Anil Sapru

Pediatric Acute Respiratory Distress Syndrome: Consensus Recommendations From the Pediatric Acute Lung Injury Consensus Conference

OBJECTIVE To describe the final recommendations of the Pediatric Acute Lung Injury Consensus Conference. DESIGN Consensus conference of experts in pediatric acute lung injury. SETTING Not applicable. SUBJECTS PICU patients with evidence of acute lung injury or acute respiratory distress syndrome. INTERVENTIONS None. METHODS A panel of 27 experts met over the course of 2 years to develop a taxonomy to define pediatric acute respiratory distress syndrome and to make recommendations regarding treatment and research priorities. When published, data were lacking a modified Delphi approach emphasizing strong professional agreement was used. MEASUREMENTS AND MAIN RESULTS A panel of 27 experts met over the course of 2 years to develop a taxonomy to define pediatric acute respiratory distress syndrome and to make recommendations regarding treatment and research priorities. When published data were lacking a modified Delphi approach emphasizing strong professional agreement was used. The Pediatric Acute Lung Injury Consensus Conference experts developed and voted on a total of 151 recommendations addressing the following topics related to pediatric acute respiratory distress syndrome: 1) Definition, prevalence, and epidemiology; 2) Pathophysiology, comorbidities, and severity; 3) Ventilatory support; 4) Pulmonary-specific ancillary treatment; 5) Nonpulmonary treatment; 6) Monitoring; 7) Noninvasive support and ventilation; 8) Extracorporeal support; and 9) Morbidity and long-term outcomes. There were 132 recommendations with strong agreement and 19 recommendations with weak agreement. Once restated, the final iteration of the recommendations had none with equipoise or disagreement. CONCLUSIONS The Consensus Conference developed pediatric-specific definitions for acute respiratory distress syndrome and recommendations regarding treatment and future research priorities. These are intended to promote optimization and consistency of care for children with pediatric acute respiratory distress syndrome and identify areas of uncertainty requiring further investigation.

Fluid balance in critically ill children with acute lung injury

Objectives: In the Fluid and Catheter Treatment Trial (NCT00281268), adults with acute lung injury randomized to a conservative vs. liberal fluid management protocol had increased days alive and free of mechanical ventilator support (ventilator-free days). Recruiting sufficient children with acute lung injury into a pediatric trial is challenging. A Bayesian statistical approach relies on the adult trial for the a priori effect estimate, requiring fewer patients. Preparing for a Bayesian pediatric trial mirroring the Fluid and Catheter Treatment Trial, we aimed to: 1) identify an inverse association between fluid balance and ventilator-free days; and 2) determine if fluid balance over time is more similar to adults in the Fluid and Catheter Treatment Trial liberal or conservative arms. Design: Multicentered retrospective cohort study. Setting: Five pediatric intensive care units. Patients: Mechanically ventilated children (age ≥1 month to <18 yrs) with acute lung injury admitted in 2007–2010. Interventions: None. Measurements and Main Results: Fluid intake, output, and net fluid balance were collected on days 1–7 in 168 children with acute lung injury (median age 3 yrs, median PaO2/FIO2 138) and weight-adjusted (mL/kg). Using multivariable linear regression to adjust for age, gender, race, admission day illness severity, PaO2/FIO2, and vasopressor use, increasing cumulative fluid balance (mL/kg) on day 3 was associated with fewer ventilator-free days (p = .02). Adjusted for weight, daily fluid balance on days 1–3 and cumulative fluid balance on days 1–7 were higher in these children compared to adults in the Fluid and Catheter Treatment Trial conservative arm (p < .001, each day) and was similar to adults in the liberal arm. Conclusions: Increasing fluid balance on day 3 in children with acute lung injury at these centers is independently associated with fewer ventilator-free days. Our findings and the similarity of fluid balance patterns in our cohort to adults in the Fluid and Catheter Treatment Trial liberal arm demonstrate the need to determine whether a conservative fluid management strategy improves clinical outcomes in children with acute lung injury and support a Bayesian trial mirroring the Fluid and Catheter Treatment Trial.

The Association Between a Darc Gene Polymorphism and Clinical Outcomes in African American Patients With Acute Lung Injury

BACKGROUND Acute lung injury (ALI) mortality is increased among African Americans compared with Americans of European descent, and genetic factors may be involved. A functional T-46C polymorphism (rs2814778) in the promoter region of Duffy antigen/receptor for chemokines (Darc) gene, present almost exclusively in people of African descent, results in isolated erythrocyte DARC deficiency and has been implicated in ALI pathogenesis in preclinical and murine models, possibly because of an increase in circulating Duffy-binding, proinflammatory chemokines like IL-8. We sought to determine the effect of the functional rs2814778 polymorphism, C/C genotype (Duffy null state), on clinical outcomes in African Americans with acute lung injury. METHODS Clinical data and biologic specimens from African American patients with ALI who enrolled in three randomized controlled trials were analyzed. Multivariate analysis accounted for proportion of African ancestry, sex, cirrhosis, and severity of illness on presentation. RESULTS Among 132 subjects, 88 (67%) were Duffy null (C/C genotype). The Duffy null state was associated with a 17% absolute risk increase (95% CI, 1.4%-33%) in mortality at 60 days, a median of 8 fewer ventilator-free days (95% CI, 1-18.5), and 4.5 fewer organ failure-free days (95% CI, 0-18) compared with individuals with the C/T or T/T genotypes (all P values < .05). Estimates were similar on multivariate analysis. In African Americans without the null variant, clinical outcomes were similar to those in patients of European descent. A subgroup analysis suggested that plasma IL-8 levels are increased in Duffy null individuals. CONCLUSIONS Our results provide evidence that the functional rs2814778 polymorphism in the gene encoding DARC is associated with worse clinical outcomes among African Americans with ALI, possibly via an increase in circulating IL-8.

Biological markers of lung injury before and after the institution of positive pressure ventilation in patients with acute lung injury

BackgroundSeveral biological markers of lung injury are predictors of morbidity and mortality in patients with acute lung injury (ALI). The low tidal volume lung-protective ventilation strategy is associated with a significant decrease in plasma biomarker levels compared to the high tidal volume ventilation strategy. The primary objective of this study was to test whether the institution of lung-protective positive pressure ventilation in spontaneously ventilating patients with ALI exacerbates pre-existing lung injury by using measurements of biomarkers of lung injury before and after intubation.Materials and methodsA prospective observational cohort study was conducted in the intensive care unit of a tertiary care university hospital. Twenty-five intubated, mechanically ventilated patients with ALI were enrolled. Physiologic data and serum samples were collected within 6 hours before intubation and at two different time points within the first 24 hours after intubation to measure the concentration of interleukin (IL)-6, IL-8, intercellular adhesion molecule 1 (ICAM-1), and von Willebrand factor (vWF). The differences in biomarker levels before and after intubation were analysed using repeated measures analysis of variance and a paired t test with correction for multiple comparisons.ResultsBefore endotracheal intubation, all of the biological markers (IL-8, IL-6, ICAM-1, and vWF) were elevated in the spontaneously breathing patients with ALI. After intubation and the institution of positive pressure ventilation (tidal volume 7 to 8 ml/kg per ideal body weight), none of the biological markers was significantly increased at either an early (3 ± 2 hours) or later (21 ± 5 hours) time point. However, the levels of IL-8 were significantly decreased at the later time point (21 ± 5 hours) after intubation. During the 24-hour period after intubation, the PaO2/FiO2 (partial pressure of arterial oxygen/fraction of the inspired oxygen) ratio significantly increased and the plateau airway pressure significantly decreased.ConclusionLevels of IL-8, IL-6, vWF, and ICAM-1 are elevated in spontaneously ventilating patients with ALI prior to endotracheal intubation. The institution of a lung-protective ventilation strategy with positive pressure ventilation does not further increase the levels of biological markers of lung injury. The results suggest that the institution of a lung-protective positive pressure ventilation strategy does not worsen the pre-existing lung injury in most patients with ALI.

4G/5G Polymorphism of Plasminogen Activator Inhibitor -1 Gene Is Associated with Mortality in Intensive Care Unit Patients with Severe Pneumonia

Background:Higher plasma and pulmonary edema fluid levels of plasminogen activator inhibitor-1 (PAI-1) are associated with increased mortality in patients with pneumonia and acute lung injury. The 4G allele of the 4G/5G polymorphism of the PAI-1 gene is associated with higher PAI-1 levels and an increased incidence of hospitalizations for pneumonia. The authors hypothesized that the 4G allele would be associated with worse clinical outcomes (mortality and ventilator-free days) in patients with severe pneumonia. Methods:The authors enrolled patients admitted with severe pneumonia in a prospective cohort. Patients were followed until hospital discharge. DNA was isolated from blood samples, and genotyping detection for the PAI-1 4G/5G polymorphism was carried out using Taqman-based allelic discrimination. Results:A total of 111 patients were available for analysis. Distribution of genotypes was 4G/4G 26 of 111 (23%), 4G/5G 59 of 111 (53%), and 5G/5G 26 of 111 (23%). Of 111 patients, 32 (29%) died before hospital discharge and 105 patients (94%) received mechanical ventilation. Patients with the 4G/4G and the 4G/5G genotypes had higher mortality (35% vs. 8%, P = 0.007) and fewer ventilator-free days (median 4 vs. 13, P = 0.04) compared to patients with the 5G/5G genotype. Conclusions:The 4G allele of the 4G/5G polymorphism in the PAI-1 gene is associated with fewer ventilator-free days and increased mortality in hospitalized patients with severe pneumonia. These findings suggest that PAI-1 may have a role in pathogenesis and that the 4G/5G polymorphism may be an important biomarker of risk in patients with severe pneumonia.

Using acupuncture for acute pain in hospitalized children

Objective: Clinical study to determine the acceptability and feasibility of acupuncture for acute postoperative pain control in hospitalized children. Design: Nonrandomized clinical trial. Setting: A single, tertiary referral pediatric intensive care unit. Patients: A total of 20 patients aged 7 months to 18 years. Eleven of the patients had posterior spinal fusion surgery and the remaining nine patients had other surgical diagnoses. Interventions: Two 10- to 15-minute sessions of acupuncture 24–48 hours apart. Outcome Measures and Results: The treatment was highly accepted (27 patients were approached and 4 patients refused; of the 23 patients enrolled, 20 patients completed the study). Acupuncture was well tolerated by patients without adverse events related to treatment. In follow-up interviews, 70% of both parents and patients believed acupuncture helped the child’s pain. Eighty-five percent of the parents said they would pay out of pocket for acupuncture if not covered by insurance. The pain scores, vital signs, and narcotic usage were recorded before and several times after acupuncture. In posterior spinal fusion patients, the mean pain scores (0–10) immediately before and 4 and 24 hours after acupuncture were: 3.7, 1.7, and 3.1, respectively, after the first acupuncture session and 3.7, 2.2, and 3.1, respectively, after the second session. In the other surgical cohort, the mean pain scores immediately before and 4 and 24 hours after the first session of acupuncture were 2.5, 0.3, and 1.6, respectively. Conclusions: Our results support that acupuncture is highly accepted and feasible in critically ill, postoperative pediatric patients with acute pain. Our findings suggest that acupuncture may be a potentially useful adjunctive tool for acute pediatric postoperative pain management. A randomized, controlled clinical trial is warranted to confirm these findings.

Performance of Bovine Pericardial Valves in the Pulmonary Position

BACKGROUND The purpose of this study is to determine the outcome and performance of bovine pericardial valves in the pulmonary position. METHODS This is a retrospective review of all patients with congenital heart disease who had pulmonary valve replacement using a bovine pericardial valve from 2002 to 2009 at a single institution. RESULTS There were 73 consecutive patients, with a median age of 17.3 years (range, 2.1 to 64.4). Their diagnosis was tetralogy of Fallot (n = 47), pulmonary stenosis (n = 11), or other (n = 15). Sixty-nine patients had 91 previous surgical procedures. The mean time from last surgery was 19.9 ± 11.6 years. Forty-three patients had concomitant surgical procedures. There were no perioperative deaths. Clinical follow-up was available in 68 patients (93%). There were no late deaths, and all patients were in New York Heart Association functional class I during a median follow-up period of 2.6 years (range, 0.2 to 8.0). One patient had endocarditis necessitating valve removal 2 years after surgery. Freedom from pulmonary valve reoperation was 100%, 97.7%, and 97.7% at 1, 3, and 5 years, respectively (95% confidence interval: 93.2% to 100%). Mean pulmonary valve gradient at follow-up was 19 ± 14 mm Hg. Degree of pulmonary insufficiency was less than moderate in 62 patients, moderate in 4, and more than moderate in 2. Freedom from moderate-severe or severe pulmonary insufficiency was 97.7%, 89.1%, and 89.1% at 1, 3, and 5 years, respectively (5-year 95% confidence interval: 77.0% to 100%). CONCLUSIONS Pulmonary valve replacement using a bovine pericardial valve can be accomplished with low perioperative morbidity and favorable midterm outcomes. Further follow-up is necessary to evaluate the long-term performance of bovine pericardial valves in the pulmonary position.

Efficacy and safety of lung recruitment in pediatric patients with acute lung injury.

Objective: To assess the safety and efficacy of a recruitment maneuver, the Open Lung Tool, in pediatric patients with acute lung injury and acute respiratory distress syndrome. Design: Prospective cohort study using a repeated-measures design. Setting: Pediatric intensive care unit at an urban tertiary childrens hospital. Patients: Twenty-one ventilated pediatric patients with acute lung injury. Intervention: Recruitment maneuver using incremental positive end-expiratory pressure. Measurements and Main Results: The ratio of partial pressure of arterial oxygen over fraction of inspired oxygen (Pao2/Fio2 ratio) increased 53% immediately after the recruitment maneuver. The median Pao2/Fio2 ratio increased from 111 (interquartile range, 73–266) prerecruitment maneuver to 170 (interquartile range, 102–341) immediately postrecruitment maneuver (p < .01). Improvement in Pao2/Fio2 ratio persisted with an increase of 80% over the baseline at 4 hrs and 40% at 12 hrs after the recruitment maneuver. The median Pao2/Fio2 ratio was 200 (interquartile range, 116–257) 4 hrs postrecruitment maneuver (p < .05) and 156 (interquartile range, 127–236) 12 hrs postrecruitment maneuver (p < .01). Compared with prerecruitment maneuver, the partial pressure of arterial carbon dioxide (Paco2) was significantly decreased at 4 hrs postrecruitment maneuver but not immediately after the recruitment maneuver. The median Paco2 was 49 torr (interquartile range, 44–60) prerecruitment maneuver compared with 48 torr (interquartile range, 43–50) immediately postrecruitment maneuver (p = .69), 45 torr (interquartile range, 41–50) at 4 hrs postrecruitment maneuver (p < .01), and 43 torr (interquartile range, 38–51) at 12 hrs postrecruitment maneuver. Recruitment maneuvers were well tolerated except for significant increase in Paco2 in three patients. There were no serious adverse events related to the recruitment maneuver. Conclusions: Using the modified open lung tool recruitment maneuver, pediatric patients with acute lung injury may safely achieve improved oxygenation and ventilation with these benefits potentially lasting up to 12 hrs postrecruitment maneuver.

Cardiac surgery in low birth weight infants: current outcomes

Low birth weight (LBW) is a risk factor for mortality in neonatal and infant heart surgery. The purpose of this study was to determine the contemporary outcomes and risk factors of cardiac surgery in low weight babies. The records of 75 consecutive infants weighing <2.5 kg having heart surgery were reviewed. The median weight was 2100 g (range 800-2500 g) and median age was 11 days (range 2-86 days). Half (n=38) of the infants were premature. Diagnoses included: arch obstruction (n=14), hypoplastic left heart syndrome (HLHS) (n=12), tetralogy of Fallot (ToF) or pulmonary atresia (PA)/ventricular septal defect (VSD) (n=11), transposition of the great arteries (TGA) (n=7), total anomalous pulmonary venous return (TAPVR) (n=5), and other (n=20). There were two early deaths. Follow-up was available on all infants with a median duration of 1320 days (range 6-3055 days). Cumulative Kaplan-Meier survival at one year was 90% [95% confidence interval (CI), 80-95%] and at five years was 88% (95% CI, 77-94%). Overall mortality amongst patients with genetic/chromosomal abnormalities was higher, 28% vs. 5.4% amongst patients without such abnormalities (P=0.008). Age, prematurity, preoperative mechanical ventilation, prostaglandins, non-cardiac organ dysfunction, extra-cardiac malformations, perioperative extracorporeal membrane oxygenation (ECMO), and type of procedure were not associated with significant differences in mortality. Cardiac surgery in LBW infants can be performed with low early and mid-term mortality. LBW infants with chromosomal/genetic anomalies have a higher risk.

Pathobiology of acute respiratory distress syndrome.

The unique characteristics of pulmonary circulation and alveolar-epithelial capillary-endothelial barrier allow for maintenance of the air-filled, fluid-free status of the alveoli essential for facilitating gas exchange, maintaining alveolar stability, and defending the lung against inhaled pathogens. The hallmark of pathophysiology in acute respiratory distress syndrome is the loss of the alveolar capillary permeability barrier and the presence of protein-rich edema fluid in the alveoli. This alteration in permeability and accumulation of fluid in the alveoli accompanies damage to the lung epithelium and vascular endothelium along with dysregulated inflammation and inappropriate activity of leukocytes and platelets. In addition, there is uncontrolled activation of coagulation along with suppression of fibrinolysis and loss of surfactant. These pathophysiological changes result in the clinical manifestations of acute respiratory distress syndrome, which include hypoxemia, radiographic opacities, decreased functional residual capacity, increased physiologic deadspace, and decreased lung compliance. Resolution of acute respiratory distress syndrome involves the migration of cells to the site of injury and re-establishment of the epithelium and endothelium with or without the development of fibrosis. Most of the data related to acute respiratory distress syndrome, however, originate from studies in adults or in mature animals with very few studies performed in children or juvenile animals. The lack of studies in children is particularly problematic because the lungs and immune system are still developing during childhood and consequently the pathophysiology of pediatric acute respiratory distress syndrome may differ in significant ways from that seen in acute respiratory distress syndrome in adults. This article describes what is known of the pathophysiologic processes of pediatric acute respiratory distress syndrome as we know it today while also presenting the much greater body of evidence on these processes as elucidated by adult and animal studies. It is also our expressed intent to generate enthusiasm for larger and more in-depth investigations of the mechanisms of disease and repair specific to children in the years to come.