Utility of Endobronchial Valves in a Patient with Bronchopleural Fistula in the Setting of COVID-19 Infection: A Case Report and Brief Review

Nazanin Sheikhan, MD¹, Elizabeth J. Benge, MD¹, Amanpreet Kaur, MD¹, Jerome K Hruska, DO², Yi McWhorter DO³, Arnold Chung MD⁴

¹Department of Internal Medicine, HCA Healthcare; MountainView Hospital, Las Vegas, NV, USA

²Department of Pulmonology, HCA Healthcare; MountainView Hospital, Las Vegas, NV, USA

³Department of Anesthesiology Critical Care Medicine, HCA Healthcare; MountainView Hospital, Las Vegas, NV, USA

⁴MountainView Cardiovascular and Thoracic Surgery Associates, HCA Healthcare; MountainView Hospital, Las Vegas, NV, USA

Abstract

Patients with COVID-19 pneumonia frequently develop acute respiratory distress syndrome (ARDS), and in severe cases, require invasive mechanical ventilation. One complication that can develop in patients with ARDS who are mechanically ventilated is a bronchopleural fistula (BPF). Although rare, the frequency of BPF in patients with COVID-19 pneumonia is increasingly recognized. Here, we present a 48-year old man with BPF associated with COVID-19 pneumonia. Treatment with a commercial endobronchial valve (EBV) system resulted in reduced air leak allowing for tracheostomy placement. Our case adds to a growing body of evidence suggesting that the presence of COVID-19 pneumonia does not hinder the utility of EBV’s in the treatment of BPF’s.

Abbreviation List

• ARDS = acute respiratory distress syndrome
• BIPAP = Bilevel Positive Airway Pressure
• BPF = Bronchopleural Fistula
• COVID-19 = Coronavirus Disease-2019
• CT = Computed Tomography
• CTA = Computed Tomography Angiography
• EBV = Endobronchial Valve
• HFNC = High Flow Nasal Cannula
• ICU = Intensive Care Unit
• RML = Right Middle Lobe
• RUL = Right Upper Lobe
• SARS-CoV-2 = Severe Acute Respiratory Syndrome Coronavirus-2
• VATS = Video-Assisted Thoracoscopic Surgery

Introduction

The COVID-19 pandemic has resulted in over one hundred million infections worldwide, in addition to millions of deaths (1). A less common sequelae of COVID-19 is bronchopleural fistula (2). A bronchopleural fistula is an abnormal sinus tract that forms between the lobar, main stem, or segmental bronchus, and the pleural space (3). BPF is typically treated by surgical repair, via a video-assisted thoracoscopic surgical approach (VATS) (3). Bronchoscopic approach with placement of airway stents, coils or transcatheter occlusion devices can be considered for those who are not suitable for surgical intervention (3).  A newer therapeutic modality for bronchopleural fistulae are endobronchial valves, which have been used successfully to treat COVID-19 patients diagnosed concurrently with bronchopleural fistulae (4). 

Here, we present a case of a critically ill patient developing a bronchopleural fistula with a concurrent COVID-19 infection, whose respiratory status was stabilized with an endobronchial valve.  To our knowledge, this is one of four case reports of a bronchopleural fistula arising in the setting of COVID-19.

Brief Review of Endobronchial Valves in COVID-19

Several other studies report success using endobronchial valves to treat bronchopleural fistulae in patients with COVID-19 pneumonia. One case series documents two cases of COVID-19 pneumonia complicated by bacterial super-infections, in which both patients experienced pneumothorax and persistent air leaks after mechanical invasive ventilation.  Both patients were successfully treated via EBV positioning. These researchers speculate that the severe inflammation associated with COVID-19 related ARDS induces inflammatory-related tissue frailty, pre-disposing lung tissue to damage via barotrauma, and the subsequent development of BPF (5).  

Another case documents the treatment of a 49-year-old male with COVID-19 pneumonia who was treated with steroids and tocilizumab. He also had a 3-week history of persistent air leak, which was successfully treated with an EBV. This team emphasizes that the thick, copious sections evident in patients afflicted by COVID-19 pose a risk for EBV occlusion. They highlight the importance of medically optimizing the patient and draining the air leak to mitigate the potential of this procedural complication developing (4).

In conjunction with the treatment course presented in our case, these case reports provide compelling evidence indicating that endobronchial valves can be successfully used to treat persistent air leaks in patients with COVID-19 pneumonia.

Case Presentation

Our patient is a 48-year-old male with a medical history significant for essential hypertension and Type 1 diabetes mellitus who presented to the emergency department complaining of acute onset generalized weakness, shortness of breath, and a near-syncopal event that had occurred the day prior. Vital signs on admission showed an oxygen saturation of 86% on ambient air, respiratory rate of 18 breaths per min, heart rate of 111 beats per min with a temperature of 37.6°C. He was tested for SARS-CoV-2 on admission and was found to be positive.

Initial computed tomography (CT) chest showed diffuse bilateral ground-glass opacities compatible with COVID-19 pneumonia. On admission, his inflammatory markers were elevated, with C-reactive protein 4.48 mg/dL, ferritin 1230 ng/ml, lactate dehydrogenase 281 IU/L, and D-dimer 0.76 mg/L. He received 1 dose of tocilizumab, convalescent plasma, as well as 5-day course of Remdesivir. His oxygen requirement increased as well as his work of breathing requiring High Flow Nasal Cannula (HFNC) and subsequently Bilevel Positive Airway Pressure (BiPAP); patient was transferred to the medical intensive care unit (ICU) 17 days after admission requiring intubation. Computed tomography angiography (CTA) chest could not be obtained to rule out pulmonary embolism as patient was too unstable. Patient was started on Heparin drip empirically which had to be discontinued due to gastrointestinal bleeding. He had worsening oxygenation, ventilator asynchrony, with P:F ratio of 47, requiring high-dose sedation and neuromuscular blockade, as well as prone positioning. Repeat CT chest on day 21 demonstrated bilateral pneumothoraces and pneumomediastinum as well as interval worsening of diffuse ground glass infiltrates (Figure 1), requiring bilateral chest tube placement.

Figure 1. Computed tomography chest showing pneumomediastinum, bilateral pneumothoraces, and diffuse ground glass attenuation of the lungs bilaterally.

On the 34th day of admission, he developed a right-sided tension pneumothorax likely secondary to ongoing severe ARDS, requiring replacement of dislodged right chest tube. Patient subsequently had worsening of right pneumothorax requiring an additional second chest tube placement. Patient developed persistent air leak concerning for right bronchopleural fistula. On hospital day 42, patient underwent intrathoracic autologous blood patch with persistence of large air leak. After interdisciplinary conference with cardiothoracic surgery, pulmonary, and the ICU team, it was decided that patient is not a surgical candidate hence interventional pulmonology was consulted for EBV placement to facilitate chest tube removal and ventilator weaning.

Patient underwent fiberoptic bronchoscopy on hospital day 52; pulmonary balloon was used to sequentially block the right mainstem, bronchus intermedius, and basilar segments. The air leak was recognized to be coming from right middle lobe (RML) and the apex of the right upper lobe (RUL) status post placement of two endobronchial valves in the medial and lateral segments of the RML (Figure 2).

Figure 2. Bronchoscopic view of endobronchial valves.

The RUL could not be entered secondary to angulation and technical inability of the instruments to achieve a sharp bend. Post-bronchoscopy, patient had 50 mL reduction in air leak resulting in improvement of his ventilator settings such that a tracheostomy could be safely performed. Left-sided chest tube was removed with resolution of pneumothorax. Repeat CT chest on hospital day 115 demonstrated persistent right bronchopleural fistula (Figure 3).

Figure 3. Computed tomography chest showing bronchopleural fistula in the right middle lobe and collapsed and shrunken right middle lobe with endobronchial occlusion stents at the central airway. Yellow arrow showing endobronchial valves and red arrows showing bronchopleural fistula

The patient is currently pending transfer to a long-term acute care hospital for aggressive physical therapy and eventual transfer to a tertiary center for lung transplantation evaluation.

Discussion

Scientific research has moved at an unprecedented speed in an attempt to shed light on the manifestations of COVID-19. The most common presentation of COVID-19 includes cough, fever, shortness of breath, and new onset anosmia and ageusia (6).

Common complications include coagulopathy, pulmonary emboli, and in severe cases, acute respiratory distress syndrome (7). Bronchopleural fistulae have emerged as a rare but known complication of COVID-19. This pathology is traditionally seen as a post-surgical complication arising from lobectomy or pneumonectomy (8). All cause mortality secondary to bronchopleural fistulae are high; with mortality rates ranging from 18-67% (8).

A relatively novel therapeutic modality for bronchopleural fistulae are endobronchial valves, which have been used in patients who are not candidates for surgery, such as our patient (9). They work as a one-way valve that allow the pathologically trapped air to exit the respiratory system, but not enter (4).

Differential diagnoses for bronchopleural fistulae include alveolar pleural fistulas and empyema (11). Alveolar pleural fistulas are abnormal communications between the pulmonary parenchyma, distal to a segmental bronchus, and the pleural space, while bronchopleural fistulas are more proximal; representing abnormal connections between a mainstem, lobar, or segmental bronchus and the pleural space (12). These pathologies are differentiated with direct visualization on bronchoscopy, as was demonstrated in our patient (12).

There are currently no official statistics on the epidemiology of bronchopleural fistulae in COVID-19. A disappointing aspect of our case was the lack of complete resolution of the patient’s air leak after the placement of the endobronchial valve. While the patient’s condition did improve after the valve was placed, he continued to suffer from respiratory illness related to his bronchopleural fistula. Although complete remission was not achieved, the endobronchial valve placement did facilitate respiratory recovery sufficient enough to facilitate a tracheostomy. The patient was then stabilized for eventual transfer to a long-term acute care facility, where he will undergo physical therapy and await lung transplantation. It is important to emphasize that while the endobronchial valve was not curative, it stabilized the patient for possible future curative treatments.  

Conclusion

Despite their rarity, bronchopleural fistulas are a pulmonary complication of COVID-19. Although the insertion of the endobronchial valve in our patient resulted in a reduction of the air leak as opposed to complete resolution, this case still emphasizes a therapeutic benefit of endobronchial valves in such instances. Overall, our case demonstrates the importance of clinical vigilance in the face of unusual pulmonary complications related to COVID-19, and that treatment of these complications requires flexibility and creativity.

References

1. WHO Coronavirus (COVID-19) Dashboard [Internet]. World Health Organization. World Health Organization; [cited 2021May31]. Available from: https://covid19.who.int/ 
2. Hopkins C, Surda P, Kumar N. Presentation of new onset anosmia during the COVID-19 pandemic. Rhinology. 2020 Jun 1;58(3):295-298. [CrossRef] [PubMed]
3. Miesbach W, Makris M. COVID-19: Coagulopathy, Risk of Thrombosis, and the Rationale for Anticoagulation. Clin Appl Thromb Hemost. 2020 Jan-Dec;26:1076029620938149. [CrossRef] [PubMed]
4. Talon A, Arif MZ, Mohamed H, Khokar A, Saeed AI. Bronchopleural Fistula as a Complication in a COVID-19 Patient Managed With Endobronchial Valves. J Investig Med High Impact Case Rep. 2021 Jan-Dec;9:23247096211013215. [CrossRef] [PubMed]
5. Donatelli P, Trenatacosti F, Pellegrino MR, et al. Endobronchial valve positioning for alveolar-pleural fistula following ICU management complicating COVID-19 pneumonia. BMC Pulm Med. 2021 Sep 27;21(1):307. [CrossRef] [PubMed]
6. Salik I, Vashisht R, Abramowicz AE. Bronchopleural fistula. StatPearls [Internet]. 2020 Aug 27. [CrossRef]
7. Cardillo G, Carbone L, Carleo F, Galluccio G, Di Martino M, Giunti R, Lucantoni G, Battistoni P, Batzella S, Dello Iacono R, Petrella L, Dusmet M. The Rationale for Treatment of Postresectional Bronchopleural Fistula: Analysis of 52 Patients. Ann Thorac Surg. 2015 Jul;100(1):251-7. [CrossRef] [PubMed]
8. Sarkar P, Chandak T, Shah R, Talwar A. Diagnosis and management bronchopleural fistula. Indian J Chest Dis Allied Sci. 2010 Apr-Jun;52(2):97-104. [PubMed]
9. Pathak V, Waite J, Chalise SN. Use of endobronchial valve to treat COVID-19 adult respiratory distress syndrome-related alveolopleural fistula. Lung India. 2021 Mar;38(Supplement):S69-S71. [CrossRef] [PubMed]
10. Musani AI, Dutau H. Management of alveolar-pleural fistula: a complex medical and surgical problem. Chest. 2015 Mar;147(3):590-592. [CrossRef] [PubMed]
11. Mehta HJ, Malhotra P, Begnaud A, Penley AM, Jantz MA. Treatment of alveolar-pleural fistula with endobronchial application of synthetic hydrogel. Chest. 2015 Mar;147(3):695-699. [CrossRef]  [PubMed]

Acknowlegements

This research was supported (in whole or in part) by HCA Healthcare and/or an HCA Healthcare affiliated entity. The views expressed in this publication represent those of the author(s) and do not necessarily represent the official views of HCA Healthcare or any of its affiliated entities. 

Cite as: Sheikhan N, Benge EJ, Kaur A, Hruska JK, McWhorter Y, Chung A. Utility of Endobronchial Valves in a Patient with Bronchopleural Fistula in the Setting of COVID-19 Infection: A Case Report and Brief Review. Southwest J Pulm Crit Care. 2021;23(4):109-14. doi: https://doi.org/10.13175/swjpcc046-21 PDF 

Management of Refractory Hypoxemic Respiratory Failure secondary to Diffuse Alveolar Hemorrhage with Venovenous Extracorporeal Membrane Oxygenation

Evanpaul Gill²

Mohamed A. Fayed^1,2,

Elliot Ho^1,2

University of California San Francisco - Fresno Medical Education Program

¹Pulmonary and Critical Care Division

²Department of Internal Medicine

Fresno, CA USA

Abstract

Uncontrolled bleeding has been a relative contraindication for the use of venovenous extracorporeal membrane oxygenation (VV ECMO), but current practice is relatively institution dependent. With the recent advances in circuit technology and anticoagulation practices, the ability to manage patients with ongoing bleeding with ECMO support has increased. We report the case of a 66-year-old patient with refractory hypoxemic respiratory failure secondary to diffuse alveolar hemorrhage (DAH) from underlying anti neutrophil cytoplasmic antibody (ANCA) associated vasculitis who was successfully supported through his acute illness with VV ECMO. ECMO is often used to manage patients with refractory hypoxemic respiratory failure but the usage in the setting of DAH is less known given the risk of bleeding while receiving anticoagulation. Our patient was successfully managed without anticoagulation during his initial ECMO course and his respiratory failure rapidly improved after cannulation. Once managed through the acute phase of his illness and treatment started for his underlying disease process, anticoagulation was started. After being de-cannulated from ECMO and a 3 week stay in the acute rehabilitation unit, our patient was discharged home with complete recovery from his illness. We highlight that patients with refractory hypoxemic respiratory failure and suspicion of DAH as an etiology, ECMO without anticoagulation should be considered as supportive salvage therapy until the underlying process can be treated.

Case Presentation

A 66-year-old man presented with cough, fever, and dyspnea for 1 week. Upon presentation he was found to be in hypoxemic respiratory failure with bilateral pulmonary infiltrates on chest x ray (Figure 1) and positive testing for Influenza A.

Figure 1. Portable AP of chest on initial presentation showing bilateral infiltrates more prominent on the right.

He had an elevated creatinine of 8.1 mg/dl and an acute anemia with a hemoglobin of 7.4 g/dl during the initial work up. He was intubated on hospital day one and transferred to our center for a higher level of care early morning on hospital day two. He developed refractory hypoxemic respiratory failure despite maximum ventilator support as well as standard acute respiratory distress syndrome (ARDS) treatment including neuromuscular blockade. Prone positioning was not possible secondary to hemodynamic instability during the initial treatment plan. Infectious and autoimmune work up was sent. A thoracic CT scan showed extensive bilateral consolidation (Figure 2).

Figure 2. A representative image from the thoracic CT scan showing extensive bilateral consolidation.

At this point a decision was made to apply venovenous double lumen (VVDL) ECMO support as a supportive salvage therapy pending further evaluation into the etiology of his respiratory failure and ARDS. Etiologies at this point included severe influenza infection and DAH from an underlying vasculitis. Anticoagulation with heparin was not initiated given the significant anemia requiring multiple blood transfusions at that point. BUN was elevated, but no other signs of acute gastrointestinal bleeding were identified. Given the underlying renal failure, continuous renal replacement therapy (CRRT) was started on hospital day 2 with citrate used as the anticoagulant. After initiation of ECMO, he improved significantly in the next 72 hours, however, he developed bleeding from the endotracheal tube on day 4. Bronchoscopy was subsequently performed and showed bloody secretions throughout the respiratory bronchial tree, consistent with DAH. His ECMO course had been unremarkable with no thrombotic complications requiring changing of the circuit. Target flows were achieved with a Cardiohelp centrifugal pump and his Avalon 31F double lumen catheter was without complication. On day 5, his autoimmune panel showed a positive ANCA, with myeloperoxidase elevated at 82 AU/ml and serine protease elevated at 314 AU/ml. His anti-nuclear antibody (ANA) was also positive with his titer at 1:2,560. After rheumatology consultation, he was diagnosed with ANCA associated vasculitis with pulmonary hemorrhage and renal failure. His influenza infection was thought to be the trigger for the exacerbation of his underlying autoimmune disease. He was initiated on pulse dose steroids and plasmapheresis with significant clinical improvement and was de-cannulated from ECMO on day 8 with extubation following shortly afterward. He later had renal biopsy performed and it showed diffuse crescentic glomerulonephritis secondary to ANCA vasculitis. He was able to discontinue dialysis after requiring 8 days of CRRT and a further 3 weeks of intermittent hemodialysis. A chest x-ray showed complete clearing of the consolidation (Figure 3).

Figure 3. Chest x-ray just prior to discharge showing complete clearing of the consolidations.

He was eventually discharged home after a 3-week period in acute inpatient rehab.  

Discussion

VV ECMO is increasingly being used as a viable treatment option in patients with refractory acute respiratory failure, especially in patients with underlying ARDS. The ability to allow lung protective ventilation by use of an extracorporeal circuit is of significant value in the acute phase of severe respiratory failure. The general principle of VV ECMO involves removing deoxygenated blood from a venous catheter and passing it through a closed circuit which is comprised of a centrifugal pump and membrane oxygenator (1). This membrane oxygenator takes over the function of the diseased lungs and allows gas exchange to occur, mainly oxygenating the blood and removing carbon dioxide.¹ This blood is then returned into the venous circulation and eventually makes it to the systemic circulation to oxygenate the tissues.

Given that native blood is being passed through an artificial circuit, the risk for thromboembolism is thought to be relatively high. The pathophysiology behind this risk stems from contact of blood components with the artificial surface of the ECMO circuit (2). Proteins found in blood, mainly albumin and fibrinogen, will stick to the artificial surface (2). This results in other blood components congregating, which leads to the formation of a protein layer that servers as an anchor for platelet activation and the formation of insoluble fibrin clots (2). Given the risk of thromboembolism, Extracorporeal Life Support (ELSO) guidelines recommend routine anticoagulation for patients undergoing extracorporeal support (3).

The major complications regarding anticoagulation in the setting of ECMO is bleeding (4). The risk generally comes from acquired thrombocytopenia and anticoagulation (2). ELSO has guidelines regarding management of anticoagulation in VV ECMO but the current practice is relatively institution dependent. This was highlighted in a systematic review done by Sklar and colleagues (4) that investigated many different approaches to anticoagulation for patients on VV ECMO. The main anticoagulant used in those studies was unfractionated heparin and the means to measure its effect was activated clotting time (ACT) and partial thromboplastin time (PTT). They concluded that currently there is no high-quality data that can be employed in decision making regarding anticoagulation for patient’s on VV ECMO support for respiratory failure and that randomized controlled trials are needed for high quality evidence (4). Our own institution’s protocol uses unfractionated Heparin for anticoagulation with a PTT goal of 60-80.

The traditional risk of anticoagulation with ECMO has improved as the component technology of the ECMO circuit has progressed (2). Development of heparin coated inner tubing along with shorter circuit lengths are recent strategies that have been employed to help decrease the amount of thrombotic complications (2). ECLS guidelines state that patients can be managed without anticoagulation if bleeding cannot be controlled with other measures and that the use of high flow rates is recommended to help prevent thrombotic complications (3). The strategies mentioned above are non-chemical ways of preventing thrombosis and could potentially allow management of VV ECMO patients without anticoagulation for the initial period. This was demonstrated in a case report done by Muellenbach and colleagues (5). In their case series, they describe three cases of trauma patients with intracranial bleeding and severe ARDS refractory to conventional mechanical ventilation that were managed with VV ECMO without systemic anticoagulation for a prolonged time period. In their situation, anticoagulation could not be given secondary to severe traumatic brain injury (TBI) and intracranial bleeding (5). They stated that because newer circuits are completely coated by heparin and because circuit lengths have been shortened by specialized diagonal pumps and oxygenators, systemic anticoagulation can be reduced (5)

VV ECLS, as mentioned above, is commonly used in acute respiratory failure but use of VVECLS in DAH is a less known use due to the risk of anticoagulation in this clinical setting. Per ECLS guidelines, one of the relative contraindications for initiation of ECLS is risk of systemic bleeding from anticoagulation (3), and patients with DAH definitely fit this risk profile. But as mentioned above; with improving shortened ECMO circuits, use of heparin coated tubing, and high flow rates, the ability to initially manage patients without systemic anticoagulation until they are stabilized is very important in clinical settings such as our patient with DAH. Many case reports have been published that highlight the successful management of acute respiratory failure due to DAH with VV ECMO (6,7). Our patient was initially managed without systemic anticoagulation and required multiple blood transfusions given the significant bleeding appreciated from the endotracheal tube. Once the diagnosis of ANCA related DAH was made and the appropriate treatment initiated, bleeding significantly decreased and the patient was able to be started on anticoagulation. This highlights that patients with suspicion of DAH as an etiology of respiratory failure not be excluded from consideration VV ECMO as supportive salvage therapy given the potential for great clinical outcome if managed through the acute phase of bleeding.

References

1. Brodie D, Bacchetta M. Extracorporeal membrane oxygenation for ARDS in adults. N Engl J Med. 2011 Nov 17;365(20):1905-14. [CrossRef] [PubMed]
2. Mulder M, Fawzy I, Lance MD. ECMO and anticoagulation: a comprehensive review. Neth J Crit Care. 2018;26:6-13.
3. Brogan TV, Lequier L, Lorusso R, MacLaren G, Peek G. Extracorporeal Life Support: The ELSO Red Book. Fifth Edition. Extracorporeal Life Support Organization; 2017. Thomas V. Brogan and Laurance Lequier (eds).
4. Sklar MC, Sy E, Lequier L, Fan E, Kanji HD. Anticoagulation practices during venovenous extracorporeal membrane oxygenation for respiratory failure. A systematic review. Ann Am Thorac Soc. 2016 Dec;13(12):2242-50. [CrossRef] [PubMed]
5. Muellenbach RM, Kredel M, Kunze E, Kranke P, Kuestermann J, Brack A, Gorski A, Wunder C, Roewer N, Wurmb T. Prolonged heparin-free extracorporeal membrane oxygenation in multiple injured acute respiratory distress syndrome patients with traumatic brain injury. J Trauma Acute Care Surg. 2012 May;72(5):1444-7. [CrossRef] [PubMed]
6. Abrams D, Agerstrand CL, Biscotti M, Burkart KM, Bacchetta M, Brodie D. Extracorporeal membrane oxygenation in the management of diffuse alveolar hemorrhage. ASAIO J. 2015 Mar-Apr;61(2):216-8. [CrossRef] [PubMed]
7. Patel JJ, Lipchik RJ. Systemic lupus-induced diffuse alveolar hemorrhage treated with extracorporeal membrane oxygenation: a case report and review of the literature. J Intensive Care Med. 2014 Mar-Apr;29(2):104-9. [CrossRef] [PubMed]

Cite as: Gill E, Fayed MA, Ho E. Management of refractory hypoxemic respiratory failure secondary to diffuse alveolar hemorrhage with venovenous extracorporeal membrane oxygenation. Southwest J Pulm Crit Care. 2019;18(5):135-40. doi: https://doi.org/10.13175/swjpcc007-19 PDF

January 2017 Critical Care Case of the Month

Seth Assar, MD

Clement U. Singarajah, MD

Pulmonary and Critical Care Medicine

Banner University Medical Center Phoenix – Phoenix

Phoenix VA Medical Center

Phoenix, AZ USA

History of Present Illness

The patient is a 48-year-old man who presented with two days of progressive shortness of breath and non-productive cough. There were no associated symptoms and the patient specifically denied fever, chills, night sweats, myalgia or other evidence of viral prodrome. He had no chest pain or tightness, nausea, vomiting, or leg swelling and he could lay flat. He had no recent travel or sick contacts and was Influenza-immunized this season.

Past Medical History

• Hypertension
• Hyperlipidemia
• Type 2 diabetes mellitus with a recent hemoglobin A1C of 11%        

Social History

• Cook at pizzeria
• Gay and lives at home with roommate of several years
• Smokes marijuana weekly.
• Prior history of cocaine use

Family History

• Noncontributory

Physical Examination

• Vitals: T 99.1º F / HR 125 / BP 193/93 / RR 24 / SpO2 88%
• General: Tachypneic. Alert and oriented X 4.
• Lungs: Crackles at bases bilaterally, no wheezes
• Heart: tachycardia
• Abdomen: NSA
• Skin: no needle marks or cellulitis

Laboratory

• CBC: WBC 11,700 cells/mcL with 80% polymorphonuclear leukocytes, otherwise normal
• Basic metabolic panel: normal
• Brain natriuretic peptide: 120 pg/ml
• Urine drug screen was negative for cocaine but positive for marijuana.
• D-dimer: 0.32 mcg/mL

Hospital Course

He was admitted to the ICU but quickly deteriorated and was intubated for hypoxemia. Empiric ceftriaxone and levofloxacin were begun.

Chest x-ray demonstrated bilateral patchy airspace opacities (Figure 1).

Figure 1. Admission chest x-ray.

Which of the following should be done next? (click on the correct answer to proceed to the second of six pages)

1. Bedside cardiac ultrasound
2. Coccidioidomycosis serology
3. CT scan of the chest
4. 1 and 3
5. All of the above

Cite as: Assar S, Singarajah CU. January 2017 critical care case of the month. Southwest J Pulm Crit Care. 2017;14(1):6-13. doi: https://doi.org/10.13175/swjpcc143-16 PDF

Corticosteroids and Influenza A associated Acute Respiratory Distress Syndrome

Philippe R. Bauer, MD, PhD

Vivek N. Iyer, MD, MPH

Pulmonary and Critical Care Medicine

Mayo Clinic

Rochester, MN USA

Abstract

The use of corticosteroids remains controversial in influenza infection, especially with lower respiratory tract infection. We present a case of moderate acute respiratory distress syndrome (ARDS) associated with influenza A that showed a dramatic improvement with combined corticosteroids and antiviral therapy. Host defense against virus infection consists of both innate and adaptive immune responses. An exuberant immune response to the primary pathogen leads to ‘collateral’ lung damage resulting in ARDS.  The use of corticosteroids to modulate this excessive immune response, although intuitive, has been associated with increased mortality when administered early in the course of severe influenza A pneumonia. The administration of corticosteroids in this case was associated with a dramatic and unequivocal improvement. This unique case highlights the potential benefits of corticosteroids use in influenza A associated ARDS and may challenge clinicians to rethink current recommendations that specifically discourage corticosteroids use in patients with Influenza A associated ARDS.   

Introduction

The impact of corticosteroids on clinical outcome in patients with influenza A associated respiratory failure is unclear (1). Retrospective studies suggest an adverse effect from early parenteral corticosteroids use in patients with pandemic influenza infection. On the other hand, in immunosuppressed patients, high dose corticosteroid given at the time of diagnosis of influenza was associated with a reduced risk for mechanical ventilation, without increased adverse effects other than delayed viral clearance. In general, the effect of corticosteroids on acute respiratory distress syndrome (ARDS) is controversial and its use is not routinely recommended. The adjunctive use of prednisone during the early phase of community-acquired pneumonia may actually reduce the development of ARDS (2). In severe influenza, early corticosteroids showed no evidence of benefit and suggested potential harm (3). We present a case of moderate ARDS associated with influenza A that showed a dramatic and unequivocal improvement after initiation of corticosteroids.

Abbreviations:

APACHE: Acute Physiology and Chronic Health Evaluation

ARDS: Acute Respiratory Distress Syndrome

ICU: Intensive Care Unit

PCR: Polymerase Chain Reaction

SOFA: Sequential Organ Failure Assessment

Case Report

A 62-year old male, nonsmoker, with a history of hypertension, dyslipidemia and depression, presented in March 2014 with chills, fever and nonproductive cough; he was initially treated for ‘bronchitis’ as an outpatient with levofloxacin. He had not received the influenza vaccine. Three days later, he developed acute hypoxemic respiratory failure with bilateral pulmonary infiltrates and was hospitalized elsewhere. Influenza testing was negative and he was started on piperacillin/tazobactam and azithromycin. He was transferred to our facility the next day because of worsening respiratory status. Initial heart rate was 80 bpm, blood pressure was 120/60 mm Hg, respirations was 22/min, and temperature was 37.7 ºC. The Acute Physiology and Chronic Health Evaluation (APACHE) IV score was 55 and the Sequential Organ Failure Assessment (SOFA) score was 8. His presentation was consistent with moderate ARDS with a PaO₂/FiO₂ ratio of 143, a chest radiograph showing bilateral pulmonary infiltrates (Figure 1) and no evidence of heart failure confirmed by bedside echocardiogram.

Figure 1. Bilateral pulmonary opacities consistent with moderate ARDS (PaO₂/FiO₂ ratio 143).

Nasal swab was again negative for influenza by polymerase chain reaction (PCR). Leukocyte count was 4.4 x 10⁹/L with lymphopenia (0.22 x 10⁹/L), hemoglobin was 11.7 g/dL, and platelet count was 216 x 10⁹/L. Sodium was 134 mmol/L, creatinine was 1 mg/dL and AST was 142 U/L. He was initiated of high flow nasal oxygen, and vancomycin and oseltamivir were added. Due to the severity of his condition, he was also started on methylprednisolone (125 mg intravenously every 8 hours). After a brief trial of noninvasive ventilation, he was intubated, sedated, paralyzed and placed on a low tidal volume strategy with an initial PEEP of 15 cm H₂O and a FiO₂ of 0.7. A broncho-alveolar lavage, performed post intubation about 16 hours after admission to our facility, showed 35% alveolar macrophages, 8% lymphocytes and 57% neutrophils and was positive for influenza A by PCR; cultures were negative for other organisms. Other tests including HIV, RSV, Mycoplasma, Legionella and urine for Streptococcus antigen were all negative. The patient improved rapidly. He was extubated two days later, and continued on prednisone (40 mg daily) for five more days when he was dismissed home without any need for supplemental oxygen, although the chest radiograph continued to show infiltrates.

Discussion

This case illustrates a patient with delayed diagnosis and treatment of influenza A associated with moderate ARDS who made a rapid and complete recovery with antiviral, antibiotic and adjunctive high dose corticosteroid therapy. 

The diagnosis of influenza A in this case meets all criteria established by Clinical Practice Guidelines of the Infectious Diseases Society of America (4). Rapid influenza testing lack sensitivity and false negative are not infrequent. ARDS is a well-defined complication of influenza infection. While the administration of corticosteroids appeared to temporally co-relate with clinical improvement, a causal link cannot be established definitively. The role of immunosuppression in influenza associated ARDS is very controversial with conflicting evidence from prospective (supportive) and retrospective (against) studies. For example, the combined use of sirolimus and prednisone was associated with significantly improved oxygenation as well as reduced organ dysfunction in mechanically ventilated patients with severe H1N1 respiratory failure (5). On the other hand, retrospective studies have shown increased mortality with the early use of high dose corticosteroids in severe influenza A pneumonia and respiratory failure. Furthermore, corticosteroids are now rarely used in ARDS and only sparingly given in case of refractory septic shock. The immune response to influenza infection depends on the virus, the host and the host response to infection. Host defense against virus infection consists of both innate and adaptive immune responses. An excessive immune response may result in ‘collateral damage’ and critical respiratory illness which may be ameliorated by the use of systemic corticosteroids. On the other hand, suppression of the host immune system may enhance viral replication and prolong critical illness. As a result of these conflicting data, major societies have been unable to firmly recommend for or against corticosteroids therapy in Influenza A associated respiratory failure.

In conclusion, we report on a case of Influenza A with ARDS and rapid improvement on corticosteroids. We have reviewed the current uncertainty surrounding the use of corticosteroids in this setting and leave open the possibility for careful consideration of this adjunctive therapy in other cases. Randomized trials are needed to further delineate the potential benefit of corticosteroids in severe influenza infection.

References

1. Rodrigo C, Leonardi-Bee J, Nguyen-Van-Tam J, Lim WS. Corticosteroids as adjunctive therapy in the treatment of influenza. Cochrane Database Syst Rev. 2016 Mar 7;3:CD010406. [CrossRef] [PubMed]
2. Blum CA, Nigro N, Briel M, et al. Adjunct prednisone therapy for patients with community-acquired pneumonia: a multicentre, double-blind, randomised, placebo-controlled trial. Lancet. 2015 Apr 18;385(9977):1511-8. [CrossRef] [PubMed]
3. Brun-Buisson C, Richard JC, Mercat A, Thiébaut AC, Brochard L; REVA-SRLF A/H1N1v 2009 Registry Group. Early corticosteroids in severe influenza A/H1N1 pneumonia and acute respiratory distress syndrome. Am J Respir Crit Care Med. 2011 May 1;183(9):1200-6. [CrossRef] [PubMed]
4. Harper SA, Bradley JS, Englund JA, et al. Seasonal influenza in adults and children--diagnosis, treatment, chemoprophylaxis, and institutional outbreak management: clinical practice guidelines of the Insert LinkInfectious Diseases Society of America. Clin Infect Dis. 2009 Apr 15;48(8):1003-32. [CrossRef] [PubMed]
5. Wang CH, Chung FT, Lin SM, Huang SY, Chou CL, Lee KY, Lin TY, Kuo HP. Adjuvant treatment with a mammalian target of rapamycin inhibitor, sirolimus, and steroids improves outcomes in patients with severe H1N1 pneumonia and acute respiratory failure. Crit Care Med. 2014 Feb;42(2):313-21. [CrossRef] [PubMed]

Cite as: Bauer PR, Iyer VN. Corticosteroids and influenza A associated acute respiratory distress syndrome. Southwest J Pulm Crit Care. 2016;13(5):248-51. doi: https://doi.org/10.13175/swjpcc102-16 PDF

Ultrasound for Critical Care Physicians: Two’s a Crowd

A 43 year old previously healthy woman was transferred to our hospital with refractory hypoxemia secondary to acute respiratory distress syndrome (ARDS) due to H1N1 influenza. She had presented to the outside hospital one week prior with cough and fevers. Chest radiography and computerized tomography of the chest revealed bilateral airspace opacities due to dependent consolidation and bilateral ground glass opacities. A transthoracic echocardiogram at the time of the patient’s admission was reported as not revealing any significant abnormalities.

At the outside hospital she was placed on mechanical ventilation with low tidal volume, high Positive end-expiratory pressure (20 cm H20), and a Fraction of inspired Oxygen (FiO2) of 1.0. Paralysis was later employed without significant improvement.

Upon arrival to our hospital, patient was severely hypoxemic with partial pressure of oxygen / FiO2  (P/F) ratio of 43. She was paralyzed with cis-atracurium and placed on airway pressure release ventilation (APRV) with the following settings (pressure high 28 cm H2O, pressure low 0 cm H2O, time high 5.5 sec, time low 0.5 sec). The patient remained severely hypoxemic with on oxygen saturation in the high 70 percent range.

A bedside echocardiogram was performed (Figures 1 and 2).

Figure 1. Subcostal long axis echocardiogram.

Figure 2. Subcostal short axis echocardiogram

What abnormality is demonstrated by the short and long axis subcostal views? (Click on the correct answer for an explanation)

1. Acute cor pulmonale likely due to ARDS
2. Acute myocardial infarction
3. Low left-sided ejection fraction
4. Pericardial tamponade

Cite as: Abukhalaf J, Boivin M. Ultrasound for critical care physicians: two's a crowd. Southwest J Pulm Crit Care. 2016 Mar;12(3):104-7. doi: http://dx.doi.org/10.13175/swjpcc028-16 PDF

Fluid in the Management of the Acute Respiratory Distress Syndrome

Sanjaya Karki* (drsanjaya.karki@yahoo.com)

Yong-Jie Yin* (corresponding author)-yongjieyin2003@yahoo.com.cn

Jing-Xiao Zhang*

Nijamudin Samani*

Dipesh Pradhan^‡

Sangeeta Singh Deuja (Karki)^†

Reshma Karki^#

Raghvendra Thakur**

Nan Zhao***

*Department of Emergency and Critical Care Medicine, Second Hospital of Jilin University, Changchun, China

^‡ First hospital of Jilin University, China

^†University of Huddersfield, UK

^#Sri Birendra Hospital, Nepal

**Second Hospital of Jilin University

***Department of Chemistry, Jilin University, Changchun, China

Abstract

Introduction

Non-cardiogenic pulmonary edema is the hallmark of the acute respiratory distress syndrome (ARDS). The amount of fluid and which fluid should be used in these patients is controversial. 

Methods

43 patients with ARDS treated in the intensive care unit (ICU) of the Second Hospital, Jilin University between November 1, 2011-November 1, 2012 were prospectively analyzed and was observational. Volume and the type of fluid administered were compared to 90 day mortality and the 24 and 72 hour sequential organ failure assessment (SOFA) score, lactate level, oxygenation index (PaO2/FiO2), duration of ICU stay, total ventilator days, and need for continuous renal replacement therapy (CRRT).

Results

Mortality was increased when hydroxylethyl starch (HES) was used in the first day or plasma substitutes were used during the first 3 days (P<0.05, both comparisons). Volumes of fluid >3000 ml during the first 24 hours or >8000 ml during the first 72 hours were associated with higher SOFA scores at 24 and 72 hours (P<0.05, both comparisons). Colloid, especially higher volume colloid use was also associated with increased SOFA scores at either 24 or 72 hours.

Conclusions

Limiting the use of colloids and the total amount of fluid administered to patients with ARDS is associated with improved mortality and SOFA scores.

Introduction

Acute lung disease secondary to non-cardiogenic pulmonary edema has been termed the adult respiratory distress syndrome (ARDS) since first described in 1967 by Ashbaugh et al. (1,2). ARDS was later defined at a consensus conference in Berlin (3). The Berlin definition is based on timing, chest imaging, origin of edema and oxygenation.

Despite the presence of fluid within the alveoli, it has been unclear whether a conservative strategy or liberal strategy improves outcomes. The ARDS Clinical Trials Network demonstrated that a conservative strategy based on pulmonary artery wedge pressures or central venous pressures improved lung function and shortened the duration of mechanical ventilation although there was no mortality benefit (4). However, whether fluid replacement with colloid or crystalloid in ARDS results in better outcomes remains unknown.

Recently, there have been reports of increased mortality with the use of hydroxylethyl starch (HES) in sepsis (5).  Because sepsis is the most common cause of ARDS (1) this caused us to examine the use of colloids in ARDS. We found that use of colloids was associated with clinically worsening and increases mortality compared to low volumes of crystalloid in ARDS.

Materials and Methods

Subjects

This was an observational study of ARDS patients admitted to the intensive care unit (ICU) of the Norman Bethune College of Medicine, Jilin University Second Hospital, Changchun, China was conducted from November 1, 2011 to November 1, 2012.

ARDS was defined using the Berlin criteria (3).

Study Procedures

Patients were randomly divided into two groups. In one group patients were administered both crystalloid and colloid for the first 3 days of their ICU admission with ARDS. In the other group only crystalloid was used. The use of which colloid and the volume administered was left to the clinical discretion of the attending physician based on the clinical needs of the patient. Other treatment modalities such as the mode of ventilation and nutritional support were also left to the discretion of the patient although the tidal volume was kept < 7ml/kg.

Data was collected for the first 3 days of admission to the ICU. Clinical data recorded included sequential organ failure assessment (SOFA) scores, the use and amount of colloid or crystalloid, duration of ICU stay, ventilator days, need for continuous renal replacement therapy (CRRT), lactate and PaO2/FIO2. When patients received both colloid and crystalloid, volume was calculated as the sum of the volume of each. Mortality was the 90 day mortality rate.

Statistics

The data was recorded and compared using SPSS software and reported as mean + standard deviation. Comparisons between groups were performed by Student’s t-test. P values of less than 0.05 were considered significant.

Results

Patients. There were 43 patients (20 F, 23 M). The mean age was 62.7 + 18.9 years (range 20 to 85 years). The causes of ARDS was serious lung infection in 16 patients,  sepsis in 9 patients, trauma in 2 patients, and pancreatitis in 2 patients. The cause was unknown in 14 patients.

Volume of fluid. The results with differing volumes of fluid administered in the first 24 hours are shown in Table 1. [Editor's note: It may be necessary to enlarge the view on your browser in order to adequately display the tables.]

Table 1. Results based on volume of fluid used in the first day.

Mortality was unaffected by the volume of fluid used in the first 24 hours. However, the SOFA score at 24 and 72 hours was increased with volumes >3000 ml administered during the first 24 hours (P<0.05, both comparisons). The lactate level and the frequency of CRRT approached significance when volumes of >3000 ml were administered during the first 24 hours (P=0.05, both comparisons).

The results with volumes of greater or less than 8 liters are shown in table 2.

Table 2. Results based on volume of fluid used in the first 72 hours.

 

There were no significant effects of administration of greater or less than 8000 ml over 72 hours.

Type of fluid. Patients who received both crystalloid and colloid received 30 + 5% of the total volume as colloid during the first day of ICU admission. The results of administration of crystalloid compared to crystalloid and colloid during the first 24 hours are shown in Figure 3.

Table 3. Results based on type of fluid used in the first day of ICU admission.

There was no difference in mortality. The use of crystalloid alone was associated with a lower SOFA score at 72 hours (P<0.05). CRRT was more often needed for those patients given both crystalloid and colloid during the first 24 hours (P=0.05).

The results when albumin was used during the first 24 hours are in Table 4.

Table 4. Results based on albumin usage during the first day.

There was no significant effect on any of the measured outcomes when albumin was used in the first 24 hours.

The results with the use of plasma during the first 24 hours are shown in Table. 5.

Table 5. Results based on plasma usage during first day.

An increase in mortality approached statistical significance if plasma was used during the first 24 hours (P=0.05). The SOFA score was significantly higher at 72 hours if plasma used during the first day (P=0.01). The remaining outcomes were unchanged.

Results with hydroxylethyl starch (HES) use are shown in Table 6.

Table 6. Results based on hydroxylethyl starch (HES) usage during the first day.

  

Mortality was significantly higher if HES was used during the first 24 hours (P<0.05). In addition the SOFA scores were significantly higher at 24 and 72 hours if HES was administered during the first 24 hours (P<0.05, both comparisons). The lactate level was also significantly higher at 24 hours and 72 hours (P<0.05, both comparisons). The need for CRRT and the PaO2/FiO2 ratio approached significance (P=0.05, both comparisons).

Volume of colloid. The use of colloids affected several outcomes. Therefore, the amount of colloid used was examined (Table 7).

Table 7. Results based on volume of colloid used during first day. 

If colloid was used, mortality approached significance based on the volume of colloid used during the first 24 hours (P=0.05). Higher volumes of administered colloid (≥1000ml) were associated with a higher SOFA score at 72 hours (P=0.01). Lactate levels were significantly higher at 24 and 72 hours if colloid was used (P=0.04, both comparisons).PaO2/FiO2 was lower higher volumes of colloid usage (P=0.04).

Plasma, albumin or plasma substitutes during the first 72 hours. Some outcomes were higher with the use of colloids during the first 24 hours. Therefore, usage of plasma or albumin during the first 3 days was examined (Table 8).

Table 8. Effect of using of plasma or albumin during the first 3 days.

There was no significant effect on any of the outcomes with the use of plasma or albumin during the first 72 hours.

The effects of plasma substitutes during the first 72 hours are shown in Table 9.

Table 9. Results of using plasma substitutes during the first 3 days.

Higher mortality was associated with the use of plasma substitutes during the first 3 days (P=0.02).  SOFA scores at 24 and 72 hours were also increased with plasma substitute usage (P=0.03 and P=0.002 respectively). Higher Lactate levels were also observed at 24 hours and 72 hours (P<0.01, both comparisons).

Discussion

In the hospital setting there are two types of fluid physicians administer to patients-colloid or crystalloid. Crystalloid is easily accessible and can be stored at room temperature. The main purpose of this study was to compare the two different fluids and the volume fluid used. We found that use of certain colloids, particularly higher volumes, was associated with increased mortality and poorer SOFA scores.

There was increased mortality with HES and plasma substitutes and plasma approached statistical significance. This is consistent with studies done in sepsis where HES has been associated with increased mortality (5).  In contrast, there was no increase in mortality with albumin or adverse clinical outcomes, suggesting it was safe to use. The mechanism accounting for the adverse effects of colloids in ARDS and sepsis is unknown. However, the pharmokinetics of HES is known to be different from albumin and may play a role in the mortality rates (6). 

We found that administration of smaller volumes of fluid was associated with improved outcomes. This confirms previous studies done in ARDS demonstrating that a conservative strategy improves outcomes. Like the ARDS Network larger, multi-center study out smaller study was unable to find a reduction in mortality with lower volumes of fluid used.  From our studies it is unclear whether volume or the type of fluid is most important in determining survival. The data would seem to suggest that both are important. We also did not correct for differences in the equivalency of colloid compared to crystalloid solutions. Some authorities suggest that the volume expansive of colloid exceed crystalloid on absolute volume basis (7). However, corrections would likely accentuate the differences in mortality seen with volume.

It had been proposed that colloid infusion might be protective of the lungs by retaining fluid in the vascular space by oncotic pressure. However, recent studies have suggested show that colloids do not lower lung water (8). Furthermore, a recent meta-analysis found no evidence trials that resuscitation with colloids reduces the risk of death, compared to resuscitation with crystalloids, in patients with trauma, burns or following surgery (9). Furthermore, the use of hydroxyethyl starch might increase mortality. Our study is consistent with these studies.

Our trial has certain limitations. First, our study was single center. Second, the design did not include hemodynamic monitoring or other therapies. How these confounding variables might have affected the results is unknown. Third, only 43 patients were included in the trial. The trial was underpowered and confirmation of the results will be needed by larger trials.

This study demonstrates that the initial volume of fluid administered has effects on outcomes in patients with ARDS. The data in this manuscript support a dry or conservative strategy for management of ARDS. Furthermore, the choice of fluid also affects outcomes. The data in this paper would recommend the maintenance of relatively stable blood pressure with low volumes of crystalloid. As colloids are not associated with an improvement in survival, are less readily available, and are more expensive than crystalloids, it is hard to see how their continued use in clinical practice can be justified.

Conflict of Interest

None of the authors declared a conflict of interest.

Acknowledgements

The concept of this research was built by Prof. Dr. Yong –Jie Yin and Dr Sanjaya Karki. However, most of the credit goes to Dr Jing Xiao Zhang in order to complete this research successfully. All the other co-authors have equally contributed.  

References

1. Matthay AM, Zimmerman AG. Acute lung injury and the acute respiratory distress syndrome. Am J Respir Cell Mol Biol. 2005;33(4),319-327. [CrossRef] [PubMed]
2. Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. Acute respiratory distress in adults. Lancet. 1967;2(7511):319-23. [CrossRef] [PubMed]
3. ARDS Definition Task Force, Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E, Camporota L, Slutsky AS. Acute respiratory distress syndrome: the Berlin Definition. JAMA. 2012;307(23):2526-33. [CrossRef] [PubMed]
4. National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network, Wiedemann HP, Wheeler AP, Bernard GR, Thompson BT, Hayden D, deBoisblanc B, Connors AF Jr, Hite RD, Harabin AL. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med. 2006;354(24):2564-75. [CrossRef] [PubMed]
5. Perner A, Haase N, Guttormsen AB, et al. Hydroxyethyl starch 130/0.42 versus Ringer's acetate in severe sepsis. N Engl J Med. 2012;367(2):124-34. [CrossRef] [PubMed]
6. Bellmann R, Feistritzer C, Wiedermann CJ. Effect of molecular weight and substitution on tissue uptake of hydroxyethyl starch: a meta-analysis of clinical studies. Clin Pharmacokinet 2012;51:225-36. [CrossRef] [PubMed]
7. The SAFE Study Investigators. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med 2004;350:2247-2256. [CrossRef] [PubMed]
8. van der Heijden M, Verheij J, van Nieuw Amerongen GP, Groeneveld AB. Crystalloid or colloid fluid loading and pulmonary permeability, edema, and injury in septic and nonseptic critically ill patients with hypovolemia. Crit Care Med. 2009;37(4):1275-81. [CrossRef]  [PubMed]
9. Perel P, Roberts I, Ker K. Colloids versus crystalloids for fluid resuscitation in critically ill patients. Cochrane Database Syst Rev. 2013 Feb 28;2:CD000567. [CrossRef] [PubMed]

Reference as: Karki S, Yin Y-J, Zhang J-X, Samani N, Pradhan D, Deuja SS, Karki R, Thakur R, Zhao N. Fluid in the management of the acute respiratory distress syndrome. Southwest J Pulm Crit Care. 2013;6(6):289-98. doi: http://dx.doi.org/10.13175/swjpcc044-13 PDF