Multiple organ failure

Single organ failure after trauma or surgery, such as renal failure or cardiogenic shock after myocardial infarction, has been recognized for decades.[1] The recognition of sequential organ failure after trauma was described by the mid-1970s.[2] The extracorporeal membrane oxygenation study in the mid-1970s also observed that multiple organ failure (MOF) correlated strongly with death after the onset of the adult respiratory distress syndrome (ARDS).[3] A further refinement of the association between ARDS and MOF was provided by Bell et al.[4]

There is legitimate scientific concern that the experimental models used to test hypotheses related to mechanisms of organ failure in ARDS do not reflect ARDS in humans. Most animal models are shortterm, but ARDS in humans develops over periods of several days. Additionally, animal models of septic shock with respiratory failure reveal that cardiac output is often greatly decreased, in contrast to the increased cardiac output observed in the clinical setting. Despite these limitations, intravascular volume resuscitation is ineffective in restoring blood flow to individual organs or in increasing cardiac output in most models of cardiorespiratory failure and ARDS, with the notable exception of hemorrhagic shock.[5-8] In this regard, reductions in cardiac output alone are not sufficient to explain the lack of responsiveness to intravascular volume infusion in these models. Rather, the absence of reversible volume depletion suggests an impairment of vascular integrity.[9] Thus, the relationship of ARDS to MOF is best studied in humans.

We therefore sought to evaluate the relationship of lung dysfunction to systemic alterations in ARDS. The purpose of this article is to characterize the epidemiology of multiple organ dysfunction (MOD) after ARDS. To determine patterns of resolution versus development of MOF after MOD, we compared the temporal relationship of MOF development in patients who died compared to that in those who survived.

Methods

The study design has been reported previously.[10] This study retrospectively examined data from patients with ARDS who were enrolled in a randomized, double-blind, clinical trial of prostaglandin [E.sub.1] ([PGE.sub.1]) therapy. We analyzed data on the epidemiology of MOD and correlated them with outcome. For this study, we selected only patients receiving placebo (n = 50), to eliminate any confounding effects of [PGE.sub.1], which was the subject of our previous publications.

Patients aged 18 years or older of both sexes (except pregnant women) were eligible for enrollment. Patients were enrolled if (1) ARDS had occurred after surgery, trauma, or sepsis; (2) a pulmonary artery catheter was in place; (3) mechanical ventilation resulted in a Pa[O.sub.2](FI[O.sub.2] ratio of 150 or less without positive end-expiratory pressure (PEEP) or 200 or less with PEEP; and (4) a chest x-ray film showed bilateral infiltrates and the pulmonary capillary wedge pressure was 18 mm Hg or less. Patients were excluded from the study for the following reasons: (1) a history of severe lung disease (such as chronic obstructive pulmonary disease); (2) a Glasgow come scores less than 8 resulting from head injury; (3) a serum bilirubin measurement greater than 4 mg/dl or a serum creatinine measurement greater than 3 mg/dl; (4) a high risk of dying within 30 days due to a condition other than ARDS (eg, terminal cancer); (5) high-dose corticosteroid therapy during the previous seven days; or (6) current experimental drug therapy.

Medical histories were obtained, and physical examinations were performed. Laboratory workups, including complete blood cell counts, electrolytes, chemistries, and urinalysis, were performed initially and at the end of seven days. White blood cell counts and serum creatinine and total bilirubin measurements were obtained daily for seven days. Chest x-ray films were obtained at diagnosis, on days 3 and 7, and two weeks later. Vital signs were recorded every 4 h during the first seven days. Fluid balance (intake and output) was determined daily. Arterial blood gas levels and hemodynamic, respiratory mechanics, and oxygen transport assessments were obtained at baseline, every 8 h during the first day, and daily for the first week.

Normally distributed data are presented as the mean [+ or -] SD. These data were analyzed using an analysis of variance repeated over time. Nonparametric data are presented as the median. An alpha value of 0.05 was used as the cutoff point for statistical significance. No corrections were made for multiple comparisons.[11]

Results

Of 50 patients, 24 (48 percent) were dead at the 30-day assessment. Statistically significant differences in oxygenation, as reflected by Pa[O.sub.2]FI[O.sub.2] ratios, were observed between patients who survived ARDS and those who did not on each of the seven study days (Table 1). Levels of PEEP were significantly greater in nonsurvivors for days 3 through 7 (p<0.05). Survivors had a significantly higher arterial oxygen content during the first four days after diagnosis (p<0.05), while increased mixed venous oxygen content was evident only on day 1 (Table 2). Peak inspiratory pressure was higher on days 2 through 5 and again on day 7 among nonsurvivors (Table 3).

[TABULAR DATA OMITTED]

Decreased diastolic blood pressure among nonsurvivors was first observed on days 1 through 3 and reappeared on day 7 (Table 4). Mean pulmonary artery pressure was elevated only on days 2 and 3 in nonsurvivors (Table 5).

[TABULAR DATA OMITTED]

Nonsurvivors were more thrombocytopenic on days 1 through 4 than were survivors (Table 6), but pH differences, first observed on day 1, reappeared on day 4 and became increasingly significant over the last four study days. By day seven, the nonsurvivor group exhibited a mean pH of 7.38 [+ or -] 0.06, whereas survivors showed a mean pH of 7.45 [+ or -] 0.04; the difference was highly significant (Table 7).

[TABULAR DATA OMIITED]

Decreases in liver function were seen among the patients who later died, but a statistically significant difference in bilirubin concentration was evident only on day 1 (p<0.05). Significant decreases in serum creatinine levels were observed only on day 7 (p<0.05). Large differences in SGOT were observed between the groups (71 [+ or -] 44 IU/L for survivors vs 399 [+ or -] 807 IU/L for nonsurvivors [p<0.05]). Alkaline phosphatase levels were also dissimilar (121 [+ or -] 53 IU/L for survivors vs 269 [+ or -] 243 IU/L for nonsurvivors).

The interrelationships among these variables are complex. For a visual depiction of the time course of the significant changes, see Table 8.

[TABULAR DATA OMITTED]

No significant differences in oxygen availability, oxygen consumption, oxygen extraction, Pa[CO.sub.2], respiratory rate, heart rate, systolic blood pressure, cardiac output, stroke index, systemic vascular resistance, or temperature were detected between patients who survived and those who died during the seven-day study period.

Discussion

Adult respiratory distress syndrome is characterized by the development of hypoxemia, pulmonary infiltrates, stiff lungs, and noncardiogenic pulmonary edema, usually occurring within 72 h of the onset of a definable risk factor.[12] Our patients were selected when they met the criteria for ARDS, yet differences in oxygenation, oxygen content, and mixed venous oxygen content were apparent between survivors and nonsurvivors. Previously we described an analysis of Pa[O.sub.2]/FI[O.sub.2] ratios in predicting survivors and nonsurvivors of ARDS.[13]

Adult respiratory distress syndrome occurs when lung endothelial permeability increases and pulmonary edema ensues. Resolution of ARDS and survival are contingent on the ability to maintain adequate tissue oxygenation, allowing the lungs to repair endothelial and epithelial defects before pulmonary fibrosis permanently alters the parenchyma. In the present study, nonsurvivors were less able to maintain adequate oxygenation and oxygen content than were survivors. Hypoxemia was greater on days 1 through 7, and decreased oxygen content was evident on days 1 through 4 in patients who did not survive.

Pulmonary involvement can occur in several ways. A primary pathologic condition, such as pneumonia or a pulmonary contusion, can be the inciting event that leads to development of the hypermetabolic response and ARDS. Secondary pathologic changes can result from a variety of nonpulmonary events (eg, sepsis and shock) and occur in a spectrum ranging from mild lung injury to fulminant ARDS. Adult respiratory distress syndrome is characterized by endothelial cell injury and destruction, deposition of platelet and WBC aggregates in clots of fibrin and cellular debris, destruction of type I alveolar pneumocytes, and an acute inflammatory response that must proceed through all the phases of injury and repair - a process not unlike wound healing in other parts of the body. These alterations become manifest clinically as decreased lung compliance, mismatching of ventilation and perfusion, arterial hypoxemia, and, frequently, pulmonary artery hypertension. All of these physiologic abnormalities were more severe in nonsurvivors.

Cardiovascular Alterations

The cardiovascular response to ARDS is characterized by high cardiac output and low systemic vascular resistance. The prime cause of this response appears to be increased peripheral demand for oxygen. Failure to generate this hyperdynamic cardiovascular response despite greater hypoxemia in nonsurvivors is associated with increased risk of mortality and usually occurs as a result of inadequate preload, preexisting cardiac disease, or acquired cardiac dysfunction.

Hemodynamic responses are complex and time-dependent; cardiac output, stroke index, systolic blood pressure, oxygen availability, and oxygen consumption were similar in survivors and nonsurvivors for days 1 through 7. However, decreased diastolic blood pressure appeared on day 7 and increased mean pulmonary artery pressure was seen on days 1 and 2 among patients who died. Adult respiratory distress syndrome is most frequently associated with sepsis, occurring in 5 to 40 percent of patients with sepsis. If the onset is sudden and severe, an acute phase of splanchnic blood pooling occurs. Decreased venous return induces preload-dependent hypotension that is similar to that seen in hypovolemic shock.[14] Release of preformed vasoactive substances may account for these changes. When the onset of ARDS is gradual, however, this initial phase may not be dramatic. The late development of decreased diastolic blood pressure may be an indication of the evolution of the late septic syndrome in nonsurvivors.

Initial "cardiovascular collapse" is followed by a phase in which the circulatory system exhibits quite different characteristics. Arterial tone is reduced, and if fluid resuscitation has been carried out, cardiac output increases above its preresuscitation baseline level despite sustained reductions in arterial pressure.[14,15] This stage is characterized by increased oxygen delivery, impaired tissue oxygen extraction, altered metabolism with lactic acidosis, depressed ventricular performance (which may be masked by coexisting hypotension), and generalized increases in microvascular permeability.[16] Increased cardiac output despite decreases in arterial tone may occur because fluid resuscitation has replenished the expanded unstressed volume of the circulation or because blood flow is diverted into vascular circulation with shorter time constraints.[17] It has been suggested that this constellation of circulatory abnormalities can be explained by defective intraorgan blood flow distribution, such that normal peripheral vascular autoregulatory mechanisms are overridden.[14,18,19] Such a process may be instrumental in producing MOD despite an apparent abundance in organ perfusion manifested by increased cardiac output. This condition is referred to as "peripheral vascular paralysis."[14]

Regulation of intraorgan blood flow may be profoundly impaired by abnormal interactions between formed blood elements and the endothelium, microvascular thrombosis, paradoxic vasoconstriction, and the humoral effects of a sustained intravascular inflammatory state. Consequently, increased local tissue oxygen demand may go unmet, and resultant tissue ischemia affecting organ performance may adversely affect remote organ function. This concept forms the basis for the aggressive resuscitative measures that take into account the comprehensive nature of septic shock. If therapy is effective or the cause of ARDS is not too overwhelming or persistent, hemodynamic improvement occurs with a return to normal circulatory and metabolic homeostasis. However, if inflammation persists or if the initial cellular insult was sufficiently severe, tissue injury may become irreversible. Reperfusion injury following hypoxic-ischemic insults may partially account for this. Transformation of xanthine dehydrogenase to xanthine oxidase in ischemic tissues promotes the production of toxic oxygen metabolites.[20] During Escherichia coli-induced septic shock in the dog, oxygen-free radical activity persisted even after polymorphonuclear leukocyte depletion.[21] This suggests that ongoing cellular damage by oxidants becomes a self-perpetuating process. In the final stages of septic shock, death becomes inevitable: cardiac output falls, oxidative phosphorylation declines, lactic acidosis worsens, and the patient becomes unresponsive to vasoactive agents.

Our patients who had ARDS but were resuscitated had the above findings, but the significant factors that separated nonsurvivors from survivors during late ARDS without resolution were decreases in arterial pH, mixed venous oxygen content, and diastolic blood pressure. Fowler et al[22] previously reported a similar relationship between arterial pH and survival.

Hepatic Alterations

In a previous study of hepatic dysfunction in patients with ARDS, we found significant differences in liver function between survivors and nonsurvivors.[23] In the present study, on the day ARDS was identified, several indicators of decreased liver function were present. These results emphasized the importance of intact nonpulmonary organ function in the maintenance of adequate host defenses and suggested that liver function may be a major determinant of survival in patients with ARDS. Thus, to the extent that the hypothesis that ARDS is a syndrome of widespread MOD is valid, it is predictable that hepatic dysfunction could account for the increased susceptibility to secondary and nosocomial infections observed in this group of patients.

Thrombocytopenia

Thrombocytopenia was a frequent observation in patients with ARDS. It was greater in nonsurvivors from day 1 to day 4. Bone et al[24] previously reported a similar finding in ARDS patients; ARDS was more severe and mortality was higher in those patients with more profound coagulation abnormalities. Microvascular thrombi in the lungs were found when autopsy was performed.

Renal Alterations

Nonsurvivors in our study demonstrated significant increases in creatinine as a late observation (found only on day 7). Acute renal failure (ARF) is a complex disease, which, like ARDS, has proved difficult to treat. Over the past 25 years the mortality rate attributable to ARF has been increasing.[25,27] This may be somewhat surprising, since modern hemodialysis techniques can maintain adequate acid-base and electrolyte status in anephric patients for years with minimal mortality. Why do ARF patients die and why is their mortality rate increasing? One explanation may be found in the clinical context in which ARF occurs. Abreo et al.[25] compared two different groups of patients treated with hemodialysis: a group treated between 1962 and 1969 and a group treated between 1979 and 1982. In the first group, acute reductions in glomerular filtration associated with transient but profound hypotension were the common causes. Since that thime, however, invasive hemodynamic monitoring and aggressive resuscitation in cases of hypovolemia have minimized this complication. In the second group of patients, ARF frequently complicated the management of other diseases. The first group tended to be oliguric for shorter intervals prior to hemodialysis, tended to have higher pretreatment creatinine and BUN values, and tended to undergo hemodialysis for shorter times than the second group.[25]

Acute renal failure appears to be a disease in evolution, owing mainly to therapeutic advances that have minimized "prerenal" causes of renal failure, allowing "renal" causes of ART to become manifest in patients who previously would have died. It appears that, despite our ability to support organ system function in critically ill patients, the inability to reverse basic mechanisms leading to tissue injury and impaired autoregulation causing the dysfunction only prolongs the dying process. Acute renal failure in the nonsurviving ARDS patient seems to be a preterminal event.

Relation of ARDS and ARF to MOF

How can we reconcile the data regarding ARDS and ARF with our knowledge of basic pathophysiologic mechanisms in MOF? Even though many insults can lead to ARDS or ARF, there appears to be little difference among etiologies in the organ-specific expression of the injury; pathologic patterns of response in the lung and kidney are limited. Different disease processes produce similar patterns of lung and kidney dysfunction. For example, ARDS secondary to acute viral pneumonia in the absence of extrapulmonary organ injury is a localized process having a better prognosis for recovery of pulmonary function than when it is complicated by MOF.[12] In contrast, ARDS caused by acute pancreatitis is associated with systemic activation of many inflammatory mediators and may lead to generalized endothelial injury in a number of organs. Both the severity of initial injury and subsequent organ system interactions may, therefore, account for the often delayed recovery, as well as the progression to MOF and death if secondary abdominal sepsis supervenes. Analogously, ARF caused by hemorrhagic shock is short-lived, as a result of more aggressive volume resuscitation (guided by hemodynamic monitoring), which stabilizes the patient. Acute renal failure releated to septic shock or acute pancreatitis, however, may have a prolonged clinical course and may be complicated by secondary infection.

Endothelial and Parenchymal Cell Injury

Little information is presently available regarding structual alterations that occur in the nonpulmonary organs of patients with ARDS. The incidence of organ failure has ranged from approximately 20 percent for the gastrointestinal organs and brain to as high as 95 percent for the liver.[9] Additional support for the development of structural and functional changes in nonpulmonary organs in ARDS has been provided by several morphologic studies in animal models of sepsis or ARDS.[27-31] Coalson et al, [29,30] using a primate model of septic shock produced by E coli infusion, described the presence of significant structural alterations in the liver and kidneys that develop synchronously with lung alterations. Natanson et al[31] reported neutrophil accumulation and myocyte necrosis in the myocardium of dogs with septic shock, which had been produced by infected intraperitoneal clots.

Additional support for the global circulatory injury hypothesis comes from several studies.[27] In a series of experiments, lung injury induced by phorbol myristate acetate was associated with concurrent infiltration of neutrophils into systemic capillary beds.[27] In addition, significant abnormalities of organ structure were associated with inflammatory cell infiltration and were most pronounced in the liver. These animal models were designed to obviate the confounding variables encountered in postmortem studies of patients with ARDS (ie, nosocomial sepsis, extended ventilatory support, and potential oxygen toxicity). Although the experimental observations from such studies do not establish a causative role for inflammatory cells in the pathogenesis of nonpulmonary organ failure in ARDS, they do suggest that activation of inflammatory cells and their mediators may play a part in the development of structural and functional changes in nonpulmonary organs.

In summary, adult respiratory distress syndrome is a systemic disease with pulmonary, cardiovascular, hepatic, renal, and coagulation abnormalities. These abnormalities develop in a temporal pattern that is different in survivors and nonsurvivors of MOF alone.

References

[ 1] Fry D, Perlstein L, Fulton R, Polk HC. Multiple system organ failure: the role of uncontrolled infection. Arch Surg 1980; 115:136-40 [ 2] Burton R, Cerra FB. The hypermetabolism multiple organ failure syndrome. Chest 1989; 96:1153-160 [ 3] Zapol WM, Snider MT, Hill JD, Fallet RJ, Bartlett RH, Edmunds LH, et al. Extracorporeal membrane oxygenation in severe acute respiratory failure: a randomized prospective study. JAMA 1979; 242:2193-196 [ 4] Bell RC, Coalson JJ, Smith JD, Johanson WG. Multiple organ system failure and infection in adult respiratory distress syndrome. Ann Intern Med 1983;99:293-98 [ 5] Dorinsky PM, Costello JL, Gadek JE. Oxygen distribution and utilization after phorbol myristate acetate-induced acute lung injury. Am Rev Respir Dis 1986; 133:999-1001 [ 6] Dorinsky PM, Hamlin RL, Gadek JE. Alterations in regional blood flow during positive end-expiratory pressure ventilation. Crit Care Med 1987; 15:106-13 [ 7] Costello JL, Gadek JE, Dorinsky PD. Comparative analysis of regional blood flow distribution during substrate limitations produced by hemorrhage vs. acute lung injury: implications for organ damage in ARDS [abstract]. Am Rev Respir Dis 1987; 135:A213 [ 8] Dorinsky PM, Gadek JE. Cyclooxygenase inhibition diminishes the adverse regional and central hemodynamic effects of septic shock on the circulation [abstract]. Am Rev Respir Dis 1987; 135:A78 [ 9] Dorinsky PM, Gadek JE. Mechanisms of multiple nonpulmonary organ failure in ARDS. Chest 1989; 96:885-92 [10] Bone RC, Slotman G, Maunder R, Silverman H, Hyers TM, Kerstein MD, et al. Randomized double-blind, multicenter study of prostaglandin [E.sub.1] in patients with the adult respiratory distress syndrome. Chest 1989; 96:114-19 [11] Rothman KJ. No adjustments are needed for multiple comparisons. Epidemiology 1990; 1:43-6 [12] Montgomery AB, Stager MA, Carrico CJ, Hudson LD. Causes of mortality in patients with the adult respiratory distress syndrome. Am Rev Respir Dis 1985; 132:485-89 [13] Bone RC, Maunder R, Slotman G, Silverman H, Hyers TM, Kerstein MD, et al. An early test of survival in patients with the adult respiratory distress syndrome: the Pa[O.sub.2]/Fl[o.sub.2] ratio and its differential response to conventional therapy. Chest 1989; 96:849-51 [14] Pinsky MR, Matuschak GM. Cardiovascular determinants of the hemodynamic response to acute endotoxemia in the dog. J Crit Care 1986; 1:18-31 [15] Carroll GC, Snyder JV. Hyperdynamic severe intravascular sepsis depends on fluid administration in cynomolgus monkeys. Am J Physiol 1982; 243:R131-41 [16] 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 1983; 76:1539-553 [17] Bressack MA, Morton NS, Hortoop J. Group B streptococcal sepsis in the piglet: effect of fluid therapy on venous return, organ edema, and organ blood flow. Circ Res 1987; 61:659-69 [18] Altura BM, Gegrewold A, Burton RW. Failure of microscopic metarterioles to elicit vasodilator response to acetylcholine, bradykinin, histamine, and substance P after ischemic shock, endotoxemia, and trauma: possible role of endothelial cells. Microcirc Endothelium Lymphatics 1985; 2:121-29 [19] Hinshaw LB, Beller BK, Chang ACK, Passey RB, Lahti RA, Flournoy DJ, et al. Effect of prior administration of steroids upon recovery from lethal sepsis. Surg Gynecol Obstet 1986; 163:335-44 [20] Buckley G. The role of oxygen free radicals in human disease processes. Surgery 1983; 94:407-14 [21] Morgan RA, Manning PB, Coran AG, Drongowski RA, Till GO, Ward PD, et al. Oxygen free radical activity during live E coli septic shock in the dog. Circ Shock 1988; 25:319-23 [22] Fowler AA, Hamman RF, Zerbe GO, Benson KN, Hyers TM. Adult respiratory distress syndrome: prognosis after onset. Am Rev Respir Dis 1985; 132:472-78 [23] Schwartz DB, Bone RC, Balk RA, Szidon JP. Hepatic dysfunction in the adult respiratory distress syndrome. Chest 1989; 95:871-75 [24] Bone RC, Francis PB, Pierce AK. Intravascular coagulation with the adult respiratory distress syndrome. Am J Med 1976; 61:585-89 [25] Abreo K. Moorthy V, Osborne M. Changing patterns and outcome of acute renal failure hemodialysis. Arch Intern Me 1986; 146:1338-341 [26] Butkus DE. Persistent high mortality in acute renal failure. Arch Intern Med 1983; 143"209-12 [27] Mizer L. Weisbrode S, Dorinsky PM. Neutrophil accumulation and structural changes in non-pulmonary organs following phorbol myristate acetate-induced acute lung injury. Am Rev Respir Dis 1989; 139:1017-029 [28] Movat HZ, Wasi S. Severe microvascular injury induced by lysosomal releasates of human polymorphonuclear leukocytes: increase in vasopermeability, hemorrhage, and microthrombosis due to degradation of subendothelial and perivascular matrices. Am J Pathol 1985; 121:404-17 [29] Coalson JJ, Hinshaw LB, Guenter CA, Berrell EL, Greenfield LJ. Pathophysiologic responses o the subhuman primate in experimental septic shock. Lab Invest 1975; 32:561-69 [30] Coalson JJ, Archer LT, Benjamin BA, Beller-Todd BK, Hinshaw LB. A morphologic study of the live Escherichia coli organisms shock in baboons. Exp Mol Pathol 1979; 31:10-22 [31] Natanson C, Cunnion RE, Barrett DA, Peart KW, Danner RL, Conklin JJ, et al. Reversible myocardial dysfunction in a canine model of septic shock is associated with myocardial microcirculatory damage and focal neutrophil infiltration [abstract]. Clin Res 1986; 34:639A

COPYRIGHT 1992 American College of Chest Physicians
COPYRIGHT 2004 Gale Group