MEDLINE Abstracts: New Treatments for ARDS

June 12, 2002

MEDLINE Abstracts: New Treatments for ARDS

What's new concerning the management and treatment of acute respiratory distress syndrome? Find out in this easy-to-navigate collection of recent MEDLINE abstracts compiled by the editors at Medscape Pulmonary Medicine.

Meyer J, Theilmeier G, Van Aken H, Bone HG, Busse H, Waurick R, Hinder F, Booke M
Anesthesia & Analgesia 86(4):753-8, 1998 Apr

Acute lung injury is characterized by hypoxemia due to pulmonary ventilation/perfusion-mismatching. IV administered prostaglandin E1 (PGE1), a vasodilator with a high pulmonary clearance, has been studied in acute lung injury. Inhalation of the vasodilators nitric oxide and prostacyclin improved oxygenation by selective dilation of the pulmonary vasculature in ventilated lung areas. In the present study, PGE1 inhalation was used for treatment of acute lung injury. Fifteen patients with acute lung injury defined as PaO2/fraction of inspired oxygen (FIO2) <160 mm Hg were treated with PGE1 inhalation in addition to standard intensive care. The drug was continuously delivered via a pneumatic nebulizer. Acute physiology and chronic health evaluation system II and multiple organ failure scores were (mean +/- SEM) 33 +/- 2 and 10 +/- 0.3, respectively. Inhaled PGE1 was administered for 103 +/- 17 h at a dose of 41 +/- 2 microg/h. The PaO2/FIO2 ratio increased from 105 +/- 9 to 160 +/- 17 mm Hg (P < 0.05) and to 189 +/- 25 mm Hg (P < 0.05) after 4 h and 24 h, respectively. PGE1 inhalation decreases in mean pulmonary artery pressure and central venous pressure were not statistically significant. Mean arterial pressure, pulmonary capillary wedge pressure, cardiac output, and heart rate remained unchanged. Intensive care unit mortality was 40%. The present data suggest that inhaled PGE1 is an effective therapeutic option for improving oxygenation in patients with acute lung injury. Whether inhaled PGE1 will increase survival in acute lung injury should be investigated in a controlled prospective trial. Implications: In patients with severe acute lung injury and multiple organ failure, inhaled prostaglandin E1 improved oxygenation and decreased venous admixture without affecting systemic hemodynamic variables. Controlled clinical trials are warranted.

Papazian L, Bregeon F, Gaillat F, Thirion X, Gainnier M, Gregoire R, Saux P, Gouin F, Jammes Y, Auffray JP
American Journal of Respiratory & Critical Care Medicine 157(2):580-5, 1998 Feb

Inhaled nitric oxide (NO) and prone position (PP) are two of the new therapeutics proposed in the setting of acute respiratory distress syndrome (ARDS). The aim of this study was to evaluate the hemodynamic and respiratory effects of NO and prone position in patients with ARDS. Fourteen patients, sedated, paralyzed, and ventilated using volume-control mode, were prospectively investigated. All patients had a radial artery catheter, a pulmonary artery catheter, and a 3-F fiberoptic thermistor catheter advanced via the femoral artery into the descending aorta. The protocol consisted of seven phases: baseline measurements in supine position, SP (T0); SP + NO (T1); baseline 2 in SP (T2); PP without NO (T3); NO + PP (T4); SP + NO (T5); and PP + NO (T6). Inhaled NO (T1) induced an increase in PO2/FI(O2) (from 128 +/- 44 to 180 +/- 75 mm Hg, p < 0.004). Prone position (T3) resulted in an increase in PO2/FI(O2) (193 +/- 83 mm Hg, p < 0.003 versus T0). The association of NO with PP (T4) resulted in a significant improvement in PO2/FI(O2) (261 +/- 98 mm Hg) when compared with T0, T1, and T3. Analysis of variance showed a significant and additive effect of NO and PP on both PO2/FI(O2) (p < 0.000) and shunt fraction (QS/QT) (p < 0.01). Since the association of NO with PP presents additive effects on oxygenation, this association can be proposed for the treatment of ARDS.

Zavala E, Ferrer M, Polese G, Masclans JR, Planas M, Milic-Emili J, Rodriguez-Roisin R, Roca J, Rossi A
Anesthesiology 88(1):35-42, 1998 Jan

Background: It is not known whether inverse I:E ratio ventilation (IRV) offers any real benefit over conventional mechanical ventilation with positive end-expiratory pressure (CMV-PEEP) at similar levels of end-expiratory pressure.
Methods: The effects of volume-controlled and pressure-controlled IRV (VC-IRV and PC-IRV, respectively) on VA/Q inequality were compared with those of CMV-PEEP at a similar level of end-expiratory pressure and with CMV without PEEP (CMV) in eight patients in the early stages of acute respiratory distress syndrome (ARDS). Respiratory blood gases, inert gases, lung mechanics, and hemodynamics were measured 30 min after the onset of each ventilatory mode.
Results: Recruitment of nonventilated, poorly ventilated (or both) but well-perfused alveoli increased the partial pressure of oxygen (PaO2) during CMV-PEEP (+13 mmHg) and IRV-VC (+10 mmHg; P < 0.05) compared with CMV. In contrast, PC-IRV did not affect PaO2 but caused a decrease in PaCO2 (-7 mmHg; P < 0.05). The latter was due to a concomitant decrease in dead space (P < 0.01) and shift to the right of VA/Q distributions. During PC-IRV, the increase in the mean of blood flow distribution (mean Q; P < 0.01) without a change in the dispersion (log SD Q) did not result in an increase in PaO2, probably because it reflected redistribution of blood flow within well-ventilated areas.
Conclusions: Short-term PC-IRV improved carbon dioxide clearance, but the lung became less efficient as an oxygen exchanger. Furthermore, based on mean airway and plateau pressures, the risk of barotrauma was not reduced with this type of ventilation.

Amato MB, Barbas CS, Medeiros DM, Magaldi RB, Schettino GP, Lorenzi-Filho G, Kairalla RA, Deheinzelin D, Munoz C, Oliveira R, Takagaki TY, Carvalho CR
New England Journal of Medicine 338(6):347-54, 1998 Feb 5

Background: In patients with the acute respiratory distress syndrome, massive alveolar collapse and cyclic lung reopening and overdistention during mechanical ventilation may perpetuate alveolar injury. We determined whether a ventilatory strategy designed to minimize such lung injuries could reduce not only pulmonary complications but also mortality at 28 days in patients with the acute respiratory distress syndrome.
Methods: We randomly assigned 53 patients with early acute respiratory distress syndrome (including 28 described previously), all of whom were receiving identical hemodynamic and general support, to conventional or protective mechanical ventilation. Conventional ventilation was based on the strategy of maintaining the lowest positive end-expiratory pressure (PEEP) for acceptable oxygenation, with a tidal volume of 12 ml per kilogram of body weight and normal arterial carbon dioxide levels (35 to 38 mm Hg). Protective ventilation involved end-expiratory pressures above the lower inflection point on the static pressure-volume curve, a tidal volume of less than 6 ml per kilogram, driving pressures of less than 20 cm of water above the PEEP value, permissive hypercapnia, and preferential use of pressure-limited ventilatory modes.
Results: After 28 days, 11 of 29 patients (38 percent) in the protective-ventilation group had died, as compared with 17 of 24 (71 percent) in the conventional-ventilation group (P<0.001). The rates of weaning from mechanical ventilation were 66 percent in the protective-ventilation group and 29 percent in the conventional-ventilation group (P=0.005): the rates of clinical barotrauma were 7 percent and 42 percent, respectively (P=0.02), despite the use of higher PEEP and mean airway pressures in the protective-ventilation group. The difference in survival to hospital discharge was not significant; 13 of 29 patients (45 percent) in the protective-ventilation group died in the hospital, as compared with 17 of 24 in the conventional-ventilation group (71 percent, P=0.37).
Conclusions: As compared with conventional ventilation, the protective strategy was associated with improved survival at 28 days, a higher rate of weaning from mechanical ventilation, and a lower rate of barotrauma in patients with the acute respiratory distress syndrome. Protective ventilation was not associated with a higher rate of survival to hospital discharge.

Dellinger RP, Zimmerman JL, Taylor RW, Straube RC, Hauser DL, Criner GJ, Davis K Jr, Hyers TM, Papadakos P
Critical Care Medicine 26(1):15-23, 1998 Jan

Objectives: To evaluate the safety and physiologic response of inhaled nitric oxide (NO) in patients with acute respiratory distress syndrome (ARDS). In addition, the effect of various doses of inhaled NO on clinical outcome parameters was assessed.
Design: Prospective, multicenter, randomized, double-blind, placebo-controlled study.
Setting: Intensive care units of 30 academic, teaching, and community hospitals in the United States.
Patients: Patients with ARDS, as defined by the American-European Consensus Conference, were enrolled into the study if the onset of disease was within 72 hrs of randomization.
Interventions: Patients were randomized to receive placebo (nitrogen gas) or inhaled NO at concentrations of 1.25, 5, 20, 40, or 80 ppm.

Measurements And Main Results: Acute increases in PaO2, decreases in mean pulmonary arterial pressure, intensity of mechanical ventilation, and oxygenation index were examined. Clinical outcomes examined were the dose effects of inhaled NO on mortality, the number of days alive and off mechanical ventilation, and the number of days alive after meeting oxygenation criteria for extubation. A total of 177 patients were enrolled over a 14-month period. An acute response to treatment gas, defined as a PaO2 increase > or =20%, was seen in 60% of the patients receiving inhaled NO with no significant differences between dose groups. Twenty-four percent of placebo patients also had an acute response to treatment gas during the first 4 hrs. The initial increase in oxygenation translated into a reduction in the FIO2 over the first day and in the intensity of mechanical ventilation over the first 4 days of treatment, as measured by the oxygenation index. There were no differences among the pooled inhaled NO groups and placebo with respect to mortality rate, the number of days alive and off mechanical ventilation, or the number of days alive after meeting oxygenation criteria for extubation. However, patients receiving 5 ppm inhaled NO showed an improvement in these parameters. In this dose group, the percentage of patients alive and off mechanical ventilation at day 28 (a post hoc analysis) was higher (62% vs. 44%) than the placebo group. There was no apparent difference in the number or type of adverse events reported among those patients receiving inhaled NO compared with placebo. Four patients had methemoglobin concentrations >5%. The mean inspired nitrogen dioxide concentration in inhaled NO patients was 1.5 ppm.
Conclusions: From this placebo-controlled study, inhaled NO appears to be well tolerated in the population of ARDS patients studied. With mechanical ventilation held constant, inhaled NO is associated with a significant improvement in oxygenation compared with placebo over the first 4 hrs of treatment. An improvement in oxygenation index was observed over the first 4 days. Larger phase III studies are needed to ascertain if these acute physiologic improvements can lead to altered clinical outcome.

Cawley MJ, Skaar DJ, Anderson HL 3rd, Hanson CW 3rd
Pharmacotherapy 18(1):140-55, 1998 Jan-Feb

Acute or adult respiratory distress syndrome (ARDS) contributes to mortality and morbidity in the intensive care environment. Appropriate application of microprocessor-controlled mechanical ventilatory support, pathophysiology of the disease, and new pharmacologic modalities are currently being investigated. Mechanical ventilation is usually begun when respiratory failure is caused by alveolar hypoventilation or hypoxia. Primary choices for this therapy are control-mode ventilation, assist-control ventilation, pressure-control ventilation, intermittent mandatory ventilation, and synchronized intermittent mandatory ventilation with the addition of positive end-expiratory pressure. Patients who deteriorate despite these interventions may require alternative modes of ventilation. Pharmacologic agents in ARDS is important due to the multifactorial pathophysiologic and pharmacodynamic processes that are part of the disease. Clinical studies will continue to determine advantageous agents. Unfortunately, no convincing data exist that any pharmacologic or nonpharmacologic strategy is superior for the support of these patients or results in a better outcome than others.