Major developments in thoracic surgery have occurred

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1 Low-Dose Steroid at an Early Phase of Postoperative Acute Respiratory Distress Syndrome Hyun-Sung Lee, MD, Jong Mog Lee, MD, Moon Soo Kim, MD, Hyae Young Kim, MD, PhD, Bin Hwangbo, MD, and Jae Ill Zo, MD, PhD Center for Lung Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Gyeonggi, Korea GENERAL THORACIC Background. The acute respiratory distress syndrome (ARDS) that develops after thoracic surgery is usually lethal. The use of corticosteroids to treat ARDS has been the subject of great controversy. Methods. Therefore we compared conventional therapy with early low-dose steroid therapy in the treatment of postoperative ARDS. Methylprednisolone was given daily as an intravenous push every 6 hours and was changed to a single oral dose or discontinued, with a loading dose of 2 mg/kg followed by 2 mg/kg per day. Results. Over 2.5 years, 523 major thoracic operations were performed with postoperative ARDS developing in 20 patients (3.8%), of which 8 were treated with conventional therapy and 12 with early low-dose steroid therapy. Early low-dose steroid therapy significantly reduced postoperative mortality, with 7 patients (58.3%) recovering without mechanical ventilation. Conclusions. We believe this is the first clinical study of low-dose methylprednisolone at an early phase of postoperative ARDS. The beneficial effects of the use of early low-dose steroids in ARDS are consistent with the hypothesis that fibroproliferation is an early response to lung injury, which is inhibited by early low-dose steroid therapy without disturbing operative wound healing. (Ann Thorac Surg 2005;79:405 10) 2005 by The Society of Thoracic Surgeons Major developments in thoracic surgery have occurred over the past 30 years, resulting in a dramatic reduction of postoperative mortality and morbidity. However, despite advances in surgical technique, anesthetic management, and postoperative care, the mortality and morbidity rates associated with thoracic surgery remain significant, with the current mortality rates after lung resection ranging from 4% to 9% after pneumonectomy and from 1% to 3% after lobectomy [1 5]. In esophageal cancer, perioperative mortality rates continue to range from 3% to 10% [6, 7]. Most of the causes of mortality and morbidity after thoracic surgery are pulmonary in origin. Among respiratory complications, acute respiratory distress syndrome (ARDS) after thoracic surgery is usually lethal. Acute respiratory distress syndrome occurs more commonly after pneumonectomy (2% to 5%) than after lobectomy ( 1%), and ARDS after pneumonectomy is often fatal, with mortality rates reported between 30% and 100% [8 12]. After esophagectomy, ARDS occurs in 10% to 20% of cases, with mortality from ARDS exceeding 50% [7, 13 16]. Thus far treatment of ARDS has consisted mainly of aggressive supportive measures, including mechanical ventilation, broad-spectrum antibiotics, diuresis, and pulmonary toilet, but all too often these measures fail to reverse severe hypoxia and prevent death. Although no clear-cut cause of ARDS has yet been identified, it is Accepted for publication July 29, Address reprint requests to Dr Zo, Center for Lung Cancer, National Cancer Center, 809 Madu-dong, Ilsan-gu, Goyang, Gyeonggi , Korea; jaylzo@ncc.re.kr. thought that excessive fluid, lymphatic interruption, barotrauma, hyperoxia and ischemia reperfusion injury by one lung ventilation, cytokine release, or activation of the complement system may be associated with the development of ARDS [17, 18]. The use of corticosteroids in treating ARDS has been the subject of great controversy and debate. Trials of short-term, high-dose steroid therapy did not show an improvement in the mortality of patients at risk of ARDS or those with early ARDS [19, 20]. However, the use of corticosteroids in the late or fibroproliferative phase of ARDS has been reported to improve lung function and survival [21 23]. During the early stages of ARDS, there is a potential for pulmonary fibroproliferation [24 27], and the use of low-dose corticosteroids at these early stages has been found to lead to a complete maintenance of in vivo and in vitro respiratory mechanics in mild acute lung injury, as well as minimizing the changes in tissue impedance and extracellular matrix components in severe lesions [28]. These findings have important implications, both for the study of repair mechanisms and for the timing of therapies. Therefore we tested the efficacy of low-dose methylprednisolone administration in patients with postoperative ARDS immediately after ARDS was confirmed, and we compared this treatment with patients who were treated with conventional therapy. Patients and Methods We identified all patients who developed ARDS after major thoracic surgery from 2001 to 2003 at the National 2005 by The Society of Thoracic Surgeons /05/$30.00 Published by Elsevier Inc doi: /j.athoracsur

2 GENERAL THORACIC 406 LEE ET AL Ann Thorac Surg EARLY LOW-DOSE STEROID FOR ARDS 2005;79: Cancer Center in Korea. Acute respiratory distress syndrome is defined as the acute onset of 1. PaO 2 /FiO Bilateral infiltrates. The infiltrates may be patchy, diffuse, homogeneous, or asymmetric, and should be consistent with pulmonary edema or the fibrotic changes of fibroproliferation. Opacities due to pleural effusions or atelectasis should not be considered. If pneumonectomy, unilateral infiltrate is included. 3. No evidence of left atrial hypertension. If measured, pulmonary artery wedge pressure 18 mm Hg. 4. The three previously cited criteria must occur together within a 24-hour interval. The first date that these criteria are met is defined as the onset of ARDS [29]. After onset, chest infiltrates had to be progressive, and chest computed tomographic scan findings had to be consistent with postoperative ARDS findings or ground glass opacities confirmed by radiologists. Twelve patients who fulfilled these criteria and had been treated with low-dose steroids immediately after diagnosis of ARDS were classified as the early low-dose steroid therapy group. The development of ARDS after thoracic surgery was explained to each patient and surrogate before the trial. Informed consent was obtained from each patient or surrogate before the trial. Although this was not a randomized controlled study, we sought a comparable group of patients who had been treated for ARDS with the methods described previously, before early low-dose steroid therapy was clinically available. We reviewed charts from 2001 to 2002, and we identified 8 patients who developed ARDS after thoracic surgery, using the identical criteria for defining ARDS. These 8 patients were classified as the conventional therapy group. The two groups were similar demographically and clinically (Table 1). Data in the control group in this study were collected retrospectively, but data in the case group were collected prospectively as soon as informed consent was obtained. Due to the favorable results from this study, we activated a prospective phase II clinical study (NCCCTS ) for early low-dose steroid therapy against ARDS. We obtained approval from the Institutional Review Board on the basis of this study. Conventional Before the introduction of low-dose corticosteroid therapy there was great uniformity in the intraoperative and postoperative management of patients undergoing thoracic surgery. Airways were managed with double-lumen endotracheal tubes, and intraoperative fluids were scrupulously restricted during pulmonary resection because of concern regarding the development of ARDS. All patients with signs of ARDS postoperatively were managed by the use of broad-spectrum antibiotics, bronchodilators, early intubation, mechanical ventilation, diuresis, and aspiration bronchoscopies. Steroids, if administered, were given after postoperative day 7 due to Table 1. Characteristics of ARDS Patients at Baseline fear of anastomosis or wound problems with intravenous methylprednisolone sodium succinate (125 mg) given every 6 or 8 hours for several days. Administration of Methylprednisolone in the Early Low-Dose Steroid Methylprednisolone sodium succinate was administered daily as an intravenous push every 6 hours (one quarter of the daily dose) and changed to a single oral dose or discontinued. A loading dose of 2 mg/kg was followed by 2 mg/kg per day as soon as ARDS was confirmed. The approximate half-life of methylprednisolone is 180 minutes, and the drug was administered at 6-hour intervals. Dosage was calculated from ideal body weight. Steroid tapering was not started until dyspnea and chest infiltrates had improved. Statistical Analysis Analysis of the data were performed with SPSS for Windows, version 11.0 (SPSS, Inc, Chicago, IL). The Mann-Whitney U test was applied to compare the means of continuous variables. Wilcox signed ranks tests with multiple comparison adjustments were used to compare PaO 2 /FiO 2 values recorded during treatment with those recorded at baseline. A p value 0.05 was considered statistically significant. Results Conventional (n 8) Early Low-Dose Steroid (n 12) Total (n 20) Age, years a Number of males (95%) Lung cancer (65%) Lobectomy pneumonectomy Esophageal cancer (35%) Onset of ARDS, days a POD (20%) POD (65%) POD (15%) a PaO 2 /FiO a Mean values standard deviation. ARDS acute respiratory distress syndrome; PaO 2 /FiO 2 the ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen; POD postoperative day. Between March 2001 and August 2003, 523 major thoracic operations for lung cancer and esophageal cancer were performed at the National Cancer Center, Korea, of which 62 (11.8%) were pneumonectomies, 320 (61.2%) were lobectomies, 100 (19.1%) were esophageal operations, and 41(7.8%) were multiple wedge resections under simulta-

3 Ann Thorac Surg LEE ET AL 2005;79: EARLY LOW-DOSE STEROID FOR ARDS Table 2. Outcome of Acute Respiratory Distress Syndrome Conventional (n 8) Early Low-Dose Steroid (n 12) p In-hospital mortality a Intensive care unit Mechanical ventilation ICU stay days b 19.5 (15 30) 1.5 (0 26)... Hospital stay days b 28 (17 57) 24.5 (14 85)... Discharge with oxygen a Any fatality occurring before hospital discharge, even if more than 30 b days postoperatively, was considered to be in-hospital mortality. - Median values (range). ICU intensive care unit. neous bilateral thoracotomies. Mortality rates were 1.28% (n 4) for lobectomy, 3.22% (n 2) for pneumonectomy, 6% (n 6) for esophageal surgery, and 0% (n 0) for bilateral multiple wedge resections; the overall mortality rate was 2.87% (n 15). The incidence of ARDS after thoracic surgery was 3.8% (3.1% for pulmonary resection and 7% for esophageal surgery). Death from ARDS accounted for 53.3% (n 8) of all deaths. Mortality after onset of ARDS was 40.0%. The mortality for the conventional therapy group was 87.5% and for the early low-dose steroid therapy group it was 8.3% (Table 2). Historical (Before Early Low-Dose Steroid ) From 2001 to 2002, 8 patients (7 men, 1 woman) developed ARDS after thoracic surgery. Five patients had 407 undergone pulmonary resection for lung cancer and 3 had undergone esophageal resection for esophageal cancer. The median length of stay in the intensive care unit was 20.5 days (range, 15 to 25 days), and the median length of stay in the hospital was 28 days (range, 17 to 57 days). Only 1 patient was discharged with an oxygen supplement through a nasal prong, for a mortality rate of 87.5%. All patients had newly developed pneumonia due to prolonged mechanical ventilation. Early Low-Dose Steroid From late 2002 to 2003, 12 patients (all men) met the criteria for ARDS after thoracic surgery. Eight patients had undergone lobectomy or pneumonectomy for lung cancer and 4 had undergone esophageal surgery for esophageal cancer. Administration of low-dose methylprednisolone at an early phase of ARDS produced an immediate increase in the PaO 2 /FiO 2 ratio for 10 of these patients. For the first 3 days after onset of ARDS, the mean PaO 2 /FiO 2 ratio increased significantly from at onset to on day 4, on day 5, and on day 6 (p 0.05) (Fig 1). PaO 2 /FiO 2 values were also significantly increased between days 3 and 4 and between days 5 and 6 (p 0.05). The median number of days before commencing to taper methylprednisolone was 4.5, with a range of 3 to 10 days. The median number of days to cease intravenous methylprednisolone or change to a single oral dose was 9.5 days. However, in the remaining 2 patients the response to early low-dose steroid therapy was not as dramatic, but these 2 patients were discharged on postoperative days 85 and 53. Of the 12 patients in the low-dose corticosteroid group, 7 (58.3%) did not require mechanical ventilation and needed only an oxygen mask with or without a reservoir bag. We did not hesitate to use mechanical ventilation if GENERAL THORACIC Fig 1. Alteration of arterial oxygenation efficiency (PaO 2 /FiO 2 ) between conventional therapy (dotted line) and early low-dose steroid therapy (solid line). In early low-dose steroid therapy an increase in the PaO 2 /FiO 2 ratio was observed in 10 patients immediately after starting low-dose methylprednisolone treatment. The mean PaO 2 /FiO 2 ratio, which was before treatment, increased to on day 4, on day 5, and on day 6 (p 0.05), and had also significantly increased between days 3 and 4 and between days 5 and 6 (p 0.05). The median number of days before tapering methylprednisolone was 4.5 (range, 3 to 10 days), and the median number of days before cessation of methylprednisolone or changing to a single oral dose was 9.5 (range, 5 to 19 days). (ARDS acute respiratory distress syndrome; immed. immediate postoperative; POD# postoperative day number; preop. preoperative.)

4 GENERAL THORACIC 408 LEE ET AL Ann Thorac Surg EARLY LOW-DOSE STEROID FOR ARDS 2005;79: Fig 2. Chest image findings at the onset and follow-up after recovery in 2 acute respiratory distress syndrome patients from the early low-dose steroid therapy group. (A C) Chest roentgenogram image and computed tomographic (CT) scans of a 65-year-old man who underwent right lower lobectomy and wedge resection of the left and right upper lobes under bilateral thoracotomies. (A) Chest infiltration was initiated 3 days postoperatively. (B) Acute respiratory distress syndrome was confirmed on day 4 and chest CT was performed. (C) Follow-up chest CT after 1 month revealed complete resolution of chest infiltration. (D F) Chest roentgenogram image and CT scans of a 67-year-old man who underwent left pneumonectomy for lung cancer. (D) Chest infiltration was initiated 2 days postoperatively. (E) Acute respiratory distress syndrome was confirmed on day 3. (F) Follow-up CT after 1 month revealed complete resolution of chest infiltration. the patient could not tolerate an oxygen mask. Three patients recovered after mechanical ventilation for just several days. Most patients showed improvement in their chest roentgenogram within 48 to 72 hours of the start of early low-dose steroid administration. All patients underwent chest computed tomography as soon as pulmonary infiltration was detected on chest roentgenogram. If possible, one month later, follow-up chest computed tomography was performed. Nine of the 12 patients (75%) were discharged with normal lung field at a median 21 days (range, 14 to 35 days). Ground glass opacities were absolutely resolved in follow-up chest computed tomography (Fig 2). The most common complication of low-dose steroid therapy group was tachyarrhythmia (n 12), which was controlled in all patients by digitalization or antiarrhythmic agents. Psychosis developed in 4 patients, which may have been induced by hypoxia or steroids. However, in 3 of these patients the psychosis was spontaneously resolved with ARDS recovery. Three patients on mechanical ventilation had the colonization of methicillinresistant staphylococcus aureus, which was treated with organism sensitive antibiotics. There was no wound infection or anastomosis dehiscence, but 2 patients with pulmonary resection suffered from prolonged air leakage; one resolved spontaneously, and the other was treated with pleurodesis after recovery from ARDS. One patient, who underwent an Ivor Lewis operation for esophageal cancer and was discharged after recovery from ARDS, was prescribed an oral prednisolone for 4 weeks. During follow-up, a new pulmonary infiltration on the right upper lung field was detected. Invasive aspergillosis was confirmed and managed with amphotericin B after cessation of steroids. Eleven of the 12 patients in this group survived with one death, which was not directly related to ARDS. This patient was an 85-year-old man who underwent right lower lobectomy and mediastinal lymph node dissection for lung cancer. He had recovered from ARDS and had tapered steroids. However, he had recurrent aspiration develop with neurologic compromise and died of sepsis from pneumonia on postoperative day 39. Comment We evaluated the efficacy and safety of low-dose methylprednisolone therapy at an early phase of ARDS after thoracic surgery. We found that early administration of low-dose methylprednisolone significantly reduced mortality from ARDS after thoracic surgery. The development of ARDS after thoracic surgery has been a difficult challenge for thoracic surgeons. The insidious onset of interstitial changes on chest roentgenogram after thoracic surgery is initiated from the contralateral or ipsilateral lung. In the past, as soon as this

5 Ann Thorac Surg LEE ET AL 2005;79: EARLY LOW-DOSE STEROID FOR ARDS complication developed, thoracic surgeons treated it aggressively with bronchial toilet by bronchoscopy, broadspectrum antibiotics, and diuresis. Frequently, however, dyspnea and pulmonary infiltration, as shown on chest roentgenogram, were so rapidly aggravated that mechanical ventilation was inevitable. Due to their fear of operative wound problems, surgeons administered a corticosteroid as an anti-inflammatory agent only as a last resort. Despite this aggressive management, a progressively downhill course often followed, with survival from ARDS after thoracic surgery disappointingly low. Although some patients recovered from ARDS, impaired health-related quality of life was common. Even 1 year after discharge from the intensive care unit, ARDS survivors frequently had persistent functional disabilities, including extrapulmonary conditions with muscle wasting and weakness being most prominent [30, 31]. Pulmonary fibrosis is often implicated as a serious consequence of ARDS. Pulmonary fibrosis after ARDS is regarded as an irreversible change of lung parenchyma, making the prevention of pulmonary fibrosis a primary goal of ARDS treatment. Fibroproliferation results in extensive fibrotic remodeling of the lung parenchyma. A number of cytokines mediate the host defense response to injury. In the absence of inhibitory signals, these mediators of the host defense response of mesenchymal cells induce deposition of extracellular matrix products and collagen, resulting in fibrosis. Thus an overaggressive and protracted host defense response, rather than the inciting condition, is likely to be the major factor influencing the outcome in ARDS. Corticosteroids inhibit the host defense response at many levels. For example, these agents have been shown to inhibit the transcription of genes encoding tissue necrosis factor, interleukin-1, interleukin-2, and interleukin-6, as well as suppressing the expression of transcripts of the phospholipase-a2, cyclooxygenase-2, and nitric oxide synthase-1 genes, thus decreasing the production of prostanoids, plateletactivation factor, and nitric oxide, which are three additional key molecules in the inflammatory pathway. In addition, corticosteroids have an inhibitory effect on fibrogenesis and the expression of adhesion molecules [32]. Thus, there appears to be some rationale for use of corticosteroids to prevent pulmonary fibrosis in ARDS. The initial enthusiasm for the use of corticosteroids to prevent and treat ARDS was based on animal and human studies. The use of corticosteroids in the late phase of ARDS was reported to improve lung function and survival [21 23]. In contrast, trials of short-term, high-dose steroid therapy failed to show an improvement in the mortality of patients at risk of ARDS or those with early ARDS [19, 20]. The use of steroids during the late phases of ARDS was based on the assumption that the fibroproliferative phase began 7 to 10 days after the onset of the insult. However, some reported that as the proliferative phase begins much sooner than previously thought, inflammatory and repair mechanisms occur simultaneously rather than subsequently. The recent finding that an increased number of myofibroblasts and cells produce procollagen types I and III in the early course of 409 ARDS suggests that the proliferative phase begins much sooner than had been previously appreciated [24 27]. The potent mitogenic activity of bronchoalveolar lavage fluid and the elevation in N-terminal procollagen peptide-iii concentrations observed at 24 hours support the hypothesis that two key mechanisms driving the deposition of lung collagen fibroblast proliferation and procollagen synthesis are rapidly up-regulated in this syndrome [26]. This result, as well as the realization that host defense mechanisms contribute to acute lung injury, suggest the need for reappraisal of methylprednisolone administration at an early phase of ARDS. In the past, the use of short-term and high-dose steroid treatment led to negative effects due to profound immunosuppression regimen or other side effects that counterbalance the positive effects of these agents. Furthermore, prolonged corticosteroid treatment of experimental ARDS was shown to be effective in decreasing lung collagen content and edema formation, whereas steroid withdrawal rapidly reverses this positive effect. These findings suggested that low-dose methylprednisolone should be administered and maintained until chest infiltration and symptoms in patients subsided. The beneficial effects of early low-dose steroid treatment have also been observed in patients with septic shock. Low-dose hydrocortisone treatment was found to inhibit systemic inflammation and to prevent overwhelming compensatory anti-inflammatory responses [33]. In addition, low-dose corticosteroid, when used at an early phase of ARDS, led to a complete maintenance of in vivo and in vitro respiratory mechanics in mild acute lung injury and minimized the changes in tissue impedance and extracellular matrix components in severe lesions [28]. These results further confirm that the administration and maintenance of low-dose methylprednisolone from the onset of ARDS should prevent pulmonary fibrosis and lung edema formation. In addition, the results shown here further suggest that the fibroproliferative phase begins much earlier than previously thought. The chest computed tomography, which was performed immediately after identification of the pulmonary infiltration on chest roentgenogram, showed that the extent of infiltration was more extensive and aggressive than originally shown in the chest roentgenogram. This finding provided support for the use of steroids at an early phase of ARDS. Initially, however, chest infiltration and symptoms in some patients were aggravated to some extent in spite of steroid loading, but most of these stabilized within 48 to 72 hours. By follow-up chest high-resolution computed tomography, we confirmed that 9 of 12 patients had complete resolution of ARDS, enabling the survivors to maintain a quality of life similar to that of patients who did not suffer from ARDS after thoracic surgery. In conclusion, we have shown here that low-dose methylprednisolone administration at an early phase of ARDS had beneficial effects on mortality. Our findings support the hypothesis that fibroproliferation is an early response to lung injury, which is inhibited by early GENERAL THORACIC

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