INTRODUCTIONThe pleural space is bounded by two

membranes, the visceral pleura covering

the lung and the parietal pleura covering

the chest wall and diaphragm. Into this

space, normal liquid and protein enter from

the systemic circulation and are removed

by the parietal pleural lymphatics.

Pleural pressure is subatmospheric and

ensures inflation of the lung. Because the

mesothelial boundaries are leaky, excess

liquid can move across into this lower-

pressure, high-capacitance space and collect

as a pleural effusion. Thus, pleural effusions

are common and of highly diverse etiologies.

These effusions can form based on disease

of the pleural membranes themselves or of

thoracic or abdominal organs.

Depending on the protein and lactate

dehydrogenase (LDH) concentrations of the

liquid and on the cellular composition, these

effusions can be categorized initially as

exudates or transudates. Exudative pleural

effusions meet at least one of the following

criteria, whereas transudative effusions meet

none (Light's criteria): pleural fluid protein–to–

serum protein ratio of more than 0.5, pleural

fluid LDH–to–serum LDH ratio of more than 0.6,

and pleural fluid LDH more than two thirds of

the upper normal limit for serum.

These two pleural membranes meet at the hilar

root of the lung. In the sheep, an animal with a

pleural anatomy similar to that of humans, the

surface area of the visceral pleura of one lung,

including that invaginating into the lung fissures,

is similar to that of the parietal pleura of one

hemithorax, approximately 1000 cm2.[1] The

normal pleural space is approximately 18 to 20 ým

in width, although it widens at its most dependent

areas. It has been shown that the pleural

membranes do not touch each other and that the

pleural space is a real, not a potential, space.

FIGURE 73-1 ▪ The pleural space is depicted in a frozen sheep thorax by reflected-light microscopy. The pleural space is seen as a continuous dark band (between arrows) between the lung and the chest wall (labeled).(Courtesy of Kurt Albertine, PhD, University of Utah School of Medicine.)

It is likely that the primary function of

the pleural membranes is to allow

extensive movement of the lung relative

to the chest wall. If the lung adhered

directly to the chest wall, its expansion

and deflation would be more limited.

The visceral pleura may also provide mechanical

support for the lung: contributing to the shape of

the lung, providing a limit to expansion, and

contributing to the work of deflation. Because the

submesothelial connective tissue is continuous with

the connective tissue of the lung parenchyma, the

visceral pleura may help to distribute the forces

produced by negative inflation pressures evenly over

the lung. In this way, overdistention of alveoli at the

pleural surface may be avoided, lessening the

chance of rupture and pneumothorax.

One more recently recognized function of the

pleural space is to provide a route by which edema

can escape the lung.[5] As has been shown in

several experimental studies of either hydrostatic

or increased permeability lung edema,[6],[7] the

pleural space can function as an additional safety

factor protecting against the development of

alveolar edema. The formation of transudative

effusions in patients with congestive heart failure

(CHF) apparently reflects the movement of edema

from the lung to a space where its effects on lung

function are relatively small.

Blood SupplyThe parietal pleura is supplied by intercostal

arteries. The visceral pleura in humans, like that in sheep, is exclusively supplied by the bronchial circulation, which drains into pulmonary veins. The drainage route via pulmonary veins may have contributed to earlier confusion about whether the visceral pleural blood supply was from a systemic (bronchial) or a pulmonary circulation. Both pleurae in humans, therefore, have a systemic circulation, although the visceral pleural bronchial circulation may have a slightly lower perfusion pressure than the parietal pleural intercostal circulation because of its drainage into a lower-pressure venous system.

LymphaticsIf one injects carbon particles into the pleural

space as a visible marker of lymphatic drainage pathways, one later finds that the black carbon has been taken up into lymphatics on the parietal side, not the visceral side . The visceral pleura has extensive lymphatics, but they do not connect to the pleural space. Demonstrated in rabbits, sheep, and now in humans, the parietal pleural lymphatics connect to the pleural space via stomata, holes of 8 to 10 ým in diameter that are formed by discontinuities in the mesothelial layer where mesothelium joins to the underlying lymphatic endothelium.

FIGURE 73-3 ▪  Macroscopic photograph of lymphatic lacunae in the parietal pleura over an intercostal space. Colloidal carbon was instilled into the pleural space to label the draining lymphatics. When one looks down upon the pleura, the lymphatic lacunae (L) appear as broad cisterns. B, blood vessel. (Original magnification ý39.)

Nerve SupplyThe parietal pleura contains sensory nerve

fibers, supplied by the intercostal and phrenic nerves, and has long been thought to be the major site of pain sensation in the pleura. The costal and peripheral diaphragmatic regions are innervated by the intercostal nerves, and pain from these regions is referred to the adjacent chest wall. The central diaphragmatic region is innervated by the phrenic nerve, and pain from this region is referred to the ipsilateral shoulder. The visceral pleura has more recently been shown to have sensory nerve fibers that may participate in pain or other sensations such as dyspnea.[19] In addition, pleural adhesions may contain pain fibers and contribute to post-thoracotomy or postpleurodesis pain.[20]

Normal Pleural Liquid and Protein Turnover

Since the 1980s, a consensus has developed

that normal pleural liquid arises from the

systemic pleural vessels in both pleurae,

flows across the leaky pleural membranes

into the pleural space, and exits the pleural

space via the parietal pleural lymphatics. In

this way, the pleural space is analogous to

other interstitial spaces of the body. There

are several lines of evidence for this view.

1.    Intrapleural pressure is lower than

the interstitial pressure of either of the

pleural tissues. This pressure difference

constitutes a gradient for liquid

movement into but not out of the pleural

space.

2.    The pleural membranes are leaky to

liquid and protein. Whether tested in

vitro[23],[24] or in situ,[25] the pleura offers

little resistance to liquid or protein

movement

3.    Mesothelial cells express various

transporters and aquaporins but these have

not been shown to have a role in reabsorption

of effusions.[26] Although normal pleural liquid

has been reported to be alkaline with higher

bicarbonate than plasma, there is no evidence

for active mesothelial participation in

generating a bicarbonate gradient, which can

more likely be explained by a passive response

to protein gradients (Donnan equlibrium).[26a]

4.    The entry of pleural liquid is slow and

compatible with known interstitial flow

rates. By noninvasive studies of the

equilibration of radiolabeled albumin, the

entry rate of pleural liquid is approximately

0.01 mL/kg/hr in a sheep, or about

0.5 mL/hr or 12 mL/day in an adult human.

[27] The halftime of pleural liquid turnover

in sheep and rabbits is 6 to 8 hours.[27],[28]

5.    The protein concentration of normal pleural

liquid is low in sheep[27] and probably in humans,

which implies sieving of the protein across a high-

pressure gradient. The protein concentration of

sheep pleural liquid (10 g/L) and pleural–to–

plasma protein concentration ratio (0.15) are

similar to those of filtrates from high-pressure

systemic vessels. By comparison, a filtrate from

low-pressure pulmonary vessels has a higher

protein concentration (45 g/L) and ratio (lymph–

to–plasma protein concentration ratio 0.69).[29

6.    The majority of liquid exits the pleural

space by bulk flow, not by diffusion or active

transport. This is evident because the protein

concentration of pleural effusions remains

constant as the effusion is absorbed, as is

expected with bulk flow. If liquid were absorbed

by diffusion or active transport, proteins would

diffuse at a slower rate, and the protein

concentration would progressively increase. In

addition, erythrocytes instilled into the pleural

space are absorbed intact and in almost the

same proportion as the liquid and protein.[18

] This indicates that the major route of exit is

via holes large enough to accommodate sheep

erythrocytes (6–8 ým diameter). The only

possible exit is via the parietal pleural stomata

(10–12 ým diameter) into the pleural

lymphatics. Of note, these lymphatics have a

large capacity for absorption. When artificial

effusions were instilled into the pleural space

of awake sheep, the exit rate (0.28 mL/kg/hr)

was nearly 30 times the baseline exit rate

(0.01 mL/kg/hr).[18]

Pleural PressureThe pleural pressure in humans is approximately

−5 cm H2O at midchest at functional residual

capacity and −30 cm H2O at total lung capacity.[30]

If the compliance of the lung decreased, pleural

pressures at the same lung volumes would be more

negative. In one study of patients undergoing

thoracentesis, those with more negative pleural

pressures had a smaller improvement in lung

volume than those with less negative pressures,

presumably reflecting the presence of underlying

diseased, noncompliant lung.[31]

Although the pleural space pressure is

subatmospheric, gases do not accumulate

there. The sum of all partial pressures of

gases in capillary blood is approximately

700 mm Hg, or 60 mm Hg below

atmospheric (water pressure [PH2O] = 47,

carbon dioxide pressure [PCO2] = 46,

partial pressure of nitrogen [PN2] = 570,

and oxygen pressure [PO2] = 40 mm Hg).

The subatmospheric pressure of

dissolved gases in capillary blood helps

to maintain the pleural space free of gas

and facilitates absorption of any gas that

does enter the pleural space. Of note, to

increase the gradient favoring absorption

of gas, one can lower the PN2 in the

blood by having a patient breathe

increased concentrations of inspired

oxygen.

The oxygen displaces alveolar nitrogen,

thereby lowering the PN2 in capillary

blood; because of the limited absorption

of oxygen due to the plateau of the

oxygen-hemoglobin dissociation curve,

the increase in inspired oxygen does not

add greatly to the PO2 in capillary blood.

PATHOPHYSIOLOGY OF THE PLEURAL SPACE

Pleural Effusions For pleural liquid to accumulate to form an

effusion, it is likely that both the entry rate of liquid must increase and the exit rate must decrease. If only the entry rate increased, it would require a sustained rate more than 30 times normal to exceed the reserve lymphatic removal capacity; if the exit rate decreased, it would take more than a month at the normal entry rate of 12 mL/day to produce an effusion detectable by chest radiograph.[22] Thus, in the clinical setting, it is most likely that excess pleural liquid accumulates due to changes in both entry and exit rates.

Increased entry of liquid may result from increased filtration across systemic or pulmonary capillaries or entry of another liqud (e.g., chyle, cerebrospinal fluid [CSF], urine, intravenous fluids). Decreased exit of liquid may result from interference with lymphatic function (e.g., obstruction of the parietal pleural stomata, inhibition of lymphatic contractility, infiltration of draining parasternal lymph nodes, or elevation of the systemic venous pressure into which the lymph drains).[22] There are few studies on the rate of removal of liquid in humans; however, decreases in lymphatic clearance have been confirmed in patients with tuberculous and malignant effusions[32] and in those with the yellow nail syndrome, a disease of lymphatic function.[33]

To determine the origin of effusions, a classic and useful distinction is between transudates and exudates (see later, “Separation of Exudates from Transudates”).[34] Transudates form by leakage of liquid across an intact capillary barrier owing to increases in hydrostatic pressures or decreases in osmotic pressures across that barrier. Transudates generally indicate that the pleural membranes are not themselves diseased. Exudates form from leakage of liquid and protein across an altered capillary barrier with increased permeability. The protein ratio, the LDH ratio, and the absolute pleural LDH concentration constitute Light's criteria.

Transudates include various low-protein liquids

that arise from noninjured capillary beds. The

majority of transudates are caused by CHF.

These transudates have been shown to form from

leakage of edema across normal pulmonary

capillaries into the pulmonary interstitium and

then across the leaky visceral pleura into the

pleural space.[6],[35] Other transudates, those

associated with the nephrotic syndrome or

atelectasis, may form because of altered

pressures (osmotic or hydrostatic) across the

pleural capillaries.

Some transudates, usually small, may develop

primarily because of an isolated decrease in

exit rate.[36] Hepatic hydrothorax and effusions

from peritoneal dialysis develop when liquid

flows from the peritoneal space into the lower

pressure pleural space across macroscopic

holes in the diaphragm. Finally, other very low

protein fluids such as urine or CSF or

intravenous liquids may find their way to the

pleural space if their normal course is

disrupted.

Exudates arise from injured capillary beds, in either the lung, the pleura, or adjacent tissues. Most exudates, such as those associated with pneumonia or pulmonary embolism, probably form following lung inflammation and injury when a high-protein lung edema leaks into the pleural space. Another large category of exudates arises from pleural injury due to inflammation, infection, or malignancy. Exudates can also form when exudative liquid in the mediastinum (esophageal rupture or chylothorax), retroperitoneum (pancreatic pseudocyst), or peritoneum (ascites with spontaneous bacterial peritonitis or Meigs’ syndrome) finds its way into the lower-pressure pleural space.

As stated, for either transudates or

exudates, lymphatic obstruction may

contribute to the accumulation of the

effusion. Nonetheless, because lymphatic

clearance does not alter the pleural fluid

protein concentration, the protein

concentration gives information about

the formation of the fluid, not its

removal.[22]

Effects of Pleural Effusions on Lung and Cardiac Function

In the presence of a space-occupying liquid in the pleural space, the lung recoils inward, the chest wall recoils outward, and the diaphragm is depressed inferiorly and is sometimes inverted.[37] If the lung and chest wall have normal compliances, the decrease in lung volume accounts for approximately a third of the volume of the pleural effusion, and the increase in the size of the hemithorax accounts for the remaining two thirds. As a result, lung volumes are reduced by less than the pleural effusion volume. If the lung is otherwise normal, there is no evidence that an effusion causes significant hypoxemia, presumably because ventilation and perfusion decrease similarly. In fact, in one study, hypoxemia was noted only after liquid was removed by thoracentesis,[38] when perfusion presumably was restored while ventilation remained inadequate.

In another study using multiple inert gas

techniques to quantify ventilation-perfusion

(V/Q) distributions, pleural effusion was

associated with a small intrapulmonary

perfusion shunt (6.9%) that did not change

significantly when measured again 30 minutes

after thoracentesis of approximately 700 mL

(6.1%).[39] It appears, therefore, that the effects

of pleural effusion and thoracentesis on

oxygenation are variable and may depend on

the underlying lung function.

Large pleural effusions may impair cardiac function, most likely by decreasing the distending pressures on the cardiac chambers and cardiac filling. In a study of 27 patients with large effusions occupying more than half the hemithorax, clinical and echocardiographic findings of cardiac tamponade were identified in most patients. These findings, including elevated jugular venous pressure, pulsus paradoxus, right ventricular diastolic collapse, or flow velocity paradoxus, resolved in all patients when studied again 24 hours after thoracentesis of more than 1.0 L.[40] Large pleural effusions, especially left-sided effusions, should be considered as potentially reversible causes of cardiac dysfunction.[41]

Common symptoms of patients with effusions

are pleuritic chest pain, cough, and dyspnea. It

appears that the three symptoms are due to

different causes. Pleuritic chest pain derives

from inflammation of the parietal pleura and

possibly the visceral pleura. Occasionally, this

symptom is accompanied by an audible or

palpable pleural rub, reflecting the movement

of abnormal pleural tissues. Cough may be due

to distortion of the lung, in the same way as

cough follows lung collapse from a

pneumothorax.

Dyspnea is most likely caused by the mechanical

inefficiency of the respiratory muscles that are

stretched by the outward displacement of the chest

wall and the downward displacement of the

diaphragm.[37] After the removal of large amounts of

pleural liquid, dyspnea is generally relieved

promptly, although the reduction in pleural liquid

volume is associated with only small increases in

lung volume and little improvement, or an actual

decrease, in PO2. In one study, nine patients

underwent removal of over 1800 mL of pleural

liquid, and despite increases in vital capacity of

only 300 mL, all patients experienced immediate

relief of dyspnea.[42]

Although the vital capacity changed little,

patients could generate a more negative

pleural pressure at the same lung volume

after thoracentesis than before, indicating an

improved efficiency of the respiratory muscles

following the return of the chest wall and

diaphragm to a more normal position after

thoracentesis. This improved efficiency of

respiration may explain the relief of dyspnea

after removal of pleural liquid.

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