ContextStudies have shown that an inflammatory response may be elicited by
mechanical ventilation used for recruitment or derecruitment of collapsed
lung units or to overdistend alveolar regions, and that a lung-protective
strategy may reduce this response.ObjectiveTo test the hypothesis that mechanical ventilation induces a pulmonary
and systemic cytokine response that can be minimized by limiting recruitment
or derecruitment and overdistention.Design and SettingRandomized controlled trial in the intensive care units of 2 European
hospitals from November 1995 to February 1998, with a 28-day follow-up.PatientsForty-four patients (mean [SD] age, 50 [18] years) with acute respiratory
distress syndrome were enrolled, 7 of whom were withdrawn due to adverse events.InterventionsAfter admission, volume-pressure curves were measured and bronchoalveolar
lavage and blood samples were obtained. Patients were randomized to either
the control group (n=19): tidal volume to obtain normal values of arterial
carbon dioxide tension (35-40 mm Hg) and positive end-expiratory pressure
(PEEP) producing the greatest improvement in arterial oxygen saturation without
worsening hemodynamics; or the lung-protective strategy group (n=18): tidal
volume and PEEP based on the volume-pressure curve. Measurements were repeated
24 to 30 and 36 to 40 hours after randomization.Main Outcome MeasuresPulmonary and systemic concentrations of inflammatory mediators approximately
36 hours after randomization.ResultsPhysiological characteristics and cytokine concentrations were similar
in both groups at randomization. There were significant differences (mean
[SD]) between the control and lung-protective strategy groups in tidal volume
(11.1 [1.3] vs 7.6 [1.1] mL/kg), end-inspiratory plateau pressures (31.0 [4.5]
vs 24.6 [2.4] cm H2O), and PEEP (6.5 [1.7] vs 14.8 [2.7] cm H2O) (P<.001). Patients in the control group
had an increase in bronchoalveolar lavage concentrations of interleukin (IL)
1β, IL-6, and IL-1 receptor agonist and in both bronchoalveolar lavage
and plasma concentrations of tumor necrosis factor (TNF) α, IL-6, and
TNF-α receptors over 36 hours (P<.05 for
all). Patients in the lung-protective strategy group had a reduction in bronchoalveolar
lavage concentrations of polymorphonuclear cells, TNF-α, IL-1β,
soluble TNF-α receptor 55, and IL-8, and in plasma and bronchoalveolar
lavage concentrations of IL-6, soluble TNF-α receptor 75, and IL-1 receptor
antagonist (P<.05). The concentration of the inflammatory
mediators 36 hours after randomization was significantly lower in the lung-protective
strategy group than in the control group (P<.05).ConclusionsMechanical ventilation can induce a cytokine response that may be attenuated
by a strategy to minimize overdistention and recruitment/derecruitment of
the lung. Whether these physiological improvements are associated with improvements
in clinical end points should be determined in future studies.

https://jamanetwork.com/journals/jama/articlepdf/190583/jce80051.pdf

Effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome: a randomized controlled trial.

The acute respiratory distress syndrome (ARDS) is an important cause of acute respiratory failure that is often associated with multiple organ failure. Several clinical disorders can precipitate ARDS, including pneumonia, sepsis, aspiration of gastric contents, and major trauma. Physiologically, ARDS is characterized by increased permeability pulmonary edema, severe arterial hypoxemia, and impaired carbon dioxide excretion. Based on both experimental and clinical studies, progress has been made in understanding the mechanisms responsible for the pathogenesis and the resolution of lung injury, including the contribution of environmental and genetic factors. Improved survival has been achieved with the use of lung-protective ventilation. Future progress will depend on developing novel therapeutics that can facilitate and enhance lung repair.

/pdf/the-acute-respiratory-distress-syndrome-2x2riqv1jv.pdf

The acute respiratory distress syndrome.

ContextAlthough electrophysiologic and histologic neuromuscular abnormalities
are common in intensive care unit (ICU) patients, the clinical incidence of
ICU-acquired neuromuscular disorders in patients recovering from severe illness
remains unknown.ObjectivesTo assess the clinical incidence, risk factors, and outcomes of ICU-acquired
paresis (ICUAP) during recovery from critical illness in the ICU and to determine
the electrophysiologic and histologic patterns in patients with ICUAP.DesignProspective cohort study conducted from March 1999 to June 2000.SettingThree medical and 2 surgical ICUs in 4 hospitals in France.ParticipantsAll consecutive ICU patients without preexisting neuromuscular disease
who underwent mechanical ventilation for 7 or more days were screened daily
for awakening. The first day a patient was considered awake was day 1. Patients
with severe muscle weakness on day 7 were considered to have ICUAP.Main Outcome MeasuresIncidence and duration of ICUAP, risk factors for ICUAP, and comparative
duration of mechanical ventilation between ICUAP and control patients.ResultsAmong the 95 patients who achieved satisfactory awakening, the incidence
of ICUAP was 25.3% (95% confidence interval [CI], 16.9%-35.2%). All ICUAP
patients had a sensorimotor axonopathy, and all patients who underwent a muscle
biopsy had specific muscle involvement not related to nerve involvement. The
median duration of ICUAP after day 1 was 21 days. Mean (SD) duration of mechanical
ventilation after day 1 was significantly longer in patients with ICUAP compared
with those without (18.2 [36.3] vs 7.6 [19.2] days; P =
.03). Independent predictors of ICUAP were female sex (odds ratio [OR], 4.66;
95% CI, 1.19-18.30), the number of days with dysfunction of 2 or more organs
(OR, 1.28; 95% CI, 1.11-1.49), duration of mechanical ventilation (OR, 1.10;
95% CI, 1.00-1.22), and administration of corticosteroids (OR, 14.90; 95%
CI, 3.20-69.80) before day 1.ConclusionsIdentified using simple bedside clinical criteria, ICUAP was frequent
during recovery from critical illness and was associated with a prolonged
duration of mechanical ventilation. Our findings suggest an important role
of corticosteroids in the development of ICUAP.

/pdf/paresis-acquired-in-the-intensive-care-unit-a-prospective-1qsiegb2rf.pdf

Paresis acquired in the intensive care unit: a prospective multicenter study.

Context Controversy and uncertainty ensue when the results of clinical research on the effectiveness of interventions are subsequently contradicted. Controversies are most prominent when high-impact research is involved. Objectives To understand how frequently highly cited studies are contradicted or find effects that are stronger than in other similar studies and to discern whether spe- cific characteristics are associated with such refutation over time. Design All original clinical research studies published in 3 major general clinical jour- nals or high-impact-factor specialty journals in 1990-2003 and cited more than 1000 times in the literature were examined. Main Outcome Measure The results of highly cited articles were compared against subsequent studies of comparable or larger sample size and similar or better con- trolled designs. The same analysis was also performed comparatively for matched stud- ies that were not so highly cited. Results Of 49 highly cited original clinical research studies, 45 claimed that the inter- vention was effective. Of these, 7 (16%) were contradicted by subsequent studies, 7 oth- ers (16%) had found effects that were stronger than those of subsequent studies, 20 (44%) were replicated, and 11 (24%) remained largely unchallenged. Five of 6 highly- cited nonrandomized studies had been contradicted or had found stronger effects vs 9 of 39 randomized controlled trials (P=.008). Among randomized trials, studies with con- tradicted or stronger effects were smaller (P=.009) than replicated or unchallenged stud- ies although there was no statistically significant difference in their early or overall cita- tion impact. Matched control studies did not have a significantly different share of refuted results than highly cited studies, but they included more studies with "negative" results. Conclusions Contradiction and initially stronger effects are not unusual in highly cited research of clinical interventions and their outcomes. The extent to which high citations may provoke contradictions and vice versa needs more study. Controversies are most common with highly cited nonrandomized studies, but even the most highly cited randomized trials may be challenged and refuted over time, especially small ones.

/pdf/contradicted-and-initially-stronger-effects-in-highly-cited-50i9s2w55w.pdf

Contradicted and Initially Stronger Effects in Highly Cited Clinical Research

Background Persistent acute respiratory distress syndrome (ARDS) is characterized by excessive fibroproliferation, ongoing inflammation, prolonged mechanical ventilation, and a substantial risk of death. Because previous reports suggested that corticosteroids may improve survival, we performed a multicenter, randomized controlled trial of corticosteroids in patients with persistent ARDS. Methods We randomly assigned 180 patients with ARDS of at least seven days' duration to receive either methylprednisolone or placebo in a double-blind fashion. The primary end point was mortality at 60 days. Secondary end points included the number of ventilator-free days and organ-failure–free days, biochemical markers of inflammation and fibroproliferation, and infectious complications. Results At 60 days, the hospital mortality rate was 28.6 percent in the placebo group (95 percent confidence interval, 20.3 to 38.6 percent) and 29.2 percent in the methylprednisolone group (95 percent confidence interval, 20.8 to 39.4 p...

Efficacy and Safety of Corticosteroids for Persistent Acute Respiratory Distress Syndrome

Context.—No pharmacological therapeutic protocol has been found effective in
modifying the clinical course of acute respiratory distress syndrome (ARDS)
and mortality remains greater than 50%.Objective.—To determine the effects of prolonged methylprednisolone therapy on
lung function and mortality in patients with unresolving ARDS.Design.—Randomized, double-blind, placebo-controlled trial.Setting.—Medical intensive care units of 4 medical centers.Participants.—Twenty-four patients with severe ARDS who had failed to improve lung
injury score (LIS) by the seventh day of respiratory failure.Interventions.—Sixteen patients received methylprednisolone and 8 received placebo.
Methylprednisolone dose was initially 2 mg/kg per day and the duration of
treatment was 32 days. Four patients whose LIS failed to improve by at least
1 point after 10 days of treatment were blindly crossed over to the alternative
treatment.Main Outcome Measures.—Primary outcome measures were improvement in lung function and mortality.
Secondary outcome measures were improvement in multiple organ dysfunction
syndrome (MODS) and development of nosocomial infections.Results.—Physiological characteristics at the onset of ARDS were similar in both
groups. At study entry (day 9 [SD, 3] of ARDS), the 2 groups had similar LIS,
ratios of PaO2 to fraction of inspired oxygen (FIO2),
and MODS scores. Changes observed by study day 10 for methylprednisolone vs
placebo were as follows: reduced LIS (mean [SEM], 1.7 [0.1] vs 3.0 [0.2]; P<.001); improved ratio of PaO2 to FIO2 (mean [SEM], 262 [19] vs 148 [35]; P<.001);
decreased MODS score (mean [SEM], 0.7 [0.2] vs 1.8 [0.3]; P<.001); and successful extubation (7 vs 0; P=.05). For the treatment group vs the placebo group, mortality associated
with the intensive care unit was 0 (0%) of 16 vs 5 (62%) of 8 (P=.002) and hospital-associated mortality was 2 (12%) of 16 vs 5 (62%)
of 8 (P=.03). The rate of infections per day of treatment
was similar in both groups, and pneumonia was frequently detected in the absence
of fever.Conclusions.—In this study, prolonged administration of methylprednisolone in patients
with unresolving ARDS was associated with improvement in lung injury and MODS
scores and reduced mortality.

https://jamanetwork.com/journals/jama/articlepdf/187709/JCE80019.pdf

A. S. Headley

Papers

Effect of Prolonged Methylprednisolone Therapy in Unresolving Acute Respiratory Distress Syndrome A Randomized Controlled Trial