REVIEWS Use of Corticosteroids in the Adult Respiratory Distress Syndrome: A Clinical Review Chaim Putterman Adult respiratory distress syndrome (ARDS) is a major cause of morbidity and mortality in critically ill patients. This form of acute respiratory failure repre- sents a stereotypic response of the lung to many injurious mediators. Adult respiratory distress syn- drome is characterized by pulmonary infiltrates, severe hypoxemia, and reduced lung compliance, and expresses clinically as an increased-permeability pulmonary edema. Despite modern treatment modal- ities, the high mortality rate (>50%) from ARDS has not appreciably decreased over the last 20 years. A major issue of controversy in the therapy of ARDS is T HE ADULT respiratory distress syndrome (ARDS) is frequently encountered in criti- cally ill patients with acute respiratory failure in intensive care units.’ This disease complex is characterized by diffuse alveolar infiltrates, se- vere hypoxemia, and reduced lung compliance. The pulmonary picture in ARDS represents a stereotypic response of the lung to an extensive variety of injurious mediators and diseases. Although ARDS was formally described more than 20 years ago,’ and continues to appear at an estimated incidence of 150,000 patients per year in the United States alone,3 mortality rates in ARDS have not measurably decreased since recognition of the syndrome. In most published series. less than 50% of patients survive ARDS, despite early diagnosis, invasive monitoring, and maximal supportive treatment.4-6 Enormous ef- fort has been invested by researchers and clini- cians alike in an only partially successful attempt to adequately describe and agree on the responsi- ble mechanisms operative in ARDS and an appropriate therapeutic response. Corticosteroids (CS) have enjoyed much popu- larity as an essential adjunct to therapy in shock states, especially in those of septic origin.7,8 Gram-negative sepsis is emerging as the most common etiology of ARDS today.‘-i’ It was thought that CS may be effective in treatment of septic shock, also through prevention of parenchy- ma1 pulmonary damage and resultant permeabil- ity edema. Moreover, steroids were recom- mended as part of the therapeutic protocol after the onset of ARDS.“-r4 Recently, however, mul- the use of corticosteroids (CS) for the prophylaxis and treatment of this syndrome. In this report, current concepts of the pathophysiology of ARDS are discussed, while focusing on potential areas of benefit of CS. Experience with steroids is then reviewed, considering human studies of CS in estab- lished ARDS and pulmonary fibrosis, and the preven- tion of ARDS in high risk petients. After considering available data, it is concluded that the use of CS cannot be recommended for the prevention or ther- apy of ARDS. 0 1990 by W. 6. Saunders Company. ticenter controlled studies have reexamined the use of CS in hundreds of septic patients, and no measurable benefit on morbidity or mortality was demonstrable.15-17 In this report, the theoretic considerations for the use of steroids in ARDS are summarized, based on modern concepts of relevant pathophys- iology. Human studies are then considered, involv- ing the use of CS both for treatment of estab- lished ARDS and for prophylaxis in patients at high risk of developing acute respiratory failure. Finally, a suggested recommendation regarding CS use in ARDS, in light of experimental and clinical evidence to date, is presented. PATHOPHYSIOLOGY OF ADULT RESPIRATORY DISTRESS SYNDROME The exact pathophysiologic sequence leading from the primary insult in ARDS to the inflam- matory response, increased pulmonary vascular permeability, and the clinical syndrome has been a focus of intense basic and clinical re- search. Mechanisms of injury in human ARDS, as known today, suggest that CS can (theoreti- cally, at least) play a beneficial role in the From the Department of Internal Medicine A. Hadassah University Hospital, Kiryat Hadassah, Jerusalem, Israel. Received July 20, 1989: accepted May 7, 1990. Address correspondence and reprint requests to Chaim Putterman, MD, Department of Internal Medicine A, Hadas- sah University Hospital, Kiryat Hadassah PO Box 12000. Jersualem 91120 Israel. 0 1990 by W.B. Saunders Company. 0883-9441/90/0504-0005$5.00/O Journal of Crirical Care, Vol5, No 4 (December), 1990: pp 241-25 1 241
Transcript
REVIEWS
Use of Corticosteroids in the Adult Respiratory Distress Syndrome: A Clinical Review
Chaim Putterman
Adult respiratory distress syndrome (ARDS) is a major cause of morbidity and mortality in critically il l patients. This form of acute respiratory failure repre- sents a stereotypic response of the lung to many injurious mediators. Adult respiratory distress syn- drome is characterized by pulmonary infiltrates, severe hypoxemia, and reduced lung compliance, and expresses clinically as an increased-permeability pulmonary edema. Despite modern treatment modal- ities, the high mortality rate (>50%) from ARDS has not appreciably decreased over the last 20 years. A major issue of controversy in the therapy of ARDS is
T HE ADULT respiratory distress syndrome (ARDS) is frequently encountered in criti-
cally ill patients with acute respiratory failure in intensive care units.’ This disease complex is characterized by diffuse alveolar infiltrates, se- vere hypoxemia, and reduced lung compliance. The pulmonary picture in ARDS represents a stereotypic response of the lung to an extensive variety of injurious mediators and diseases.
Although ARDS was formally described more than 20 years ago,’ and continues to appear at an estimated incidence of 150,000 patients per year in the United States alone,3 mortality rates in ARDS have not measurably decreased since recognition of the syndrome. In most published series. less than 50% of patients survive ARDS, despite early diagnosis, invasive monitoring, and maximal supportive treatment.4-6 Enormous ef- fort has been invested by researchers and clini- cians alike in an only partially successful attempt to adequately describe and agree on the responsi- ble mechanisms operative in ARDS and an appropriate therapeutic response.
Corticosteroids (CS) have enjoyed much popu- larity as an essential adjunct to therapy in shock states, especially in those of septic origin.7,8 Gram-negative sepsis is emerging as the most common etiology of ARDS today.‘-i’ It was thought that CS may be effective in treatment of septic shock, also through prevention of parenchy- ma1 pulmonary damage and resultant permeabil- ity edema. Moreover, steroids were recom- mended as part of the therapeutic protocol after the onset of ARDS.“-r4 Recently, however, mul-
the use of corticosteroids (CS) for the prophylaxis and treatment of this syndrome. In this report, current concepts of the pathophysiology of ARDS are discussed, while focusing on potential areas of benefit of CS. Experience with steroids is then reviewed, considering human studies of CS in estab- lished ARDS and pulmonary fibrosis, and the preven- tion of ARDS in high risk petients. After considering available data, it is concluded that the use of CS cannot be recommended for the prevention or ther- apy of ARDS. 0 1990 by W. 6. Saunders Company.
ticenter controlled studies have reexamined the use of CS in hundreds of septic patients, and no measurable benefit on morbidity or mortality was demonstrable.15-17
In this report, the theoretic considerations for the use of steroids in ARDS are summarized, based on modern concepts of relevant pathophys- iology. Human studies are then considered, involv- ing the use of CS both for treatment of estab- lished ARDS and for prophylaxis in patients at high risk of developing acute respiratory failure. Finally, a suggested recommendation regarding CS use in ARDS, in light of experimental and clinical evidence to date, is presented.
PATHOPHYSIOLOGY OF ADULT RESPIRATORY DISTRESS SYNDROME
The exact pathophysiologic sequence leading from the primary insult in ARDS to the inflam- matory response, increased pulmonary vascular permeability, and the clinical syndrome has been a focus of intense basic and clinical re- search. Mechanisms of injury in human ARDS, as known today, suggest that CS can (theoreti- cally, at least) play a beneficial role in the
From the Department of Internal Medicine A. Hadassah University Hospital, Kiryat Hadassah, Jerusalem, Israel.
Received July 20, 1989: accepted May 7, 1990. Address correspondence and reprint requests to Chaim
Putterman, MD, Department of Internal Medicine A, Hadas- sah University Hospital, Kiryat Hadassah PO Box 12000. Jersualem 91120 Israel.
0 1990 by W.B. Saunders Company. 0883-9441/90/0504-0005$5.00/O
Journal of Crirical Care, Vol5, No 4 (December), 1990: pp 241-25 1 241
242 CHAIM PUTTERMAN
prevention and therapy of ARDS. In order to better understand the potential of CS in ARDS therapy, a short review of ARDS pathophysiol- ogy follows. For a more detailed discussion, the interested reader is referred to several recent comprehensive reviews.1,4*18-20
Complement-induced granulocyte aggrega- tion and activation are considered instrumental in the initiation of ARDS pathophysiology.‘8‘20 Activation of complement or coagulation se- quences by any of the etiologies associated with ARDS leads to pulmonary leukostasis and entrap- ment of activated polymorphonuclear cells. Acti- vated neutrophils and eosinophils release pro- teases, thus activating a number of interlocking and self perpetuating inflammatory pathways. These include coagulation and fibrinolysis cas- cades, kinin system, complement pathways, -and arachidonic acid metabolism.
Neutrophils are considered pivotal in the pul- monary injury in ARDS, although ARDS has been described in neutropenic patients. Acti- vated neutrophils can damage the pulmonary endothelium in several ways’9*20: (1) direct endo- thelial damage (cytotoxicity), (2) release of pro- teases (elastase, collagenase), (3) simultaneous activation of coagulation and fibrinolysis, (4) release of arachidonic acid metabolites, and (5) release of oxygen-free radicals.
The crucial pathophysiologic event in the in- flammatory response is injury to the pulmonary capillary endothelium, leading to increased mi- crovascular permeability, and pathognomonic low-pressure pulmonary edema. Culprits impli- cated in the membrane injury include histamine, leukotrienes, prostaglandins, products of coagula- tion, eosinophil cationic protein, and toxic oxy- gen radicals,21-23 which are released after cell activation as part of the inflammatory process. These factors contribute to the capillary endothe- lial insult, both by direct injury, and by a chemotactic effect. The additional neutrophils, thrombocytes, and erythrocytes attracted am- plify and perpetuate the activated pathogenetic cascades and mechanisms,‘9’8 overwhelming the lungs’ normal repair mechanisms. Once alveolar- capillary membrane integrity is compromised, edema fluid leaks into the alveoli, and the full- blown syndrome of acute respiratory failure does not lag far behind.
CELLULAR MECHANISMS OF CORTICOSTEROID ACTION
Corticosteroids influence cellular metabolic processes through two major pathways.24v25 In the nonnuclear pathway, CS action is mediated at the subcellular level by intracytoplasmatic glucocorticosteroid receptors. Instead of interact- ing with a membrane-bound receptor, the ste- roids move easily through the cell membrane and attach specifically to a cytoplasmic receptor. In the more important nuclear pathway, the steroid- cytoplasmic complex translocates to the cell nucleus. The complex attaches to nuclear DNA and causes transcription of specific messenger RNA. In turn, these RNA are exported to the cytoplasm to direct production of specific pro- teins that are the effecters of CS action. Involve- ment of the nuclear pathway explains the often- demonstrated experimental finding that to show CS efficacy, the drug must be given prior to the inflammatory stimulus; a timing consideration which detracts, of course, from the clinical attrac- tiveness of CS in many clinical settings.
THEORETICAL AND EXPERIMENTAL CONSIDERATIONS
Corticosteroids possess many experimental ac- tions, some of which are of potential benefit to the patient with ARDS. These effects either interfere specifically and directly with the patho- physiologic sequence described above, or may potentially assist in general medical support of the patient.
High-dose CS inhibit complement-induced granulocyte aggregation and subsequent leukoem- bolization (in vivo and in vitro). Previously aggre- gated neutrophils are disaggregated, and the rate of association between cell receptors and acti- vated complement is slowed.26,27 In high doses, CS reduce chemotaxis of neutrophils, though intracellular killing is unaffected. Inhibited chemotaxis may prevent movement of activated neutrophils toward a chemoattractant stimulus in the lung interstitial spaces, and the subsequent release of inflammatory mediators.28 Sibbald et a128 have demonstrated that steroids change cell surface properties of granulocyte membranes and affect adherence. By decreasing neutrophil adherence to the pulmonary endothelium, neutro- phi1 aggregation and degranulation is prevented and lung microcirculatory flow improved.28*29
CORTICOSTEROIDS IN ARDS 243
Arachidonic acid metabolites have been found to contribute to the pathophysiology of ARDS, particularly to the deranged right heart hemodynamics. ‘*q3’ Steroids stimulate the devel- opment of a factor inhibitory to phospholipase A,, which prevents activation both of the cycloox- ygenase and lipooxygenase pathways of pros- taglandin metabolism. 31 Recently, dexametha- sone has been shown to block the increases in leukotriene B, (a product of the lipooxygenase path -lay) in plasma and pulmonary lavage fluid after endotoxin administration in pigs.32
Administration of tumor necrosis factor (cachectin) to laboratory animals reproduces many of the clinical effects of sepsis and endotox- emia, including septic ARDS.33 Dexamethasone was found to suppress endotoxin-stimulated tran- scription and translation of cachectin RNA in macrophages. However, if dexamethasone was given 2 hours after endotoxin induction (posttran- scription phase), it did not block cachectin synthesis.34
Mediator release in ARDS can be prevented or attenuated by CS, through cell and lysosomal membrane stabilization.‘4 Pretreatment of sheep with methylprednisolone before endotoxin chal- lenge blocked an increase in the blood level of lysosomal enzymes.35 Methylprednisolone was shown to increase intracellular cyclic adenosine monophosphate levels in leukocytes and decrease release of lysosomal contents from activated neutrophils.28*36 In a different study, both lysoso- ma1 enzyme release and superoxide production in granulocytes were shown to decrease with CS.37
Among the mediators through which activated neutrophils injure the endothelium, a major role is assigned to oxygen radicals. These highly toxic, unstable chemicals cause severe endothe- lial damage and increased capillary permeability by lipid oxidation, hydroperoxide release, and enzyme inactivation.38*39 High-dose CS prevent superoxide and hydrogen peroxide release from activated neutrophils.37 Corticosteroids can also associate with endothelial membrane fatty acids4’ and limit membrane damage by free radicals.
The crucial pathologic event in the pathophys- iology of ARDS is the injury to the integrity of the pulmonary alveolar-capillary membrane and the resultant increase in microvascular permeabil- ity. In the chronically instrumented sheep model,4’ both Demling et al42 and Brigham et al43
demonstrated that prophylactic treatment with methylprednisolone prevented the late (3 to 5 hours postinjury) increase in lung microvascular permeability. In this model, results were ob- tained by observing the relative reduction in measured pulmonary lymph flow. However, us- ing a different technique (increasing pressure in the left atrium and calculating the osmotic reflec- tion coefficient), Andreasson et al could not prevent the postoperative increase in permeabil- ity with high-dose CS.44 In patients with septic ARDS, Sibbald and Driedger studied the perme- ability of the alveolar-capillary membrane by clearance of radiolabeled albumin. Corticoster- oids reduced permeability significantly when used early in the illness, ‘2,28*45 though no such benefit of steroids could be demonstrated in terminally ill patients.
Corticosteroids have also been purported as having effects beneficial in the supportive cardiop- ulmonary management of the patient with ARDS. Cardiovascular effects include mild positive inotropism,46 decrease in total peripheral resistance,47 and pulmonary vascular resistance,48 all leading to increased cardiac output.49 Steroids also improve cardiac function by inhibiting the action of various vasoconstrictor substances,50 and by preventing reticuloendothelial release of myocardial depressant factors.5’ Corticosteroids can also positively affect oxygen delivery not only by increasing cardiac output, but also by increas- ing erythrocyte 2,3 DPGS2 and decreasing red cell hemoglobin oxygen affinity.53
Side effects of CS in the dose range suggested for the therapy of ARDS (multiple doses of methylprednisolone 30 mg/kg, or equivalent) cannot be ignored. Pulmonary shunt can be increased by interference with hypoxic vasocon- striction of the blood vessels leading to poorly ventilated areas of the lung.s4 Suppression of the immune system and interference in the body’s defense mechanisms against infection are also major matters of concern.* Bactericidal activity of neutrophils and monocytes are impaired by steroids,55 as were cellular immunity and macro- phage function.56.57 Clinically, recent studies re- garding high-dose CS administration in septic shock have shown higher infectious morbidity and mortality in steroid-treated patients.‘5-‘7
244 CHAIM PUtTERMAN
USE OF CORTICOSTEROIDS IN THERAPY OF ADULT RESPIRATORY DISTRESS SYNDROME
AND PULMONARY FIBROSIS
Previous reviews discussing the use of steroids in ARDS30V58-60 based their conclusions almost entirely on data from studies of patients with gram-negative sepsis and shock. However, stud- ies of CS in septic states were naturally more focused on overall survival from sepsis and shock, and not on the development and evolution of ARDS. Furthermore, septic ARDS may not be representative of other etiologies of ARDS. This report concentrates primarily on studies focusing on ARDS as a separate disease entity. As previ- ously mentioned, ARDS represents a final com- mon pathway of lung response to a variety of disease states and a multitude of different injuri- ous mediators. As such, the pathophysiology of ARDS is similar in the diseases considered be- low. Therefore, although a separate consider- ation of steroid efficacy for each entity may seem somewhat artificial, the discussion will be pre- sented in parts for didactic purposes.
The discussion that follows is divided into two major sections: studies regarding use of steroids for the prophylaxis of ARDS, and studies discuss- ing effects of steroids on various aspects of the established syndrome. For the sake of simplicity, studies in which steroid therapy was begun be- fore criteria for ARDS were fulfilled are consid- ered under “prophylaxis,” though it could be argued that the results were affected by the continuation of therapy after onset of ARDS.
Use of Corticosteroids for the Therapy of Adult Respiratory Distress Syndrome
Therapeutically, steroids have been studied regarding effect on morbidity and mortality from ARDS, and for the presence of an effect regard- ing a specific pathologic manifestation of ARDS, that of pulmonary fibrosis.
Early clinical studies demonstrated dramatic effects of CS when used in the therapy of ARDS. Sladen,13 in an open study with no controls, examined the effect of CS therapy on ARDS secondary to hypotension or gram negative shock in 1976. Ten patients with “shock lung” were treated with 30 mg/kg methylprednisolone every 6 hours for 48 hours, after which steroid therapy was abruptly terminated. All patients required mechanic ventilatory support, and were given
similar supportive therapy. Effects of CS therapy were dramatic: arterial oxygenation progres- sively improved in all patients, with radiologic clearing in pulmonary edema; nine of 10 patients survived to discharge from the intensive care unit; no adverse effects were found attributable to sudden discontinuation of steroids.
Sibbald et al’* examined the affect of high- dose CS therapy on alveolar-capillary permeabil- ity in human ARDS of septic etiology. Permeabil- ity was assessed by measuring the change in appearance of intravenously-administered hu- man serum albumin (radiolabeled with 113’) into bronchoalveolar secretions before and after ste- roid therapy. Fourteen patients received 30 mg/kg of methylprednisolone, and five patients received 4 mg/kg of dexamethasone. After a single dose of CS, patients could be divided into two groups, depending on response to therapy. In one group of 14 patients (receiving either methyl- prednisolone or dexamethasone), steroid therapy resulted in a significant decrease in appearance of radiolabeled albumin from the blood to bron- cho-alveolar secretions, when compared with val- ues before injection (“CS responders”). This signified to Sibbald et al’* a parallel decrease in microvascular permeability in these patients. In the remaining group of five patients (receiving only methylprednisolone), no significant change in clearance occurred (“CS nonresponders”). Although pulmonary arterial pressure and intra- pulmonary shunt tended to decrease in both groups after CS therapy, this change was not significant.
All five patients in the nonresponding group died within 24 hours, versus only a 20% mortality rate (3 of 14) in the group demonstrating de- creased permeability in response to steroids. Time to death in the group of responders was consistently greater than 5 days.
Several investigatorsU-62 have criticized the study by Sibbald et al.‘* Nonresponders were more critically ill, as evident by significantly increased alveolar-arterial O2 difference and in- trapulmonary shunt fraction at the study onset. Moreover, steroid therapy caused pulmonary vascular resistance to increase in nonresponders, while decreasing resistance in responders. It is, therefore, possible to interpret the decrease in clearance as secondary to the reduction in mi- crovascular driving force, and not due to any
CORTICOSTEROIDS IN ARDS 245
change in vascular permeability. Sibbald’s re- sults were also very different from findings in animals, in which steroids were effective in pre- venting increased permeability if given before lung injury, but not once lung injury had fully developed.43
Bernard et a163 recently reported the results of the only prospective, randomized, double-blind, controlled study performed in humans examining the role of steroids in established ARDS. In this multicenter study of 99 patients, ARDS was diagnosed by the presence of refractory hypox- emia, diffuse bilateral pulmonary infiltrates, and absence of congestive heart failure. The major etiologies of ARDS were sepsis (27 patients), aspiration pneumonia (18 patients), and mixed causes. Patients were given 30 mg/kg of methyl- prednisolone every 6 hours for 24 hours (50 patients) or a placebo (49 patients).
No therapeutic benefit of methylprednisolone was discovered in any of the categories of the study end-points. Severity of ARDS was unaf- fected, as judged by the various physiologic parameters monitored. A similar percentage of patients had reversal of ARDS (18 of 50 patients in the treatment group versus 19 of 49 of the patients receiving placebo). Forty-five days after study entry, no differences in mortality were found between the groups, although wide confi- dence limits made it impossible to exclude a small effect of treatment. On subset analysis, the group of patients in which sepsis was a contribut- ing factor to ARDS (44% of the study popula- tion) did not benefit from steroid therapy either. No increase in infectious complications was ob- served in patients receiving CS.
EJects of Corticosteroids on Pulmonary Fibrosis in Adult Respiratory Distress Syndrome
The histologic appearance of the lung response in ARDS is conventionally divided into three pathologic stages’,64? (1) early exudative stage (24 to 96 hours), (2) proliferative stage (3 to 10 days), (3) late diffuse fibrotic stage (commencing 7 to 10 days postinjury).
The third stage of fibrosis in ARDS has been likened histologically to the lung process in idiopathic pulmonary fibrosis.67-70
Severe pulmonary fibrosis developing in pa- tients with ARDS is associated with a poor
prognosis. Hill et al” found that, despite inten- sive treatment (including extracorporeal mem- brane oxygenation), only 3 of 22 patients with biopsy-proven pulmonary fibrosis survived ARDS. Zap01 et al72 reported similar figures, with no survival among 12 patients with ARDS-related pulmonary fibrosis. In addition to the exception- ally high mortality rate, lung fibrosis in ARDS is also characterized by a relatively rapid course from onset to death, ie, 3 to 4 weeks, versus a prolonged 1 to 6 month course in idiopathic pulmonary fibrosis. Steroid treatment is re- garded as an effective therapeutic modality in idiopathic pulmonary fibrosis,73 leading to inves- tigation of the possible role of steroids in the pathogenesis and treatment of ARDS-related pulmonary fibrosis.
Asbaugh and Maier studied 10 consecutive critically ill patients with ARDS who did not respond to conventional treatment.74 After pulmo- nary fibrosis was histologically documented by study of tissue obtained by open lung biopsy, aggressive therapy with high-dose CS was insti- tuted. Two patients (20%) died of uncontrollable sepsis, attributable to steroid therapy. However, 8 patients (80%) survived-a much higher per- centage than would be expected from comparison with historic controls with ARDS of this severity. Based on this small, uncontrolled series, the investigators suggested74 that open lung biopsy may be indicated in the course of patients with relentless ARDS. If fibrosis is documented, ad- junctive therapy with steroids might be war- ranted to prevent the rapid deterioration and almost certain death occurring in these patients.
Auler et a175 attempted recently to provide a scientific basis for the use of CS in ARDS, particularly in the late stage of fibrosis. Therapeu- tic response to steroids in interstitial lung disease correlated with levels of tissue glucocorticoid receptors. 76 These receptors app ear to be essen- tial for the expression of the cellular effect of steroids. Auler et al” examined lung tissue from five patients with ARDS after cardiopulmonary bypass. Mean steroid receptor content from pa- tients with ARDS was not statistically different from the level found in control patients’ lungs. Another interesting finding was the tissue fibrosis observed. Although biopsies were done only 4 to 7 days after the primary insult, evidence of active collagen secretion was found even at this early
246 CHAIM PUTTERMAN
stage. The lack of change in steroid receptors found in this study suggested to Auler et a175 that CS do not hold great potential for the therapy of fibrosis in late-stage ARDS.
USE OF CORTICOSTEROIDS FOR THE PREVENTION OF ADULT RESPIRATORY
DISTRESS SYNDROME
Established ARDS is associated with a signifi- cant mortality rate. It was postulated that early specific treatment would prevent amplification of the inflammatory cascades, and if not prove effective in totally reversing ARDS, would at least limit the pulmonary damage.
Many diseases have been associated with the causation of ARDS. However, only a few, well- defined groups of patients carry a definite high risk for development of the syndrome. By contin- uation of the logic above, steroids given to pa- tients in high risk groups before ARDS develops would result in increased benefit, relative to intervention after disease onset. Prophylactic use of steroids in different groups of high-risk pa- tients has been studied, including patients who have experienced trauma, aspiration, cardiopul- monary bypass, major surgery, fat embolism, or sepsis syndrome.
Use of Corticosteroids for Patients With Trauma
Svennevig and colleagues77-7g examined the efficacy of steroids in the lung contusion syn- drome following blunt chest trauma. Ten pa- tients were randomized to receive 30 mg/kg of methylprednisolone at admission, and again at 8 and 16 hours thereafter. This group was com- pared with a conventionally treated group of 10 patients. Both pulmonary vascular resistance and total peripheral resistance decreased in the treat- ment group, and cardiac index increased. Addi- tionally, steroid-treated patients required a shorter period of mechanical ventilation and hospital recuperation. Steroids had no effect on mortality; all patients survived in both groups.
Lucas and Ledgerwood” examined 114 seri- ously injured patients, at high risk of developing ARDS due to multiple trauma, hemorrhagic shock, and multiple transfusions. As part of their resuscitation, 54 of these patients received 1 g of methylprednisolone bolus, followed by 15 mg/kg for 3 successive days. Steroids had no effect on
the degree of physiologic shunt, but caused a significant deterioration in the mean PO,/FiO, ratio. Mortality rate was insignificantly in- creased in the steroid group, relative to the control group (9 of 54 vs 2 of 60, respectively).
In an additional study of patients with severe trauma, Van Der Merwe et alsl studied 92 patients with injury severity scores of 20 points and above. In this open, randomized trial, two doses of 20 mg/kg methylprednisolone (at admis- sion and 4 hours later) were administered to 47 of these patients, in addition to standard resuscita- tive measures. Only three patients in the CS group developed ARDS; a significantly lowered incidence than in the control group (11 of 45). No side effects of steroids were noted. Data regarding ultimate survival was not reported.
Use of Steroids in Patients With Sepsis and Septic Shock
Lucas and Ledgerwood” tested the effects of high-dose CS in 48 patients with septic shock, 23 of whom were randomized to receive 6 mg/kg of dexamethasone over 48 hours. Dexamethasone was found detrimental to pulmonary function. Oxygenation deteriorated in steroid-treated pa- tients (as reflected by decreased PO,/FiO,), and pulmonary shunt increased. Mortality was unaf- fected.
The study of CS in ARDS has also benefited from the recent multicenter trials studying ste- roid therapy in sepsis and septic shock. Sprung and colleagues’5~83 studied the effect of steroids on development of ARDS in 59 patients with septic shock. In a randomized, partially blinded study, patients received 30 mg/kg methylpred- nisolone, 6 mg/kg of dexamethasone, or no steroids at randomization. Complement levels were also studied in 42 of these patients. Steroids were not found to be helpful in preventing ARDS, which developed in approximately 25% of each study group (4 of 16 methylprednisolone, 3 of 13 dexamethasone, 2 of 13 control). No consistent correlation was found between comple- ment pathway activation and development of ARDS. Corticosteroids were also found to have no affect on mortality, and no significant differ- ence in survival rates was observed between the groups.
One criticism of the Sprung study was the relatively long time between diagnosis and the
COATlCOSTEROlDS IN ARDS 247
beginning of steroid treatment (mean 17.5 hours). Bone et al’6,84 assessed the affect of early steroid therapy (12 hours of diagnosis) on the material- ization of ARDS in patients with the sepsis syndrome. In a prospective, double-blind study, 304 patients were randomized to receive four doses of methylprednisolone given every 6 hours, or a placebo. Corticosteroids conferred no advan- tage on the prevention of ARDS, the syndrome eventuating in 32% (52 of 152) of patients in the CS group, but only in 25% (38 of 152) in patients not receiving steroids. Among steroid-treated patients developing ARDS, ARDS reversal was seriously impeded. Fourteen-day survival was significantly decreased in this subgroup of pa- tients, due, in part, to secondary infection.
Lute et alss studied 75 patients with early septic shock, randomized to receive 30 mg/kg of methylprednisolone or mannitol placebo every 6 hours, for a total of four doses. In this random- ized, prospective, double-blind study, possible steroid effects both on development of ARDS and on milder forms of septic parenchymal lung injury were sought for. A similar percentage of patients in both groups developed ARDS (13 of 38 CS group, 14 of 37 placebo group). Time to resolution of ARDS in methylprednisolone- treated patients was significantly increased. No other effect was found regarding modification of milder lung injury, as judged by the lung injury score computed, or by separate analysis of the score components (compliance, chest roentgenog- raphy, and PaO,/PAO,). Mortality in the ste- roid group was 22 of 38 patients, not significantly different from the 20 of 37 patients found in the placebo group.
Use of Corticosteroids in the Prevention of Adult Respiratory Distress Syndrome in Other High-Risk Groups
Pulmonary dysfunction after cardiopulmonary bypass is a major cause of postoperative morbid- ity after open heart surgery. Caffin et als6 admin- istered 30 mg/kg methylprednisolone preopera- tively to 50 adult patients undergoing elective surgery for cardiopulmonary bypass. The group of patients surviving for more than 12 hours after surgery was compared with an historic control group of 43 patients. Patients receiving steroids were adversly affected, as judged by a longer period of mechanical ventilation required, an in-
creased fraction of wasted ventilation (V,/V,) at 8 hours postoperatively, and a higher inci- dence of a low cardiac output syndrome. Data regarding long-term survival was not given.
In an open, nonrandomized study, Wolfe et als7 studied the use of steroids in patients with bronchoscopy-proven aspiration of gastric con- tents. Twenty-five of 43 patients with confirmed aspiration were given a varying dose of steroids (mean 2 10 + 40 mg prednisone), usually within 4 hours of diagnosis. Treatment was given every 4 hours for several days. Though development of ARDS was not specifically adressed, the mortal- ity rate difference between the groups was not significant. Morbidity was increased in the ste- roid-treated group, in terms of a significantly higher occurrence of gram-negative pneumonia, and a meaningful decrease in hemoglobin levels.
Du Toit et al theorized** that prophylactic CS therapy in elderly patients undergoing total hip replacement would inhibit arachidonic acid me- tabolism and reduce prostaglandin product levels and incidence of ARDS. In this open study, 10 of 22 patients received 30 mg/kg methylpred- nisolone at a mean of 34 minutes before anesthe- sia induction. Only one patient in the treatment group developed ARDS, versus five patients in the control group. All patients developing ARDS (in both groups) had significantly elevated levels of thromboxane B,, relative to patients not devel- oping the syndrome.
Weigelt et al89,9o randomized 81 patients with early pulmonary failure (by blood gas criteria) in a surgical intensive care unit to receive CS or mannitol placebo. The steroids given were 30 mg/kg methylprednisolone every 6 hours for 48 hours. Corticosteroids magnified the degree of pulmonary deterioration, as reflected in a signifi- cantly increased rate of appearance of pulmo- nary dysfunction, and ARDS, in patients receiv- ing methylprednisolone. Sixty-three percent of steroid-treated patients developed full-blown ARDS, versus only 27% of the control group. Though mortality in both groups was virtually identical, infectious complications were signifi- cantly increased in the CS group.
Fat embolism syndrome is characterized by a petechial rash, hypoxemia, confusion, and diffuse pulmonary infiltrates, appearing 24 to 48 hours after trauma. In some patients, the syndrome may progress to severe respiratory failure.” Al-
248 CHAIM PUl-fERMAN
though benefit has been claimed for CS given therapeutically in fat embolism, no controlled trials exist to support this theory.92 Several au- thors examined whether prophylactic CS ther- apy for patients at high risk would be of value in preventing fat embolism. Alho et a193 random- ized 60 consecutive patients with trauma and fractures of the lower extremities to receive 10 mg/kg placebo or methylprednisolone every 8 hours for a total of three doses. Manifestation of the fat embolism syndrome was significantly lower in the CS group. In particular, fulminant respiratory failure occurred in 13% (4 of 31) of control patients, versus only in 3% (1 of 29) in the methylprednisolone group. Nevertheless, the in- vestigators concluded that, in most instances, vigorous respiratory care and effective immobili- zation of fractures were adequate in preventing adverse respiratory sequelae. Prophylactic use of CS in patients with multiple fractures was not recommended by these researchers, although no complications were observed with this modality. In a prospective, double-blind study conducted in high-risk patients, Schonfeld et a194 found that the incidence of fat embolism decreased from 22% (9 of 41) in the placebo group, to 0% (0 of 21) in the patient group receiving high dose methylprednisolone, with no complications found related to CS therapy. Finally, Lindeque et a195 recently administered two doses of 30 mg/kg methylprednisolone or placebo, to 55 patients with lower extremity fractures, in a double-blind, randomized trial. Patients receiving CS main- tained higher arterial oxygen levels, had stabiliza-
tion of free fatty acid levels, and showed de- creased risk for fat embolism, although no effect could be demonstrated on levels of C,,.
CONCLUSION
Are high-dose CS indicated for the prevention or therapy of ARDS? Articles reviewing the use of steroids for therapy of ARDS over recent years have not been unanimous in their recom- mendations. Opinions were divided between those enthusiastically endorsing steroid therapy,14s64, 66V96-98 other authors as strongly opposed,60*99T’0’ and yet other physicians holding equivocal positions. 30,58,59.102,103
In the review of the literature as presented in this report, it is evident that at least some studies offered some basis for optimism for CS therapy in ARDS. On the whole, however, these studies did not conform to the methodologic gold stan- dards of clinical trial design.
Several studies performed recently allow the clinician to reach more rational conclusions re- garding CS therapy for prevention and treatment of ARDS. Although of potential benefit, adverse effects outweigh any benefits reaching the pa- tient. On the balance of current evidence, CS have not positively affected the prognosis of ARDS, and have not been demonstrated as capable of preventing disease onset in high-risk patients. Nevertheless, research into use of ste- roids for some indications considered should not be abandoned.63,74’94 Until further data becomes available, CS can not be recommended for the prophylaxis or therapy of the ARDS.
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