Acute respiratory distress syndrome due to severe pulmonary tuberculosis treated with extracorporeal membrane oxygenation: A case report and review of the literature


Mortality in patients with pulmonary tuberculosis remains high, especially in those who develop acute respiratory distress syndrome (ARDS). We report on a-48-year-old man with ARDS due to severe pulmonary tuberculosis who was rescued by extracorporeal membrane oxygenation (ECMO). He was initially hospitalized in the intensive care unit and noninvasive positive-pressure ventilation started. He was also administered anti-tuberculosis drugs and received systemic corticosteroid therapy. Six days later, further deterioration of gas exchange prompted the decision to intubate. However, he experienced progressive deterioration of arterial oxygenation despite conventional ventilatory support. We therefore decided to administer ECMO on day 9. After initiation of these treatments and ECMO support, pulmonary infiltrate and oxygenation status gradually improved and ECMO was discontinued on day 52. The patient was finally discharged from our hospital without severe disability. ECMO should be considered one of the treatment options for the management of ARDS due to severe pulmonary tuberculosis.


  • ARDS, acute respiratory distress syndrome;
  • ECMO, extracorporeal membrane oxygenation;
  • ICU, intensive care unit;
  • MV, mechanical ventilation;
  • PTB, pulmonary tuberculosis

1. Introduction

In-hospital mortality of tuberculosis patients remains high, especially among those requiring admission to the intensive care unit (ICU) and mechanical ventilation (MV)[1] and [2]. Tuberculosis patients requiring ICU care may also develop acute respiratory distress syndrome (ARDS) [1] and [3]. In the management of patients with ARDS, extracorporeal membrane oxygenation (ECMO) has been successfully used as salvage therapy. ARDS severe enough to require ECMO support is estimated to occur in nearly 5 to 10 cases per million population per year [4]. The effectiveness of ECMO in ARDS patients with pneumonia, influenza A (H1N1) and trauma has recently been described but is less certain in ARDS patients with pulmonary tuberculosis (PTB) [5] and [6]. We report a patient with ARDS due to severe PTB who was rescued by ECMO.

2. Case report

A-48-year-old man was admitted to our hospital because of dyspnea. His sputa were strongly smear-positive and the mycobacteria obtained from culture were identified as M. tuberculosis. Routine blood tests showed white blood cell count of 12800/mm3, platelets of 35.0 × 104/mm3, C-reactive protein of 22.0 mg/dl, albumin level of 1.9 g/dl and a negative HIV ELISA test. His chest X-ray and computed tomography showed diffuse bilateral infiltration and cavity (Fig. 1A, B), and blood gas test showed PaO2/FiO2 131.0. This patient was initially hospitalized in the ICU and noninvasive positive-pressure ventilation started. Anti-tuberculosis drugs, including isoniazid, refampicin, streptomycin and pyrazinamide; antibiotics including meropenem and ciprofloxacin; and intravenous methylprednisolone (1.0 mg/kg/day) were introduced.

Chest X-ray and computed tomography images. (A) and (B): On the day of admission ...
Fig. 1.

Chest X-ray and computed tomography images. (A) and (B): On the day of admission to our hospital. (C) and (D): 3 days after the discontinuation of extracorporeal membrane oxygenation. (E) and (F): 2 weeks after weaning from mechanical ventilation.

Six days later, further deterioration of gas exchange prompted the decision to intubate and steroid pulse therapy consisting of intravenous methylprednisolone (1000 mg/day for 3 days) followed by intravenous methylprednisolone (1.0 mg/kg/day) was administered. However, on the 3rd day of intubation arterial blood gas analyses showed severe hypoxemia (PaO2/FiO2 60.4) refractory to conventional MV, and we decided to administer veno-venous ECMO. Ventilator settings were adjusted to provide lung rest (pressure controlled ventilation with peak pressure of 20 cmH2O, PEEP of 10 cmH2O, and ventilation frequency of 8 per minute).

Hemoptysis was observed on day 27 after the start of ECMO but ceased with adjustment to a lower dosage of heparin. No other ECMO-related major complications were evident during treatment. The pulmonary infiltrate and oxygenation status gradually improved (Fig. 1C, D, E, F), and the systemic corticosteroid was tapered. ECMO was discontinued on day 52 and we successfully weaned the patient from MV 106 days after the start of administration of ECMO. After a hospital stay and rehabilitation of 10 months, he was discharged from our hospital without severe disability.

3. Discussion

ECMO is considered one of the treatment options for severe ARDS [5], [6] and [7]. ARDS is an infrequent but serious complication of PTB [8]. The mortality of ARDS patients with PTB requiring MV is relatively high compared with that of patients with ARDS from other causes [9]. Five patients with acute respiratory failure due to PTB were recently reported to be successfully rescued by ECMO [10], [11], [12], [13], [14] and [15] (Table 1). Given the high mortality rate of ARDS patients with PTB, ECMO could be an important treatment option.

Table 1.Previously reported patients with pulmonary tuberculosis treated with ECMO.

Age Sex Underlying condition Treatment Use of corticosteroid Length of ECMO Outcome Author/year
58 F None None None 5 days Death Homan W 1975 [10]
15 F None INH/RFP/EB/PZA None 6 days (152 h) Recovery Petrillo TM 2001 [11]
20 M None INH/RFP/EB/PZA None 89 days Recovery Mauri T 2012 [12]
14 F Histiocytic hemophagocytosis INH/RFP/EB/PZA Methylprednisolone 2mg/kg/day 6 days recovery Monier B 2013 [13]
24 F Laryngeal papilloma INH/RFP/EB/PZA Methylprednisolone 250mg/day 36 days Recovery Andresen M 2013[14]
20 M None INH/RFP/EB/PZA None 89 days Recovery Cogliandro V 2014 [15]
EB = ethambutol; ECMO = extracorporeal membrane oxygenation; INH = isoniazid; PZA = pyrazinamide; RFP = refampicin.

An innovative aspect of this case is the duration of ECMO, which was longer than that in ARDS from other causes. The clinical courses of patients with PTB often become indolent and the healing rate of PTB is characteristically slow. In addition, our patient showed severe hypoxia compared with previous patients with ARDS from PTB treated with MV [9]. A previous study reported that PTB patients with greater disease extent and severity showed persistent inflammation and required longer treatment [16]. While there is some concern that long-term use of ECMO may lead to a higher risk of complications, recent progress in the techniques and equipment used in ECMO have made prolonged ECMO support feasible. In fact, the survival of prolonged ECMO patients has improved significantly compared with previous years [17]. Another report supporting this described a case of indolent infection caused by Nocardia cyriacigeorgica and Burkholderia cepacia that was rescued by ECMO [18].

In this patient the adjunctive use of systemic corticosteroid therapy led to rapid clinical improvement and allowed us to wean the patient off ECMO earlier. Andresen et al. similarly reported that systemic corticosteroid therapy during ECMO support led to progressive improvement of respiratory function [14]. Several other studies have also suggested the effectiveness of adjunctive use of corticosteroids for PTB [19],[20] and [21]. The steroid dose we used in this case was higher than that in the previous reports. Although evidence for high dose steroid therapy for PTB is still lacking, our aim in using this high dose was to get quicker and stronger results and to decrease the need for long-term steroid use [22].

In conclusion, we have reported here a patient with ARDS due to severe PTB who was rescued by ECMO. The healing rate of PTB is characteristically slow, which may lead the long-term use of ECMO. There is increasing recent evidence for the effectiveness of ECMO, and advances in the techniques and devices have made prolonged ECMO support feasible. ECMO should therefore be considered among the treatment options in patients with ARDS due to severe PTB when conventional ventilatory support is inadequate.

Does Aspirin Reduce the Risk of Developing Acute Respiratory Distress Syndrome?

Effect of Aspirin on Development of ARDS in At-Risk Patients Presenting to the Emergency Department: The LIPS-A Randomized Clinical Trial

Kor DJ, Carter RE, Park PK, et al; US Critical Illness and Injury Trials Group: Lung Injury Prevention with Aspirin Study Group (USCIITG: LIPS-A)
JAMA. 2016 May 15. [Epub ahead of print]


Acute respiratory distress syndrome (ARDS) is among the most common and feared respiratory conditions in critically ill patients.[1] ARDS is a form of acute inflammatory lung injury, most often due to sepsis, severe trauma, aspiration, pancreatitis and other systemic injuries, and inflammatory disorders.[2]

Although we do not yet have effective drug therapies for ARDS, much attention has focused on prevention of ARDS. The authors of this study sought to follow up prior observations studies suggesting a role for aspirin in preventing ARDS,[3-5] to determine whether aspirin may prevent the development of ARDS if given early in patients at moderate to high risk.[6]

In the study, 400 emergency department patients at risk for ARDS (Lung Injury Prediction Score ≥ 4) were randomly assigned to receive treatment with aspirin (325 mg initial dose and 81 mg daily for 7 days) or placebo.[7] ARDS developed in 10.3% of patients receiving aspiring and 8.7% of those receiving placebo (P=.53), and there were no differences between groups in terms of mortality or length of stay in the hospital or intensive care unit. The authors concluded that aspirin is ineffective for preventing ARDS.


The difficulty in treating ARDS has led to increased interest in prevention as a more effective strategy. Although this is appealing and clinically important, the same challenges that have led to failed ARDS trials (heterogeneous causes of ARDS, sufficient understanding of disease pathogenesis, and other factors) is equally problematic for studies of prevention.

In this case, there was a growing body of literature about the role of platelets in ARDS and the association between aspirin therapy and either lower rates of ARDS or improved outcomes.[3-5] It was reasonable to pursue the possibility that something as simple as aspirin could prevent this severe, life-threatening condition. Unfortunately, aspirin therapy neither prevented ARDS nor demonstrated efficacy for any other measurable outcome, aside from a change in interleukin 2 values at day 1.

Aspirin Therapy Fails to Reduce ARDS

Initiating aspirin therapy to emergency room patients at risk of lung injury does not influence the chance that these patients will experience acute respiratory distress syndrome(ARDS), researchers reported here.

The development of ARDS occurred within 7 days in 20 of 195 patients (10.3%) assigned to aspirin and in 17 of 195 patients (8.7%) presenting in the emergency room (P=0.53), reported Daryl Kor, MD, of the Mayo Clinic in Rochester, Minn.

n presenting their research at the annual meeting of the American Thoracic Society, additionally, Kor and colleagues reported no statistically significant differences in ventilator-free days, in length of stay in the intensive care unit, in hospital length of stay, in 28-day survival, or in bleeding events. The study was published online in the Journal of American Medical Association simultaneously with its presentation here.
“Among at-risk patients presenting to the emergency department, the use of aspirin compared with placebo did not reduce the risk of ARDS at 7 days,” Kor reported. “The findings of this Phase 2b trial do not support continuation to a larger Phase 3 trial.”
Patients who were included in the trial received a loading dose of aspirin 325 mg, followed by daily 81 mg doses within 24 hours of emergency department presentation and continued to hospital day 7, discharge, or death. The median age of the patients was 57 years, and 48% of the patients included in the study were women. Patients were evaluated on the basis of the Lung Injury Prediction Score — with a score of 4 or greater the threshold for the aspirin therapy.
The researchers suggested that aspirin might make a difference in outcomes “based on the body of existing experimental data demonstrating alterations in platelet function during the development of ARDS. Platelet activation, aggregation, and sequestration, as well as modulation of anti-inflammatory lipid mediators, including leukotrienes, thromboxane, and prostaglandins,have all been implicated as important mediators of ARDS progression and severity. Aspirin directly modifies these mechanistic pathways, making it a plausible preventive and therapeutic measure in this setting.”
But in the clinical trial, treatment with aspirin didn’t improve outcomes.
Ventilator-free days through day 28 were 24.9 among the patients on aspirin; 25.2 among those on placebo (P=0.72).
Intensive care unit length of stay was 5.2 days among patients treated with aspirin; 5.4 days among patients who received placebo (P=0.87).
Hospital length of stay was 8.8 days among the aspirin-treated patients; 9.0 days among those on placebo (P=0.79).
Survival at 28 days was 90% for both cohorts (P=0.92).
One-year estimated survival was 73% among the patients on aspirin and 75% among the placebo patients (P=0.79).
No statistically significant differences were found in measures of safety. Eleven patients or 5.6% of those on aspirin experienced bleeding events compared with 5 patients or 2.6% of patients on placebo (P=0.13).

Kor reported that the trial results were likely shaped by a less than expected rate of ARDS in the population. The rate of 9.5% was far lower than the predicted 18% rate, he reported. “In addition to the lower than expected rate of ARDS, low rates of mechanical ventilation, acute kidney injury, and mortality suggest that the enrolled study population may have had a more modest overall severity of illness than what was anticipated at study onset,” the researchers stated. “As a result, the external validity of our findings in a cohort of critically ill patients with greater severity of illness remains unclear. Still, the results of this trial appear robust and consistent between the clinical and biomarker outcome measures.”
In an editorial that accompanied the study in JAMA, John Reilly, MD, instructor in medicine, and Jason Christie, MD, professor of medicine at the University of Pennsylvania, wrote:
“The attributable mortality associated with ARDS in the setting of critical illness is controversial, but ARDS is associated with increased length of intensive care unit stay, duration of ventilatory support, and poor long-term function and neurocognitive outcomes.
“Preventing ARDS is a worthy goal; however, ARDS is not a patient-centered outcome, nor a validated surrogate outcome for patient-centered outcomes,” they suggested. “Additionally, preventing ARDS does not ensure either improved survival or post-hospitalization quality of life. It is possible that an intervention may decrease ARDS risk but actually increase mortality.
“For example, if aspirin reduced ARDS incidence but resulted in significant bleeding complications or other unforeseen effects, the therapy should be avoided. Alternatively, an immunomodulatory therapy that reduces ARDS risk also may reduce pathogen clearance in patients with sepsis, resulting in overall negative effects.
“Conventional ARDS trials have chosen mortality as a primary outcome. In an ARDS prevention trial with mortality of 9%, as seen in the LIPS-A study, conducting a larger trial with sufficient power to detect mortality effects would be excessively expensive and likely infeasible.
“Ideally, future trials would both aim to prevent ARDS but also focus on mortality, functional status, or hospital costs in a population selected to be at highest risk and most likely to respond to a specific therapy,” they suggested.

Meta-analysis shows some benefits of steroids in CAP

The use of steroids in people with community acquired pneumonia (CAP) led to shorter recovery time and fewer hospital days, with the added benefits of reduced mortality and acute respiratory distress syndrome (ARDS), in a systematic review and meta-analysis.

Corticosteroid therapy reduced the length of hospital day by an average of 1 day in six trials with 1,500 patients and the time to clinical stability by an average of 1.22 days in five trials with over 1,100 patients. It was also associated with 3 percent lower mortality in a subgroup of patients with severe CAP and 5 percent reduction in need for mechanical ventilation. [Ann Intern Med 2015;163:519-528]

“The analysis offers high-quality evidence for the benefits of adjunctive corticosteroids in hospitalized patients with CAP,” said researchers led by Dr. Reed Siemieniuk of Mc Master University in Hamilton, Ontario, Canada.  There was an increased risk of hyperglycaemia that required treatment, but not gastrointestinal haemorrhage, rehospitalisation or neuropsychiatric symptoms.

Current guidelines for CAP do not recommend corticosteroids. Several randomized controlled trials (RCTS) of corticosteroids have demonstrated benefits, but others have come up empty. Siemieniuk and colleagues sought to investigate if the anti-inflammatory action of corticosteroids can improve outcomes in patients with CAP. The analysis mainly focused on 13 RCTs comparing corticosteroids with placebo or no treatment and looked into one of several outcomes that included clinical stability, length of hospital stay, all-cause mortality, use of mechanical ventilation, ARDS or ICU admission. Sixty percent of patients were men (median age, 60 years).

In 12 trials looking at all-cause mortality, the relative risk (RR) was 0.67 in favour of corticosteroids (risk difference [RD], 2.8 percent) whereas in three studies with 950 patients, the RR for ICU admission was 0.69.

The benefit may be greater in severely ill patients, said the researchers.

In an accompanying editorial, Drs. Marcos Restrepo, Antonio Anzueto and Antoni Torres of the University of Texas Health Science Center at San Antonio in San Antonio, Texas, US praised the rigorousness of the analysis but cautioned that clinicians need to balance the benefits and harms of corticosteroid therapy to provide optimal care for patients with CAP. They also suggested the use of C-reactive protein (CRP) biomarker to measure the systemic inflammation characteristic of pneumonia and identify hospitalized patients who would best respond to corticosteroid treatment.

“Proning” Benefits Patients with Severe ARDS.

Acute respiratory distress syndrome–associated 28-day mortality was halved in patients who spent most of the day face down.


Patients with acute respiratory distress syndrome (ARDS) commonly develop consolidation of the dependent lung regions. For many years, physicians have transitioned severely hypoxemic patients from supine to prone position to improve aeration of these areas and gas exchange. Small studies of “proning” demonstrated improved oxygenation without affecting more important outcomes; meta-analyses suggested proning could lower ARDS-associated mortality (Intensive Care Med 2010; 36:585).

This large French trial involved 466 patients with moderate-to-severe ARDS (ratio of partial pressure of arterial oxygen to fraction of inspired oxygen [PaO2:FiO2] <150, with FiO2 0.6; positive end-expiratory pressure, 5 cm H2O). All patients received low tidal-volume ventilation and were randomized to daily prone positioning or to supine positioning only. Intervention patients were placed in the prone position within 1 hour of randomization and underwent an average of four sessions of proning (mean duration per daily session, 17.3 hours). At randomization, >80% of patients were receiving neuromuscular blockade, and approximately 40% were receiving glucocorticoids. Mortality at 28 days was 16% in the prone group and 33% in the supine group.

Comment: These results give new life to the practice of proning. Although this intervention is not suitable for all patients with acute respiratory distress syndrome (e.g., those with recent sternotomy or facial trauma), proning should be considered early for most patients with severe disease. Almost all patients in this study received neuromuscular blockade, which reinforces earlier administering of short-term paralytics for severe hypoxemia. Patients in this study were proned for prolonged periods. Delivering care safely to patients in this position for most of the day will require additional training of nurses and other providers.


Source: Journal Watch General Medicine

Use of Prone Positioning During Ventilatory Support Found Superior in ARDS.

In patients with acute respiratory distress syndrome (ARDS), use of the prone position during ventilatory support roughly doubled survival at the 1- and 3-month marks, according to a New England Journal of Medicinestudy.

Researchers followed outcomes in nearly 500 patients with severe ARDS who were randomized either to prone positioning for at least 16 consecutive hours a day, or to being left supine. By 28 days, mortality was 16% in the prone group, versus 33% in the supine group; at 90 days, the prone-positioning advantage held: 24% versus 41%.

An editorialist calls the results “compelling,” and the treatment effect “virtually unprecedented in modern medicine.” He cautions, however, that the logistics of turning patients to the prone position from supine requires teamwork to avoid kinking and extubation. The article includes a video showing how this can be accomplished with three people.

Source: NEJM 

Efficacy of ibuprofen and pentoxifylline in the treatment of phosgene-induced acute lung injury.

Phosgene, a highly reactive former warfare gas, is a deep lung irritant which produces adult respiratory distress syndrome (ARDS)-like symptoms following inhalation. Death caused by phosgene involves a latent, 6-24-h, fulminating non-cardiogenic pulmonary edema. The following dose-ranging study was designed to determine the efficacy of a non-steroidal anti-inflammatory drug, ibuprofen (IBU), and a methylxanthine, pentoxifylline (PTX). These drugs were tested singly and in combination to treat phosgene-induced acute lung injury in rats. Ibuprofen, in concentrations of 15-300 mg kg-1 (i.p.), was administered to rats 30 min before and 1 h after the start of whole-body exposure to phosgene (80 mg m-3 for 20 min). Pentoxifylline, 10-120 mg kg-1 (i.p.), was first administered 15 min prior to phosgene exposure and twice more at 45 and 105 min after the start of exposure. Five hours after phosgene inhalation, rats were euthanized, the lungs were removed and wet weight values were determined gravimetrically. Ibuprofen administered alone significantly decreased lung wet weight to body weight ratios compared with controls (P < or = 0.01) whereas PTX, at all doses tested alone, did not. In addition, the decrease in lung wet weight to body weight ratio observed with IBU+PTX could be attributed entirely to the dose of IBU employed. This is the first study to show that pre- and post-treatment with IBU can significantly reduce lung edema in rats exposed to phosgene.

Source: Journal of applied Toxicology

Respiratory distress syndrome in patients with advanced cancer treated with pentoxifylline: a randomized study.


The inappropriate endogenous secretion of tumour necrosis factor (TNF) could play a role in the pathogenesis of acute respiratory distress syndrome (ARDS), one of the most frequent causes of death in cancer patients. Because of its capacity to inhibit TNF secretion in vitro, pentoxifylline (PTX) could be extremely useful in ARDS therapy. In this study 30 advanced cancer patients with ARDS were randomized to receive either the conventional care or conventional care plus PTX (100 mg i.v. twice a day for 7 days followed by an oral administration of 400 mg three times a day) to evaluate the efficacy of PTX in reducing TNF serum levels and in improving the symptoms of this syndrome. Serum levels of TNF were measured before and after 7 days of therapy. The percentage of patients alive at 7 days was significantly higher in the PTX-treated group than in the controls (12/15 versus 3/15; P < 0.001). The mean survival time was significantly higher in the PTX-treated group than in the controls. A clinical and/or radiological improvement was obtained in 11/15 patients treated with PTX and in only 2/15 patients in the conventional care group (P < 0.01). TNF mean levels significantly decrease in the PTX-treated group. These data confirm in vivo the capacity of PTX to inhibit TNF secretion in patients with ARDS. Moreover PTX therapy may improve the symptoms related to ARDS without particular toxic effects.