Airways, Consent, Fluid Resuscitation, Home Ventilation


Airways Disorders

Quadrupling the inhaled glucocorticoid dose in those with deteriorating asthma control: Zone 2 asthma

Asthma exacerbations account for most asthma-associated health-care costs and are a key outcome for successful asthma management programs. Inhaled corticosteroid (ICS) forms the cornerstone of asthma maintenance therapy.

Previously published data show that:

Most therapeutic benefit of budesonide was achieved at dose range of 400-1000 µg/day (Masoli et al. Eur Respir J. 2004;23:552).

Doubling ICS dose was ineffective in preventing acute asthma exacerbations (Harrison et al. Lancet. 2004;363:271. FitzGerald et al. Thorax. 2004;59: 550).

Increasing ICS dose was unlikely to reduce systemic glucocorticoid use or hospitalization for asthma exacerbations(Kew et al. Cochrane Database Syst Rev. 2016;6:CD007524).

A recent open-label pragmatic study, published in the New England Journal of Medicine, included 1,922 adolescents and adults with asthma. The authors observed a small reduction in severe asthma exacerbations (Hazard ratio 0.81 for time to first severe exacerbation) by quadrupling the dose of ICS during periods of worsening asthma control (McKeever et al. N Engl J Med. 2018;378:902).

This study does create opportunities for cost-benefit by decreasing health-care utilization, decrease in systemic steroid exposure in some patients, and increase in patient awareness of asthma control allowing self-management. Although statistically significant, the treatment effect was small, with 45% of subjects in the ‘quadrupling dose’ arm still experiencing severe exacerbations. Intervention arm also experienced increased rate of adverse effects.

Additional studies are needed before this strategy can be broadly applied. In the same issue of NEJM, quintupling the dose of ICS in children was not associated with decrease in exacerbations (Jackson et al. N Engl J Med. 2018;378:891). The fact that nearly half of asthmatics who quadrupled ICS dose had exacerbations is disconcerting. This highlights an urgent need to understand treatment-responsive phenotypes, mechanisms of steroid sensitivity, and modalities to improve them, if we are to reduce asthma morbidity in the community.

Navitha Ramesh, MD

Steering Committee Member

Mahesh Padukudru Anand, MBBS, FCCP

Steering Committee Member

Clinical Research

Informed consent: Do we need to change our practice?

Informed consent is the keystone of clinical research and helps respect and protect the rights of the participants/subjects. While the informed consent process has been standardized, some challenges still remain, such as pieces of information that should be disclosed, how to disclose information and document understanding of participants, and how detailed that disclosure should be (Grady, N Engl J Med. 2015;372:855). Digital technology can and has been used to improve the process of obtaining informed consent.

Substituting long and complex written forms with electronic consent (e-consent), however, has issues. Few people read through online agreements before clicking “agree,” which may lead to participants consenting without a clear understanding of what they are consenting to. On the other hand, it is also possible to use e-consent to improve comprehension by including videos and graphics. Interactive quizzes can assess the understanding of the participants, embedded links to audios or videos can further enhance the grasp of information. With e-consents, queries from participants can be answered via phone call or email. When e-consent is obtained remotely, the identity can be confirmed by electronic signatures, username, password, or biometrics.

E-consent has advantages, can be done remotely, no paper is needed, etc. It has potential disadvantages like being costly, videos can add time to the process, and multicenter international trials can be difficult (Grady, et al. N Engl J Med, 2017; 376:e43). Studying e-consents to identify gaps in communication between the researcher and the participant in the digitalized world may help improve the process and allow research to proceed with better understanding of the risks and benefits of involvement in clinical research.

Mohsin Ijaz, MD, FCCP

Steering Committee Member

Critical Care

Fluid Resuscitation in ICU Patients With Sepsis

Appropriate fluid resuscitation is a major goal in sepsis management. Debate remains regarding fluid choice and the impact on acute kidney injury (AKI), renal replacement therapy (RRT), and mortality. Normal saline solution (NS) may be associated with hyperchloremic metabolic acidosis, AKI, and death, but study results have been inconsistent. A large before-after study revealed that balanced crystalloids (BC) were associated with lower rates of AKI and RRT but did not impact mortality (Yunos et al. JAMA. 2012;308:1566). A meta-analysis specifically examining patients with sepsis failed to find a significant difference in RRT or mortality, although this conclusion was of low certainty (Rochwerg, et al., Intensive Care Med. 2015;41:1561).

Earlier this year, a large RCT comparing NS vs BC demonstrated a reduction in major adverse kidney events using BC. Independent rates of new RRT, mortality, and persistent renal dysfunction were not significant, but when combined as a composite outcome, the difference was significant. A 30-day mortality reduction was significant in patients with sepsis (25.2% BC vs 29.4% NS) and in patients with large infusions of NS (Semler et al., N Engl J Med. 2018;378:829). Given these results, a move toward a “balanced approach” to fluid resuscitation seems prudent and may be the next step toward improving outcomes in sepsis. These results are likely related to the large infusions of fluid in patients with sepsis or to the inflammatory effects of the disease. Finally, the applicability of these outcomes to the overall critically ill population is still open to debate.

Margaret Disselkamp, MD

Steering Committee Member


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