The risks of the new morbidities acquired during pediatric onco-critical care and their life-shortening effects

Abstract Objective: The authors investigated the functional status at ICU admission and at hospital discharge, and the impact of dysfunctions on survivors' lifespan. Method: Single-center retrospective cohort. The FSS (Functional Status Scale) was calculated at ICU admission and at hospital discharge. A new morbidity was defined as an increase in FSS ≥ 3. Results: Among 1002 patients, there were 855 survivors. Of these, 194 (22.6%) had died by the end of the study; 45 (5.3%) had a new morbidity. Means in the motor domain at admission and discharge were 1.37 (SD: 0.82) and 1.53 (SD 0.95, p = 0.002). In the feeding domain, the means were 1.19 (SD 0.63) and 1.30 (SD 0.76), p = 0.002; global means were 6.93 (SD 2.45) and 7.2 (SD 2.94), p = 0.007. Acute respiratory failure requiring mechanical ventilation, the score PRISM IV, age < 5 years, and central nervous system tumors were independent predictors of new morbidity. New morbidity correlated with lower odds of survival after hospital discharge, considering all causes of death (p = 0.014), and was independently predictive of death (Cox hazard ratio = 1.98). In Weibull models, shortening in the life span of 14.2% (p = 0.014) was estimated as a new morbidity. Conclusions: New morbidities are related to age, disease severity at admission, and SNC tumors. New morbidities, in turn, correlate with lower probabilities of survival and shortening of the remaining life span. Physical rehabilitation interventions in this population of children may have the potential to provide an increase in lifespan.

Prevalence and functional status of children with complex chronic conditions in Brazilian PICUs during the COVID-19 pandemic

Abstract Objective The proportion of children with complex chronic conditions is increasing in PICUs around the world. We determined the prevalence and functional status of children with complex chronic conditions in Brazilian PICUs during the COVID-19 pandemic. Methods The authors conducted a point prevalence cross-sectional study among fifteen Brazilian PICUs during the COVID-19 pandemic. The authors enrolled all children admitted to the participating PICUs with complex chronic conditions on three different days, four weeks apart, starting on April 4th, 2020. The authors recorded the patient's characteristics and functional status at admission and discharge days. Results During the 3 study days from March to June 2020, the authors enrolled 248 patients admitted to the 15 PICUs; 148 had CCC (prevalence of 59.7%). Patients had a median of 1 acute diagnosis and 2 chronic diagnoses. The use of resources/devices was extensive. The main mode of respiratory support was conventional mechanical ventilation. Most patients had a peripherally inserted central catheter (63.1%), followed by a central venous line (52.5%), and 33.3% had gastrostomy or/and tracheostomy. The functional status score was significantly better at discharge compared to admission day due to the respiratory status improvement. Conclusions The prevalence of children with CCC admitted to the Brazilian PICUs represented 59.7% of patients during the COVID-19 pandemic. The functional status of these children improved during hospitalization, mainly due to the respiratory component.

Tracheostomy practices in children on mechanical ventilation: a systematic review and meta-analysis

Abstract Objective: To evaluate current practices of tracheostomy in children regarding the ideal timing of tracheostomy placement, complications, indications, mortality, and success in decannulation. Source of data: The authors searched PubMed, Embase, Cochrane Library, Google Scholar, and complemented by manual search. The guidelines of PRISMA and MOOSE were applied. The quality of the included studies was evaluated with the Newcastle-Ottawa Scale. Information extracted included patients' characteristics, outcomes, time to tracheostomy, and associated complications. Odds ratios (ORs) with 95% CIs were computed using theMantel-Haenszel method. Synthesis of data: Sixty-six articles were included in the qualitative analysis, and 8 were included in the meta-analysis about timing for tracheostomy placement. The risk ratio for "death in hospital outcome" did not show any benefit from performing a tracheostomy before or after 14 days of mechanical ventilation (p = 0.49). The early tracheostomy before 14 days had a great impact on the days of mechanical ventilation (-26 days in mean difference, p < 0.00001). The authors also found a great reduction in hospital length of stay (-31.4 days, p < 0.008). For the days in PICU, the mean reduction was of 14.7 days (p < 0.007). Conclusions: The meta-analysis suggests that tracheostomy performed in the first 14 days of ventilation can reduce the time spent on the ventilator, and the length of stay in the hospital, with no effect on mortality. The decision to perform a tracheostomy early or late may be more dependent on the baseline disease than on the time spent on ventilation.

Oxigenação por membrana extracorpórea na insuficiência respiratória em crianças: os anos antes e depois da pandemia de H1N1 de 2009 / Extracorporeal membrane oxygenation for respiratory failure in children: the years before and after the 2009 H1N1 pandemic

RESUMO Objetivo: Avaliar o impacto no número de casos de oxigenação por membrana extracorpórea e as taxas de sobrevivência nos anos seguintes à pandemia de H1N1 de 2009. Métodos: Avaliaram-se dois períodos distintos de utilização de oxigenação por membrana extracorpórea como suporte para insuficiência respiratória em crianças, por meio da análise de conjuntos de dados da Extracorporeal Life Support Organization. Foram construídos modelos autorregressivos integrados de médias móveis para estimar os efeitos da pandemia. O ano de 2009 foi o ano de intervenção (epidemia de H1N1) em um modelo de séries temporais interrompidas. Os dados colhidos entre 2001 e 2010 foram considerados pré-intervenção e os obtidos entre 2010 e 2017 como pós-intervenção. Resultados: Em comparação com o período entre 2001 e 2010, o período entre 2010 e 2017 mostrou aumento das taxas de sobrevivência (p < 0,0001), com melhora significante da sobrevivência quando se realizou oxigenação por membrana extracorpórea nos casos de insuficiência aguda por pneumonia viral. Antes do ponto de nível de efeito (2009), o modelo autorregressivo integrado de médias móveis mostrou aumento de 23 casos de oxigenação por membrana extracorpórea ao ano. Em termos de sobrevivência, a curva mostra que não houve aumento significante das taxas de sobrevivência antes de 2009 (p = 0,41), porém o nível de efeito foi próximo à significância após 2 anos (p = 0,05), com aumento de 6% na sobrevivência. Em 4 anos, ocorreu aumento de 8% (p = 0,03) na sobrevivência, e, 6 anos após 2009, a sobrevivência mostrou aumento de até 10% (p = 0,026). Conclusão: Nos anos após 2009, ocorreu significante e progressivo aumento global das taxas de sobrevivência com oxigenação por membrana extracorpórea para todos os casos, principalmente em razão de melhoras tecnológicas e dos protocolos de tratamento para insuficiência respiratória aguda relacionada à pneumonia viral e a outras condições respiratórias.

ABSTRACT Objective: To evaluate whether there was any impact on the number of pediatric extracorporeal membrane oxygenation runs and survival rates in the years subsequent to the 2009 pandemic. Methods: We studied two different periods of extracorporeal membrane oxygenation support for respiratory failure in children by analyzing datasets from the Extracorporeal Life Support Organization. Autoregressive integrated moving average models were constructed to estimate the effect of the pandemic. The year 2009 was the year of intervention (the H1N1 epidemic) in an interrupted time series model. Data collected from 2001 - 2010 were considered preintervention, and data collected from 2010 - 2017 were considered postintervention. Results: There was an increase in survival rates in the period 2010 - 2017 compared to 2001 - 2010 (p < 0.0001), with a significant improvement in survival when extracorporeal membrane oxygenation was performed for acute respiratory failure due to viral pneumonia. The autoregressive integrated moving average model shows an increase of 23 extracorporeal membrane oxygenation runs per year, prior to the point of the level effect (2009). In terms of survival, the preslope shows that there was no significant increase in survival rates before 2009 (p = 0.41), but the level effect was nearly significant after two years (p = 0.05), with a 6% increase in survival. In four years, there was an 8% (p = 0.03) increase in survival, and six years after 2009, there was up to a 10% (p = 0.026) increase in survival. Conclusion: In the years following 2009, there was a significant, global incremental increase in the extracorporeal membrane oxygenation survival rates for all runs, mainly due to improvements in the technology and treatment protocols for acute respiratory failure related to viral pneumonia and other respiratory conditions.

Práticas clínicas relacionadas a cânulas nasais de alto fluxo em terapia intensiva pediátrica no Brasil em comparação com as de outros países: um inquérito brasileiro / Clinical practices related to high-flow nasal cannulas in pediatric critical care in Brazil compared to other countries: a Brazilian survey

RESUMO Objetivo: Descrever as práticas clínicas atuais relacionadas à utilização de cânula nasal de alto fluxo por intensivistas pediátricos brasileiros e compará-las com as de outros países. Métodos: Para o estudo principal, foi administrado um questionário a intensivistas pediátricos em países das Américas do Norte e do Sul, Ásia, Europa e Austrália/Nova Zelândia. Comparou-se a coorte brasileira com coortes dos Estados Unidos, Canadá, Reino Unido e Índia. Resultados: Responderam ao questionário 501 médicos, dos quais 127 eram do Brasil. Apenas 63,8% dos participantes brasileiros tinham disponibilidade de cânula nasal de alto fluxo, em contraste com 100% dos participantes no Reino Unido, no Canadá e nos Estados Unidos. Coube ao médico responsável a decisão de iniciar a utilização de uma cânula nasal de alto fluxo segundo responderam 61,2% dos brasileiros, 95,5% dos localizados no Reino Unido, 96,6% dos participantes dos Estados Unidos, 96,8% dos médicos canadenses e 84,7% dos participantes da Índia; 62% dos participantes do Brasil, 96,3% do Reino Unido, 96,6% dos Estados Unidos, 96,8% do Canadá e 84,7% da Índia relataram que o médico responsável era quem definia o desmame ou modificava as regulagens da cânula nasal de alto fluxo. Quando ocorreu falha da cânula nasal de alto fluxo por desconforto respiratório ou insuficiência respiratória, 82% dos participantes do Brasil considerariam uma tentativa com ventilação não invasiva antes da intubação endotraqueal, em comparação com 93% do Reino Unido, 88% dos Estados Unidos, 91,5% do Canadá e 76,8% da Índia. Mais intensivistas brasileiros (6,5%) do que do Reino Unido, Estados Unidos e Índia (1,6% para todos) afirmaram utilizar sedativos com frequência concomitantemente à cânula nasal de alto fluxo. Conclusão: A disponibilidade de cânulas nasais de alto fluxo no Brasil ainda não é difundida. Há algumas divergências nas práticas clínicas entre intensivistas brasileiros e seus colegas estrangeiros, principalmente nos processos e nas tomadas de decisão relacionados a iniciar e desmamar o tratamento com cânula nasal de alto fluxo.

ABSTRACT Objective: To describe current clinical practices related to the use of high-flow nasal cannula therapy by Brazilian pediatric intensivists and compare them with those in other countries. Methods: A questionnaire was administered to pediatric intensivists in North and South America, Asia, Europe, and Australia/New Zealand for the main study. We compared the Brazilian cohort with cohorts in the United States of America, Canada, the United Kingdom, and India Results: Overall, 501 physicians responded, 127 of which were in Brazil. Only 63.8% of respondents in Brazil had a high-flow nasal cannula available, in contrast to 100% of respondents in the United Kingdom, Canada, and the United States. The attending physician was responsible for the decision to start a high-flow nasal cannula according to 61.2% respondents in Brazil, 95.5% in the United Kingdom, 96.6% in the United States, 96.8% in Canada, and 84.7% in India. A total of 62% of respondents in Brazil, 96.3% in the United Kingdom, 96.6% in the United States, 96.8% in Canada, and 84.7% in India reported that the attending physician was responsible for the decision to wean or modify the high-flow nasal cannula settings. When high-flow nasal cannula therapy failed due to respiratory distress/failure, 82% of respondents in Brazil would consider a trial of noninvasive ventilation before endotracheal intubation, compared to 93% in the United Kingdom, 88% in the United States, 91.5% in Canada, and 76.8% in India. More Brazilian intensivists (6.5%) than intensivists in the United Kingdom, United States, and India (1.6% for all) affirmed using sedatives frequently with high-flow nasal cannulas. Conclusion: The availability of high-flow nasal cannulas in Brazil is still not widespread. There are some divergences in clinical practices between Brazilian intensivists and their colleagues abroad, mainly in processes and decision-making about starting and weaning high-flow nasal cannula therapy.

ALVEOLAR RECRUITMENT MANEUVERS FOR CHILDREN WITH CANCER AND ACUTE RESPIRATORY DISTRESS SYNDROME: A FEASIBILITY STUDY.

OBJECTIVE: Acute respiratory distress syndrome (ARDS) can be a devastating condition in children with cancer and alveolar recruitment maneuvers (ARMs) can theoretically improve oxygenation and survival. The study aimed to assess the feasibility of ARMs in critically ill children with cancer and ARDS. METHODS: We retrospectively analyzed 31 maneuvers in a series of 12 patients (median age of 8.9 years) with solid tumors (n=4), lymphomas (n=2), acute lymphoblastic leukemia (n=2), and acute myeloid leukemia (n=4). Patients received positive end-expiratory pressure from 25 up to 40 cmH20, with a delta pressure of 15 cmH2O for 60 seconds. We assessed blood gases pre- and post-maneuvers, as well as ventilation parameters, vital signs, hemoglobin, clinical signs of pulmonary bleeding, and radiological signs of barotrauma. Pre- and post-values were compared by the Wilcoxon test. RESULTS: Median platelet count was 53,200/mm3. Post-maneuvers, mean arterial pressure decreased more than 20% in two patients, and four needed an increase in vasoactive drugs. Hemoglobin levels remained stable 24 hours after ARMs, and signs of pneumothorax, pneumomediastinum, or subcutaneous emphysema were absent. Fraction of inspired oxygen decreased significantly after ARMs (FiO2; p=0.003). Oxygen partial pressure (PaO2)/FiO2 ratio increased significantly (p=0.0002), and the oxygenation index was reduced (p=0.01), but all these improvements were transient. Recruited patients' 28-day mortality was 58%. CONCLUSIONS: ARMs, although feasible in the context of thrombocytopenia, lead only to transient improvements, and can cause significant hemodynamic instability.

Undernutrition as an Aggravating Risk for Hospital Death in Critically Ill Children with Cancer.

OBJECTIVES: Undernourished children with cancer are at major risk for adverse outcomes. We intended to model nutritional status as risk factor for hospital death. METHODS: Retrospective analysis of two cohorts of children admitted in an oncology/hematology intensive care unit. Logistic regression was used for model building. RESULTS: The derivation cohort had 155 patients, with a median age of 104.9 mo., and 36 deaths (23.2%). Twenty-eight children (18.1%) had the z score of the body mass index < -2. A multivariate model with the variables "relapse of oncological disease" (Odds Ratio 3.14, P = 0.025), "surgical case" (OR 0.22, P = 0.002), "intubation/mechanical ventilation" (OR 8.38, P = 0.000) and "body mass index z score < -2" (OR 3.21, P = 0.024) generated a logit with good predictive capacity for "hospital death". In the validation cohort, with 450 patients (median age of 92.7 mo.), the model was able to predict 55.5 of the 58 observed deaths (Standardized Mortality Rate = 1.04, 95% CI 0.80-1.34, P = 0.72), with P = 0.68 in the Hosmer test. The AUC was 0.90 (95% CI 0.86-0.93). CONCLUSION: Undernutrition increases the risk of death, and is a variable that should be included in predictive mortality algorithms.

Pulmonary Function in Long-Term Survivors of Childhood and Adolescence Osteosarcoma: Case Report / Função Pulmonar em Sobreviventes de Osteossarcoma da Infância e Adolescência: Relato de Caso / Función Pulmonar en Sobrevivientes de Osteosarcoma en la Infancia y la Adolescencia: Relato de Caso

Introduction: Chemotherapy used in osteosarcoma have the potential to cause lung damage. The objectives were to analyze lung volumes and capacities, and respiratory muscle strength of patients treated with chemotherapy and surgery for osteosarcoma. The study was designed as a prospective case-series of patients, through the analysis of spirometry,impulse, oscillometry, and manovacuometry tests. Case report: In twenty-one patients, the median age at diagnosis was 15 years, and at inclusion, 30 years. The median disease-free survival time was 10 years. Eight different chemotherapeutic agents were used: cisplatin, doxorubicin, methotrexate, carboplatin, ifophosphamide, epidoxorubicin, cyclophosphamide and etoposide. There were test abnormalities in 14 patients (66.6%), with mild obstructive disorders on spirometry in three patients (14.3%), and obstructive patterns on oscillometry in seven patients (33.3%). On spirometry, the mean ± standard deviation (SD) values of forced vital capacity (FVC) were 91.9%±12.2; for forced expiratory volume in one second (FEV1) were 87.4%±12.2 and FEV1/FVC ratios, 95.4%±7.9. On oscillometry, mean ± SD values for resistance at 5 Hz were 126.2%±36.2; for resistance at 20 Hz, 128.4%±32.4; reactance at 5 Hz, -0.75±0.68 kPa/L/s; for resonant frequency, 15.6±4.2 Hz. Nine patients (42.8%) had reduced maximum pressures on the manovacuometry: Maximum Expiratory Pressure (MEP) were reduced in eight patients, and inspiratory (MIP) in three. The mean ± SD MIP was 89.4±29.5; MEP, 88±37.7. Conclusion: Mild abnormalities in pulmonary function tests in this series of patients were observed years after treatment for osteosarcoma

Introdução: A quimioterapia usada no osteossarcoma tem potencial para causar danos aos pulmões. Os objetivos deste trabalho foram analisar os volumes e capacidades pulmonares e a força respiratória de pacientes tratados com quimioterapia e cirurgia para osteossarcoma, em uma série prospectiva de casos, em um hospital pediátrico oncológico, por meio da análise de espirometria, oscilometria de impulso e manovacuometria. Relato de caso: Em 21 pacientes, a mediana de idade ao diagnóstico foi de 15 anos e na inclusão de 30 anos. O tempo médio de sobrevida livre de doença foi de dez anos. Houve alterações nos exames em 14 pacientes (66,6%), com distúrbios obstrutivos leves na espirometria em três pacientes (14,3%) e padrões obstrutivos na oscilometria em sete pacientes (33,3%). Na espirometria, os valores de média ± desvio padrão (DP) da capacidade vital forçada (CVF) foram 91,9%±12,2; para o volume expiratório forçado no primeiro segundo (VEF1) foram 87,4%±12,2 e as relações VEF1/CVF, 95,4%±7,9. Na oscilometria, os valores médios ± DP para resistência em 5 Hz foram 126,2%±36,2; para resistência a 20 Hz, 128,4% ± 32,4; reatância a 5 Hz, -0,75 ± 0,68 kPa/L/s; para frequência de ressonância, 15,6±4,2 Hz. Na manovacuometria, nove pacientes (42,8%) apresentaram redução nas pressões: as pressões expiratórias máximas (PEmáx) foram reduzidas em oito pacientes e as inspiratórias (PImáx) em três. A média ± DP da PImáx foi 89,4±29,5; PEmáx, 88±37,7. Conclusão: Observaram-se alterações leves nos testes de função pulmonar anos após o tratamento do osteossarcoma

Introducción: La quimioterapia utilizada en osteosarcoma puede causar daño a los pulmones. Los objetivos de este trabajo fueron analizar los volúmenes y capacidades pulmonares y la fuerza respiratoria en pacientes tratados para osteosarcoma, en una serie prospectiva de casos, en un hospital de oncología pediátrica, mediante el análisis de espirometría, oscilometría de impulsos y manuvacuometría. Relato de caso: En 21 pacientes, la mediana de edad al diagnóstico fue de 15 años y en la inclusión de 30 años. La supervivência media libre de enfermedad fue de diez años. Hubo alteraciones en los exámenes en 14 pacientes (66,6%), con alteraciones obstructivas leves en la espirometría en tres (14,3%), y obstrucción en la oscilometría en siete (33,3%). En espirometría, las medias ± desviación estándar (DE) de la capacidad vital forzada (CVF) fueron 91,9%±12,2; para el volumen espiratorio forzado en el primer segundo (VEF1) fue 87,4%±12,2 y el cociente VEF1/CVF fue 95,4%±7,9. En oscilometría, los valores medios ± DE para la resistencia a 5 Hz fueron 126,2%±36,2; para resistencia a 20 Hz, 128,4%±32,4; reactancia a 5 Hz, -0,75±0,68 kPa/L/s; para la frecuencia de resonancia, 15,6±4,2 Hz. En manuvacuometría, nueve pacientes (42,8%) mostraron una reducción de las presiones: las presiones espiratorias máximas (PEmáx) se redujeron en ocho pacientes y las presiones inspiratorias (PImáx) en tres. La media ± DE del PImáx fue 89,4 ± 29,5; PEmáx, 88±37,7. Conclusión: Se observaron ligeros cambios en las pruebas de función pulmonar años después del tratamiento del osteosarcoma

Alveolar recruitment maneuvers for children with cancer and acute respiratory distress syndrome: a feasibility study / Manobras de recrutamento alveolar em crianças com câncer e síndrome do desconforto respiratório agudo: um estudo de viabilidade

ABSTRACT Objective: Acute respiratory distress syndrome (ARDS) can be a devastating condition in children with cancer and alveolar recruitment maneuvers (ARMs) can theoretically improve oxygenation and survival. The study aimed to assess the feasibility of ARMs in critically ill children with cancer and ARDS. Methods: We retrospectively analyzed 31 maneuvers in a series of 12 patients (median age of 8.9 years) with solid tumors (n=4), lymphomas (n=2), acute lymphoblastic leukemia (n=2), and acute myeloid leukemia (n=4). Patients received positive end-expiratory pressure from 25 up to 40 cmH20, with a delta pressure of 15 cmH2O for 60 seconds. We assessed blood gases pre- and post-maneuvers, as well as ventilation parameters, vital signs, hemoglobin, clinical signs of pulmonary bleeding, and radiological signs of barotrauma. Pre- and post-values were compared by the Wilcoxon test. Results: Median platelet count was 53,200/mm3. Post-maneuvers, mean arterial pressure decreased more than 20% in two patients, and four needed an increase in vasoactive drugs. Hemoglobin levels remained stable 24 hours after ARMs, and signs of pneumothorax, pneumomediastinum, or subcutaneous emphysema were absent. Fraction of inspired oxygen decreased significantly after ARMs (FiO2; p=0.003). Oxygen partial pressure (PaO2)/FiO2 ratio increased significantly (p=0.0002), and the oxygenation index was reduced (p=0.01), but all these improvements were transient. Recruited patients' 28-day mortality was 58%. Conclusions: ARMs, although feasible in the context of thrombocytopenia, lead only to transient improvements, and can cause significant hemodynamic instability.

RESUMO Objetivo: A síndrome do desconforto respiratório agudo (SDRA) pode ser uma condição devastadora em crianças com câncer e as manobras de recrutamento alveolar (MRA) podem melhorar a oxigenação e a sobrevida. O objetivo foi avaliar a viabilidade das MRA em crianças gravemente doentes com câncer e SDRA. Métodos: Analisamos retrospectivamente 31 manobras em 12 pacientes (idade mediana de 8,9 anos), com tumores sólidos (n=4), linfomas (n=2) e leucemias linfoide (n=2) e mieloide agudas (n=4). Os pacientes receberam pressão expiratória final positiva de 25 a 40 cmH20, com delta de pressão de 15 cmH2O por 60 segundos. Gasometrias foram analisadas pré e pós-manobras, bem como os parâmetros de ventilação, sinais vitais, hemoglobina, sinais clínicos de sangramento pulmonar e sinais radiológicos de barotrauma. Valores foram comparados com o teste de Wilcoxon. Resultados: A contagem mediana de plaquetas era de 53.200/mm3. Após as manobras, em dois pacientes, a pressão arterial média declinou mais de 20%, e quatro necessitaram de aumento de drogas vasoativas. A hemoglobina permaneceu estável 24 horas após a MRA, sem sinais de pneumotórax, pneumomediastino ou enfisema subcutâneo. Houve diminuição significativa nas frações inspiradas de oxigênio (FiO2; p=0,003). A relação pressão arterial de oxigênio (PaO2)/FiO2 aumentou (p=0,002), e o índice de oxigenação caiu (p=0,01), mas essas melhoras foram transitórias. A mortalidade em 28 dias foi de 58%. Conclusões: As MRA, embora viáveis no contexto da trombocitopenia, levam apenas a melhorias transitórias e podem causar instabilidade hemodinâmica significativa.

The Impact of the Novel Coronavirus on Brazilian PICUs.

OBJECTIVES: To study the impact of the coronavirus disease 2019 pandemic, considering the physical distancing and schools closing, on the characteristics of admission and epidemiology on Brazilian PICUs. DESIGN: Observational, multicenter, time series analysis, of electronic medical records from 15 PICU in Brazil. Data consisted of all March, April, and May PICU admissions from 2017 to 2020. SETTING: Fifteen private PICUs in Brazil. PATIENTS: Pediatric patients admitted to the PICU from March to May since 2017. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The period from March 11, 2020, to March 17, 2020, was considered the "intervention point" studied, corresponding to the suspension of school activities and the beginning of physical distancing in Brazil. During the pandemic period studied, there were 28 cases of coronavirus disease 2019 (one death). The mean age was higher (p = 0.000), the length of stay was shorter (p = 0.000), but mortality rates were similar among the periods (p = 0.36). The model estimated a reduction of 1,483 PICU admissions from March 2020 to May 2020. At the end of May, there was an estimated drop of -146.6 bronchiolitis admissions (95% CI, -242.8 to -50.3; p = 0.016); -71 asthma admissions (95% CI, -93.6 to -48.63; p = 0.000); and -59 community-acquired pneumonia admissions (95% CI, -74.7 to -43.3; p = 0.000) per period. The model showed no effect of the "intervention" (physical distancing) on hospitalization rates for epilepsy, diarrhea, sepsis, bacterial meningitis, or surgery when analyzed individually. When assessed together, the model estimated a reduction of 73.6 admissions (95% IC, -132 to -15.2; p = 0.43). CONCLUSIONS: The coronavirus disease 2019 pandemic strongly affected Brazilian PICUs, reducing admissions, length of stay, and the epidemiological profile. The measures to oppose the coronavirus disease 2019 pandemic may have prevented thousands of PICU hospitalizations across the country.

The zero impact of the Vehicle Inspection Program on public health in São Paulo, SP.

OBJECTIVE To analyze the impact of two interventions (implementation and suspension of mandatory vehicle inspection) on morbidity and mortality due to conditions related to air pollution, from 2008 to 2017. METHODS Interrupted time series (ARIMA models), using data available in public repositories. RESULTS A total of 229,337 children of up to 5 years old were hospitalized due to respiratory diseases, and 1,053 died (average monthly mortality ratio for this population: 1.12/100,000). Exact 137,876 individuals over 40 years old were hospitalized for an acute myocardial infarction, and 19,492 died (3.7/100,000). A total of 11,010 individuals over 40 years old were hospitalized with malignant neoplasms of the respiratory system; 2,898 died (0.5/100,000). A total of 20,807 individuals over 60 years old were hospitalized with chronic obstructive pulmonary diseases; 2,627 died (1.5/100,000). As for strokes, 69,180 individuals were hospitalized, and 10,866 died (2.1/100,000). We found no significant regression coefficient for the implementation or suspension of the program regarding hospitalizations and deaths. 38,207 children of up to 14 years old were hospitalized with asthma, and 25 of them died (0.007/100,000). The coefficients show a monthly increase of 0.05 deaths/100,000 people (p = 0.01) in the post-inspection period. We found no correlation between the measured concentrations of the pollutants PM2.5 and CO - in a monitoring station, in the central region of the municipality - and the implementation or suspension of the inspection. CONCLUSIONS No evidence confirms that the program had a measurable beneficial impact on morbidity and mortality due to respiratory and circulatory diseases.

The zero impact of the vehicle inspection program on public health in São Paulo, SP / O impacto nulo do programa de inspeção veicular na saúde pública em São Paulo, SP

ABSTRACT OBJECTIVE To analyze the impact of two interventions (implementation and suspension of mandatory vehicle inspection) on morbidity and mortality due to conditions related to air pollution, from 2008 to 2017. METHODS Interrupted time series (ARIMA models), using data available in public repositories. RESULTS A total of 229,337 children of up to 5 years old were hospitalized due to respiratory diseases, and 1,053 died (average monthly mortality ratio for this population: 1.12/100,000). Exact 137,876 individuals over 40 years old were hospitalized for an acute myocardial infarction, and 19,492 died (3.7/100,000). A total of 11,010 individuals over 40 years old were hospitalized with malignant neoplasms of the respiratory system; 2,898 died (0.5/100,000). A total of 20,807 individuals over 60 years old were hospitalized with chronic obstructive pulmonary diseases; 2,627 died (1.5/100,000). As for strokes, 69,180 individuals were hospitalized, and 10,866 died (2.1/100,000). We found no significant regression coefficient for the implementation or suspension of the program regarding hospitalizations and deaths. 38,207 children of up to 14 years old were hospitalized with asthma, and 25 of them died (0.007/100,000). The coefficients show a monthly increase of 0.05 deaths/100,000 people (p = 0.01) in the post-inspection period. We found no correlation between the measured concentrations of the pollutants PM2.5 and CO - in a monitoring station, in the central region of the municipality - and the implementation or suspension of the inspection. CONCLUSIONS No evidence confirms that the program had a measurable beneficial impact on morbidity and mortality due to respiratory and circulatory diseases.

RESUMO OBJETIVO Analisar o impacto de duas intervenções (introdução e suspensão da inspeção veicular obrigatória) sobre a morbidade e mortalidade por condições associadas à poluição do ar no período de 2008 a 2017. MÉTODOS Séries temporais interrompidas (método Arima), com dados disponíveis em repositórios públicos. RESULTADOS Houve 229.337 internações por doenças respiratórias em crianças até 5 anos de idade, com 1.053 óbitos (coeficiente médio de mortalidade mensal para a população da idade: 1,12/100.000). Para infarto agudo do miocárdio em maiores de 40 anos, houve 137.876 internações, com 19.492 óbitos (3,7/100.000). Para as neoplasias malignas do aparelho respiratório em maiores de 40 anos, foram 11.010 internações, com 2.898 óbitos (0,5/100.000). Para doenças pulmonares obstrutivas crônicas em maiores de 60 anos, foram 20.807 internações, com 2.627 óbitos (1,5/100.000). Para os acidentes vasculares cerebrais, foram 69.180 internações e 10.866 óbitos (2,1/100.000). Não houve nenhum coeficiente de regressão significativo para a introdução ou suspensão do programa em relação às internações e óbitos. Para asma em crianças até 14 anos, houve 38.207 internações e 25 óbitos (0,007/100.000), e os coeficientes mostram aumento de 0,05 óbitos/100.000 pessoas por mês (p = 0,01) no período pós-introdução da inspeção. Em modelo para os poluentes MP2,5 e CO, em estação de monitoramento da região central do município, não houve correlação entre as concentrações medidas e a introdução ou a suspensão da inspeção. CONCLUSÕES Não há evidências de que o programa tenha tido qualquer efeito benéfico mensurável sobre a morbidade e a mortalidade por doenças respiratórias e do aparelho circulatório.

Practices related to assessment of sedation, analgesia and delirium among critical care pediatricians in Brazil / Práticas relacionadas à avaliação de sedação, analgesia e delirium entre pediatras intensivistas no Brasil

ABSTRACT Objective To understand the use of tools, protocols and comfort measures related to sedation/analgesia, and to screen the occurrence of delirium in pediatric intensive care units. Methods A survey with 14 questions was distributed by e-mail to Brazilian critical care pediatricians. Eight questions addressed physician and hospital demographics, and six inquired practices to assess sedation, analgesia, and delirium in pediatric intensive care units. Results Of 373 questionnaires sent, 61 were answered (16.3%). The majority of physicians were practicing in the Southeast region (57.2%). Of these, 46.5% worked at public hospitals, 28.6% of which under direct state administration. Of respondents, 57.1% used formal protocols for sedation and analgesia, and the Ramsay scale was the most frequently employed (52.5%). Delirium screening scores were not used by 48.2% of physicians. The Cornell Assessment of Pediatric Delirium was the score most often used (23.2%). The majority (85.7%) of physicians did not practice daily sedation interruption, and only 23.2% used non-pharmacological measures for patient comfort frequently, with varied participation of parents in the process. Conclusion This study highlights the heterogeneity of practices for assessment of sedation/analgesia and lack of detection of delirium among critical care pediatricians in Brazil.

RESUMO Objetivo Compreender o uso de ferramentas, protocolos e medidas de conforto relacionadas à sedação/analgesia, além de rastrear a presença de delirium em unidades de terapia intensiva pediátricas. Métodos Um inquérito com 14 questões foi distribuído, por meio de correio eletrônico, para médicos pediatras intensivistas brasileiros. Oito questões eram sobre os dados demográficos dos médicos e dos hospitais, e seis questões eram sobre as práticas na avaliação da sedação, analgesia e delirium em unidades de terapia intensiva pediátrica. Resultados Responderam ao inquérito 61 médicos dos 373 e-mails enviados (taxa de resposta de 16,3%). A maioria dos médicos era da Região Sudeste (57,2%) e 46,5% trabalhavam em hospitais públicos, sendo 28,6% sob administração direta do Estado. Dos respondedores, 57,1% utilizavam protocolos formais de sedação e analgesia, sendo a escala de Ramsay a mais utilizada (52,5%). Não utilizavam escores de rastreamento de delirium 48,2% dos médicos, e o Cornell Asssessment of Pediatric Delirium (23,2%) foi o mais utilizado. A maioria (85,7%) dos médicos não utilizou a prática da interrupção diária da sedação, e apenas 23,2% utilizavam medidas não farmacológicas para o conforto do paciente com frequência, com a participação heterogênea dos pais nesse processo. Conclusão Este estudo destaca a heterogeneidade nas práticas de avaliação da sedação/analgesia e insuficiência de rastreamento de delirium entre os intensivistas pediátricos brasileiros.

T helper type cytokines in sepsis: time-shared variance and correlation with organ dysfunction and hospital mortality.

OBJECTIVE: We evaluated the kinetics of cytokines belonging to the T helper1 (Th1), Th2, and Th17 profiles in septic patients, and their correlations with organ dysfunction and hospital mortality. METHODS: This was a prospective observational study in a cohort of septic patients admitted to the intensive care units (ICU) of three Brazilian general hospitals. A total of 104 septic patients and 53 health volunteers (controls) were included. Plasma samples were collected within the first 48h of organ dysfunction or septic shock (0D), after seven (D7) and 14 days (D14) of follow-up. The following cytokines were measured by flow cytometry: Interleukin-1ß (IL-1ß), IL-2, IL-6, IL-8, IL-10, IL-12/23p40, IL-17, IL-21, tumor necrosis factor-α (TNF-α), granulocyte-macrophage colony stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF). RESULTS: IL-6, IL-8, G-CSF and IL-10 concentrations were higher in septic patients than in controls (p<0.001), while IL-12/23p40 presented higher levels in the controls (p=0.003). IL-6, IL-8 and IL-17 correlated with Sequential [Sepsis-related] Organ Failure Assessment (SOFA) D0, D1 and D3 (except for IL-6 at D0). IL-8 was associated with renal and cardiovascular dysfunction. In a mixed model analysis, IL-10 estimated means were lower in survivors than in deceased (p=0.014), while IL-21 had an estimated mean of 195.8pg/mL for survivors and 98.5 for deceased (p=0.03). Cytokines were grouped in four factors according to their kinetics over the three dosages (D0, D7, D14). Group 1 encompassed IL-6, IL-8, IL-10, IL-1ß, and G-CSF while Group 3 encompassed IL-17 and IL-12/23p40. Both correlated with SOFA (D0) (p=0.039 and p=0.003, respectively). IL-21 (Group 4) was higher in those who survived. IL-2, TNF-α and GM-CSF (Group 2) showed no correlation with outcomes. CONCLUSION: Inflammatory and anti-inflammatory cytokines shared co-variance in septic patients and were related to organ dysfunctions and hospital mortality.

T helper type cytokines in sepsis: time-shared variance and correlation with organ dysfunction and hospital mortality

ABSTRACT Objective: We evaluated the kinetics of cytokines belonging to the T helper1 (Th1), Th2, and Th17 profiles in septic patients, and their correlations with organ dysfunction and hospital mortality. Methods: This was a prospective observational study in a cohort of septic patients admitted to the intensive care units (ICU) of three Brazilian general hospitals. A total of 104 septic patients and 53 health volunteers (controls) were included. Plasma samples were collected within the first 48 h of organ dysfunction or septic shock (0D), after seven (D7) and 14 days (D14) of follow-up. The following cytokines were measured by flow cytometry: Interleukin-1β (IL-1β), IL-2, IL-6, IL-8, IL-10, IL-12/23p40, IL-17, IL-21, tumor necrosis factor-α (TNF-α), granulocyte-macrophage colony stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF). Results: IL-6, IL-8, G-CSF and IL-10 concentrations were higher in septic patients than in controls (p < 0.001), while IL-12/23p40 presented higher levels in the controls (p = 0.003). IL-6, IL-8 and IL-17 correlated with Sequential [Sepsis-related] Organ Failure Assessment (SOFA) D0, D1 and D3 (except for IL-6 at D0). IL-8 was associated with renal and cardiovascular dysfunction. In a mixed model analysis, IL-10 estimated means were lower in survivors than in deceased (p = 0.014), while IL-21 had an estimated mean of 195.8 pg/mL for survivors and 98.5 for deceased (p = 0.03). Cytokines were grouped in four factors according to their kinetics over the three dosages (D0, D7, D14). Group 1 encompassed IL-6, IL-8, IL-10, IL-1β, and G-CSF while Group 3 encompassed IL-17 and IL-12/23p40. Both correlated with SOFA (D0) (p = 0.039 and p = 0.003, respectively). IL-21 (Group 4) was higher in those who survived. IL-2, TNF-α and GM-CSF (Group 2) showed no correlation with outcomes. Conclusion: Inflammatory and anti-inflammatory cytokines shared co-variance in septic patients and were related to organ dysfunctions and hospital mortality.

Síndrome do desconforto respiratório agudo relacionada à sepse em crianças com câncer: dinâmica respiratória de uma condição devastadora / Sepsis-related acute respiratory distress syndrome in children with cancer: the respiratory dynamics of a devastating condition

RESUMO Objetivo: Avaliar a evolução clínica e os parâmetros respiratórios de crianças com câncer submetidas à ventilação mecânica que apresentavam síndrome do desconforto respiratório agudo relacionada à sepse. Métodos: Este estudo longitudinal, prospectivo e observacional de coorte com duração de 2 anos incluiu 29 crianças e adolescentes. Dados clínicos, avaliações de gasometria sanguínea e parâmetros ventilatórios foram coletados em quatro momentos diferentes. As flutuações entre as avaliações e as diferenças entre as médias estimadas foram analisadas por meio de modelos lineares mistos, tendo como parâmetro primário (endpoint) a ocorrência de óbito dentro de 28 dias após o início da síndrome do desconforto respiratório agudo. Resultados: Ocorreram 17 óbitos dentro de 28 dias após o início da síndrome do desconforto respiratório agudo, e outros 7 entre 29 e 60 dias. Apenas cinco pacientes sobreviveram por mais de 60 dias. Nove (31%) pacientes faleceram como consequência direta de hipoxemia refratária, e os demais em razão de falência de múltiplos órgãos e choque refratário a catecolaminas. Em 66% das avaliações, o volume corrente demandado para obter saturação de oxigênio igual ou acima de 90% foi superior a 7mL/kg. As médias estimadas de complacência dinâmica foram baixas e similares para sobreviventes e não sobreviventes, porém com inclinação negativa da reta entre a primeira e última avaliações, acompanhada por uma inclinação negativa da reta para volume corrente nos não sobreviventes. Os não sobreviventes tiveram significantemente mais hipoxemia, com relações PaO2/FiO2 que demonstravam médias mais baixas e inclinação negativa da reta nas quatro avaliações. As pressões pico, expiratória e média das vias aéreas demonstraram inclinações positivas na reta para os não sobreviventes, que também apresentaram mais acidose metabólica. Conclusões: Na maioria de nossas crianças com câncer, a sepse e a síndrome do desconforto respiratório agudo evoluíram com deterioração dos índices ventilatórios e progressiva disfunção de órgãos, o que tornou esta tríade praticamente fatal em crianças.

ABSTRACT Objective: To evaluate the clinical course and respiratory parameters of mechanically ventilated children with cancer suffering from sepsis-related acute respiratory distress syndrome. Methods: This 2-year prospective, longitudinal, observational cohort study enrolled 29 children and adolescents. Clinical data, measurements of blood gases and ventilation parameters were collected at four different time points. Fluctuations between measurements as well as differences in estimated means were analyzed by linear mixed models in which death within 28 days from the onset of acute respiratory distress syndrome was the primary endpoint. Results: There were 17 deaths within 28 days of acute respiratory distress syndrome onset and another 7 between 29 - 60 days. Only 5 patients survived for more than 60 days. Nine (31%) patients died as a direct consequence of refractory hypoxemia, and the others died of multiple organ failure and catecholamine-refractory shock. In 66% of the measurements, the tidal volume required to obtain oxygen saturation equal to or above 90% was greater than 7mL/kg. The estimated means of dynamic compliance were low and were similar for survivors and non-survivors but with a negative slope between the first and final measurements, accompanied by a negative slope of the tidal volume for non-survivors. Non-survivors were significantly more hypoxemic, with PaO2/FiO2 ratios showing lower estimated means and a negative slope along the four measurements. Peak, expiratory and mean airway pressures showed positive slopes in the non-survivors, who also had more metabolic acidosis. Conclusions: In most of our children with cancer, sepsis and acute respiratory distress syndrome progressed with deteriorating ventilation indexes and escalating organic dysfunction, making this triad nearly fatal in children.

Sepsis-related acute respiratory distress syndrome in children with cancer: the respiratory dynamics of a devastating condition. / Síndrome do desconforto respiratório agudo relacionada à sepse em crianças com câncer: dinâmica respiratória de uma condição devastadora.

OBJECTIVE:: To evaluate the clinical course and respiratory parameters of mechanically ventilated children with cancer suffering from sepsis-related acute respiratory distress syndrome. METHODS:: This 2-year prospective, longitudinal, observational cohort study enrolled 29 children and adolescents. Clinical data, measurements of blood gases and ventilation parameters were collected at four different time points. Fluctuations between measurements as well as differences in estimated means were analyzed by linear mixed models in which death within 28 days from the onset of acute respiratory distress syndrome was the primary endpoint. RESULTS:: There were 17 deaths within 28 days of acute respiratory distress syndrome onset and another 7 between 29 - 60 days. Only 5 patients survived for more than 60 days. Nine (31%) patients died as a direct consequence of refractory hypoxemia, and the others died of multiple organ failure and catecholamine-refractory shock. In 66% of the measurements, the tidal volume required to obtain oxygen saturation equal to or above 90% was greater than 7mL/kg. The estimated means of dynamic compliance were low and were similar for survivors and non-survivors but with a negative slope between the first and final measurements, accompanied by a negative slope of the tidal volume for non-survivors. Non-survivors were significantly more hypoxemic, with PaO2/FiO2 ratios showing lower estimated means and a negative slope along the four measurements. Peak, expiratory and mean airway pressures showed positive slopes in the non-survivors, who also had more metabolic acidosis. CONCLUSIONS:: In most of our children with cancer, sepsis and acute respiratory distress syndrome progressed with deteriorating ventilation indexes and escalating organic dysfunction, making this triad nearly fatal in children.

Vancomycin serum concentrations in pediatric oncologic/hematologic intensive care patients.

BACKGROUND: Usual treatment regimens with vancomycin often fail to provide adequate serum levels in patients with severe infections. METHODS: Retrospective analysis of vancomycin trough serum measurements. The following parameters were calculated by Bayesian analysis: vancomycin clearance, distribution volume, and peak estimated concentrations. The area under the concentration curve (AUC) (total daily dose/24 h clearance of vancomycin) was used to determine the effectiveness of treatment through the ratio of AUC/minimum inhibitory concentration (MIC) above 400, using MIC=1 µg/mL, based on isolates of Staphylococci in cultures. RESULTS: Sixty-one vancomycin trough measurements were analyzed in 31 patients. AUC/MIC>400 was obtained in 34 out of 61 dosages (55.7%), but the mean vancomycin dose required to achieve these levels was 81 mg/kg/day. In cases where the usual doses were administered (40-60 mg/kg/day), AUC/MIC>400 was obtained in nine out of 18 dosages (50%), in 13 patients. Trough serum concentrations above 15 mg/L presented a positive predictive value of 100% and a negative predictive value of 71% for AUC/MIC>400. CONCLUSION: Higher than usual vancomycin doses may be required to treat staphylococcal infections in children with oncologic/hematologic diseases. Since the best known predictor of efficacy is the AUC/MIC ratio, serum trough concentrations must be analyzed in conjunction with MICs of prevalent Staphylococci and pharmacokinetic tools such as Bayesian analysis.

Vancomycin serum concentrations in pediatric oncologic/hematologic intensive care patients

BACKGROUND: Usual treatment regimens with vancomycin often fail to provide adequate serum levels in patients with severe infections. METHODS: Retrospective analysis of vancomycin trough serum measurements. The following parameters were calculated by Bayesian analysis: vancomycin clearance, distribution volume, and peak estimated concentrations. The area under the concentration curve (AUC) (total daily dose/24 h clearance of vancomycin) was used to determine the effectiveness of treatment through the ratio of AUC/minimum inhibitory concentration (MIC) above 400, using MIC = 1 µg/mL, based on isolates of Staphylococci in cultures. RESULTS: Sixty-one vancomycin trough measurements were analyzed in 31 patients. AUC/MIC > 400 was obtained in 34 out of 61 dosages (55.7%), but the mean vancomycin dose required to achieve these levels was 81 mg/kg/day. In cases where the usual doses were administered (40-60 mg/kg/day), AUC/MIC > 400 was obtained in nine out of 18 dosages (50%), in 13 patients. Trough serum concentrations above 15 mg/L presented a positive predictive value of 100% and a negative predictive value of 71% for AUC/MIC > 400. CONCLUSION: Higher than usual vancomycin doses may be required to treat staphylococcal infections in children with oncologic/hematologic diseases. Since the best known predictor of efficacy is the AUC/MIC ratio, serum trough concentrations must be analyzed in conjunction with MICs of prevalent Staphylococci and pharmacokinetic tools such as Bayesian analysis.

Heparina intermitente não é eficaz em impedir a retirada por obstrução de cateteres centrais inseridos perifericamente em recém-nascidos de termo e prematuros / Intermittent heparin is not effective at preventing the occlusion of peripherally inserted central venous catheters in preterm and term neonates

OBJETIVO: Verificar se a heparina em lavagens intermitentes é eficaz em reduzir oclusões de cateteres centrais inseridos perifericamente em recém-nascidos. MÉTODOS: Estudo randomizado, aberto, controlado, prospectivo. Os recém-nascidos foram alocados em dois grupos para receber lavagens ("flushes") com 0,5 mL da solução de heparina 10UI/mL (Grupo 1, n = 64) ou com 0,5 mL de salina (Grupo 2, n = 69), a cada 4 horas através do cateter central inserido perifericamente. Foram realizadas manobras de desobstrução por pressão negativa ("3-way stopcock method") nos casos de oclusão. RESULTADOS: Foram incluídos 133 recém-nascidos. Não houve diferença significativa no número de oclusões inéditas entre os grupos (26 no grupo 1, ou 31/1000 dias de cateter; 36 no grupo 2, ou 36/1000 dias de cateter, P = 0,19). No grupo 1, 5 cateteres apresentaram 9 recidivas da obstrução, após uma tentativa de desobstrução bem sucedida. No grupo 2, 19 cateteres apresentaram 40 recidivas (P <0,0001), mostrando papel protetor da heparina contra recidivas da obstrução (risco relativo = 0,36). Contudo, a heparina não evitou a retirada por oclusão definitiva (3 cateteres no grupo 1 e 8 no grupo 2, P = 0,24). CONCLUSÃO: A heparina intermitente não é eficaz em evitar oclusão dos cateteres centrais inseridos perifericamente neonatais. Apenas reduz as recidivas, se realizadas manobras de desobstrução.

OBJECTIVE: To evaluate the effectiveness of intermittent 10 U/mL heparin flushes in reducing the occlusion of peripherally inserted central catheters in neonates. METHODS: In this randomized, open-label, prospective, controlled study, neonates were allocated either to receive 0.5 mL flushes of heparin (Group 1: n = 64) or saline (Group 2: n = 69) every 4 hours. Actions were taken to restore patency by using negative pressure (3-way stopcock method) in cases of occlusion. RESULTS: A total of 133 neonates were included. No significant intergroup difference was observed in the number of new occlusions (26 in Group 1, or 31/1,000 catheter-days; 36 in Group 2, or 36/1,000 catheter-days; P = 0.19). In Group 1, 5 catheters had 9 recurrent obstructions after successful clearance maneuvers. In Group 2, 19 catheters had 40 relapses (P < 0.0001), showing heparin's protective role against recurrence of obstruction (Relative Risk = 0.36). However, heparin failed to prevent catheter withdrawal due to permanent occlusion (3 catheters in Group 1 and 8 in Group 2; P = 0.24). CONCLUSION: Intermittent heparin is not effective for preventing the occlusion of peripherally inserted central catheters in neonates but reduces relapses when clearance maneuvers were successful.