Organ Dysfunction In Children Research Articles

Executive summary: surviving sepsis campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children.

In 2001, the Surviving Sepsis Campaign (SSC) began to develop evidence-based guidelines and recommendations for the resuscitation and management of patients with sepsis. With the 2016 edition, the Society of Critical Care Medicine and European Society of Intensive Care Medicine recommended a separate task force be dedicated to guideline formulation for children. The objective of the “Surviving Sepsis Campaign International Guidelines for the Management of Septic Shock and Sepsis-associated Organ Dysfunction in Children” is to provide guidance for the care of infants, children, and adolescents with septic shock and other sepsis-associated organ dysfunction. Recommendations are intended to guide “best practice” rather than to establish a treatment algorithm or to define standard of care and cannot replace the clinician's decision-making capability when presented with a patient's unique set of clinical variables.

Concurrent Use of Calcium Chloride and Arginine Vasopressin Infusions in Pediatric Patients with Acute Cardiocirculatory Failure.

Acute heart failure (AHF) can cause low cardiac output and poor end-organ perfusion. Inotropic agents along with vasodilators can improve organ perfusion. Arginine vasopressin (AVP) and calcium chloride (CaCl) infusions are increasingly being used in low cardiac output states in pediatric AHF. We retrospectively reviewed 77 patients (0-18years) with AHF admitted between January 2014 and May 2017 who received concurrent AVP and CaCl infusions. Surrogates of cardiac output and organ perfusion included hemodynamic vital signs, laboratory parameters, and urine output (UO). Organ dysfunction and vasopressor inotropic scores were also calculated. Median (IQR) age was 0.88 years (0, 3.75), and median weight was 6.62kg (3.5, 13.7). Congenital heart disease was present in 70% (46/77) patients. Univentricular physiology was present in 25% (25/77) patients. None of the patients were in the immediate postoperative period. Median durations of AVP and CaCl were 2 days (1, 3) and 3 days (2, 6), respectively. Using Wilcoxon-signed rank test and Bonferroni correction, post hoc comparison showed that at 8h post infusion, all systolic blood pressure (SBP) and diastolic blood pressure (DBP) results, and UO were greater than those 1h prior to infusion. Median SBP increased from 79mmHg (71, 92) 1 h prior to 97mmHg (84, 107) 8h post. Median DBP increased from 44 mm Hg (35, 52) 1 h prior to 54 mm Hg (44, 62) 8h post. Heart rate showed a decrease between measurements 1 h prior to infusion and 8h post, with median scores 146 (127, 162) and 136 (114, 150) beats per minute, respectively. Within first 8h, median UO continuously increased from 6mL/h. (0, 25) at 1h post infusion to 20mL/h. (2, 62) at 8h post infusion. Median pediatric logarithmic organ dysfunction scores on days 4 through 7 post infusion were lower compared to day 1; median vasopressor inotropic scores on day 2 through 7 post infusion were lower compared to day 1. Serum lactate level, arterial pH, and base excess all showed favorable trend. Concurrent use of AVP and CaCl infusions may improve surrogates of cardiac output, and intensive care outcomes, and prevent organ dysfunction in children with AHF.

The Prevalence of Chronic Diseases in Children who Have Undergone Critical Periods with A Different Severity of Organ Dysfunction in the Neonatal Period: A Retrospective Cohort Study

It is assumed that the severity of the multiple organ dysfunctions syndrome (MODS) in children who have experienced critical conditions in the neonatal period may influence the prevalence of chronic diseases in the preschool age.The aim of the studywas to study the relationship between the severity of organ dysfunction in children who had undergone critical conditions in the neonatal period, and the prevalence of chronic diseases in preschool age.Methods.The study included children with MODS, the severity of which was assessed on the NEOMOD scale (moderate dysfunction ≤4 points, severe ≥5 points). Data on the prevalence of chronic diseases were obtained from the history of the child’s development (form № 112/y), a card for preventive medical examination of a minor (form № 030-PO/y-12), objective examination data, laboratory and instrumental survey methods, examination data by narrow specialists.Results.The study included 198 children, 100 of them with severe manifestations of SPON and 98 with moderate manifestations of SPON. The groups were comparable by sex, age, social factors (age and level of education of parents), place of residence (city/ village). Chronic diseases in preschool age occurred in 54% and 26% of cases, respectively, p<0.001. The most frequent were psychiatric and behavioral disorders: 40% and 16%, p<0.001, including coarse psychomotor development delay (PDD) of 18% and 1%, p <0.001; diseases of the nervous system: 30 and 14%, p=0.010, including cerebral palsy (CP) 25% and 8%, p=0.002; diseases of the eye: 28% and 24%, p=0.517, including amblyopia 8% and 3% of cases, p=0.113, respectively. Disability occurred in 19 (19%) cases in the main group, and in 5 (5%) cases in the comparison group (p=0.003).The conclusion.Severe manifestations of MODS in the neonatal period are associated with a higher frequency of coarse PDD and CP in preschool age than mild manifestations of MODS, severe manifestations of MODS are not associated with an increase in the frequency of pathology of the eye.

Early Immune Function and Duration of Organ Dysfunction in Critically III Children with Sepsis.

Late immune suppression is associated with nosocomial infection and mortality in adults and children with sepsis. Relationships between early immune suppression and outcomes in children with sepsis remain unclear. Prospective observational study to test the hypothesis that early innate and adaptive immune suppression are associated with longer duration of organ dysfunction in children with severe sepsis or septic shock. Children younger than 18 years of age meeting consensus criteria for severe sepsis or septic shock were sampled within 48 hours of sepsis onset. Healthy control subjects were sampled once. Innate immune function was quantified by whole blood ex vivo LPS-induced TNF-α (tumor necrosis factor-α) production capacity. Adaptive immune function was quantified by ex vivo phytohemagglutinin-induced IFN-γ production capacity. One hundred two children with sepsis and 35 healthy children were enrolled. Compared with healthy children, children with sepsis demonstrated lower LPS-induced TNF-α production (P < 0.0001) and lower phytohemagglutinin-induced IFN-γ production (P < 0.0001). Among children with sepsis, early innate and adaptive immune suppression were associated with greater number of days with multiple organ dysfunction syndrome and greater number of days with any organ dysfunction. On multivariable analyses, early innate immune suppression remained independently associated with increased multiple organ dysfunction syndrome days (adjusted relative risk, 1.2; 95% confidence interval, 1.03-1.5) and organ dysfunction days (adjusted relative risk, 1.2; 95% confidence interval, 1.1-1.3). Critically ill children with severe sepsis or septic shock demonstrate early innate and adaptive immune suppression. Early innate and adaptive immune suppression are associated with longer durations of organ dysfunction and may be useful markers to help guide future investigations of immunomodulatory therapies in children with sepsis.

Predictive Modeling for Organ Dysfunction in Children with Suspected Sepsis in the Emergency Department

Predictive Modeling for Organ Dysfunction in Children with Suspected Sepsis in the Emergency Department

Predictive Modeling for Organ Dysfunction in Children with Suspected Sepsis in the Emergency Department

Purpose: Sepsis recognition is a key challenge in the pediatric emergency department (ED). Targeting aggressive therapy to those at highest risk of morbidity and mortality may help to improve outcomes. We sought to develop a predictive model for the development of organ dysfunction in the first three hospital days among children with suspected sepsis in the ED. Methods: Prospective cohort study in a tertiary care emergency department with over 90,000 visits annually. …

Chronic sacral nerve electrostimulation in treatment of neurogenic pelvic organ dysfunction in children

the review aim is to describe the technique and results of chronic sacral neurostimulation in treatment of pelvic organ disorders in children, which have been reported in the international literature. An obligatory condition for application of chronic sacral neurostimulation (CSNS) is a positive clinical response to test electrostimulation of the S3 nerve root. The test period duration is 1-3 weeks. In the case of a positive effect, a permanent system is implanted for neurostimulation of the S3 nerve root. On treatment with CSNS, children with severe urinary incontinence had a significant decrease in the rate of incontinence episodes, and patients with urinary retention had no or reduced need for periodic catheterization. Therefore, the accumulated experience of using CSNS in children with spinal cord diseases indicates the need in further study of the technique capabilities for correction of pelvic organ dysfunctions.

Multiple organ dysfunction in children mechanically ventilated for acute respiratory failure

目的 独立于脓毒症及肺损伤严重度，肺外脏器功能不全对儿童急性呼吸衰竭预后的影响并不明确。本研究旨在了解儿童急性呼吸衰竭时肺外脏器功能不全发生频率、时机及危险因素，并了解多脏器功能不全综合征(multiple organ dysfunction syndrome，MODS)与预后的独立相关性。 设计 对2009至2013年实行的RESTORE组群随机前瞻性临床试验进行二次观察分析。 场所 31家美国学术型PICU。 对象 RESTORE研究中2 449例因急性呼吸衰竭行机械通气的患儿。 方法和主要结果 根据儿童脓毒症发布标准定义脏器功能不全。MODS定义为呼吸功能不全合并≥1个肺外脏器功能不全。本研究采用多因素Logistic回归分析确定MODS危险因素，采用Logistic或相对风险回归分析法比较临床预后。所有分析均考虑PICU为群组变量。总体来说，73%患儿出现肺外脏器功能不全，包括1 547例(63%)于住院0/1 d即确定合并MODS，244例(10%)于住院2 d或之后新发MODS。多数因脓毒症导致间接肺损伤患儿(93%)合并MODS，而直接肺损伤患儿中合并MODS及新发MODS者分别为56%及12%。合并MODS风险因素包括大年龄、疾病严重度、脓毒症、肿瘤及中/重度肺损伤。新发MODS风险因素包括中/重度肺损伤及神经肌肉阻滞。校正脓毒症、中/重度肺损伤及其他基线特点后，并发MODS及新发MODS均与住院90 d病死率有关(并发MODS：校正OR 6.54，95% CI 3.00－14.25;新发MODS：校正OR 3.21，95%CI 1.48－6.93)。 结论 肺外脏器功能不全较为常见，多数与呼吸功能不全并发(尤其在脓毒症时)，且为儿童急性呼吸衰竭死亡的主要危险因素。

Multiple Organ Dysfunction in Children Mechanically Ventilated for Acute Respiratory Failure.

The impact of extrapulmonary organ dysfunction, independent from sepsis and lung injury severity, on outcomes in pediatric acute respiratory failure is unclear. We sought to determine the frequency, timing, and risk factors for extrapulmonary organ dysfunction and the independent association of multiple organ dysfunction syndrome with outcomes in pediatric acute respiratory failure. Secondary observational analysis of the Randomized Evaluation of Sedation Titration for Respiratory Failure cluster-randomized prospective clinical trial conducted between 2009 and 2013. Thirty-one academic PICUs in the United States. Two thousand four hundred forty-nine children mechanically ventilated for acute respiratory failure enrolled in Randomized Evaluation of Sedation Titration for Respiratory Failure. Organ dysfunction was defined using criteria published for pediatric sepsis. Multiple organ dysfunction syndrome was defined as respiratory dysfunction one or more extrapulmonary organ dysfunctions. We used multivariable logistic regression to identify risk factors for multiple organ dysfunction syndrome, and logistic or proportional hazards regression to compare clinical outcomes. All analyses accounted for PICU as a cluster variable. Overall, 73% exhibited extrapulmonary organ dysfunction, including 1,547 (63%) with concurrent multiple organ dysfunction syndrome defined by onset on day 0/1 and 244 (10%) with new multiple organ dysfunction syndrome with onset on day 2 or later. Most patients (93%) with indirect lung injury from sepsis presented with concurrent multiple organ dysfunction syndrome, whereas patients with direct lung injury had both concurrent (56%) and new (12%) multiple organ dysfunction syndrome. Risk factors for concurrent multiple organ dysfunction syndrome included older age, illness severity, sepsis, cancer, and moderate/severe lung injury. Risk factors for new multiple organ dysfunction syndrome were moderate/severe lung injury and neuromuscular blockade. Both concurrent and new multiple organ dysfunction syndrome were associated with 90-day in-hospital mortality (concurrent: adjusted odds ratio, 6.54; 95% CI, 3.00-14.25 and new: adjusted odds ratio, 3.21; 95% CI, 1.48-6.93) after adjusting for sepsis, moderate/severe lung injury, and other baseline characteristics. Extrapulmonary organ dysfunction was common, generally occurred concurrent with respiratory dysfunction (especially in sepsis), and was a major risk factor for mortality in pediatric acute respiratory failure.

Elevated soluble thrombomodulin is associated with organ failure and mortality in children with acute respiratory distress syndrome (ARDS): a prospective observational cohort study.

IntroductionThe significance of endothelial injury in children with the acute respiratory distress syndrome (ARDS) has not been well studied. Plasma levels of soluble thrombomodulin (sTM), an endothelial surface protein involved in coagulation, have been associated with endothelial injury. We hypothesized that elevated plasma sTM would correlate with mortality and organ failure in children with ARDS.MethodsWe conducted a multicenter prospective observational study of pediatric patients with ARDS between 2008 and 2014. sTM was measured in plasma collected less than 24 hours from ARDS diagnosis. Outcomes were intensive care unit mortality and organ dysfunction by pediatric logistic organ dysfunction scores. Logistic regression was used to adjust for clinically relevant covariates.ResultsPlasma sTM was higher in patients with indirect lung injury compared to direct lung injury (100 ng/mL vs. 86 ng/mL, p = 0.02). Increased sTM levels were correlated with more organ dysfunction in the entire study population (Spearman’s rho = 0.37, p < 0.01). Overall mortality was 16 %. sTM levels were associated with increased mortality in patients with indirect lung injury (OR 2.7 per log(sTM), p = 0.02). These relationships were independent of age, oxygenation defect, or presence of acute kidney injury.ConclusionElevated plasma sTM levels are associated with organ dysfunction in children with ARDS and with higher mortality in children with indirect lung injury. These findings highlight the importance of endothelial injury in children with ARDS and may guide the development of future therapies targeted toward endothelial stabilization, repair, or functional replacement in this population.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-015-1145-9) contains supplementary material, which is available to authorized users.

Early Goal-Directed Therapy in Pediatric Septic Shock

To evaluate the effect of intermittent central venous oxygen saturation monitoring (ScvO(2)) on critical outcomes in children with septic shock, as continuous monitoring may not be feasible in most resource-restricted settings. Prospective cohort study. PICU of a tertiary care teaching hospital. Consecutive children younger than 17 years with fluid refractory septic shock admitted to our ICU from November 2010 to October 2012 were included. Enrolled children were subjected to subclavian/internal jugular catheter insertion. Those in whom it was successful formed the "exposed" group (ScvO(2) group), whereas the rest constituted the control group (no ScvO(2) group). In the former group, intermittent ScvO(2) monitoring at 1, 3, and 6 hours was used to guide resuscitation, whereas in the latter, only clinical variables were used. The major outcomes were in-hospital mortality and achievement of therapeutic goals within first 6 hours. One hundred twenty children were enrolled in the study-63 in the ScvO(2) group and 57 in the no ScvO(2) group. Baseline characteristics including the organ dysfunction and mortality risk scores were comparable between the groups. Children in the ScvO(2) group had significantly lower in-hospital mortality (33.3% vs 54%; relative risk, 0.61; 95% CI, 0.4, 0.93; number needed to treat, 5; 95% CI, 3, 27). A greater proportion of children in exposed group achieved therapeutic endpoints in first 6 hours (43% vs 23%, p = 0.02) and during entire ICU stay (71% vs 51%, p = 0.02). The mean number of dysfunctional organs was also significantly lesser in ScvO(2) group in comparison with no ScvO(2) group (2 vs 3, p < 0.001). Early goal-directed therapy using intermittent ScvO(2) monitoring seemed to reduce the mortality rates and improved organ dysfunction in children with septic shock as compared with those without such monitoring.

Ionized hypocalcemia is an early event and is associated with organ dysfunction in children admitted to the intensive care unit

PurposeThe purpose was to determine the frequency and risk factors of ionized hypocalcemia and to evaluate this disturbance as a predictor of mortality in a pediatric intensive care unit (ICU). Materials and MethodsIn a prospective cohort study, 337 children admitted consecutively to an ICU were monitored regarding serum ionized calcium concentrations during the first 10 days of admission. The following variables were analyzed as independent of hypocalcemia: age; malnutrition; sepsis; Pediatric Index of Mortality 2; first 3 days organ dysfunction score (Pediatric Logistic Organ Dysfunction); and use of steroids, furosemide, and anticonvulsants. Hypocalcemia was defined as a serum ionized calcium concentration less than 1.15 mmol/L. ResultsThe rate of hypocalcemia was 77.15%. In a multivariate model, higher Pediatric Logistic Organ Dysfunction scores during the first 3 days of ICU stay were independently associated with hypocalcemia (odds ratio, 2.24; 95% confidence interval, 1.23-4.07; P = .008). Medications associated with hypocalcemia were furosemide (dose ≥2 mg/[kg d]) and methylprednisolone (dose ≥2 mg/[kg d]). No significant association was found between hypocalcemia and 10-day mortality. ConclusionsIonized hypocalcemia is common during the ICU stay, particularly in the first 3 days of admission. This disturbance was not found to be a predictor of mortality, but it is independently associated with more severe organ dysfunction.

Biomarker response to drotrecogin alfa (activated) in children with severe sepsis

REsearching severe Sepsis and Organ dysfunction in children: A gLobal perspective (RESOLVE), a phase III trial of drotrecogin alfa (activated) in pediatric severe sepsis, examined biomarker changes in inflammation and coagulation. This report describes biomarker profiles in early severe sepsis and the pharmacodynamic assessment of drotrecogin alfa (activated) in RESOLVE. Serial measurements of interleukin-1β, interleukin-6, interleukin-8, interleukin-10, tissue necrosis factor-α, procalcitonin, D-dimer, and thrombin-antithrombin complex were performed at baseline and daily over the first five study days. Protein C levels were performed at baseline and at the end of the 96-hr study drug infusion. Analysis of variance-based log-transformed data compared the treatment groups for each measured variable. : One hundred four pediatric intensive care units in 18 countries. Four hundred seventy-seven children between 38 wks corrected gestational age and 17 yrs with sepsis-induced cardiovascular and respiratory dysfunction. Drotrecogin alfa (activated). Pharmacodynamic activity of drotrecogin alfa (activated) compared with placebo was observed with reduction of D-dimer on day 1 (p < .01) and thrombin-antithrombin complex on days 1-4 (p < .05). There were no significant changes by treatment in multiple cytokines or procalcitonin. In the overall population, a median protein C difference was not observed (p > .05) with drotrecogin alfa (activated) administration compared with placebo, although a difference (median percentage change from baseline) in favor of drotrecogin alfa (activated) was observed in patients >1 yr old (p = .0449). While children in the RESOLVE trial were similar to adults in that they showed a relationship between severity of coagulation and inflammation abnormalities and mortality, their pharmacodynamic response to drotrecogin alfa (activated) differed with respect to changes in protein C activity and systemic inflammation.

Drotrecogin alfa (activated) did not reduce mortality at 28 or 90 days in patients with septic shock

ACP Journal Club21 August 2012Drotrecogin alfa (activated) did not reduce mortality at 28 or 90 days in patients with septic shockChristian Brun-Buisson, MDChristian Brun-Buisson, MDCHU Henri Mondor, AP-HP, Créteil, France (C.B.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-157-4-201208210-02011 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Source CitationRanieri VM, Thompson BT, Barie PS, et al; PROWESS-SHOCK Study Group. Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med. 2012;366:2055-64. https://pubmed.ncbi.nlm.nih.gov/22616830Clinical Impact RatingsHospitalists: Infectious Disease: Critical Care: References1 Bernard GR, Vincent JL, Laterre PF, et al; Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001;344:699-709. [PMID: 11236773] Google Scholar2 Nadel S, Goldstein B, Williams MD, et al; REsearching severe Sepsis and Organ dysfunction in children: a gLobal perspective (RESOLVE) study group. Drotrecogin alfa (activated) in children with severe sepsis: a multicentre phase III randomised controlled trial. Lancet. 2007;369:836-43. [PMID: 17350452] Google Scholar3 Abraham E, Laterre PF, Garg R, et al; Administration of Drotrecogin Alfa (Activated) in Early Stage Severe Sepsis (ADDRESS) Study Group. Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med. 2005;353:1332-41. [PMID: 16192478] Google Scholar Author, Article, and Disclosure InformationAuthors: Christian Brun-Buisson, MDAffiliations: CHU Henri Mondor, AP-HP, Créteil, France (C.B.)This article was published at Annals.org on 7 August 2012. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 21 August 2012Volume 157, Issue 4Page: JC2-11KeywordsDrugsHemorrhageMortalityResuscitationSaline solutionsSepsisSerious adverse eventsShockVasopressorsWeaning ePublished: 21 August 2012 Issue Published: 21 August 2012 Copyright & PermissionsCopyright © 2012 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...

Adjunctive corticosteroid therapy in pediatric severe sepsis: Observations from the RESOLVE study*

To assess whether corticosteroids, used as adjunctive therapy for pediatric severe sepsis, is associated with improved outcomes. Retrospective cohort study examining the clinical database derived from the RESOLVE (REsearching severe Sepsis and Organ dysfunction in children: a gLobal perspective, F1K-MC-EVBP) trial of activated protein C for pediatric severe sepsis. A total of 104 pediatric centers in 18 countries from which data were originally gathered. Children with severe sepsis (n = 477), requiring both vasoactive-inotropic infusions and mechanical ventilation. Within this cohort, 193 children received corticosteroids during their septic episode and 284 did not. None. Baseline summary characteristics demonstrated that children receiving or not receiving corticosteroids had similar demographics and disease severity as indicated by age, gender, mean Pediatric Risk of Mortality scores, and mean number of organ dysfunctions. Use of adjunctive corticosteroids increased during the F1K-MC-EVBP trial. Indications for corticosteroid prescription were therapeutic (89%, mostly shock) and prophylactic (13%). All cause 28-day mortality among children receiving and not receiving corticosteroids was 15.1% and 18.8%, respectively, p = .30. There was no difference in mean vasoactive-inotropic infusion days between the corticosteroid and no corticosteroid groups, 4.5 days vs. 4.3 days, respectively, p = .59. Similarly there was no difference in mean ventilator days between the corticosteroid and no corticosteroid groups, 8.3 days vs. 7.7 days, respectively, p = .38. Children with severe sepsis who received adjunctive corticosteroid therapy exhibited similar illness severity compared with those who did not. No definitive improvement in outcomes can be attributable to adjunctive corticosteroid therapy in the largest pediatric sepsis trial conducted to date.

The future in paediatric respirology

The authors were given the charge of providing a vision of the future in paediatric respirology. Themes selected for being ripe for this visionary analysis include bronchopulmonary dysplasia (BPD), asthma, cystic fibrosis (CF), lung infections, obstructive sleep disordered breathing (OSDB) and pulmonary diagnostics and monitoring. A profound reduction or elimination of BPD is seen. Given the strong genetic component of this disease, genetic biomarkers will likely be identified that will permit much earlier recognition of BPD susceptibility and potentially the ability to modify disease course by altering gene expression. The ultimate prevention of BPD will be to prevent prematurity, but recognition of both the genetic basis of BPD and the inflammatory background should lead to improved prevention and therapy. A clear understanding and definition of asthma phenotypes will lead to more specific and targeted therapy, earlier detection and prevention, better monitoring of severity and adherence to therapy, lower mortality and decreased inappropriate diagnosis of asthma. The greatest opportunities in asthma care will likely come through tools to improve adherence to effective therapy. Also, areas are identified where better therapies are needed such as in patients with severe mucus hypersecretion (secretory hyperresponsiveness) especially in those with life-threatening asthma. The future of CF is easier to foresee with early successes seen in clinical trials. After the expected ability to correct the CF transmembrane regulator, care will need to change and additional research will be needed. Additionally, the face of CF is changing with more adults than children presently having the disease. This will necessitate changes to our approach to treating this disease in a fortunately aging population. If we are going to affect the worldwide lung health of children, we will need to address respiratory infections particularly pneumonia, tuberculosis and HIV-associated infections. Preventive, diagnostic and treatment strategies will shape the future face of these problems. The availability of inexpensive, readily available, and rapid molecular techniques to identify true infection (including HIV and tuberculosis) may permit earlier use of effective therapy while preventing the inappropriate use of antibiotics for common viral diseases. Sleep medicine will continue to be an important aspect of paediatric pulmonology. The evaluation of OSDB cannot rely on full-night attended polysomnography due to limited access. Identifying reliable markers of end organ dysfunction in children with OSDB may permit more rapid identification of patients in need of intervention like CPAP and assisted breathing. In addition, management options, as an alternative to adenotonsilectomy, are listed with a call for further research. Pulmonary diagnostics and monitoring will see the development and refinement of tools like the lung clearance index and the analysis of exhaled gases, volatiles and dissolved biomarkers of inflammation as techniques that might help clinicians identify both the initiation of inflammation while it is more amenable to therapy, and to identify more readily the early changes associated with chronic lung diseases in children. The authors hope that these visionary articles will generate comments, arguments, inspiration, and perhaps even motivate funding agencies.

Intensive plasma exchange increases a disintegrin and metalloprotease with thrombospondin motifs-13 activity and reverses organ dysfunction in children with thrombocytopenia-associated multiple organ failure*

Thrombocytopenia-associated multiple organ failure (TAMOF) is a poorly understood syndrome in critically ill children. A disintegrin and metalloprotease with thrombospondin motifs (ADAMTS-13), formerly known as von Willebrand factor (VWF) cleaving protease, is decreased in adults with VWF-mediated thrombotic microangiopathy, and intensive plasma exchange (PEx) both replenishes ADAMTS-13 and improves outcome in these patients. To determine whether: 1) critically ill children with TAMOF syndrome have decreased ADAMTS-13 activity, 2) ADAMTS-13 activity correlates with platelet counts and VWF antigen, 3) the autopsies from patients who died with reduced ADAMTS-13 activity have VWF-rich microthrombi, and 4) intensive PEx will restore ADAMTS-13 activity and facilitate organ failure resolution. First study: observational. Second study: randomized control trial. Single center university pediatric intensive care unit. First study: thirty-seven consecutive children (17 males and 20 females; ages ranging from 9 days to 23 years) identified with > or = 2 organs dysfunction were enrolled. Seventy-six percent of these children had thrombocytopenia (platelet counts < 100,000/mm3). Five additional critically ill children without MOF were also enrolled. In the second study, children with severe TAMOF (platelet counts < 100,000/mm3 and > 3 organ failure) were randomized to PEx or standard therapy. Primary physicians and parents agreed to enrollment in 10 of the 20 eligible patients with ages ranging from 1 year to 18 years. Five patients received PEx and 5 patients received standard therapy. First study: children with TAMOF (n = 28) had decreased ADAMTS-13 activity, but similar plasminogen activator inhibitor-1 activity and prothrombin time compared to children with MOF without thrombocytopenia (n = 9, p < 0.05). All non-survivors (n = 7) had TAMOF, reduced ADAMTS-13 activity, and VWF-rich microvascular thromboses at autopsy. In the second study, PEx (n = 5, median 12 days, 4-28 days) restored ADAMTS-13 activity and organ function, compared to standard therapy (n = 5, p < 0.05). Children with TAMOF syndrome can have VWF-mediated thrombotic microangiopathy. Similar to adult experience, PEx can replenish ADAMTS-13 activity and reverse organ failure.

Drotrecogin alfa (activated) in children with severe sepsis: a multicentre phase III randomised controlled trial

Drotrecogin alfa (activated) (DrotAA) is used for the treatment of adults with severe sepsis who have a high risk of dying. A phase 1b open-label study has indicated that the pharmacokinetics and pharmacodynamics of DrotAA are similar in children and adults. We initiated the RESOLVE (REsearching severe Sepsis and Organ dysfunction in children: a gLobal perspectiVE) trial to investigate the efficacy and safety of the drug in children. Children aged between 38 weeks' corrected gestational age and 17 years with sepsis-induced cardiovascular and respiratory failure were randomly assigned to receive placebo or DrotAA (24 microg/kg/h) for 96 h. We used a prospectively defined, novel primary endpoint of Composite Time to Complete Organ Failure Resolution (CTCOFR) score. Secondary endpoints were 28-day mortality, major amputations, and safety. Analysis was by intention-to-treat. This trial is registered with clinicaltrials.gov, number NCT00049764. 477 patients were enrolled; 237 received placebo, and 240 DrotAA. Our results showed no significant difference between groups in CTCOFR score (p=0.72) or in 28-day mortality (placebo 17.5%; DrotAA, 17.2%; p=0.93). Although there was no difference in overall serious bleeding events during the 28-day study period (placebo 6.8%; DrotAA 6.7%; p=0.97), there were numerically more instances of CNS bleeding in the DrotAA group (11 [4.6%], vs 5 [2.1%] in placebo, p=0.13), particularly in children younger than 60 days. For CTCOFR score days 1-14, correlation coefficient was -0.016 (95% CI -0.106 to 0.74); relative risk for 28-day mortality was 1.06 (95% CI 0.66 to 1.46) for DrotAA compared with placebo. Although we did not record any efficacy of DrotAA in children with severe sepsis, serious bleeding events were similar between groups and the overall safety profile acceptable, except in children younger than 60 days. However, we gained important insights into clinical and laboratory characteristics of childhood severe sepsis, and have identified issues that need to be addressed in future trials in critically ill children.

RESOLVE-ing sepsis in children – not yet!

The Researching Severe Sepsis and Organ Dysfunction in Children: A Global Perspective study of drotrecogin alfa activated versus placebo was the largest study of adjunctive therapy ever performed in children with severe sepsis. Despite this, the study failed to show any significant differences in outcome between the treatment and placebo groups. The results raise questions about how we should perform meaningful clinical trials in relatively rare conditions such as paediatric sepsis, where the easily measurable endpoints (such as death) are infrequent. A radical rethink of the design of such studies is urgently needed.

Biological and psychological differences in the child and adolescent transplant recipient

Solid organ transplantation has become accepted therapy for the treatment of end-stage organ dysfunction in children. As early management of the pediatric transplant recipient has improved, important age-related differences in long-term patient outcomes have become apparent. Late morbidity and mortality can, in most cases, be attributed to the consequences of long-term immunosuppression: graft loss from under-immunosuppression or an increased incidence of cancer, hypertension, renal failure or diabetes from over-immunosuppression. Age-related differences in both biological and psychological factors play an important role in the optimization of therapy in the transplanted child. Important age-related differences have been demonstrated in all phases of pharmacokinetics: absorption, distribution, metabolism and elimination. Information regarding specific age-related pharmacokinetic differences is lacking for many immunosuppressive medications. Further study using physiologically based pharmacokinetic (PBPK) models will lead to more specific recommendations for age-based immunosuppression protocols. Non-adherence is common among solid organ transplant recipients of all ages and the consequences of non-adherence include increased rejection, late graft loss and death. The biological and psychological developmental changes that occur during adolescence place the transplanted adolescent at an even higher risk of non-adherence and poor outcome than other age groups. Further studies to elucidate the importance of both age-related pharmacokinetic and behavioral factors are needed to formulate therapeutic interventions that would improve adherence and patient outcomes.