreads along both pulmonary venous trunks and along the pulmonary arterial and bronchial trunks. The liquid can accumulate in sufficient quantities in the bronchioles, which leads to narrowing of the airways and is recognized by the occurrence of wheezing. The rales that develop on exhalation (cardiac asthma) are sometimes found in patients with pulmonary edema, which arose secondary to congestive heart failure. It is interesting that the bronchospasm accompanying such conditions can be stopped with the appointment of bronchodilators.

</ u> Since water in comparison with air hasa large density for X-rays, pulmonary edema on X-rays reveals itself by the presence of areas of increased density and can be detected by radiography of the chest before the first clinical signs appear. Acquaintance with various changes that develop in conditions accompanied by an increase in water in the lungs, and which are set forth in Table 1, will help to make a differential diagnosis between these conditions and atelectasis, pneumonia and chronic lung diseases. The presence or absence of signs of pulmonary edema on the roentgenogram often depends not only on the cause leading to edema (ARDS, fluid overload), but also from concomitant pulmonary disease. For example, minimal changes in radiographs for malignant pulmonary edema are found in those patients in whom certain areas of the lung tissue are poorly perfused (as is the case with emphysema or pulmonary infarction). Nevertheless, in most patients in critical condition, chest X-ray is the best indicator of the amount of water in the lungs.

</ u> Understanding the processes leading to pulmonary edema,requires familiarity with the fundamental mechanisms that are responsible for maintaining the balance of water in the lungs. The most commonly used equation describing the process of liquid exit from capillaries is called the Starling equation. The history of compiling this equation helps to delve into its essence. The main merit of Starling (1866-1927) was the understanding that the plasma produced osmotic pressure prevents the formation of edema by balancing the hydrostatic pressure in the vessels. He found that a decrease in the concentration of plasma proteins leads to the development of edema. Thus, Starling outlined his concept as follows:

where Jv = velocity of fluid outflow fromcapillary, Pc = hydrostatic pressure in the capillary, and ps = colloid osmotic pressure. Subsequently, the researchers realized that the interstitial space surrounding the capillary also has its own hydrostatic and colloid osmotic pressure. Thus, the pressure controllers controlling the process of fluid transfer were arranged in Equation 2, which takes into account the differences between capillary and interstitial pressures.

Jv = (Pc-Pt) - (ps-pt) (2)

where Pt and nt = interstitial (tissue)hydrostatic and colloid osmotic pressure, respectively. It was later shown that the permeability of the capillary membrane for plasma proteins is an important factor in the process of liquid exchange. If the membrane becomes more permeable, plasma proteins have less influence on the filtration of the liquid, since the differences in concentrations are lost. The reflection coefficient (sigma), which can take values ​​from 0 to 1, is a mathematical representation of that fraction of plasma proteins that "reflects" from the capillary membrane. To be able to take into account the permeability of the membrane, the filtration factor (Kf) was introduced. So, the equation now looks like this:

J v = Kf ((Pc-Pt) - sigma (n-pt)) (3)

edema of easy treatment concept

The components of the Starling equation

</ u> Hydrostatic pressure in pulmonary capillaries(Pc) is the main force that facilitates the flow of liquid from the capillary into the interstitium. The wedging pressure in the pulmonary capillaries (DZLK) is often confused with Pc. DZLK is used to estimate pressure in the left atrium (DLP) and reflects the pressure in the distal parts of the pulmonary capillaries of the small circle of the circulation. In order for the fluid to be able to move from the right heart through the lungs to the left atrium, the DLP should be lower than the Pc. Under normal conditions, the gradient between these two indices is small, for example, within 1-2 mm Hg. The quantitative difference between DZLK and Pc depends on the pulmonary venous resistance.

With congestive heart failure, the pressurein the left atrium increases due to reduced contractility and fluid retention. This increased pressure is transmitted to the upstream areas of the pulmonary blood flow and leads to an increase in Pc. If such an increase is significant, the fluid enters the interstitium so quickly that pulmonary edema occurs. The described mechanism of pulmonary edema is often called "cardiogenic." The meaning of this term is that the increase in Pc is caused by the increase in DZLK (DLP). However, in pulmonary hypertension, the quantitative difference between DZLK and Pc can be significantly increased. Developing in septic conditions, pulmonary hypertension leads to a dramatic increase in pulmonary venous resistance, and in this case, Pc can grow, while DZLK decreases. Thus, under certain conditions hydrostatic edema can develop even against a background of normal or decreased DZLK. This was demonstrated experimentally in animals that received endotoxins to induce RDS. This technique leads to the development of a significant pulmonary edema in just a few hours. However, when we injected nitroprusside sodium (NPN) infusion to reduce pulmonary hypertension, pulmonary edema did not occur even when DLP remained unchanged (Figure 1).

Pulmonary hypertension with certain pathologicalstates such as sepsis and ARDS, can lead to pulmonary edema, even in cases where DZLK remains normal or decreased. Investigating his patients, Gattinoni et al. found that the amount of edematous fluid with pulmonary edema is directly proportional to the pressure in the pulmonary artery, and not DZLK at all. A certain part of the excess pressure in the pulmonary arteries is transferred to the pulmonary capillary system, but never reaches the left atrium.

The main problem faced byresearchers of fluid balance in the lungs, is the difficulty of measuring the magnitude of Pc. Pc was evaluated in immobilized animals on the basis of data obtained by dissecting isolated lungs. However, the data obtained in the preparation of isolated lungs do not accurately reflect the situation in vivo. The study of the curve of movements of the pulmonary artery during inflation of a special balloon is the most promising technique that can be performed at the patient's bed, but the optimal mathematical model for its description has not yet been selected. To assess the above curve of movements, computer analysis may be necessary, which will allow to optimize the data processing process. The normal value of Pc, most likely, is about 8 mm Hg. Art.

Colloid osmotic pressure in capillaries(ps) reflects the osmotic pressure produced by that fraction of plasma proteins that do not pass well through the capillary membrane. The colloidal osmotic pressure in the capillary is the main force opposing Pc. Thus, a decrease in ps indicates an increase in the yield of liquid from the capillary (Jv), which can lead to the formation of edema. The method of direct measurement of the value (ps) involves the use of an artificial membrane with certain pore sizes, however the capillary membrane consists of pores of various sizes. Since the artificial membrane does not accurately reproduce the structure of the capillary membrane, many researchers first measure the protein concentration, and then calculate the value (ps) using the equations. The normal (ps) is 24 mm Hg. Art.

The reflection coefficient (sigma) reflects the fractionprotein, which is reflected from the capillary membrane and does not pass through it. This is an indicator of the relative permeability of the membrane, indicating how much the osmotic gradient will affect the filtration of the liquid under specific conditions. Some tissues, such as the brain, are impermeable to proteins, the sigma coefficient is equal to 1. In contrast, the sigma coefficient in the liver approaches zero; this means that the hepatic capillary is completely permeable to plasma proteins, and the amount of liquid that is filtered directly into the liver parenchyma depends almost entirely on the magnitude of the hydrostatic pressure. The index of sigma in the lung is 0.7. The capillary membrane in the lungs works according to the sieve principle, extracting plasma proteins from the liquid leaving the capillary, allowing only a third of the total number of plasma proteins to penetrate into the interstitium. For this reason, the protein concentration in the filtered liquid is less than in the plasma. Certain substances or diseases lead to a decrease in the sigma index in the pulmonary capillaries (permeability increases).

The filtration coefficient (Kf) reflects the physicalmembrane characteristics, such as water permeability and total surface area. Like Pc, the Kf value can be measured on isolated lungs, but it is difficult to define it in vivo. An increase in the total surface area of ​​the capillary membrane or an increase in its permeability to water leads to the release of more water into the interstitium, even if other parameters remain unchanged.

The effect of increased permeability

</ u> Figure 2 shows the effect of the changethe permeability values ​​for the accumulation of water in the lungs. A continuous line shows that under normal permeability conditions, the pressure in the capillary should increase by at least 15 mm Hg. Art. Only under such conditions this will result in the accumulation of a significant amount of water in the lungs. When the permeability of the membrane is increased, the formation of edema occurs by analogy only when the pressure in the capillary increases, but this requires a smaller absolute pressure (dashed line).

An analysis of equation 3 shows that the increase in Pcor a decrease in ps or sigma results in an increase in the yield of liquid from the capillary (Jv) into the interstitium. A moderate increase in Jv does not necessarily lead to edema, since there are anti-edematous safety factors. Figure 2 shows the interval within which the increase in Pc is not accompanied by a significant accumulation of edematous fluid (extravascular fluid - EVV) in the lungs of the waking sheep. Under normal conditions, the magnitude of EVE, which does not lead to edema, is 3.9 + -0.1, but only in the presence of normal Pc. The data presented indicate that Pc can be increased by 10-15 mm Hg. Art. compared with the baseline, before there is a significant accumulation of water in the lungs. The greatest clinical interest is a decongestant factor, such as an increase in the rate of lymph flow.

Increased speed of lymph flow. The fluid entering the interstitial fluid is removed by the lymphatic system. The increase in the rate of fluid entry into the interstitium is compensated by an increase in the rate of lymph flow. Such an increase in the rate of lymph flow in the lungs occurs by significantly reducing the resistance of lymphatic vessels and a slight increase in tissue pressure. However, the speed of lymph flow can not increase without limit. If the fluid penetrates the interstitium faster than it can be drained from there, then swelling develops. There are other ways to remove excess interstitial fluid, including through the pleura and mediastinum. The importance of these alternative ways of draining excess fluid is still being studied. The factors leading to the disruption of the functioning of the lymph system also lead to a slowdown in the evacuation of the edematous fluid along these alternative outflow pathways.

</ u> The previous section discussed the issue ofan increase in the rate of lymph flow as a mechanism that prevents the formation of edema. Any factor leading to a decrease in the rate of lymph flow, increases the likelihood of edema. Lymphatic vessels of the lung fall into the veins on the neck, which, in turn, flow into the upper vena cava. Central venous pressure (CVP) is thus the force that lymph has to overcome on the way to its drainage into the venous system. At one time it was believed that the lymph vessels can develop enough pressure to overcome any clinically important CVP. However, as shown in Figure 3, the lymph flow rate under normal conditions directly depends on the magnitude of the CVP (solid circles). With edema, this dependence varies in such a way that, for any given value of CVP, the lymph flow rate is higher than under normal conditions (open circles). This increase in the rate of lymph flow in the lungs is accomplished by a small increase in tissue pressure and a significant decrease in resistance in the lymphatic system. Thus, an increase in CVP can significantly reduce the rate of lymph flow, which leads to a reduction in the drainage of excess interstitial fluid and promotes the development of edema. This is demonstrated in Figure 4. The dashed line shows an example with a sheep, in an experiment with which CVP (or rather, venous pressure in the superior vena cava (DVPV)) was increased to 20 mm Hg. Art. With a control value of Pc, no increase in water in the lungs was found even under conditions of elevated DVP. Each subsequent increase in Pc was accompanied by a significant increase in the amount of water in the lungs. Increase CVP can contribute to the formation of pulmonary edema, as with elevated CVP, the process of removing excess fluid through the lymphatic ways is disrupted. This fact is of great clinical importance due to the fact that many therapeutic measures in critically ill patients, for example, ventilation with constant positive pressure, infusion therapy and the use of vasoactive drugs, lead to an increase in CVP. Routine therapy can cause the edema to build up or slow down the process of resorption.

We found similar changes when DVBVwas only increased by 7 mm Hg. Art. in an experiment with endotoxins (Figure 5). These data show that endotoxins disrupt the function of the lymphatic system and even a slight increase in CVP in patients with sepsis can lead to a significant accumulation of edematous fluid in the lungs.

Although elevated CVPs aggravate the accumulation processfluid in swelling of the lungs, which was caused by increased pressure in the left atrium or increased permeability of the membrane, measures to reduce CVP represent a risk for the cardiovascular system of patients in critical condition. An alternative are measures that allow the lymphatic liquid to flow into systems with lower pressure. For example, the effect of drainage of the thoracic lymphatic duct was studied with pulmonary edema that developed against the background of increased pressure in the left atrium. The installation of drainage in the thoracic lymphatic duct made it possible to significantly reduce the severity of pulmonary edema (Figure 6) and reduced the amount of pleural effusion.

</ u> With the development of pulmonary edema in the patientthey reveal a wide variety of clinical symptoms. In patients with mild edema of the lungs, due to fluid overload or congestive heart failure, only tachypnea is often found in a clinical examination. Patients with malignant form of ARDS can develop massive pulmonary edema, which leads to respiratory failure and hypoxemia, which implies prolonged mechanical ventilation and intubation. The main danger in swelling of the lungs is a life-threatening violation of gas exchange. Even in cases where it is possible to avoid hypoxemia, carrying out in patients in critical condition measures aimed at reducing pulmonary edema, allows to reduce lethality.

</ u> Lung edema develops when the increase in pressure in thethe left atrium leads to an increase in Pc to values ​​at which the action of decongestant safety factors is reduced to none. Therapy of pulmonary edema in such a situation is aimed at reducing pressure in the vessels. Usually, diuretics such as furosemide are used for such purposes, which allows to reduce the volume of circulating blood, and, consequently, intravascular pressure, including Pc. Рс try to reduce so that the rate of fluid entering the interstitium is lower than the rate at which this fluid is removed from there (lymph flow velocity). In addition, furosemide appears to have a venodilating effect and reduces intravascular pressure, and therefore promotes resorption of the edema.

In patients with congestive heart failurecentral venous pressure is often elevated. As noted above, increased CVP not only promotes the formation of edema of the legs, but also makes it difficult to eliminate excess fluid from the lungs.

</ u> Numerous reports in the literature andanimal experiments confirm the occurrence of pulmonary edema during active inspiratory attempts in conditions where the vocal cavity is closed, as there is a temporary but significant decrease in intrathoracic pressure. Apparently, negative intrathoracic pressure is transmitted to the interstitium of the lungs and leads to a significant increase in the gradient of hydrostatic pressure, which increases the yield of fluid from the pulmonary blood flow system. Such cases can be treated with expectant treatment, although some patients require round-the-clock treatment using an endotracheal tube and mechanical ventilation.

Resuscitation: evaluation of the use of crystalloid and colloidal solutions

</ u> Treatment and prevention of hypovolemia canrequire the infusion of a large number of replacement solutions to prevent tissue hypoperfusion. The main goal of such perioperative therapy is to maintain a volume of circulating blood sufficient to protect the kidneys, but which does not develop pulmonary edema. If the patient requires infusion of large quantities of fluid, the simultaneous achievement of these two goals is often a difficult task. The question of what the optimal replacement solution should be is still a matter of much debate. Clinical studies have led to directly opposite conclusions, probably because of the complexity of the exact measurement of the various components of the Starling equation, as well as the difficulty of taking into account all the most diverse factors that affect patients in the critical state.

The use of hypertonic solutions has its owncertain advantages. Indications for the use of this method of therapy are related to the fact that the recovery of intravascular volume of blood occurs, among other things, by mobilization of the interstitial fluid. Currently, accurate clinical indications for the use of hypertonic solutions are being developed.

Swelling of lungs of neurogenic origin

</ u> This type of pulmonary edema occurs in somecases with strokes. Damage to the nervous system leads to a massive release of catecholamines, especially norepinephrine. These vasoactive hormones can cause a brief but time-consuming increase in pressure in the pulmonary capillaries. If such a pressure jump is sufficiently prolonged or significant, the fluid leaves the pulmonary capillaries, despite the action of decongestant safety factors. Despite the fact that the pressure eventually normalizes, the resorption of the swelling does not occur immediately. There are data indicating that acute damage to the nervous system is accompanied by a violation of the permeability of the capillary membrane. Therapy of such patients should be aimed at maintaining adequate gas exchange and reducing pressure in the pulmonary vessels.

Elevated airway pressure

</ u> Laboratory studies have shown that highpositive airway pressure or overdischarge of lungs lead to the development of pulmonary edema due to increased pressure in the capillaries and an increase in the permeability of the capillary membrane. The development of pulmonary edema, most likely depends primarily on the magnitude of peak pressure in the airways and whether there are any previous lesions in the lung. Overexpansion of the lungs in itself can cause increased membrane permeability. The possibility of clinical application of the results of these studies in patients in critical condition requires further study.

</ u> A lot of disputes cause the problemthe most suitable method for infusion correction of pulmonary diseases, such as ARDS, which may be accompanied by an increase in the permeability of capillaries. Swelling of the leg, which develops against the background of increased permeability, is often considered without taking into account the effect of the pressure factor in the capillary. In fact, the increase in pressure in the capillary becomes even more important in the case when the permeability is increased. As noted earlier, pulmonary hypertension can increase the accumulation of water in the lungs, even when the wedge pressure in the pulmonary capillaries (DZLK) is less than 20 mm Hg. Art. Thus, the relief of pulmonary hypertension may be crucial for the elimination of pulmonary edema in patients with increased permeability of capillaries, for example those suffering from ARDS. For the treatment of ARDS, a wide variety of vasodilators have been tried, but their purpose has been unsuccessful. More recently, such patients began to carry out inhalation of nitric oxide (NO), which, as it turned out, is an effective pulmonary vasodilator. The inhalation form of the pulmonary vasodilator has potential advantages over preparations from the same group for intravenous use. The inhalation form of the vasodilator only penetrates the ventilated alveoli. If perfusion of these alveoli is increased, then the ratio V / Q increases, and gas exchange improves. In contrast, the intravenous form of the vasodilator only penetrates those parts of the lung tissue that are perfused, but may not be ventilated at all or poorly ventilated. If there is an increase in perfusion in such sections of the pulmonary parenchyma, this can lead to a decrease in the V / Q ratio and an aggravation of hypoxia.

Some studies have shown thata possible reduction in pulmonary edema in patients with acute respiratory failure can improve the outcome of the disease. There are many reasons for this. The main efforts should be aimed at maintaining the intravascular volume and, hence, the pressure in the capillaries at the lowest possible level at which preload on the left ventricle remains at a satisfactory level and does not lead to the development of hypovolemia and tissue ischemia. Monitoring DZLK allows you to control almost all the necessary quantities. One drawback of this method is that DZLK does not accurately reflect changes in the final diastolic volume in the left ventricle.

The interest in measuring the quantityextravascular water in the lungs by the method of double dilution, which allows to control the implementation of infusion therapy in patients with ARDS. At the same time, the dye dilution curve is used to estimate the "volume of blood in the central bloodstream", which is considered to be an excellent indicator for estimating preload. Accompanying the infusion therapy, repeated measurements of the volume of blood in the central blood stream, allow to prevent the development of hyperhydration and therefore help to minimize pulmonary edema. Moreover, conducting "quantitative measurements of the water content in the lungs at the patient's bed" allows the clinician to catch the moment when the infusion therapy should be stopped. Eisenberg et al. studied patients with ARDS or sepsis, who initially had pronounced pulmonary edema. They noted that treatment leads to better results if it is conducted under the control of repeated measurements of DZLK. Direct measurements of preload and water content in the lungs minimize the chances of pulmonary edema, allow to abandon mechanical ventilation at an earlier time, shorten the stay in the intensive care unit, reduce the number of complications and improve the outcome.

And, finally, another way to reduce pulmonary edemawith ARDS is to increase the outflow of excess fluid from the lungs. The installation of drainage in the chest lymphatic duct leads to a significant reduction in pulmonary edema, as was shown in animal experiments. Researchers noted a significant decrease in the severity of symptoms on the part of the lungs in patients with congestive heart failure after he had a drainage of the thoracic lymphatic duct. Other studies have demonstrated improved gas exchange functions after the drainage of the thoracic lymphatic duct in patients with ARDS and concomitant pancreatitis. These studies were conducted in patients who required correction of the volume of circulating blood in order to improve hemodynamic parameters with such a quantity of liquid, which at the same time could contribute to the growth of pulmonary edema, and drainage of the thoracic lymphatic duct in this connection was a direct necessity and could improve the outcome of the disease.

</ u> When it comes to rational methodsprevention and treatment of pulmonary edema, it is first of all necessary to clearly realize that this pathological condition is influenced not only by those factors that regulate the fluid outlet from the capillary, but also those that control the elimination of excess water from the interstitium. Pressure in the left atrium or its approximate equivalent (DZLK) may not accurately reflect the fluctuations in the actual value of Pc, the exponent expressing the main force, under the influence of which the liquid leaves the capillary. Increasing the permeability of the capillary membrane and increasing the intra-capillary pressure exert a mutually potent effect, which contributes to the formation of pulmonary edema. Elevated central venous pressure presents another serious problem for critically ill patients, as it reduces the rate of lymph drainage from the lungs and reduces the effect of decongestant safety factors.

Prevention of the accumulation of significant quantitiesfluid during pulmonary edema in patients in critical condition can improve the outcome of the disease. Thus, methods that allow for accurate monitoring of preload and water content in the lungs can provide significant assistance in the successful treatment of this category of patients.

Table 1. Radiographic signs of pulmonary edema.

Increase the size of the heart shadow.

The appearance of Curly A lines (long, located in the center of the pulmonary field)

The appearance of Curly B lines (short, located on the periphery)

Infiltration in peribronchial areas

The appearance of the silhouette of a "bat" or "butterfly"

Pleural effusion