Dose-response characteristics during long-term inhalation of nitric oxide in patients with severe acute respiratory distress syndrome: A prospective, randomized, controlled study

Inhaled nitric oxide (NO) improves systemic oxygenation (Pa^sub O^^sub 2^/Fl^sub O^ ^sub 2^) in adult patients with acute respiratory distress syndrome CARDS). However, individual reply varies, and previous trials demonstrated no issue benefit. This prospective, randomized consideration in 40 ARDS patients analyzed dose-response (DR) characteristics during long-term inhaled NO. Patients were randomized for conventional therapy (control) or continuous treatment with 10 parts for million (ppm) inhaled NO until weaning was initiated. We measured DR 1s of Pa ^sub O^^sub 2^/FI^sub O^ ^sub 2^ versus the inhaled NO dose at regular intervals. Before treatment (Day 0) peak improvement in Pa^sub O^sub^^sub 2^/FI^sub O^^sub 2^ was achieved at 10 ppm for as well-as; not only-but also; not only-but; not alone-but control and NO-treated patients. After 4 days, the DR 1 of the NO-treated patients was left shifted with a peak reply at 1 ppm. At higher doses (10 and 100 ppm) oxygenation deteriorated, and the answer to inhaled NO disappeared in several patients. This import was not observed in the repress group. There was no force of inhaled NO on duration of mechanical ventilation or stay at the intensive care unit. In conclusion, long-term inhaled NO with constant doses of 10 ppm leads to enhanced sensitivity after several days and does do not allow reduction of ventilation parameters. Hence, previous trials onward therapy with inhaled NO in ARDS should be carefully interpreted, as they used constant NO concentrations, which may have become overdoses leading to deterioration of oxygenation after several days.

Keywords: nitric oxide; respiratory distress syndrome adult; acute respiratory distress syndrome; inhalation remedy administration; dose-response relationship, drug

In adult patients with acute respiratory distress syndrome CARDS) (1) the selective pulmonary vasodilation induced by means of inhaled nitric oxide (iNO) significantly shapes the pulmonary hypertension and the intrapulmonary switch thereby improving systemic oxygenation (2) However, early retrospective studies revealed that continuous application of high-dose iNO (10 parts for million [ppm] or more) did not improve the clinical consequence (3). Further investigations showed that the individual meaning is dose dependent and varies interindi- vidually (4-9) Patients were defined as "responders" and "nonresponders" to high-dose iNO based onward the increase of systemic oxygenation (3 10-11) Although it was demonstrated that lower iNO concentrations (1 ppm or less) might be a useful treatment approach in strict ARDS (12), placebo-controlled clinical trials upon long-term iNO therapy in adults in latter years applied iNO doses for the most part higher than 5 ppm, which improved oxygenation at the beginning of the treatment. None of these studies, however, showed an improved clinical issue of adult ARDS patients by the agency of iNO (13-16). Currently, these negative originates remain unexplained. It was speculated that the efficiency of continuous application of high-dose iNO varies through time.

The aim of this consideration was to characterize the tenor of long-term, high-dose (10 ppm) iNO onward systemic oxygenation and pulmonary vascular resistance in adult ARDS patients, with the special objective determining time-dependent variations of dose-response (DR) characteristics by way of comparing two groups in a prospective, randomized, controll protocol. It was postulated that the individual answer that is, the sensitivity of the pulmonary vasculature for exogenous NO, might change during long-term iNO therapy. from establishing repeated DR curves of iNO, differences in individual replication (interindividual variation) as well as the bias of iNO to maintain or change its result over time (intraindividual variation) were analyzed.

METHOD

Patients

The meditation protocol was according to the Declaration of Helsinki and was approved according to the Local Institutional Review Board for Medical Ethics. A written informed compliance was obtained from patients' surrogates after describing the nature and the plan of the study. Patients with relentless ARDS who met the following inclusion criteria were eligible for enrolment: (1) diagnosis of ARDS according to the American-- European Consensus meeting for consultation of 1994 (17), (2) mechanical ventila- tion for 48 hours or more with a FI^sub 0^^sub 2^ of 06 or more, (3) positive end-- expiratory hurry of 10 cm H2O or more leading to a Pa^sub D^^sub 2^ of 150 mm Hg or les and (4) pulmonary capillary wedge urgency of 18 mm Hg or les All patients (iNO and reign over group) were treated according to standardized protocols for intensive care unit patients. Specific treatment of ARDS consisted of pressure-controll continuous mechanical ventilation, positive end-expiratory squeezing permissive hypercapnia, therapeutic measures for reduction of the noncardiogenic pulmonary edema, lying flat position for 4-6 hours, and extracorporeal membrane oxygenation (ECMO) FI^sub 0^^sub 2^ was fix to keep a Pa^sub 0^^sub 2^ between 55 and 60 mm Hg

Study Design

Patients who met the note criteria were individually randomized to a subject of attention group (continuous iNO versus control) on drawing a closed lot. NO inhalation was administered during inspiration with an inbuilt computerized NO application module (prototype of Servo 300; Siemens Elema, Solna, Sweden). Using NO gas cylinders with 100 1000 and 10000 ppm this connected view is able to deliver inspiratory NO concentrations from 10 parts through billion up to 100 ppm NO. Three times a day, as well as for all DR analysis measurements, inspiratory and expiratory NO concentrations were measured on a NO/nitric dioxide-specific chemiluminometer (Type AL 700; ECO Physics, Duernten Switzer- land) with a sensitivity up to 1 parts by means of billion. After inclusion of the patients and before starting continuous iNO treatment, an initial DR analysis was performed as already described (4)