Acute and sustained effects of early administration of inhaled nitric oxide to children with acute respiratory distress syndrome

OBJECTIVE: To determine the acute and sustained effects of early inhaled nitric oxide on some oxygenation indexes and ventilator settings and to compare inhaled nitric oxide administration and conventional therapy on mortality rate, length of stay in intensive care, and duration of mechanical ventilation in children with acute respiratory distress syndrome. DESIGN: Observational study. SETTING: Pediatric intensive care unit at a university-affiliated hospital. PATIENTS: Children with acute respiratory distress syndrome, aged between 1 month and 12 yrs. INTERVENTIONS: Two groups were studied: an inhaled nitric oxide group (iNOG, n = 18) composed of patients prospectively enrolled from November 2000 to November 2002, and a conventional therapy group (CTG, n = 21) consisting of historical control patients admitted from August 1998 to August 2000. MEASUREMENTS AND MAIN RESULTS: Therapy with inhaled nitric oxide was introduced as early as 1.5 hrs after acute respiratory distress syndrome diagnosis with acute improvements in Pao(2)/Fio(2) ratio (83.7%) and oxygenation index (46.7%). Study groups were of similar ages, gender, primary diagnoses, pediatric risk of mortality score, and mean airway pressure. Pao(2)/Fio(2) ratio was lower (CTG, 116.9 +/- 34.5; iNOG, 62.5 +/- 12.8, p <.0001) and oxygenation index higher (CTG, 15.2 [range, 7.2-32.2]; iNOG, 24.3 [range, 16.3-70.4], p <.0001) in the iNOG. Prolonged treatment was associated with improved oxygenation, so that Fio(2) and peak inspiratory pressure could be quickly and significantly reduced. Mortality rate for inhaled nitric oxide-patients was lower (CTG, ten of 21, 47.6%; iNOG, three of 18, 16.6%, p <.001). There was no difference in intensive care stay (CTG, 10 days [range, 2-49]; iNOG, 12 [range, 6-26], p >.05) or duration of mechanical ventilation (TCG, 9 days [range, 2-47]; iNOG, 10 [range, 4-25], p >.05). CONCLUSIONS: Early treatment with inhaled nitric oxide causes acute and sustained improvement in oxygenation, with earlier reduction of ventilator settings, which might contribute to reduce the mortality rate in children with acute respiratory distress syndrome. Length of stay in intensive care and duration of mechanical ventilation are not changed. Prospective trials of inhaled nitric oxide early in the setting of acute lung injury in children are needed.

Ventilator-induced lung injury and acute respiratory distress syndrome: a basic science review

Acute respiratory distress syndrome is the most severe manifestation of acute lung injury and it is associated with high mortality rate. Despite better understanding of ARDS pathophysiology, its mechanism is still unclear. Mechanical ventilation is the main ARDS supportive treatment. However, mechanical ventilation is a non-physiologic process and complications are associated with its application. Mechanical ventilation may induce lung injury, referred to as ventilator-induced lung injury. Frequently, VILI is related to macroscopic injuries associated with alveolar rupture. The present article is a review of the literature on ventilator-induced lung injury in acute respiratory distress syndrome. Animal and human studies were reviewed. We mainly selected publications in the past 5 years, but did not exclude commonly referenced and highly regarded older publications.

How large is the lung recruitability in early acute respiratory distress syndrome: a prospective case series of patients monitored by computed tomography

Introduction: The benefits of higher positive end expiratory pressure (PEEP) in patients with acute respiratory distress syndrome (ARDS) have been modest, but few studies have fully tested the "open-lung hypothesis". This hypothesis states that most of the collapsed lung tissue observed in ARDS can be reversed at an acceptable clinical cost, potentially resulting in better lung protection, but requiring more intensive maneuvers. The short-/middle-term efficacy of a maximum recruitment strategy (MRS) was recently described in a small physiological study. The present study extends those results, describing a case-series of non-selected patients with early, severe ARDS submitted to MRS and followed until hospital discharge or death. Methods: MRS guided by thoracic computed tomography (CT) included two parts: a recruitment phase to calculate opening pressures (incremental steps under pressure-controlled ventilation up to maximum inspiratory pressures of 60 cmH(2)O, at constant driving-pressures of 15 cmH(2)O); and a PEEP titration phase (decremental PEEP steps from 25 to 10 cmH2O) used to estimate the minimum PEEP to keep lungs open. During all steps, we calculated the size of the non-aerated (-100 to +100 HU) compartment and the recruitability of the lungs (the percent mass of collapsed tissue re-aerated from baseline to maximum PEEP). Results: A total of 51 severe ARDS patients, with a mean age of 50.7 years (84% primary ARDS) was studied. The opening plateau-pressure was 59.6 (+/- 5.9 cmH(2)O), and the mean PEEP titrated after MRS was 24.6 (+/- 2.9 cmH(2)O). Mean PaO2/FiO(2) ratio increased from 125 (+/- 43) to 300 (+/- 103; P < 0.0001) after MRS and was sustained above 300 throughout seven days. Non-aerated parenchyma decreased significantly from 53.6% (interquartile range (IQR): 42.5 to 62.4) to 12.7% (IQR: 4.9 to 24.2) (P < 0.0001) after MRS. The potentially recruitable lung was estimated at 45% (IQR: 25 to 53). We did not observe major barotrauma or significant clinical complications associated with the maneuver. Conclusions: MRS could efficiently reverse hypoxemia and most of the collapsed lung tissue during the course of ARDS, compatible with a high lung recruitability in non-selected patients with early, severe ARDS. This strategy should be tested in a prospective randomized clinical trial.

Association Between Use of Lung-Protective Ventilation With Lower Tidal Volumes and Clinical Outcomes Among Patients Without Acute Respiratory Distress Syndrome A Meta-analysis

Context Lung-protective mechanical ventilation with the use of lower tidal volumes has been found to improve outcomes of patients with acute respiratory distress syndrome (ARDS). It has been suggested that use of lower tidal volumes also benefits patients who do not have ARDS. Objective To determine whether use of lower tidal volumes is associated with improved outcomes of patients receiving ventilation who do not have ARDS. Data Sources MEDLINE, CINAHL, Web of Science, and Cochrane Central Register of Controlled Trials up to August 2012. Study Selection Eligible studies evaluated use of lower vs higher tidal volumes in patients without ARDS at onset of mechanical ventilation and reported lung injury development, overall mortality, pulmonary infection, atelectasis, and biochemical alterations. Data Extraction Three reviewers extracted data on study characteristics, methods, and outcomes. Disagreement was resolved by consensus. Data Synthesis Twenty articles (2822 participants) were included. Meta-analysis using a fixed-effects model showed a decrease in lung injury development (risk ratio [RR], 0.33; 95% CI, 0.23 to 0.47; I-2, 0%; number needed to treat [NNT], 11), and mortality (RR, 0.64; 95% CI, 0.46 to 0.89; I-2, 0%; NNT, 23) in patients receiving ventilation with lower tidal volumes. The results of lung injury development were similar when stratified by the type of study (randomized vs nonrandomized) and were significant only in randomized trials for pulmonary infection and only in nonrandomized trials for mortality. Meta-analysis using a random-effects model showed, in protective ventilation groups, a lower incidence of pulmonary infection (RR, 0.45; 95% CI, 0.22 to 0.92; I-2, 32%; NNT, 26), lower mean (SD) hospital length of stay (6.91 [2.36] vs 8.87 [2.93] days, respectively; standardized mean difference [SMD], 0.51; 95% CI, 0.20 to 0.82; I-2, 75%), higher mean (SD) PaCO2 levels (41.05 [3.79] vs 37.90 [4.19] mm Hg, respectively; SMD, -0.51; 95% CI, -0.70 to -0.32; I-2, 54%), and lower mean (SD) pH values (7.37 [0.03] vs 7.40 [0.04], respectively; SMD, 1.16; 95% CI, 0.31 to 2.02; I-2, 96%) but similar mean (SD) ratios of PaO2 to fraction of inspired oxygen (304.40 [65.7] vs 312.97 [68.13], respectively; SMD, 0.11; 95% CI, -0.06 to 0.27; I-2, 60%). Tidal volume gradients between the 2 groups did not influence significantly the final results. Conclusions Among patients without ARDS, protective ventilation with lower tidal volumes was associated with better clinical outcomes. Some of the limitations of the meta-analysis were the mixed setting of mechanical ventilation (intensive care unit or operating room) and the duration of mechanical ventilation. JAMA. 2012;308(16):1651-1659 www.jama.com

Changes in respiratory mechanics and gas exchange during the acute respiratory distress syndrome

BACKGROUND: The time course of impairment of respiratory mechanics and gas exchange in the acute respiratory distress syndrome (ARDS) remains poorly defined. We assessed the changes in respiratory mechanics and gas exchange during ARDS. We hypothesized that due to the changes in respiratory mechanics over time, ventilatory strategies based on rigid volume or pressure limits might fail to prevent overdistension throughout the disease process. METHODS: Seventeen severe ARDS patients {PaO2/FiO2 10.1 (9.2-14.3) kPa; 76 (69-107) mmHg [median (25th-75th percentiles)] and bilateral infiltrates} were studied during the acute, intermediate, and late stages of ARDS (at 1-3, 4-6 and 7 days after diagnosis). Severity of lung injury, gas exchange, and hemodynamics were assessed. Pressure-volume (PV) curves of the respiratory system were obtained, and upper and lower inflection points (UIP, LIP) and recruitment were estimated. RESULTS: (1) UIP decreased from early to established (intermediate and late) ARDS [30 (28-30) cmH2O, 27 (25-30) cmH2O and 25 (23-28) cmH2O (P=0.014)]; (2) oxygenation improved in survivors and in patients with non-pulmonary etiology in late ARDS, whereas all patients developed hypercapnia from early to established ARDS; and (3) dead-space ventilation and pulmonary shunt were larger in patients with pulmonary etiology during late ARDS. CONCLUSION: We found a decrease in UIP from acute to established ARDS. If applied to our data, the inspiratory pressure limit advocated by the ARDSnet (30 cmH2O) would produce ventilation over the UIP, with a consequent increased risk of overdistension in 12%, 43% and 65% of our patients during the acute, intermediate and late phases of ARDS, respectively. Lung protective strategies based on fixed tidal volume or pressure limits may thus not fully avoid the risk of lung overdistension throughout ARDS.

Acute respiratory distress syndrome secondary to antisynthetase syndrome is reversible with tacrolimus

Polymyositis and interstitial lung diseases, predominantly nonspecific interstitial pneumonia (NSIP), are known to be frequent in antisynthetase syndrome, where anti-aminoacyl-tRNA synthetase antibodies are often identified. An unusual case of acute respiratory distress syndrome, secondary to such proven NSIP of cellular type with predominant CD8 lymphocytes, is described herein. The patient described in the present case study initially had a poor recovery with high dose of steroids, but this was followed by a good improvement after the prescription of tacrolimus and a low dose of prednisone. A precise diagnosis in similar circumstances may be life-saving, allowing the successful application of new immunosuppressants.

Influence of inspiration to expiration ratio on cyclic recruitment and derecruitment of atelectasis in a saline lavage model of acute respiratory distress syndrome*

OBJECTIVE Cyclic recruitment and derecruitment of atelectasis can occur during mechanical ventilation, especially in injured lungs. Experimentally, cyclic recruitment and derecruitment can be quantified by respiration-dependent changes in PaO2 (ΔPaO2), reflecting the varying intrapulmonary shunt fraction within the respiratory cycle. This study investigated the effect of inspiration to expiration ratio upon ΔPaO2 and Horowitz index. DESIGN Prospective randomized study. SETTING Laboratory investigation. SUBJECTS Piglets, average weight 30 ± 2 kg. INTERVENTIONS At respiratory rate 6 breaths/min, end-inspiratory pressure (Pendinsp) 40 cm H2O, positive end-expiratory pressure 5 cm H2O, and FIO2 1.0, measurements were performed at randomly set inspiration to expiration ratios during baseline healthy and mild surfactant depletion injury. Lung damage was titrated by repetitive surfactant washout to induce maximal cyclic recruitment and derecruitment as measured by multifrequency phase fluorimetry. Regional ventilation distribution was evaluated by electrical impedance tomography. Step changes in airway pressure from 5 to 40 cm H2O and vice versa were performed after lavage to calculate PO2-based recruitment and derecruitment time constants (TAU). MEASUREMENTS AND MAIN RESULTS In baseline healthy, cyclic recruitment and derecruitment could not be provoked, whereas in model acute respiratory distress syndrome, the highest ΔPaO2 were routinely detected at an inspiration to expiration ratio of 1:4 (range, 52-277 torr [6.9-36.9 kPa]). Shorter expiration time reduced cyclic recruitment and derecruitment significantly (158 ± 85 torr [21.1 ± 11.3 kPa] [inspiration to expiration ratio, 1:4]; 25 ± 12 torr [3.3 ± 1.6 kPa] [inspiration to expiration ratio, 4:1]; p < 0.0001), whereas the PaO2/FIO2 ratio increased (267 ± 50 [inspiration to expiration ratio, 1:4]; 424 ± 53 [inspiration to expiration ratio, 4:1]; p < 0.0001). Correspondingly, regional ventilation redistributed toward dependent lung regions (p < 0.0001). Recruitment was much faster (TAU: fast 1.6 s [78%]; slow 9.2 s) than derecruitment (TAU: fast 3.1 s [87%]; slow 17.7 s) (p = 0.0078). CONCLUSIONS Inverse ratio ventilation minimizes cyclic recruitment and derecruitment of atelectasis in an experimental model of surfactant-depleted pigs. Time constants for recruitment and derecruitment, and regional ventilation distribution, reflect these findings and highlight the time dependency of cyclic recruitment and derecruitment.

Epidemiology of Acute Lung Injury and Acute Respiratory Distress Syndrome in children in Vietnam

Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS) are life- threatening disorders that can result from many severe conditions and diseases. Since the American European Consensus Conference established the internationally accepted definition of ALI and ARDS, the epidemiology of pediatric ALI/ARDS has been described in some developed countries. In the developing world, however, there are very few data available regarding the burden, etiologies, management, outcome, and factors associated with outcomes of ALI/ARDS in children. ^ Therefore, we conducted this observational, clinical study to estimate the prevalence and case mortality rate of ALI/ARDS among a cohort of patients admitted to the pediatric intensive care unit (PICU) of the National Hospital of Pediatrics in Hanoi, the largest children's hospital in Vietnam. Etiologies and predisposing factors, and management strategies for pediatric ALI/ARDS were described. In addition, we determined the prevalence of HIV infection among children with ALI/ARDS in Vietnam. We also identified the causes of mortality and predictors of mortality and prolonged mechanical ventilation of children with ALI/ARDS. ^ A total of 1,051 patients consecutively admitted to the pediatric intensive care unit from January 2011 to January 2012 were screened daily for development of ALI/ARDS using the American-European Consensus Conference Guidelines. All identified patients with ALI/ARDS were followed until hospital discharge or death in the hospital. Patients' demographic and clinical data were collected. Multivariable logistic regression models were developed to identify independent predictors of mortality and other adverse outcome of ALI/ARDS. ^ Prevalence of ALI and ARDS was 9.6% (95% confidence interval, 7.8% to 11.4%) and 8.8% (95% confidence interval, 7.0% to 10.5%) of total PICU admissions, respectively. Infectious pneumonia and sepsis were the most common causes of ALI/ARDS accounting for 60.4% and 26.7% of cases, respectively. Prevalence of HIV infection among children with ALI/ARDS was 3.0%. The case fatality rate of ALI/ARDS was 63.4% (95% confidence interval, 53.8% to 72.9%). Multiple organ failure and refractory hypoxemia were the main causes of death. Independent predictors of mortality and prolonged mechanical ventilation were male gender, duration of intensive care stay prior to ALI/ARDS diagnosis, level of oxygenation defect measured by PaO2/FiO2 ratio at ALI/ARDS diagnosis, presence of non-pulmonary organ dysfunction at day one and day three after ALI/ARDS diagnosis, and presence of hospital acquired infection. ^ The results of this study demonstrated that ALI/ARDS was a common and severe condition in children in Vietnam. The level of both pulmonary and non-pulmonary organ damage influenced survival of patients with ALI/ARDS. Strategies for preventing ALI/ARDS and for clinical management of the disease are necessary to reduce the associated risks.^

Conservative fluid management or deresuscitation for patients with sepsis or acute respiratory distress syndrome following the resuscitation phase of critical illness: a systematic review and meta-analysis

Background

It is unknown whether a conservative approach to fluid administration or deresuscitation (active removal of fluid using diuretics or renal replacement therapy) is beneficial following haemodynamic stabilisation of critically ill patients.

Purpose

To evaluate the efficacy and safety of conservative or deresuscitative fluid strategies in adults and children with acute respiratory distress syndrome (ARDS), sepsis or systemic inflammatory response syndrome (SIRS) in the post-resuscitation phase of critical illness.

Methods

We searched Medline, EMBASE and the Cochrane central register of controlled trials from 1980 to June 2016, and manually reviewed relevant conference proceedings from 2009 to the present. Two reviewers independently assessed search results for inclusion and undertook data extraction and quality appraisal. We included randomised trials comparing fluid regimens with differing fluid balances between groups, and observational studies investigating the relationship between fluid balance and clinical outcomes.

Results

Forty-nine studies met the inclusion criteria. Marked clinical heterogeneity was evident. In a meta-analysis of 11 randomised trials (2051 patients) using a random-effects model, we found no significant difference in mortality with conservative or deresuscitative strategies compared with a liberal strategy or usual care [pooled risk ratio (RR) 0.92, 95 % confidence interval (CI) 0.82–1.02, I2 = 0 %]. A conservative or deresuscitative strategy resulted in increased ventilator-free days (mean difference 1.82 days, 95 % CI 0.53–3.10, I2 = 9 %) and reduced length of ICU stay (mean difference −1.88 days, 95 % CI −0.12 to −3.64, I2 = 75 %) compared with a liberal strategy or standard care.

Conclusions

In adults and children with ARDS, sepsis or SIRS, a conservative or deresuscitative fluid strategy results in an increased number of ventilator-free days and a decreased length of ICU stay compared with a liberal strategy or standard care. The effect on mortality remains uncertain. Large randomised trials are needed to determine optimal fluid strategies in critical illness.