May 2017 Phoenix Pulmonary/Critical Care Journal Club

The Berlin definition of ARDS is: bilateral radiographic opacities (not effusion, atelectasis or nodules) of <1 week duration, not fully explained by cardiac failure or fluid overload, associated with PaO₂/FiO₂ <300 (1). This definition is highly inclusive. A recent international epidemiologic study showed that ARDS accounts for 10% of ICU admissions and about a quarter of patients requiring mechanical ventilation. ARDS is often undiagnosed and undertreated (2). Survival is associated with PaO₂/FiO₂ ratio and is 45% in patients with P/F <100 (1,2).

Banner Health is embarking on a quality improvement effort focused on management of patients with ARDS and the aim of our journal club was to develop an evidence-based clinical practice for ARDS. We reviewed what we considered the ten most influential articles regarding ARDS published since 2000. We did not include interventions for which no benefit in important clinical outcomes has been demonstrated (for instance, the choice of one ventilator mode over another, or adjunctive therapies such as inhaled nitric oxide or corticosteroids for ARDS).

Each of the articles was critically appraised. In each case we considered whether a recommendation for clinical practice could be made based on three criteria: the strength of evidence, the magnitude of clinical benefit and the risk/cost associated with the intervention. Also, we suggested a process variable related to each recommendation that could be electronically tracked to follow the effect of any subsequent associated quality improvement efforts. Clinical decision support system (CDSS) logic can potentially be programmed to track each recommendation process measure and alert clinicians if recommendations are being overridden. The strength of recommendation can be used to support future decisions regarding how CDSS logic might be operationalized, i.e., weak recommendations should not be the basis of interruptive computerized decision support.  

Recommendations for patients with ARDS:

1) Tidal volume should be 6mL/kg predicted body weight (PBW) and plateau pressure <30cmH₂O. Tidal volumes in the range of 4-8mL/kg PBW are allowable if necessary depending on the clinical situation as long as plateau pressure < 30 cmH₂O is maintained. Tidal volumes should not exceed 8mL/kg PBW.

Strength of evidence: multicenter RCT (3)

Clinical benefit: Survival, NNT= 11

Risk/cost: low – no increase in the number of days requiring sedation or neuromuscular blockade, but could theoretically lead to higher sedation doses in some patients. Permissive hypercapnia may necessitate bicarbonate infusion in some patients.

Strongly Recommended.

Measures: Percentage of mechanically-ventilated patients with TV >8mL/kg PBW, Percentage of patients with P_plat >30cmH₂O.

2) PEEP should be equal to or exceed “Low PEEP” settings as defined by ARDSnet consensus.

Strength of evidence: no evidence that one PEEP setting is better than another (4), but the concept of optimized PEEP is supported by sound physiological rationale.

Clinical benefit: unclear.

Risk/cost: low – no increased risk of barotrauma with higher PEEP levels.

Recommended.

Measure: deferred to driving pressure recommendation below.

3) Conservative fluid balance should be maintained once shock resuscitation is achieved.

Strength of evidence: single-center RCT (5).

Clinical benefit: Increase ventilator-free days by 2.5 days, increase ICU-free days by 2.2 days

Risk/cost: No increase in the incidence or prevalence of shock; no increase in need for renal replacement therapy.

Recommended.

Measure: Percentage of patients with >100mL/kg cumulative positive fluid balance not receiving intravenous vasopressors.

4) Adjunctive therapies (neuromuscular blockade, proning, ECMO center triage) should be considered early in the course of patients with moderate-severe ARDS with PaO₂/FiO₂ ratio < 150.

Strength of evidence: single-center RCTs.

Clinical benefit: neuromuscular blockade: survival NNT=11 (6); proning: survival, NNT=6 (7); ECMO triage: survival without disability NNT=6 (8).  

Risk/cost: neuromuscular blockage – low, no increase in critical care weakness; proning – intermediate, requires experienced nursing team, some risk of displacing catheters; ECMO triage: high – many potential complications, high cost.

Comment: Patients with moderate to severe ARDS have 40-45% mortality, but further research is needed to reach consensus on best therapeutic approach.

Recommended.

Measure: Percentage of patients with PaO₂/FiO₂ ratio < 150 evaluated for adjunctive therapies by telemedicine ICU team.  

5) Driving pressure should be monitored.

Strength of evidence: retrospective non-interventional meta-analysis (9).

Clinical benefit: survival.

Risk/cost: unknown, but likely low and similar to those of low-tidal volume ventilation.

Comment: Strong observational evidence shows that driving pressure, (not tidal volume, plateau pressure or PEEP) is the major determinant of treatment-related mortality in ARDS. Driving pressure could reasonably be used by an individual physician to optimize PEEP, but interventional studies are needed before that recommendation can be made.

Weakly Recommended.

Measure: % of patients with driving pressure > 22cmH₂O (one standard deviation above mean).

Recommendation for mechanically-ventilated patients without ARDS.

6) Tidal volume should be 6mL/kg predicted body weight (PBW) and plateau pressure <30cmH₂O.

Strength of evidence: meta-analysis (10).

Clinical benefit: survival NNT=23.

Risk/cost: low.

Comment: Prospective RCT needed. We cannot currently reliably differentiate ARDS from non-ARDS patients through the EMR using CDSS logic.

Weakly Recommended.

Measure: Percentage of mechanically-ventilated patients with TV >8mL/kg PBW, Percentage of patients with P_plat >30cmH₂O.

Robert Raschke MD

University of Arizona College of Medicine Phoenix

Phoenix, AZ USA

We appreciated the participation of Banner Health Quality Improvement experts Ethel Utter and Nathan Cosa.

References

1. The ARDS Definition Task Force. Acute respiratory distress syndrome: The Berlin definition. JAMA. 2012;307:2526-33. [CrossRef] [PubMed]
2. Bellani G, Laffey JG, Pham T, Fan E, Brochard L, for the LUNG SAFE Investigators; ESICM Trials Group. Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries. JAMA. 2016;315:788-800. [CrossRef] [PubMed]
3. The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med. 2000; 342:1301-8. [CrossRef] [PubMed]
4. The National Heart, Lung, and Blood Institute ARDS Clinical Trials Network. Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med. 2004; 351:327-36. [CrossRef] [PubMed]
5. The National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med. 2006; 354:2564-75. [CrossRef] [PubMed]
6. Papazian L, Forel J-M, Gacouin A, Penot-Ragon C for the ACURASYS Study Investigators. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010; 363:1107-16. [CrossRef] [PubMed]
7. Guérin C, Reignier J, Richard J-C, Beuret P, Gacouin A for the PROSEVA Study Group. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med. 2013; 368:2159-68. [CrossRef] [PubMed]
8. Peek GJ, Mugford M, Tiruvoipati R, Wilson A, for the CESAR trial collaboration. Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial. Lancet. 2009;374:1351-63. [CrossRef] [PubMed]
9. Amato MBP, Meade MO, Slutsky AS, Brochard L, et al. Driving pressure and survival in the acute respiratory distress syndrome. N Engl J Med. 2015;372:747-55. [CrossRef] [PubMed]
10. Neto, AS, Cardoso SO, Manetta JA, Pereira VGM et al. Association between use of lung-protective ventilation with lower tidal volumes and clinical outcomes among patients without acute respiratory distress syndrome. JAMA. 2012;308:1651-59. [CrossRef] [PubMed] 

Cite as: Raschke RA. May 2017 Phoenix pulmonary/critical care journal club. Southwest J Pulm Crit Care. 2017;14(6):279-82. doi: https://doi.org/10.13175/swjpcc070-17 PDF

October 2015 Phoenix Pulmonary Journal Club: Lung Volume Reduction

The October 2015 pulmonary journal club focused on the review of older studies evaluating lung volume reduction surgery and how this has transitioned toward the development of non-surgical modes of lung volume reduction. The physiology behind dyspnea in chronic obstructive pulmonary disease (COPD) is a complex process. One of the proposed mechanisms has been hyperinflation associated with air trapping. In the mid 1990s studies by Cooper and Peterson (1) offered a promising approach in which lung volume reduction (LVR) could improve ventilatory mechanics and improve dyspnea. As the procedure gained more popularity, additional larger scale trials were performed to support its validity.

We reviewed 2 studies looking at lung volume reduction. The first was "The Effect of Lung Volume Reduction Surgery In Patients With Severe Emphysema” (2) . This was a smaller, randomized controlled trial (RCT) that looked at 2 groups of 24 patients. Once group received LVR while the other received medical therapy. The primary outcome was mortality at 6 months and change in FEV1. The study did not show any mortality benefit but showed there was an increase in FEV1 of 150 ml by 6 months in the surgical group whereas the medical group showed no improvement. We reviewed a larger subsequent study, “A Randomized Trial Comparing Lung Volume Reduction Surgery with Medical Therapy for Severe Emphysema”, a RCT that included 1218 patients divided into 2 groups of 608 pts (surgical) and 610 pts (medical) (3). The primary outcome was mortality at 2 years and exercise capacity. The results showed that there was no overall mortality benefit, but there was an overall increase in exercise capacity. A subgroup analysis showed that patients that had poor baseline exercise tolerance and upper lobe predominant emphysema did the best with lower mortality rate and increased exercise capacity. This study was useful in defining a subset of patients most likely to benefit from LVR surgery.

The cost, expertise and risk of complications associated with lung volume reduction surgery led to expanding the physiology of reducing lung volumes via nonsurgical approaches. The use of one way endobronchial valves in allowing air to leave bronchial segments to promote lung volume reduction via atelectasis has been explored for over a decade. Our group was involved in the earlier trials which evaluated efficacy and safety of endobronchial valves (4) . The results from our experience did not show that the endobronchial valves reduced lung volumes. 

A subsequent study, "A Randomized Study of Endobronchial Valves for Advanced Emphysema" was reviewed (5). This was a large RCT that divided a total of 321 pts in a 2:1 format to 2 groups of 220 patients that received endobronchial valves pts and 101 patients that received medical treatment. The primary outcome was change in FEV1 and distance in 6 minute walk test. The placement of endobronchial valves was via bronchoscopy was guided based on emphysema seen on CT of the chest. The large majority of valves were placed in either right upper lobe (52%) or left upper lobe (14%). The study did show a mild increase in FEV1 of 4.3% in the patients treated with endobronchial valves and also resulted in an increase in 6 min walk distance of 9.3 m. However, patients receiving the endobronchial valves also noted higher rates of hemoptysis and COPD exacerbations. The reason for less than optimal results has been explained by the persistence of hyperinflation through collateral ventilation.

The physiologic basis why lung volume reduction may work in COPD remains the same. The surgical resection of apical emphysematous regions may be of some benefit in patients with apical emphysema and decreased exercise tolerance. The role of volume reduction via use of endobronchial valves may become useful if subsequent studies show that collateral ventilation does not lead to persistent hyperinflation and the reduction n volumes shows a sustained increase in FEV1 and 6 min walk test.

Manoj Mathew, MD FCCP

References

1. Cooper JD, Patterson GA. Lung volume reduction surgery for severe emphysema. Semin Thorac Cardiovasc Surg. 1996;8(1):52-60. [PubMed]
2. Geddes D, Davies M, Koyama H, Hansell D, Pastorino U, Pepper J, Agent P, Cullinan P, MacNeill SJ, Goldstraw P. Effect of lung-volume-reduction surgery in patients with severe emphysema. N Engl J Med. 2000;343(4):239-45. [CrossRef] [PubMed]
3. Fishman A, Martinez F, Naunheim K, Piantadosi S, Wise R, Ries A, Weinmann G, Wood DE; National Emphysema Treatment Trial Research Group. A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema. N Engl J Med. 2003;348(21):2059-73. [CrossRef] [PubMed]
4. Shah PL, Slebos DJ, Cardoso PF, Cetti E, Voelker K, Levine B, Russell ME, Goldin J, Brown M, Cooper JD, Sybrecht GW; EASE trial study group. Bronchoscopic lung-volume reduction with Exhale airway stents for emphysema (EASE trial): randomised, sham-controlled, multicentre trial. Lancet. 2011;378(9795):997-1005. [CrossRef] [PubMed]
5. Sciurba FC, Ernst A, Herth FJ, Strange C, Criner GJ, Marquette CH, Kovitz KL, Chiacchierini RP, Goldin J, McLennan G; VENT Study Research Group. A randomized study of endobronchial valves for advanced emphysema. N Engl J Med. 2010 Sep 23;363(13):1233-44. [CrossRef] [PubMed] 

Cite as: Mathew M. October 2015 Phoenix pulmonary journal club: lung volume reduction. Southwest J Pulm Crit Care. 2015;11(5):215-6. doi: http://dx.doi.org/10.13175/swjpcc138-15 PDF

September 2015 Tucson Pulmonary Journal Club: Genomic Classifier for Lung Cancer

Silvestri GA, Vachani A, Whitney D, et al. A bronchial genomic classifier for the diagnostic evaluation of lung cancer. N Engl J Med. 2015;373(3):243-51. [CrossRef] [PubMed]

Pulmonary lesions are a common diagnostic dilemma for clinicians. Current literature describes the sensitivity of bronchoscopic techniques to be between 34 and 88%; which varies significantly depending on size and location of the biopsied lesion (1). Previously described gene expression patterns have been found to be associated with malignancy in healthy epithelial cells of the proximal airways\(2). The primary aim of this study was to prospectively validate a specific gene expression classifier in patients undergoing bronchoscopic biopsy for suspected lung cancer.

The study involved two independent, prospective, multicenter, observational studies (AEGIS-1 and AEGIS-2) conducted in the U.S., Canada and Ireland at 28 sites. Patients were excluded if they were never smokers, under age 21, or current cancer or former lung cancer patients. Patients were followed for 12 months after bronchoscopy or until a diagnosis was established. A wide array of bronchoscopic and surgical techniques were used to ultimately make a diagnosis. Prior to undergoing invasive diagnostic testing, the treating physician was asked to estimate the patient’s pre-test probability of cancer.

The overall prevalence of lung cancer in the two cohorts was 76.5%. Bronchoscopy alone had 74% sensitivity (95% CI, 68 to 79) in AEGIS-1 and 76% (CI 95%, 71 to 81) in AEGIS-2 with a combined specificity of 100%. When combining the gene classifier with bronchoscopy, the sensitivity increased to 96% (95% CI, 93 to 98) in AEGIS-1 and 98% (95% CI, 96 to 99) in AEGIS-2 with a combined specificity of 47.9%.

The poor specificity of the gene classifier limits its clinical utility as an adjunct to bronchoscopy. Although the sensitivity was high, the low specificity makes this additional test of low diagnostic value for definitively ruling in cancer. When bronchoscopy was negative, the prevalence of lung cancer remained high, approximately 45%, and the resulting post-test probability of a positive gene-classifier test was 58% and the post-test probability of a negative test was 16%. Neither value is sufficiently predictive to avoid further invasive testing to definitely determine the presence or absence of cancer in this intermediate risk population. The racial composition of study participants was predominately white with a majority being males.  The age range of study participants was between 55 and 71. Because of that, the generalizability is more limited.  However, the gene classifier might have limited clinical utility for patients who are poor candidates for additional invasive testing.  A positive result might tilt the balance in favor of additional testing whereas a negative result might warrant watchful waiting. Overall, this dual approach to diagnostic assessment for lung nodules suspicious of being lung cancer is not ready for widespread implementation. 

Joshua Dill DO; Joe Gerald, MD, Ph.D.; Christian Bime MD, MSc and James Knepler MD.

University of Arizona

Tucson, Arizona USA

References

1. Rivera MP, Mehta AC, Wahidi MM. Establishing the diagnosis of lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013;143:Suppl 5: e142S-e165S. [CrossRef] [PubMed]
2. Spira A, Beane JE, Shah V, et al. Airway epithelial gene expression in the diagnostic evaluation of smokers with suspect lung cancer. Nat Med. 2007;13:361-6. [CrossRef] [PubMed] 

Cite as: Dill J, Gerald J, Bime C, Knepler J. September 2015 Tucson pulmonary journal club: genomic classifier for lung cancer. Southwest J Pulm Crit Care. 2015;11(3):119-20. doi: http://dx.doi.org/10.13175/swjpcc125-15 PDF

April 2015 Phoenix Pulmonary Journal Club: Endo-Bronchial Ultrasound in Diagnosing Tuberculosis

Lin SM, Chung FT, Huang CD, Liu WT, Kuo CH, Wang CH, Lee KY, Liu CY, Lin HC, Kuo HP. Diagnostic value of endobronchial ultrasonography for pulmonary tuberculosis. J Thorac Cardiovasc Surg. 2009;138(1):179-84. [CrossRef] [PubMed]

The diagnosis of tuberculosis in patients with inability to produce sputum or in patients that remain acid-fast bacilli (AFB) smear negative with high index of clinical suspicion remains a challenge and often results in treatment delay. This study examined the role in using endobronchial ultrasound (EBUS) to locate parenchymal infiltrates to allow for more accurate sampling of bronchial lavage fluid and transbronchial biopsies. The study examined 121 patients divided into 2 groups, 73 patients received EBUS guided bronchoscopy and 48 pts received conventional bronchoscopy with bronchoalveolar lavage (BAL) and transbronchial biopsies. It should be noted that patients undergoing transbronchial biopsies in the non-EBUS group appeared to have biopsies done without the use of fluoroscopy. The results showed that when EBUS was used to locate the parenchymal infiltrate the BAL smear was positive 31% vs 12% in non-EBUS patients and the transbronchial biopsies were positive in 24% vs 4.2% in non-EBUS. The study had several limitations as it did not utilize fluoroscopic guided biopsies or fluid sampling which would of likely increased the diagnostic yield in the non EBUS group. The study however does point out a seldom used approach to transbronchial biopsy by using EBUS to look for air bronchograms and tissue echogenicity. Perhaps utilizing EBUS in more centrally located infiltrates or nodules may offer a benefit over performing blind biopsies or biopsies in which fluoroscopy may be of limited view.

Geake J, Hammerschlag G, Nguyen P, Wallbridge P, Jenkin GA, Korman TM, Jennings B, Johnson DF, Irving LB, Farmer M, Daniel P. Steinfort DP. Utility of EBUS-TBNA for diagnosis of mediastinal tuberculous lymphadenitis: a multicentre Australian experience. J Thorac Dis 2015;7 (3):439-48. [CrossRef]

This was a retrospective study that evaluated the utility of EBUS guided mediastinal lymph node biopsy and culture in patients with suspected mediastinal tuberculosis. Mediastinal tuberculosis was based on clinical suspicion with no lung parenchymal lesions seen on CT scan. 159 patients received EBUS guided biopsy and culture. A total of 39 patients were diagnosed with mediastinal tuberculosis either based on culture (23 patients) or pathology showing granulomatous inflammation with negative cultures and response to tuberculosis treatment. 120 patients were negative for tuberculosis but did receive an alternative diagnosis. Alternative diagnosis of sarcoidosis (78 patients) and reactive lymphoid tissue (20 patients) were the most common alternative diagnosis. Although no mediastinoscopy was performed to confirm truly negative specimens, the presence of alternative diagnosis is reassuring that the combination of negative culture and pathology could results in the reported 98% negative predictive value. The study was limited by its design and smaller sample size, however using EBUS as a first line diagnostic modality makes sense as it may yield either the suspected or an alternative diagnosis in a large proportion of the cases.

Manoj Mathew MD, FCCP, MCCM

Banner University Good Samaritan Medical Center

Phoenix, AZ

Reference as: Mathew M. April 2015 Phoenix pulmonary journal club: endo-bronchial ultrasound in diagnosing tuberculosis. Southwest J Pulm Crit Care. 2015;10(4):197-8. doi: http://dx.doi.org/10.13175/swjpcc061-15 PDF

February 2015 Tucson Pulmonary Journal Club: Fibrinolysis for PE

Meyer G, Vicaut E, Danays T, et al. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014;370(15):1402-11. [CrossRef] [PubMed]

The role of fibrinolytic therapy among patients with intermediate-risk pulmonary embolism (PE) is controversial (1). When right ventricular dysfunction and myocardial injury are associated with PE, there is an increased risk of adverse events (2). However, the risk of bleeding with fibrinolytic therapy has previously been thought to outweigh the benefits among patients without overt hemodynamic collapse.

The Pulmonary Embolism Thrombolysis (PEITHO) trial was a multi-center, double-blind, placebo-controlled randomized trial designed to investigate the efficacy and safety of single-bolus injection with tenecteplase plus heparin anticoagulation versus heparin anticoagulation alone among normotensive patients with intermediate risk PE (3). The study included 1005 adult patients who were randomized within fifteen days of symptom onset; randomization occurred when both right ventricular dysfunction (echocardiography or spiral computed tomography) and myocardial injury (troponin I or T) were present. All patients were followed for 30 days. The primary outcome was death or hemodynamic collapse within 7 days of randomization. Safety outcomes included major extra cranial and intracranial hemorrhage within 7 days.

Fibrinolytic therapy was associated with less frequent hemodynamic collapse or death within 7 days of treatment (2.6% vs 5.6%, p=0.02). The result was primarily driven by fewer instances of hemodynamic collapse in tenecteplase group (1.6% vs 5.0%, p=0.002). At 30 days, there was no difference in mortality from any cause between the tenecteplase and usual care groups, 2.5% versus 3.2%, respectively (p=0.42). However, tenecteplase therapy was associated with higher risk of major bleeding and stroke than usual care, 11.5% versus 2.4% (p<0.001) and 2.4% versus 0.2% (p=0.003), respectively. Subgroup analysis showed a trend towards increased bleeding in patients older than 75 years though this was not significant (p=0.09).

PEITHO is a relatively large, expensive, randomized controlled trial that provides little guidance on the optimal care of patients with intermediate risk PE. While improvement in the composite outcome of death or hemodynamic decompensation was significant (Odds Ratio 0.44, CI_95% 0.23-0.87), the benefit was primarily driven by less frequent hemodynamic compromise. Furthermore, any treatment benefit must be weighed against a substantially increased risk of major bleeding (Odds Ratio 5.55, CI_95% 2.3-13.39) or stroke (Odds Ratio 12.10, CI_95% 1.57-93.39). Given that follow-up is limited to 30 days and no patient-reported/patient-centered outcomes are available, it is difficult to provide patients or clinicians with the evidence they need to weigh the risks and benefits. Until better data are available, thrombolytic therapy for intermediate risk PE still remains weakly supported due to unclear efficacy and high risks of major bleeding or stroke, particularly among older patients.

Aarthi Ganesh MD, Christian Bime MD, and Joe Gerald PhD

University of Arizona

Tucson, AZ

References

1. Konstantinides S, Goldhaber SZ. Pulmonary embolism: risk assessment and management. Eur Heart J. 2012;33:3014-22. [CrossRef] [PubMed]
2. Konstantinides S. Acute pulmonary embolism. N Engl J Med. 2008;359:2804-13. [CrossRef] [PubMed]
3. Meyer G, Vicaut E, Danays T, et al; PEITHO Investigators. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014;370(15):1402-11. [CrossRef] [PubMed] 

Reference as: Ganesh A, Bime C, Gerald J. February 2015 Tucson pulmonary journal club: fibrinolysis for PE. Southwest J Pulm Crit Care. 2015;10(2):97-8. doi: http://dx.doi.org/10.13175/swjpcc028-15 PDF