Dinesh Yogaratnam

OBJECTIVE: To evaluate the published clinical literature on the role of pirfenidone for the treatment of idiopathic pulmonary fibrosis (IPF). DATA SOURCES: A systematic literature search was performed using the key words pirfenidone or Esbriet, alone and in combination, with IPF or idiopathic pulmonary fibrosis (expanded using MESH terminology). MEDLINE (1948-September 2012) was the primary database used for search purposes. In addition, all available articles and abstracts referenced by the articles identified via literature search were included. STUDY SELECTION AND DATA EXTRACTION: The search was limited to English-language publications. All available clinical trials of pirfenidone pertinent to its pharmacology, pharmacokinetics, efficacy, and safety were included. DATA SYNTHESIS: Pirfenidone is the first agent specifically developed for the treatment of IPF. It has been approved for use in Europe and Japan, but not in the US. Although Phase 3 trials have shown pirfenidone to improve certain clinical (6-minute walk test) and functional (change in forced vital capacity) outcomes in patients with IPF, an independent benefit on either mortality or acute exacerbation rates has yet to be demonstrated. Until more definitive supportive data are available, international guidelines have recommended against using pirfenidone to treat most patients with IPF. CONCLUSIONS: Although pirfenidone appears to be an effective treatment for IPF, additional clinical trials are needed to better delineate its risk-benefit profile.

Introduction: While propofol is associated with an infusion syndrome (PRIS) that may cause death, the incidence of PRIS is unknown. Determining the incidence of PRIS and the frequency of PRIS-related clinical manifestations are key steps prior to the completion of any controlled studies investigating PRIS. This prospective, multicenter study sought to determine the incidence of PRIS and PRIS-related clinical manifestations in a large cohort of critically ill adults prescribed propofol. Methods: Critically ill adults from 11 academic medical centers administered an infusion of propofol for [>/=] 24 hours were monitored at baseline and then on a daily basis until propofol was discontinued for the presence of 11 different PRIS-associated clinical manifestations and risk factors derived from 83 published case reports of PRIS. Results: Among 1017 patients [medical (35%), neurosurgical (25%)], PRIS (defined as metabolic acidosis plus cardiac dysfunction and [>/=] 1 of: rhabdomyolysis, hypertriglyceridemia or renal failure occurring after the start of propofol therapy) developed in 11 (1.1%) patients an average of 3 (1-6) [median (range)] days after the start of propofol. While most (91%) of the patients who developed PRIS were receiving a vasopressor (80% initiated after the start of propofol therapy), few received a propofol dose >83 mcg/kg/min (18%) or died (18%). Compared to the 1006 patients who did not develop PRIS, the APACHE II score (25 +/- 6 vs 20 +/- 7, P = 0.01) was greater in patients with PRIS but both the duration of propofol use (P = 0.43) and ICU length of stay (P = 0.82) were similar. Conclusions: Despite using a conservative definition for PRIS, and only considering new-onset PRIS clinical manifestations, the incidence of PRIS slightly exceeds 1%. Future controlled studies focusing on evaluating whether propofol manifests the derangements of critical illness more frequently than other sedatives will need to be large. These studies should also investigate the mechanism(s) and risk factors for PRIS.