Effect of mechanical ventilator weaning protocols on respiratory outcomes in infants and children: a randomized controlled trial

Randolph AG, Wypij D, Venkataraman ST, Hanson JH, Gedeit RG, Meert KL, Luckett PM, Forbes P, Lilley M, Thompson J, Cheifetz IM, Hibberd P, Wetzel R, Cox PN, Arnold JH,

JAMA 2002 Nov;288(20):2561-8

PMID: 12444863


CONTEXT: Ventilator management protocols shorten the time required to wean adult patients from mechanical ventilation. The efficacy of such weaning protocols among children has not been studied.

OBJECTIVE: To evaluate whether weaning protocols are superior to standard care (no defined protocol) for infants and children with acute illnesses requiring mechanical ventilator support and whether a volume support weaning protocol using continuous automated adjustment of pressure support by the ventilator (ie, VSV) is superior to manual adjustment of pressure support by clinicians (ie, PSV).

DESIGN AND SETTING: Randomized controlled trial conducted in the pediatric intensive care units of 10 children’s hospitals across North America from November 1999 through April 2001.

PATIENTS: One hundred eighty-two spontaneously breathing children (<18 years old) who had been receiving ventilator support for more than 24 hours and who failed a test for extubation readiness on minimal pressure support.

INTERVENTIONS: Patients were randomized to a PSV protocol (n = 62), VSV protocol (n = 60), or no protocol (n = 60).

MAIN OUTCOME MEASURES: Duration of weaning time (from randomization to successful extubation); extubation failure (any invasive or noninvasive ventilator support within 48 hours of extubation).

RESULTS: Extubation failure rates were not significantly different for PSV (15%), VSV (24%), and no protocol (17%) (P =.44). Among weaning successes, median duration of weaning was not significantly different for PSV (1.6 days), VSV (1.8 days), and no protocol (2.0 days) (P =.75). Male children more frequently failed extubation (odds ratio, 7.86; 95% confidence interval, 2.36-26.2; P<.001). Increased sedative use in the first 24 hours of weaning predicted extubation failure (P =.04) and, among extubation successes, duration of weaning (P<.001).

CONCLUSIONS: In contrast with adult patients, the majority of children are weaned from mechanical ventilator support in 2 days or less. Weaning protocols did not significantly shorten this brief duration of weaning.

The feasibility of conducting clinical trials in infants and children with acute respiratory failure

Randolph AG, Meert KL, O’Neil ME, Hanson JH, Luckett PM, Arnold JH, Gedeit RG, Cox PN, Roberts JS, Venkataraman ST, Forbes PW, Cheifetz IM,

Am. J. Respir. Crit. Care Med. 2003 May;167(10):1334-40

PMID: 12615617


Designing robust clinical trials in critically ill, mechanically ventilated children requires an understanding of the epidemiology and course of pediatric respiratory failure. As part of a clinical trial, we screened all mechanically ventilated children in nine large pediatric intensive care units (ICUs) across North America for 6 consecutive months. Of 6,403 total ICU admissions, 1,096 (17.1%) required mechanical ventilator support for a minimum of 24 hours. Of these, 701 (64%) met one or more exclusion criteria for trial enrollment. Common reasons for exclusion were upper airway obstruction (13.5%) and cyanotic congenital heart disease (11.5%). Life support interventions were restricted for 9.7% of patients, and 5.5% were chronically ventilator dependent. In the patients who were eligible for respiratory failure studies, 62.4% had an acute primary diagnosis of pulmonary disease, 14.2% neurologic disease, and 8.9% cardiac disease. Chronic underlying conditions were present in 43.2% of the patients. The most common acute diagnosis was bronchiolitis in infants (43.6%) and pneumonia in children 1 year old and older (24.5%). Mortality was rare (1.6%), and the median duration of ventilation was 7 days. The design of clinical trials in critically ill children is feasible but must account for the diverse population, infrequent mortality, and short duration of mechanical ventilation.

Effect of exogenous surfactant (calfactant) in pediatric acute lung injury: a randomized controlled trial

Willson DF, Thomas NJ, Markovitz BP, Bauman LA, DiCarlo JV, Pon S, Jacobs BR, Jefferson LS, Conaway MR, Egan EA,

JAMA 2005 Jan;293(4):470-6

PMID: 15671432


CONTEXT: Despite evidence that patients with acute lung injury (ALI) have pulmonary surfactant dysfunction, trials of several surfactant preparations to treat adults with ALI have not been successful. Preliminary studies in children with ALI have shown that instillation of a natural lung surfactant (calfactant) containing high levels of surfactant-specific protein B may be beneficial.

OBJECTIVE: To determine if endotracheal instillation of calfactant in infants, children, and adolescents with ALI would shorten the course of respiratory failure.

DESIGN, SETTING, AND PATIENTS: A multicenter, randomized, blinded trial of calfactant compared with placebo in 153 infants, children, and adolescents with respiratory failure from ALI conducted from July 2000 to July 2003. Twenty-one tertiary care pediatric intensive care units participated. Entry criteria included age 1 week to 21 years, enrollment within 48 hours of endotracheal intubation, radiological evidence of bilateral lung disease, and an oxygenation index higher than 7. Premature infants and children with preexisting lung, cardiac, or central nervous system disease were excluded.

INTERVENTION: Treatment with intratracheal instillation of 2 doses of 80 mL/m2 calfactant or an equal volume of air placebo administered 12 hours apart.

MAIN OUTCOME MEASURES: Ventilator-free days and mortality; secondary outcome measures were hospital course, adverse events, and failure of conventional mechanical ventilation.

RESULTS: The calfactant group experienced an acute mean (SD) decrease in oxygenation index from 20 (12.9) to 13.9 (9.6) after 12 hours compared with the placebo group’s decrease from 20.5 (14.7) to 15.1 (9.0) (P = .01). Mortality was significantly greater in the placebo group compared with the calfactant group (27/75 vs 15/77; odds ratio, 2.32; 95% confidence interval, 1.15-4.85), although ventilator-free days were not different. More patients in the placebo group did not respond to conventional mechanical ventilation. There were no differences in long-term complications.

CONCLUSIONS: Calfactant acutely improved oxygenation and significantly decreased mortality in infants, children, and adolescents with ALI although no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was observed.

Severity of illness and organ dysfunction scoring in children

Lacroix J, Cotting J,

Pediatr Crit Care Med 2005 May;6(3 Suppl):S126-34

PMID: 15857545


OBJECTIVE: To describe predictive and descriptive general scores that can be used to estimate the severity of illness in critically ill children.

DESIGN: Review of the medical literature.

SETTING: Pediatric intensive care units (PICUs).

PATIENTS: Critically ill children.


MEASUREMENTS AND MAIN RESULTS: Two predictive scores are frequently used in PICUs: the Pediatric Risk of Mortality III score and the Pediatric Index of Mortality 2. The data considered in these scores are collected at baseline. Predictive scores can be used to compare expected and observed mortality in PICUs or to estimate the balance in the baseline severity of illness of patients included in the different arms of a randomized clinical trial. Only one descriptive score is validated to estimate the severity of cases of multiple organ dysfunction syndrome in PICUs, namely, the Pediatric Logistic Organ Dysfunction score. The data required to calculate this score are collected from baseline to discharge from the PICU or up to 2 hrs before death in the PICU. The Pediatric Logistic Organ Dysfunction score can be used to describe the clinical outcome of patients during their stay in a PICU.

CONCLUSION: Pediatric Risk of Mortality III, Pediatric Index of Mortality 2, and Pediatric Logistic Organ Dysfunction scores are the best available tools to estimate the severity of illness in critically ill children.

Cumulative fluid intake minus output is not associated with ventilator weaning duration or extubation outcomes in children

Randolph AG, Forbes PW, Gedeit RG, Arnold JH, Wetzel RC, Luckett PM, O’Neil ME, Venkataraman ST, Meert KL, Cheifetz IM, Cox PN, Hanson JH,

Pediatr Crit Care Med 2005 Nov;6(6):642-7

PMID: 16276328


OBJECTIVE: The effect of fluid balance on respiratory outcomes for critically ill children has not been evaluated. The only indicator of fluid balance routinely recorded across our intensive care units was estimated fluid intake and output. We sought to determine whether cumulative intake minus output (I-O) at the start of weaning predicted weaning duration and whether cumulative I-O at extubation predicted extubation failure.

DESIGN: Prospective observational study.

SETTING: Ten pediatric intensive care units.

PATIENTS: Cumulative I-O was recorded daily for 301 mechanically ventilated children (<18 yrs of age) from November 1999 through April 2001.

INTERVENTIONS: Cumulative I-O was recorded during a study of weaning strategies and extubation failure in which mechanical ventilation of the majority of patients during weaning and extubation was managed according to a protocol that did not include fluid balance indicators. Outcomes were the time to successful removal of ventilatory support and the rate of initial extubation failure.

MEASUREMENTS AND MAIN RESULTS: Relationships between cumulative I-O and outcomes were assessed by means of proportional hazards and logistic regression. The mean cumulative I-O per kilogram of ideal body weight at the start of weaning was 101 mL (sd, 180). Cumulative I-O at the time weaning was initiated did not predict duration of mechanical ventilator weaning. The mean cumulative I-O per kilogram of ideal body weight at extubation was 136 mL (sd, 237). Cumulative I-O at extubation did not predict extubation outcome. There was an association between cumulative I-O at extubation and the duration of weaning in cases not managed by a protocol.

CONCLUSION: Although routinely recorded, cumulative fluid I-O does not appear to have clinical utility in cases managed according to a mechanical ventilator protocol in which tidal volume and oxygenation on minimal levels of ventilator support are systematically tested.

Transfusion strategies for patients in pediatric intensive care units

Lacroix J, Hébert PC, Hutchison JS, Hume HA, Tucci M, Ducruet T, Gauvin F, Collet JP, Toledano BJ, Robillard P, Joffe A, Biarent D, Meert K, Peters MJ, , ,

N. Engl. J. Med. 2007 Apr;356(16):1609-19

PMID: 17442904


BACKGROUND: The optimal hemoglobin threshold for erythrocyte transfusions in critically ill children is unknown. We hypothesized that a restrictive transfusion strategy of using packed red cells that were leukocyte-reduced before storage would be as safe as a liberal transfusion strategy, as judged by the outcome of multiple-organ dysfunction.

METHODS: In this noninferiority trial, we enrolled 637 stable, critically ill children who had hemoglobin concentrations below 9.5 g per deciliter within 7 days after admission to an intensive care unit. We randomly assigned 320 patients to a hemoglobin threshold of 7 g per deciliter for red-cell transfusion (restrictive-strategy group) and 317 patients to a threshold of 9.5 g per deciliter (liberal-strategy group).

RESULTS: Hemoglobin concentrations were maintained at a mean (+/-SD) level that was 2.1+/-0.2 g per deciliter lower in the restrictive-strategy group than in the liberal-strategy group (lowest average levels, 8.7+/-0.4 and 10.8+/-0.5 g per deciliter, respectively; P<0.001). Patients in the restrictive-strategy group received 44% fewer transfusions; 174 patients (54%) in that group did not receive any transfusions, as compared with 7 patients (2%) in the liberal-strategy group (P<0.001). New or progressive multiple-organ dysfunction syndrome (the primary outcome) developed in 38 patients in the restrictive-strategy group, as compared with 39 in the liberal-strategy group (12% in both groups) (absolute risk reduction with the restrictive strategy, 0.4%; 95% confidence interval, -4.6 to 5.4). There were 14 deaths in each group within 28 days after randomization. No significant differences were found in other outcomes, including adverse events.

CONCLUSIONS: In stable, critically ill children a hemoglobin threshold of 7 g per deciliter for red-cell transfusion can decrease transfusion requirements without increasing adverse outcomes. (Controlled-trials.com number, ISRCTN37246456 [controlled-trials.com].).

Anemia, blood loss, and blood transfusions in North American children in the intensive care unit

Bateman ST, Lacroix J, Boven K, Forbes P, Barton R, Thomas NJ, Jacobs B, Markovitz B, Goldstein B, Hanson JH, Li HA, Randolph AG,

Am. J. Respir. Crit. Care Med. 2008 Jul;178(1):26-33

PMID: 18420962


RATIONALE: Minimizing exposure of children to blood products is desirable.

OBJECTIVES: We aimed to understand anemia development, blood loss, and red blood cell (RBC) transfusions in the pediatric intensive care unit (PICU). Methods: Prospective, multicenter, 6-month observational study in 30 PICUs. Data were collected on consecutive children (<18 yr old) in the PICU for 48 hours or more.

MEASUREMENTS AND MAIN RESULTS: Anemia development, blood loss, and RBC transfusions were measured. A total of 977 children were enrolled. Most (74%) children were anemic in the PICU (33% on admission, 41% developed anemia). Blood draws accounted for 73% of daily blood loss; median loss was 5.0 ml/day. Forty-nine percent of children received transfusions; 74% of first transfusions were on Days 1-2. After adjusting for age and illness severity, compared with nontransfused children, children who underwent transfusion had significantly longer days of mechanical ventilation (2.1 d, P < 0.001) and PICU stay (1.8 d, P = 0.03), and had increased mortality (odds ratio [OR], 11.6; 95% confidence interval [CI], 1.43-90.9; P = 0.02), nosocomial infections (OR, 1.9; 95% CI, 1.2-3.0; P = 0.004), and cardiorespiratory dysfunction (OR, 2.1; 95% CI, 1.5-3.0; P < 0.001). High blood loss per kilogram body weight from blood draws (OR, 1.11; 95% CI, 1.03-1.2; P = 0.01) was associated with RBC transfusion more than 48 hours after admission. The most common indication for transfusion was low hemoglobin (42%). Pretransfusion hemoglobin values varied greatly (mean, 9.7 +/- 2.7 g/dl).

CONCLUSIONS: Critically ill children are at significant risk for developing anemia and receiving blood transfusions. Transfusion in the PICU was associated with worse outcomes. It is imperative to minimize blood loss from blood draws and to set clear transfusion thresholds.

Post hoc analysis of calfactant use in immunocompromised children with acute lung injury: Impact and feasibility of further clinical trials

Tamburro RF, Thomas NJ, Pon S, Jacobs BR, Dicarlo JV, Markovitz BP, Jefferson LS, Willson DF,

Pediatr Crit Care Med 2008 Sep;9(5):459-64

PMID: 18679142


OBJECTIVE: To assess the impact of calfactant (a modified natural bovine lung surfactant) in immunocompromised children with acute lung injury and to determine the number of patients required for a definitive clinical trial of calfactant in this population.

DESIGN: Post hoc analysis of data from a previous randomized, control trial.

SETTING: Tertiary care pediatric intensive care units.

PATIENTS: All children, defined as immunocompromised, enrolled in a multicenter, masked, randomized, control trial of calfactant for acute lung injury conducted between July 2000 and July 2003.

INTERVENTIONS: Patients received either an intratracheal instillation of calfactant or an equal volume of air placebo in a protocolized manner.

MEASUREMENTS AND MAIN RESULTS: Eleven of 22 (50%) calfactant-treated patients died when compared with 18 of 30 (60%) placebo patients (absolute risk reduction 10.0%, 95% confidence interval [CI] -17.3, 37.3). Among the 23 patients with an initial oxygen index (OI) >/=13 and

CONCLUSIONS: These preliminary data suggest a potential benefit of calfactant in this high-risk population. A clinical trial powered to appropriately assess these findings seems warranted and feasible.

Comparison of two red-cell transfusion strategies after pediatric cardiac surgery: a subgroup analysis

Willems A, Harrington K, Lacroix J, Biarent D, Joffe AR, Wensley D, Ducruet T, Hébert PC, Tucci M, , ,

Crit. Care Med. 2010 Feb;38(2):649-56

PMID: 19789443


OBJECTIVE: To determine the impact of a restrictive vs. a liberal transfusion strategy on new or progressive multiple organ dysfunction syndrome in children post cardiac surgery. The optimal transfusion threshold after cardiac surgery in children is unknown.

DESIGN: Randomized, controlled trial.

SETTING: Tertiary pediatric intensive care units.

PATIENTS: Participants are a subgroup of pediatric patients post cardiac surgery from the TRIPICU (Transfusion Requirements in Pediatric Intensive Care Units) study. Exclusion criteria specific to the cardiac surgery subgroup included: age <28 days and patients remaining cyanotic.

INTERVENTION: Critically ill children with a hemoglobin < or = 95 g/L within 7 days of pediatric intensive care unit admission were randomized to receive prestorage leukocyte-reduced red-cell transfusion if their hemoglobin dropped either <70 g/L (restrictive) or 95 g/L (liberal).

MEASUREMENTS AND MAIN RESULTS: Postoperative cardiac patients (n = 125) from seven centers were enrolled. The restrictive (n = 63) and liberal (n = 62) groups were similar at baseline in age (mean +/- standard deviation = 31.4 +/- 38.1 mos vs. 26.4 +/- 39.1 mos), surgical procedure, severity of illness (Pediatric Risk of Mortality score = 3.4 +/- 3.2 vs. 3.2 +/- 3.2), multiple organ dysfunction syndrome (46% vs. 44%), mechanical ventilation (62% vs. 60%), and hemoglobin (83 vs. 80 g/L). Mean hemoglobin remained 21 g/L lower in the restrictive group after randomization. No significant difference was found in new or progressive multiple organ dysfunction syndrome (primary outcome) in the restrictive group vs. liberal group (12.7% vs. 6.5%; p = .36), pediatric intensive care unit length of stay (7.0 +/- 5.0 days vs. 7.4 +/- 6.4 days) or 28-day mortality (3.2% vs. 3.2%).

CONCLUSION: In this subgroup analysis of cardiac surgery patients, a restrictive red-cell transfusion strategy, as compared with a liberal one, was not associated with any significant difference in new or progressive multiple organ dysfunction syndrome, but this evidence is not definitive.

Red blood cell transfusion threshold in postsurgical pediatric intensive care patients: a randomized clinical trial

Rouette J, Trottier H, Ducruet T, Beaunoyer M, Lacroix J, Tucci M, ,

Ann. Surg. 2010 Mar;251(3):421-7

PMID: 20118780


BACKGROUND: The optimal transfusion threshold after surgery in children is unknown. We analyzed the general surgery subgroup of the TRIPICU (Transfusion Requirements in Pediatric Intensive Care Units) study to determine the impact of a restrictive versus a liberal transfusion strategy on new or progressive multiple organ dysfunction syndrome (MODS).

METHODS: The TRIPICU study, a prospective randomized controlled trial conducted in 17 centers, enrolled a total of 648 critically ill children with a hemoglobin equal to or below 9.5 g/dL within 7 days of pediatric intensive care unit (PICU) admission to receive prestorage leukocyte-reduced red-cell transfusion if their hemoglobin dropped below either 7.0 g/dL (restrictive) or 9.5 g/dL (liberal). A subgroup of 124 postoperative patients (60 randomized to restrictive and 64 to the liberal group) were analyzed. This study was registered at http://www.controlled-trials.com and carries the following ID ISRCTN37246456.

RESULTS: Participants in the restrictive and liberal groups were similar at randomization in age (restrictive vs. liberal: 53.5 +/- 51.8 vs. 73.7 +/- 61.8 months), severity of illness (pediatric risk of mortality [PRISM] score: 3.5 +/- 4.0 vs. 4.4 +/- 4.0), MODS (35% vs. 29%), need for mechanical ventilation (77% vs. 74%), and hemoglobin level (7.7 +/- 1.1 vs. 7.9 +/- 1.0 g/dL). The mean hemoglobin level remained 2.3 g/dL lower in the restrictive group after randomization. No significant differences were found for new or progressive MODS (8% vs. 9%; P = 0.83) or for 28-day mortality (2% vs. 2%; P = 0.96) in the restrictive versus liberal group. However, there was a statistically significant difference between groups for PICU length of stay (7.7 +/- 6.6 days for the restrictive group vs. 11.6 +/- 10.2 days for the liberal group; P = 0.03).

CONCLUSIONS: In this subgroup analysis of pediatric general surgery patients, we found no conclusive evidence that a restrictive red-cell transfusion strategy, as compared with a liberal one, increased the rate of new or progressive MODS or mortality.