Bruce M. Greenwald

Clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock: 2007 update from the American College of Critical Care Medicine

Background:The Institute of Medicine calls for the use of clinical guidelines and practice parameters to promote “best practices” and to improve patient outcomes. Objective:2007 update of the 2002 American College of Critical Care Medicine Clinical Guidelines for Hemodynamic Support of Neonates and Children with Septic Shock. Participants:Society of Critical Care Medicine members with special interest in neonatal and pediatric septic shock were identified from general solicitation at the Society of Critical Care Medicine Educational and Scientific Symposia (2001–2006). Methods:The Pubmed/MEDLINE literature database (1966–2006) was searched using the keywords and phrases: sepsis, septicemia, septic shock, endotoxemia, persistent pulmonary hypertension, nitric oxide, extracorporeal membrane oxygenation (ECMO), and American College of Critical Care Medicine guidelines. Best practice centers that reported best outcomes were identified and their practices examined as models of care. Using a modified Delphi method, 30 experts graded new literature. Over 30 additional experts then reviewed the updated recommendations. The document was subsequently modified until there was greater than 90% expert consensus. Results:The 2002 guidelines were widely disseminated, translated into Spanish and Portuguese, and incorporated into Society of Critical Care Medicine and AHA sanctioned recommendations. Centers that implemented the 2002 guidelines reported best practice outcomes (hospital mortality 1%–3% in previously healthy, and 7%–10% in chronically ill children). Early use of 2002 guidelines was associated with improved outcome in the community hospital emergency department (number needed to treat = 3.3) and tertiary pediatric intensive care setting (number needed to treat = 3.6); every hour that went by without guideline adherence was associated with a 1.4-fold increased mortality risk. The updated 2007 guidelines continue to recognize an increased likelihood that children with septic shock, compared with adults, require 1) proportionally larger quantities of fluid, 2) inotrope and vasodilator therapies, 3) hydrocortisone for absolute adrenal insufficiency, and 4) ECMO for refractory shock. The major new recommendation in the 2007 update is earlier use of inotrope support through peripheral access until central access is attained. Conclusion:The 2007 update continues to emphasize early use of age-specific therapies to attain time-sensitive goals, specifically recommending 1) first hour fluid resuscitation and inotrope therapy directed to goals of threshold heart rates, normal blood pressure, and capillary refill ≤2 secs, and 2) subsequent intensive care unit hemodynamic support directed to goals of central venous oxygen saturation >70% and cardiac index 3.3–6.0 L/min/m2.

Treatment of Late Infantile Neuronal Ceroid Lipofuscinosis by CNS Administration of a Serotype 2 Adeno-Associated Virus Expressing CLN2 cDNA

Late infantile neuronal ceroid lipofuscinosis (LINCL) is an autosomal recessive, neurodegenerative lysosomal storage disease affecting the CNS and is fatal by age 8 to 12 years. A total average dose of 2.5 10(12) particle units of an adeno-associated virus (AAV) serotype 2 vector expressing the human CLN2 cDNA (AAV2 CU h-CLN2) was administered to 12 locations in the CNS of 10 children with LINCL. In addition to safety parameters, a neurological rating scale (primary variable) and three quantitative magnetic resonance imaging (MRI) parameters (secondary variables) were used to compare the rate of neurological decline for 18 months in treated subjects compared with untreated subjects. Although there were no unexpected serious adverse events that were unequivocally attributable to the AAV2 CU hCLN2 vector, there were serious adverse effects, the etiology of which could not be determined under the conditions of the experiment. One subject died 49 days postsurgery after developing status epilepticus on day 14, but with no evidence of CNS inflammation. Four of the 10 subjects developed a mild, mostly transient, humoral response to the vector. Compared with control subjects, the measured rates of decline of all MRI parameters were slower, albeit the numbers were too small for statistical significance. Importantly, assessment of the neurologic rating scale, which was the primary outcome variable, demonstrated a significantly reduced rate of decline compared with control subjects. Although the trial is not matched, randomized, or blinded and lacked a contemporaneous placebo/sham control group, assessment of the primary outcome variable suggests a slowing of progression of LINCL in the treated children. On this basis, we propose that additional studies to assess the safety and efficacy of AAV-mediated gene therapy for LINCL are warranted.

Mortality rates in pediatric septic shock with and without multiple organ system failure

Objectives To determine the current mortality rates for pediatric patients with septic shock and the frequency and outcome of associated multiple organ system failure. Design Retrospective chart review. Setting Multidisciplinary pediatric intensive care unit. Patients Children age 1 month to 21 yrs admitted to the pediatric intensive care unit from January 1, 1998, to December 31, 1999, with a diagnosis of septic shock. Interventions None. Measurements and Main Results A database of all admissions to the pediatric intensive care unit was queried, and cases with diagnoses of sepsis and septic shock were reviewed. The final study cohort consisted of 96 episodes of septic shock in 80 patients. Septic shock was defined as a clinical suspicion of sepsis manifested by hyperthermia or hypothermia accompanied by hypotension and/or alteration in perfusion. Multiple organ system failure was defined by established criteria. Data were analyzed by using Fisher’s exact test. The overall mortality rate for the study cohort was 13.5%. There were differences in case mortality rates between patients requiring one inotropic agent (0%) and patients requiring multiple inotropic agents (42.9%), between oncology patients who had undergone bone marrow transplantation (38.5%) and oncology patients without bone marrow transplantation (5.5%), and between patients with multiple organ system failure (18.6%) and those without multiple organ system failure (0%); p < .05. There did not appear to be differences in the case mortality rates between oncology and nononcology patients or among patients with varying degrees of neutropenia. Conclusions The mortality rate in pediatric septic shock is lower than has been previously reported. Oncologic illness in the absence of bone marrow transplantation does not appear to be associated with an increased mortality rate in children with septic shock. Bone marrow transplantation patients have an increased mortality rate compared with other patients with septic shock. Mortality from septic shock occurs most frequently in the context of multiple organ system failure.

Mortality and Functional Morbidity After Use of PALS/APLS by Community Physicians

OBJECTIVES: To test the hypothesis that pediatric shock is a common cause of death and functional morbidity and that pediatric advanced life support (PALS)/advanced pediatric life support (APLS) resuscitation in the community hospital setting improves child health outcomes. METHODS: This study included all children consecutively transported to 5 regional, tertiary care childrens hospitals over 4 years, and is a prospective cohort study comparing outcomes in children who did or did not receive PALS/APLS resuscitation in the community hospital. RESULTS: Shock occurred in 37% of the patients transferred to the tertiary centers. Regardless of trauma status, children with shock had an increased mortality rate compared with those without shock (all patients: 11.4% vs 2.6%), trauma patients (28.3% vs 1.2%), and nontrauma patients (10.5% vs 2.8%). Early shock reversal was associated with reduced mortality (5.06% vs 16.37%) and functional morbidity (1.56% vs 4.11%) rates. Early use of PALS/APLS-recommended interventions was associated with reduced mortality (8.69% vs 15.01%) and functional morbidity (1.24% vs 4.23%) rates. After controlling for center, severity of illness, and trauma status, early reversal of shock and use of PALS/APLS-recommended interventions remained associated with reduced morbidity and mortality rates. CONCLUSIONS: Shock is common in children who are transferred for tertiary care. Pediatric shock recognition and resuscitation in the community hospital improves survival and functional outcome regardless of diagnostic category. The development of shock/trauma systems for children with and without trauma seems prudent.

Impact of computerized prescriber order entry on the incidence of adverse drug events in pediatric inpatients.

OBJECTIVES. This study was conducted to determine the impact of a computerized physician order entry system with substantial decision support on the incidence and types of adverse drug events in hospitalized children. METHODS. A prospective methodology was used for the collection of adverse drug events and potential adverse drug events from all patients admitted to the pediatric intensive care and general pediatric units over a 6-month period. Data from a previous adverse drug event study of the same patient care units before computerized physician order entry implementation were used for comparison purposes. RESULTS. Data for 1197 admissions before the introduction of computerized physician order entry were compared with 1210 admissions collected after computerized physician order entry implementation. After computerized physician order entry implementation, it was observed that the number of preventable adverse drug events (46 vs 26) and potential adverse drug events (94 vs 35) was reduced. Reductions in overall errors, dispensing errors, and drug-choice errors were associated with computerized physician order entry. There were reductions in significant events, as well as those events rated as serious or life threatening, after the implementation of computerized physician order entry. Some types of adverse drug events continued to persist, specifically underdosing of analgesics. There were no differences in length of stay or patient disposition between preventable adverse drug events and potential adverse drug events in either study period. CONCLUSIONS. This study demonstrated that a computerized physician order entry system with substantive decision support was associated with a reduction in both adverse drug events and potential adverse drug events in the inpatient pediatric population. Additional system refinements will be necessary to affect remaining adverse drug events. Preventable events did not predict excess length of stay and instead may represent a sign, rather than a cause, of more complicated illness.

Cornell Assessment of Pediatric Delirium: A Valid, Rapid, Observational Tool for Screening Delirium in the PICU*

Objective:To determine validity and reliability of the Cornell Assessment of Pediatric Delirium, a rapid observational screening tool. Design:Double-blinded assessments were performed with the Cornell Assessment of Pediatric Delirium completed by nursing staff in the PICU. These ratings were compared with an assessment by consultation liaison child psychiatrist using the Diagnostic and Statistical Manual IV criteria as the “gold standard” for diagnosis of delirium. An initial series of duplicate Cornell Assessment of Pediatric Delirium assessments were performed in blinded fashion to assess interrater reliability. Nurses recorded the time required to complete the Cornell Assessment of Pediatric Delirium screen. Setting:Twenty-bed general PICU in a major urban academic medical center over a 10-week period, March–May 2012. Patients:One hundred eleven patients stratified over ages ranging from 0 to 21 years and across developmental levels. Intervention:Two hundred forty-eight paired assessments completed. Measurements and Main Results:The Cornell Assessment of Pediatric Delirium had an overall sensitivity of 94.1% (95% CI, 83.8–98.8%) and specificity of 79.2% (95% CI, 73.5–84.9%). Overall Cronbach’s &agr; of 0.90 was observed, with a range of 0.87–0.90 for each of the eight items, indicating good internal consistency. A scoring cut point of 9 demonstrated good interrater reliability of the Cornell Assessment of Pediatric Delirium when comparing results of the screen between nurses (overall &kgr; = 0.94; item range &kgr; = 0.68–0.78). In patients without significant developmental delay, sensitivity was 92.0% (95% CI, 85.7–98.3%) and specificity was 86.5% (95% CI, 75.4–97.6%). In developmentally delayed children, the Cornell Assessment of Pediatric Delirium showed decreased specificity of 51.2% (95% CI, 24.7–77.8%) but sensitivity remained high at 96.2% (95% CI, 86.5–100%). The Cornell Assessment of Pediatric Delirium takes less than 2 minutes to complete. Conclusions:With an overall prevalence rate of 20.6% in our study population, delirium is a common problem in pediatric critical care. The Cornell Assessment of Pediatric Delirium is a valid, rapid, observational nursing screen that is urgently needed for the detection of delirium in PICU settings.

ACUTE HYPOXEMIC RESPIRATORY FAILURE IN CHILDREN FOLLOWING BONE MARROW TRANSPLANTATION: AN OUTCOME AND PATHOLOGIC STUDY

OBJECTIVES To describe the pulmonary pathology and clinical outcome in children with acute hypoxemic respiratory failure after bone marrow transplantation. DESIGN Review of medical records and pathologic material of patients diagnosed with acute hypoxemic respiratory failure after bone marrow transplantation. SETTING Pediatric intensive care unit (ICU) of a teaching hospital. PATIENTS AND METHODS Retrospective review of a consecutive cohort of children, with a history of bone marrow transplantation admitted to the pediatric ICU during a 7-yr study period, and who met a published definition of acute hypoxemic respiratory failure. For each admission, the pediatric ICU course and outcome were reviewed. Pathologic material that was obtained from the patients was reexamined and assigned to one of the following categories: acute or organizing diffuse alveolar damage, pulmonary hemorrhage, nonspecific interstitial pneumonitis, or infectious pneumonia. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Forty-three patients satisfied criteria for inclusion in the study group. Indications for bone marrow transplantation were: solid tumor (30%), leukemia (44%), congenital immunodeficiency (19%), and aplastic anemia (7%). Patients were admitted to the pediatric ICU a median of 1 month (range 0 to 126) after bone marrow transplantation. Thirty-eight (88%) patients died in the pediatric ICU. Tissue histologic material was available from 21 (49%) patients. Six (29%) of 21 patients had acute diffuse alveolar damage; one (5%) had organizing diffuse alveolar damage; three (14%) had nonspecific interstitial pneumonitis; and two (10%) had pulmonary hemorrhage. Infectious pneumonia occurred in nine (43%) cases (five fungal; four viral). CONCLUSIONS The acute mortality rate (88%) for children with acute hypoxemic respiratory failure after bone marrow transplantation is similar to that reported for adults with this combination of conditions. Diffuse alveolar damage, the histologic hallmark of adult respiratory distress syndrome, was present in a minority (33%) of patients. Infectious pneumonia was the most frequent cause of acute hypoxemic respiratory failure in patients who had pathologic tissue available, emphasizing the need for aggressive diagnostic studies and early institution of antifungal and antiviral therapy.

Novel Influenza A(H1N1) in a Pediatric Health Care Facility in New York City During the First Wave of the 2009 Pandemic

OBJECTIVE To describe the burden of care experienced by our pediatric health care facility in New York, New York, from May 3, 2009, to July 31, 2009, during the novel influenza A(H1N1) pandemic that began in spring 2009. DESIGN Retrospective case series. SETTING Pediatric emergency departments and inpatient facilities of New York-Presbyterian Hospital. Patients Children presenting to the emergency departments with influenza-like illness (ILI) and children aged 18 years or younger hospitalized with positive laboratory test results for influenza A from May 3, 2009, to July 31, 2009. MAIN OUTCOME MEASURES Proportion of children with ILI who were hospitalized and proportion of hospitalized children with influenza A with respiratory failure, bacterial superinfection, and mortality. RESULTS When compared with the same period in 2008, the pediatric emergency departments experienced an excess of 3750 visits (19.9% increase). Overall, 27.7% of visits were for ILI; 2.5% of patients with ILI were hospitalized. Of the 115 hospitalized subjects with confirmed influenza A (median age, 4.3 years), 93 (80.9%) had underlying conditions. Four (3.5%) had identified bacterial superinfection, 1 (0.9%) died, and 35 (30.4%) were admitted to a pediatric intensive care unit; of these 35 patients, 11 had pneumonia and required mechanical ventilation, including high-frequency oscillatory ventilation (n = 3). CONCLUSIONS At our center, 2.5% of children with ILI presenting to the emergency departments during the first wave of the 2009 novel influenza A(H1N1) pandemic were hospitalized. Of the 115 hospitalized children with confirmed influenza A, 9.6% had respiratory failure and 0.9% died. These findings can be compared with the disease severity of subsequent waves of the 2009 novel influenza A(H1N1) pandemic.

Pediatric delirium and associated risk factors: a single-center prospective observational study.

Objective: To describe a single-institution pilot study regarding prevalence and risk factors for delirium in critically ill children. Design: A prospective observational study, with secondary analysis of data collected during the validation of a pediatric delirium screening tool, the Cornell Assessment of Pediatric Delirium. Setting: This study took place in the PICU at an urban academic medical center. Patients: Ninety-nine consecutive patients, ages newborn to 21 years. Intervention: Subjects underwent a psychiatric evaluation for delirium based on the Diagnostic and Statistical Manual IV criteria. Measurements and Main Results: Prevalence of delirium in this sample was 21%. In multivariate analysis, risk factors associated with the diagnosis of delirium were presence of developmental delay, need for mechanical ventilation, and age 2–5 years. Conclusions: In our institution, pediatric delirium is a prevalent problem, with identifiable risk factors. Further large-scale prospective studies are required to explore multi-institutional prevalence, modifiable risk factors, therapeutic interventions, and effect on long-term outcomes.

American College of Critical Care Medicine Clinical Practice Parameters for Hemodynamic Support of Pediatric and Neonatal Septic Shock

Objectives: The American College of Critical Care Medicine provided 2002 and 2007 guidelines for hemodynamic support of newborn and pediatric septic shock. Provide the 2014 update of the 2007 American College of Critical Care Medicine “Clinical Guidelines for Hemodynamic Support of Neonates and Children with Septic Shock.” Design: Society of Critical Care Medicine members were identified from general solicitation at Society of Critical Care Medicine Educational and Scientific Symposia (2006–2014). The PubMed/Medline/Embase literature (2006–14) was searched by the Society of Critical Care Medicine librarian using the keywords: sepsis, septicemia, septic shock, endotoxemia, persistent pulmonary hypertension, nitric oxide, extracorporeal membrane oxygenation, and American College of Critical Care Medicine guidelines in the newborn and pediatric age groups. Measurements and Main Results: The 2002 and 2007 guidelines were widely disseminated, translated into Spanish and Portuguese, and incorporated into Society of Critical Care Medicine and American Heart Association/Pediatric Advanced Life Support sanctioned recommendations. The review of new literature highlights two tertiary pediatric centers that implemented quality improvement initiatives to improve early septic shock recognition and first-hour compliance to these guidelines. Improved compliance reduced hospital mortality from 4% to 2%. Analysis of Global Sepsis Initiative data in resource rich developed and developing nations further showed improved hospital mortality with compliance to first-hour and stabilization guideline recommendations. Conclusions: The major new recommendation in the 2014 update is consideration of institution—specific use of 1) a “recognition bundle” containing a trigger tool for rapid identification of patients with septic shock, 2) a “resuscitation and stabilization bundle” to help adherence to best practice principles, and 3) a “performance bundle” to identify and overcome perceived barriers to the pursuit of best practice principles.