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hamer JH, Parrillo JE. Responses of left ventricular function in survivors and nonsurvivors of septic shock. J Crit Care 1989; 4 (in press) Parker MM, McCarthy KE, Ognibene FE Parrillo JE. Similar patterns of left and right ventricular dysfunction in survivors and nonsurvivors of septic shock in humans. Crit Care Med 1988; 16:393 Ognibene FE Parker MM, Natanson C, Shelhamer JH, Parrillo JE. Depressed left ventricular performance: response to volume infusion in patients with sepsis and septic shock. Chest 1988; 93:903-10 Parker MM, Shelhamer JH, Natanson C, Alling D~ Parrillo JE. Serial cardiovascular variables in survivors and nonsurvivors of human septic shock. Crit Care Med 1987; 15:923-29 Cunnion RE, Schaer GL, Parker MM, Natanson C, Parrillo JE. The coronary circulation in human septic shock. Circulation 1986; 73:637-44 Lefer AM, Martin J. Origin of myocardial depressant factor in shock. Am J Physiol1970; 218:1423-27 Carli A, Auclair M-C, Benassayag C, Nunez E. Evidence for an early lipid soluble cardiodepressant factor in rat serum after a sublethal dose of endotoxin. Circ Shock 1981; 8:301-12 Greene LJ, Shapanka R, Glenn TM, Lefer AM. Isolation of myocardial depressant factor from plasma ofdogs in hemorrhagic shock. Biochem Biophys Acta 1977; 491:275-85 Parrillo JE, Burch C, Shelhamer JH, Parker MM, Natanson C, Schuette W A circulating myocardial depressant substance in humans with septic shock. J Clin Invest 1985; 76:1539-53 Schuette WH, Burch C, Roach PO, Parrillo JE. Closed loop television tracking of beating heart cells in vitro. Cytometry 1987; 8:101-03 Reilly JM, Cunnion RE, Burch-Whitman C, Parker MM, Shelhamer JH, Parrillo JE. A circulating myocardial depressant substance is associated with cardiac dysfunction and peripheral hypoperfusion (lactic acidemia) in patients with septic shock. Chest 1989; 95:1072-80 Hollenberg SM, Cunnion RE, Lawrence M, Kelly JL, Parrillo JE. Tumor necrosis factor depresses myocardial cell function: results using an in vitro assay of myocyte performance. Clin Res 1989; 37 (in press) Danner RL, Parrillo JE. The role of endotoxin in human septic shock: therapeutic potential of Lipid A analogs. In: Roth BL, Nielsen TB, McKee AE, eds. Molecular and cellular mechanisms of septic shock. New York: AR Liss, Inc, 1989:183-96 Beutler B, Cerami AC. Cachectin and tumor necrosis factor as two sides of the same coin. Nature 1986; 320:584-88 Dinarello CA, Cannon JG, Mier J~ Bernheim HA, LoPreste G, Lynn DL, et ale Multiple biological activities of human recombinant interleukin 1. J Clin Invest 1986; 77:1734-39 Ognibene FE Rosenberg SA, Lotze M, Skibber J, Parker MM, Shelhamer JH, et al. Interleukin-2 administration causes reversible hemodynamic changes and left ventricular dysfunction similar to those seen in septic shock. Chest 1988; 94:750-54 Natanson C, Eichenholz P~ Danner RL, Eichacker PQ, Hoffman WD, Kuo GC, et ale Endotoxin and tumor necrosis

factor challenges in dogs simulate the cardiovascular profile of

human septic shock. J Exp Med 1989; 169 (in press) 21 Natanson C, Eichacker PQ, Hoffman WD, Banks SM, MacVittie TJ, Parrillo JE. Human recombinant interleukin-l produced minimal effects on canine cardiovascular function. Clin Res 1989; 37 (in press) 22 Suffredini AF, Parker MM, Brenner M, Schlesinger T, Parrillo JE. Endotoxin administration produces abnormal cardiovascular responses in normal humans. Clin Res 1987; 35:386A 23 Natanson C, Fink ME Ballantyne HK, Conklin J, MacVittie TJ, Parrillo JE. Gram-negative bacteremia produces both severe systolic and diastolic cardiac dysfunction in a canine model that

simulates human septic shock. J Clin Invest 1986; 78:259-70 24 Natanson C, Danner RL, Fink M~ MacVittie TJ, Walker RI, Conklin JJ, et ale Cardiovascular performance with E. coli challenges in a canine model of human sepsis. Am J Physiol 1988; 254(Heart Cire Physiol23):H558-69 25 Natanson C, Danner RL, Elin RJ, Hosseini JM, Peart K~ MacVittie TJ, et ale Role of endotoxemia in cardiovascular dysfunction and mortality: E. coli and S. aumu challenges in a canine model of human septic shock. J Clin Invest 1989; 83:24351 26 Doerfler ME, Danner RL, Shelhamer JH, Parrillo JE. Bacterial lipopolysaccharides prime human neutrophils for enhanced production ofleukotriene 84. J Clin Invest 1989; 83 (in press) 27 Danner RL, Elin RJ, Hosseini JM, Schlesinger T, Reilly JM, Parrillo JE. Endotoxin determinations in 100 patients with septic shock. Clio Res 1988; 36:453A 28 Danner RL, Joiner KA, Parrillo JE. The inhibition of endotoxin induced priming of human neutrophils by Lipid X and 3-AzaLipid X. J Clin Invest 1987; 80:605-12 29 Ognibene FE Parker MM, Burch-Whitman C, Natanson C, Shelhamer JH, Schlesinger T, et ale Neutrophil aggregating activity and septic shock in humans: neutrophil aggregation by a C5a-like material occurs more frequently than complement component depletion and correlates with depression of systemic vascular resistance. J Crit Care 1988; 3:103-11

The Sun Should Never set on a Parapneumonic Effusion It has been documented that pleural effusions are frequently associated with pneumonia, whether it be pneumococcal, staphylococcal, Gram-negative aerobic, or anaerobic. l -4 The most common cause of an empyema or complicated parapneumonic effusion today is anaerobic pulmonary infection. 5 This is largely related to the pathogenesis of anaerobic pulmonary infection, since the disease frequently occurs in the alcoholic patient or in those with impaired consciousness and has an insidious course that does not prompt immediate medical attention. Medical consultation usually is sought seven to ten days after initial inoculation of anaerobes in the lung, when necrotization occurs in the form of necrotizing pneumonia, lung abscess, or empyema. 2 Due to the delay in initiation the patient frequently has a of antibiotic therap~ pleural effusion by this time. The stage of the pneumonia and of the parapneumonic effusion is critical to the outcome. If the patient can be treated early in their course with appropriate antibiotics, resolution of the pleural effusion occurs with minimal pleural sequelae. If too much time elapses, allowing the inHammatory process to proceed unimpeded in the pleural space, control of pleural sepsis and resolution of the pleural inHammation cannot occur without pleural space drainage. This often necessitates a thoracotomy or prolonged open drainage. Therefore, time is of the essence in the treatment CHEST I 95 I 5 I MA~

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of parapneumonic effusion. The first rule is that in patients with pneumonia, one should carefully search the chest roentgenogram for a pleural effusion, including decubitus views. If the effusion is free-flowing and greater than 1 cm from the inside of the chest wall to the pleural fluid line on the lateral decubitus vie~ immediate diagnostic thoracocentesis should be done. If loculated, thoracocentesis should be done under ultrasonic guidance. Following notation of the character of the fluid (including odor), the most important diagnostic tests to order are Gram stain and culture, pH, glucose, and LDH. The pleural Huid pH must be handled meticulously as an arterial pH and drawn anaerobically into a syringe rinsed with 0.2 ml of 1:1,000 heparin and placed on ice until analyzed; the pH is stable for at least 6 h using this procedure. 6 The fluid for glucose measurement must be placed in a tube with an antiglycolytic substance to prevent in vitro glycolysis, which can occur with the numerous PMNs present in the fluid. The pH, glucose, and LDH are related, either directly (pH and glucose) or inversely (pH and LDH, glucose and LDH) in parapneumonic effusions. In uncomplicated parapneumonic effusions, the pH is >7.30, the glucose 60 > mwdl, or the pleural fluid to serum ratio >0.5, and the LDH is <1,000 UIL, usually less than 500 UIL. In contrast, patients with complicated parapneumonic effusions (including empyema) have a pH <7.10, a glucose <40 mwdl, and an LDH >1,000 UIL.4-8 All three should be measured in parapneumonic effusions. If only a single measurement is performed and it is spurious, an incorrect therapeutic decision can be made. The pH is most likely to be spurious, either because room air is allowed

to accumulate in the syringe causing a false elevation of pH, or the syringe remains at room temperature allowing glycolysis to occur causing the reported pH to be falsely low 9 The clinician also must be cautious in interpreting the pH value in the setting ofacidemia. When acidemia is present, pleural fluid acidosis is defined as a pH at least 0.15 pH units lower than blood pH. The pH cutoff for chest tube insertion in acidemia is unknown, but probably is at least 0.30 units less than blood pH. If the fluid is purulent (empyema) on thoracocentesis, drainage must be instituted, either through tube thoracostomy or at thoracotom~ In nonpurulent fluid, the Gram stain results and biochemical characteristics should be used to aid in decision making. The pleural fluid should be drained if the Gram stain is positive, pleural fluid pH is <7.10, or pleural fluid glucose is <40 mWdl. If indications for drainage are present, the procedure should be carried out immediately, as it may only take a few hours for free-flowing fluid to loculate and greatly increase the morbidity and even mortality of the patient. A free-Howing nonpurulent 948

fluid can usually be drained adequately with a single chest tube, while the loculated pleural space commonly needs to be evacuated at surgery. Ifthe patient has a free-flOwing, nonpurulent pleural fluid with borderline biochemical parameters (a pH between 7.29 and 7.10, glucose between 40 and 60 mwdl, and an LDH <1,000 UIL), appropriate antibiotic treatment should be started and the patient observed over the next six to 12 h. At that time, thoracocentesis should be repeated. If the pleural fluid measurements are stable or improving, continued observation with antibiotic therapy is warranted; if there is a worsening of these measurements, chest tube drainage is generally necessary for resolution. We tend to be aggressive with our recommendation for tube drainage, since we would rather have a few too many chest tubes placed than obtain a result requiring thoracotom~ empyectom~ and decortication if the drainage had not been done or was delayed. We think that the adage "the sun should never set on a pleural effusion" should be modified to read "the sun should never set on a parapneumonic effusion," because timing is most critical in appropriate management. A final note: the value of pleural fluid in aiding the decision on pleural space drainage is only relevant to parapneumonic effusions and should not be used as a criterion for drainage in other causes of low pH effusions such as rheumatoid pleurisy, tuberculosis, malignanc); or lupus pleuritis. 10 Steven A. Sahn, M.D., F.C.C.P.;* Charleston, SC and Richard W Light, M.D., F.C.C.P.t Long Beach, CA *Professor of Medicine; Director, Division of Pulmonary/Critical Care Medicine, Medical University of South Carolina. tACOS Research and Development, Veterans Administration Hospital. Reprint requests: Dr. Sahn, Pulmonary Medicine, Bldg 812 CSB, Ext 3161, Medical University of South Carolina, Charleston 29425

REFERENCES 1 Wiita RM, Cartwright RR, Davis JG. Staphylococcal pneumonia in adults. AJR 1961; 86:1083-91 2 Bartlett JG, Finegold SM. Anaerobic infections of the lung and pleural space. Am Rev Respir Dis 1974; 110:56-77 3 Taryle DA, Potts DE, Sahn SA. The incidence and clinical correlates of parapneumonic effusions in pneumococcal pneumonia. Chest 1978; 74:170-73 4 Light R~ Girard WM, Jenkinson SG, George RB. Parapneumonic effusions. Am J Med 1980;69:985-86 5 Bartlett JG, Gorbach SL, Thadepalli H, Finegold SM. Bacteriology of empyema. Lancet 1974; 1:338-40 6 Light ~ MacGregor MI, Ball WC Jr, Luchsinger PC. Diagnostic significance of pleural fluid pH and Pco2 • Chest 1973; 64:591-96 7 Potts DE, Levin DC, Sahn SA. Pleural fluid pH in parapneumonic effusions. Chest 1976; 70:328-31 8 Potts DE, Taryle DA, Sahn SA. The glucose-pH relationship in Editorials

parapneumonic effusions. Arch Intern Moo 1978; 138:1378-80 9 Sahn SA, Reller LB, Taryle DA, Antony VB, Good JT Jr. The contribution of leukocytes and bacteria to the low pH of empyema fluid. Am Rev Respir Dis 1983; 128:811-15 10 Good JT Jr, Kaplan RL, Maulitz RM, Taryle DA, Sahn SA. The diagnostic value of pleural fluid pH. Chest 1980; 78:55-59

Atrial Natriuretic Factor The evidence is clear that the heart is an endocrine gland in the classic sense. In response to certain stimuli, a chemical messenger is released into the systemic circulation to activate physiologic responses in one or more target organs at distant sites. The humoral factor is a peptide referred to as atrial natriuretic factor (ANF). The peptide is localized to granules within atrial myocardial cells. ANF is formed by the proteolytic release of the final 28 amino acids from the C-terminal of a 126 amino acid precursor protein. Most fascinating, perhaps, is that the prohormone for ANF may be the source of several other peptides that also exhibit ANF-like activity. Several atriopeptins may therefore exist that could prove to be of therapeutic importance. In response to an increase in atrial transmural pressure with associated atrial stretch, ANF is released. Atrial stretch results from IV volume overloading, vasoconstrictor agents, salt loading, and certain drugs. The physiologic role of ANF is to activate homeostatic mechanisms that restore normal blood pressure and electrolyte levels. Not surprisingl~ the sites of action of ANF, therefore, are the kidne~ the adrenals, vascular smooth muscle, and possibly the CNS. ANF inhibits adrenal aldosterone secretion directly and also indirectly by suppression of renin secretion, relaxes vascular smooth muscle, increases

renal diuresis and natriuresis, and, in addition, may have a central role in suppression of fluid and salt intake (drinking and salt appetite, respectively) and of vasopressin secretion, actions that again would result in processes leading to reduction in body salt and fluid levels and peripheral blood pressure. Conversely, ANF levels (in dogs) are reduced during hypotension due to hemorrhage, thus protecting the hypovolemic organism from further volume loss. Thus, ANF contributes to the reestablishment of intravascular volume homeostasis in states of acute volume overload or depletion. ANF may also regulate volume distribution by shifting fluid between the extravascular and intravascular compartments. It is interesting, therefore, to note the increased levels of "atrial natriuretic factor in the pleural fluid of congestive heart failure patients" as demonstrated by Vesely et al in this issue of Chest (see p 1107). ANF was found in high concentrations in the pleural fluid of all the patients studied. The authors suggest that ANF secreted locally by the lung may provide a protective mechanism to prevent the formation offluid in the lung. Thus, ANF is apparently also synthesized at sites other than the myocardium, such as the lung, to possibly participate in a diverse number of physiologic roles. ANF fulfills all the criteria necessary to be considered a hormone; therefore, the term atriopeptin might be a better designation, especially since it is argued by some that it is not unequivocally established that the atrial peptide exerts an important influence on sodium excretion under normal physiologic conditions. Mac E. Hadley, Ph.D. Tucson Professor of Anatomy and Molecular and Cellular Biology, University of Arizona Health Sciences Center.

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