ICU Admission in Children With Acute Lymphoblastic Leukemia in Sweden: Prevalence, Outcome, and Risk Factors.

OBJECTIVES: Despite progress in the treatment of childhood acute lymphoblastic leukemia, severe complications are common, and the need of supportive care is high. We explored the cumulative prevalence, clinical risk factors, and outcomes of children with acute lymphoblastic leukemia, on first-line leukemia treatment in the ICUs in Sweden. DESIGN: A nationwide prospective register and retrospective chart review study. SETTING: Children with acute lymphoblastic leukemia were identified, and demographic and clinical data were obtained from the Swedish Childhood Cancer Registry. Data on intensive care were collected from the Swedish Intensive Care Registry. Data on patients with registered ICU admission in the Swedish Childhood Cancer Registry were supplemented through questionnaires to the pediatric oncology centers. PATIENTS: All 637 children 0-17.9 years old with acute lymphoblastic leukemia diagnosed between June 2008 and December 2016 in Sweden were included. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Twenty-eight percent of the children (178/637) were admitted to an ICU at least once. The Swedish Intensive Care Registry data were available for 96% of admissions (241/252). An ICU admission was associated with poor overall survival (hazard ratio, 3.25; 95% CI, 1.97-5.36; p ≤ 0.0001). ICU admissions occurred often during early treatment; 48% (85/178) were admitted to the ICU before the end of the first month of acute lymphoblastic leukemia treatment (induction therapy). Children with T-cell acute lymphoblastic leukemia or CNS leukemia had a higher risk of being admitted to the ICU in multivariable analyses, both for early admissions before the end of induction therapy and for all admissions during the study period. CONCLUSIONS: The need for intensive care in children with acute lymphoblastic leukemia, especially for children with T cell acute lymphoblastic leukemia and CNS leukemia, is high with most admissions occurring during early treatment.

Extracorporeal Membrane Oxygenation Support in Children With Hematologic Malignancies in Sweden.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is used in severe respiratory and/or circulatory failure when conventional critical care fails. Studies on patients with hematologic malignancies on ECMO have shown contradictory results; immunosuppression and coagulopathy are relative contraindications to ECMO. OBSERVATIONS: This nationwide Swedish retrospective chart review identified 958 children with hematologic malignancies of whom 12 (1.3%) required ECMO support. Eight patients survived ECMO, 7 the total intensive care period, and 6 survived the underlying malignancy. CONCLUSIONS: ECMO may be considered in children with hematologic malignancy. Short-term and long-term survival, in this limited group, was similar to that of children on ECMO at large.

Does extracorporeal membrane oxygenation attenuate hypoxic pulmonary vasoconstriction in a porcine model of global alveolar hypoxia?

BACKGROUND: During severe respiratory failure, hypoxic pulmonary vasoconstriction (HPV) is partly suppressed, but may still play a role in increasing pulmonary vascular resistance (PVR). Experimental studies suggest that the degree of HPV during severe respiratory failure is dependent on pulmonary oxygen tension (PvO2 ). Therefore, it has been suggested that increasing PvO2 by veno-venous extracorporeal membrane oxygenation (V-V ECMO) would adequately reduce PVR in V-V ECMO patients. OBJECTIVE: Whether increased PvO2 by V-V ECMO decreases PVR in global alveolar hypoxia. METHODS: Nine landrace pigs were ventilated with a mixture of oxygen and nitrogen. After 15 minutes of stable ventilation and hemodynamics, the animals were cannulated for V-V ECMO. Starting with alveolar normoxia, the fraction of inspiratory oxygen (FI O2 ) was stepwise reduced to establish different degrees of alveolar hypoxia. PvO2 was increased by V-V ECMO. RESULTS: V-V ECMO decreased PVR (from 5.5 [4.5-7.1] to 3.4 [2.6-3.9] mm Hg L-1  min, P = .006) (median (interquartile range),) during ventilation with FI O2 of 0.15. At lower FI O2 , PVR increased; at FI O2 0.10 to 4.9 [4.2-7.0], P = .036, at FI O2 0.05 to 6.0 [4.3-8.6], P = .002, and at FI O2 0 to 5.4 [3.5 - 7.0] mm Hg L-1  min, P = .05. CONCLUSIONS: The effect of increased PvO2 by V-V ECMO on PVR depended highly on the degree of alveolar hypoxia. Our results partly explain why V-V ECMO does not always reduce right ventricular afterload at severe alveolar hypoxia.

Long-term pulmonary function and quality of life in adults after extracorporeal membrane oxygenation for respiratory failure.

BACKGROUND: There is a significant long-term burden on survivors after acute respiratory distress syndrome, even 5 years after discharge. This is not well investigated in patients treated with extracorporeal membrane oxygenation. The objective of this study was to describe very-long-term (⩾3 years) disability in lung function and morphology, quality of life, mood disorders, walking capacity, and return to work status in extracorporeal membrane oxygenation survivors. METHODS: Single-center retrospective cohort study on long-term survivors treated with extracorporeal membrane oxygenation for respiratory failure between 1995 and 2010 at a tertiary referral center in Sweden. Eligible patients were approached, and those who consented were interviewed and investigated during a day at the hospital. RESULTS: A total of 38 patients were investigated with a median follow-up time of 9.0 years. Quality of life was reduced in several Short form 36 (SF-36) subscales and all domains of the St George's Respiratory Questionnaire, similar to previous studies in conventionally managed acute respiratory distress syndrome survivors. A reduced diffusion capacity of carbon monoxide was seen in 47% of patients, and some degree of residual lung parenchymal pathology was seen in 82%. Parenchymal pathology correlated with reductions in quality of life and diffusion capacity. Symptoms of anxiety and depression were seen in 22% and 14%, respectively. CONCLUSION: A significant long-term burden remains even 3-17 years after extracorporeal membrane oxygenation treatment, similar to conventionally managed acute respiratory distress syndrome survivors. Future prospective studies are needed to elucidate risk factors for these sequelae.

Unnecessary harm is avoided by reliable paediatric index of mortality2 scores without arterial gas sampling.

AIM: To investigate whether unnecessary harm could be avoided in children admitted to paediatric intensive care (PICU), we analysed the impact of arterial blood gas on the paediatric index of mortality score2 (PIM2) and the derived predicted death rate (PDR). METHODS: From January 1, 2008 to December 31, 2010, 1793 consecutive admissions, newborn infants to 16 years of age (median 0.71 years) from a single, tertiary PICU in Gothenburg Sweden, were collected. Admission information on arterial oxygen tension (PaO2 ) and fraction of inspired oxygen (FiO2 ) was extracted from 990 admissions. RESULTS: There was close agreement between PIM2 score and PDR regardless of whether the PaO2 /FiO2 ratio was omitted or not. In the subgroup of admissions with a respiratory admission diagnosis, the inclusion of the PaO2 /FiO2 ratio increased the accuracy of the PIM2 score as well as the PDR. The standard mortality ratio was slightly but not significantly overestimated by excluding the PaO2 /FiO2 ratio. CONCLUSION: To avoid unnecessary harm to children admitted to PICU, an arterial blood gas analysis should only be performed if clinically indicated or if the child has a respiratory admission diagnosis. Estimation of the PIM2 score and PDR will not be less accurate by this approach.

Survival after PICU admission: The impact of multiple admissions and complex chronic conditions.

OBJECTIVE: Factors predicting survival over time after pediatric intensive care unit (PICU) admissions are not fully understood. The primary aim of the current study was to investigate whether multiple admissions (MADM) compared to single PICU admissions (SADM) were associated with poor survival over time after being admitted to PICU facilities. Our secondary aim was to investigate if the presence of a complex chronic condition (CCC) would further impair prognosis. DESIGN: A closed cohort of all children up to 16 years of age admitted to the three PICUs in Sweden between 2008 and 2010 was prospectively collected and followed until 2012, providing survival data for at least one but up to four years of follow-up. SETTING: Three Swedish tertiary referral centers for pediatric intensive care and extracorporeal membrane oxygenation (ECMO) care were used. PATIENTS: In total, 3,688 Swedish children with 5,019 PICU admissions were included. INTERVENTIONS: No interventions were conducted. MEASUREMENTS: An extensive data set was recorded, including up to four-year survival information following first PICU admission. The patients were assigned to seven admission diagnostic groups, which were then divided into SADM or MADM groups. The difference in survival over time and mortality rates (MR) and mortality rate ratios (MRR) were calculated. SADM and MADM groups with and without an existing CCC were formed. The difference in survival over time between groups was calculated. MAIN RESULTS: A highly significant difference in survival over time was noted between SADM and MADM patients (p<0.0001), which was intensified by the presence of a CCC. MADM patients with a CCC had the worst outcome, while SADM patients without a CCC had the best outcome. MADM patients with no CCC demonstrated decreased survival over time compared to SADM patients with a CCC. Survival over time was statistically worsened for patients with MADM compared to SADM for the following admission diagnostic groups: Cardiovascular, Gastrointestinal/Renal, Respiratory, Neurological, and Miscellaneous. The mortality rate (deaths/patient year of follow-up) during the time of follow-up was 0.023 for SADM and 0.062 for MADM patients. The mortality rate ratio (MRR) between these groups was 2.69. CONCLUSION: Compared to single admissions, multiple admissions to PICU were associated with a significant decrease in survival over time in some but not all diagnostic groups. Regarding our secondary aim, we found that when the presence of a CCC is factored into the survival analysis, survival over time is further impaired.

Long-Term Cognitive Outcome and Brain Imaging in Adults After Extracorporeal Membrane Oxygenation.

OBJECTIVES: To investigate the presence of cognitive dysfunction and brain lesions in long-term survivors after treatment with extracorporeal membrane oxygenation for severe respiratory failure, and to see whether patients with prolonged hypoxemia were at increased risk. DESIGN: A single-center retrospective cohort study. SETTING: Tertiary referral center for extracorporeal membrane oxygenation in Sweden. PATIENTS: Long-term survivors treated between 1995 and July 2009. Seven patients from a previously published study investigated with a similar protocol were included. INTERVENTIONS: Brain imaging, neurocognitive testing, interview. MEASUREMENTS AND MAIN RESULTS: Thirty-eight patients (i.e., n = 31 + 7) were enrolled and investigated in median 9.0 years after discharge. Only memory tests were performed in 10 patients, mainly due to a lack of formal education necessary for the test results to be reliable. Median full-scale intelligence quotient, memory index, and executive index were 97, 101, and 104, respectively (normal, 100 ± 15). Cognitive function was not reduced in the group with prolonged hypoxemia. Brain imaging showed cerebrovascular lesions in 14 of 38 patients (37%), most commonly in the group treated with venoarterial extracorporeal membrane oxygenation (7/11, 64%). In this group, memory function and executive function were significantly reduced. CONCLUSIONS: Patients treated with extracorporeal membrane oxygenation for respiratory failure may have normal cognitive function years after treatment, if not affected by cerebrovascular lesions. Permissive hypoxemia was not correlated with long-term cognitive dysfunction in the present study. Further prospective studies with minimal loss to follow-up are direly needed to confirm our findings.

Long-Term Survival in Adults Treated With Extracorporeal Membrane Oxygenation for Respiratory Failure and Sepsis.

OBJECTIVE: The use of extracorporeal membrane oxygenation in adults with respiratory failure and sepsis is steadily increasing, but the knowledge on long-term survival in this group is scarce. The aim of the present study was to investigate the 5-year survival rates and causes of late death in this group of patients. DESIGN: Single-center retrospective cohort study. SETTING: Karolinska University Hospital, Stockholm, Sweden. PATIENTS: Adult patients treated with extracorporeal membrane oxygenation for respiratory failure and sepsis between the service being established for adults in 1995 and December 2013. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Survival status was attained from a national Causes of Death registry. Minimal patient background data, along with data on survival and causes of death were collected. Survival rates were calculated using the Kaplan-Meier method. Of 255 subjects, 64% survived to discharge. The median follow-up time in survivors was 4.4 years. There was a high mortality rate within the first months after discharge. In the group of patients who survived the first 90 days after treatment, the 5-year survival rate was 87% and was particularly beneficial in patients treated for infectious diseases (88-100%). Late deaths were seen in most diagnostic groups, but the Kaplan-Meier curves flattened out over time. CONCLUSIONS: Extracorporeal membrane oxygenation treatment in adult patients with respiratory failure and sepsis can be lifesaving in appropriately selected patients. For patients who survive the first months after extracorporeal membrane oxygenation treatment, long-term survival seems good, especially in patients treated for infections.

Long-Term Survival and Causes of Late Death in Children Treated With Extracorporeal Membrane Oxygenation.

OBJECTIVE: Extracorporeal membrane oxygenation has been used in patients with severe circulatory or respiratory failure since the 1970s, but the knowledge on long-term survival in this group is scarce. The aim of the present study was to investigate the 10-year survival rates and causes of late death in children treated with extracorporeal membrane oxygenation. DESIGN: Single-center, retrospective cohort study. SETTING: Tertiary referral center for extracorporeal life support. PATIENTS: Neonatal and pediatric patients treated with extracorporeal membrane oxygenation from 1987 to December 2013. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Survival status was obtained from the national Causes of Death registry. Patient background data along with data on survival and causes of death were collected. Survival rates were calculated using the Kaplan-Meier method. Of 400 subjects, 76% survived to discharge. The median follow-up time in survivors was 7.2 years. There was a high mortality rate within the first months after discharge. In the group of patients who survived the first 90 days after treatment, the 10-year survival rates were 93% in neonates and 89% in pediatric patients and were particularly beneficial in patients whose indication for extracorporeal membrane oxygenation was meconium aspiration syndrome, trauma, or infectious diseases. Late deaths were seen in some diagnostic groups, but the Kaplan-Meier curves plateaued over time. CONCLUSIONS: Children who survive the first months after treatment with extracorporeal membrane oxygenation have a high long-term survival rate. The prognosis is especially favorable in patients with reversible conditions.

Does permissive hypoxaemia during extracorporeal membrane oxygenation cause long-term neurological impairment?: A study in patients with H1N1-induced severe respiratory failure.

BACKGROUND: The Extracorporeal Life Support Organisation accepts permissive hypoxaemia in adult patients during extracorporeal membrane oxygenation (ECMO). The neurological long-term outcome of this approach has not yet been studied. OBJECTIVES: We investigated the prevalence of brain lesions and cognitive dysfunction in survivors from the Influenza A/H1N1 2009 pandemic treated with permissive hypoxaemia during ECMO for severe acute respiratory distress syndrome (ARDS). Our hypothesis was that this method is reasonable if tissue hypoxia is avoided. DESIGN: Long-term follow-up study after ECMO. SETTING: Karolinska University Hospital, Sweden, from October 2012 to July 2013. PATIENTS: Seven patients treated with ECMO for severe influenza A/H1N1-induced ARDS were studied 3.2 years after treatment. Blood lactate concentrations were used as a surrogate for tissue oxygenation. INTERVENTIONS: Neurocognitive outcome was studied with standardised cognitive tests and MRI of the brain. MAIN OUTCOME MEASURES: Cognitive functioning and hypoxic brain lesions after permissive hypoxaemia during ECMO. The observation period was the first 10 days of ECMO or the entire treatment period if shorter than 10 days. RESULTS: Eleven of 13 patients were still alive 3 years after ECMO. We were able to contact seven of these patients (mean age 31 years), who all agreed to participate in this study. Mean ±â€ŠSD peripherally measured arterial saturation during the observation period was 79 ±â€Š10%. Full-scale Intelligence Quotient was within one standard deviation or above from the mean of a healthy population in five patients, and was 1.5 SD below the mean in one patient. In one other patient, it could not be determined because of a lack of formal education. Memory functioning was normal in all patients. MRI showed no changes related to cerebral hypoxia. CONCLUSIONS: Permissive hypoxaemia during ECMO might not negatively affect long-term cognitive outcome if adequate organ perfusion is maintained. TRIAL REGISTRATION: at Clinicaltrials.gov NCT01763060.

Autologous Peripheral Blood Mononuclear Cells as Treatment in Refractory Acute Respiratory Distress Syndrome.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a devastating disorder. Despite enormous efforts in clinical research, effective treatment options are lacking, and mortality rates remain unacceptably high. OBJECTIVES: A male patient with severe ARDS showed no clinical improvement with conventional therapies. Hence, an emergent experimental intervention was performed. METHODS: We performed intratracheal administration of autologous peripheral blood-derived mononuclear cells (PBMCs) and erythropoietin (EPO). RESULTS: We found that after 2 days of initial PBMC/EPO application, lung function improved and extracorporeal membrane oxygenation (ECMO) support was reduced. Bronchoscopy and serum inflammatory markers revealed reduced inflammation. Additionally, serum concentration of miR-449a, b, c and miR-34a, a transient upregulation of E-cadherin and associated chromatin marks in PBMCs indicated airway epithelial differentiation. Extracellular vesicles from PBMCs demonstrated anti-inflammatory capacity in a TNF-α-mediated nuclear factor-x03BA;B in vitro assay. Despite improving respiratory function, the patient died of multisystem organ failure on day 38 of ECMO treatment. CONCLUSIONS: This case report provides initial encouraging evidence to use locally instilled PBMC/EPO for treatment of severe refractory ARDS. The observed clinical improvement may partially be due to the anti-inflammatory effects of PBMC/EPO to promote tissue regeneration. Further studies are needed for more in-depth understanding of the underlying mechanisms of in vivo regeneration.

[Good long-term survival after ECMO treatment]. / God långtidsöverlevnad efter ECMO-behandling.

ECMO is used more and more globally, and to date more than 60,000 patients have undergone ECMO treatment. At the ECMO Center Karolinska in Stockholm, Sweden, more than 900 neonatal, pediatric and adult patients with primarily respiratory failure have been treated since 1987. This study investigated 217 consecutive patients of all ages who were treated 1995-2005 at our center, of which 76 % survived treatment. The mean follow-up time was 7.9 years. Of the patients who survived more than 90 days after treatment, 91 % were alive at follow-up 5 years later, similar in all age categories (89-93 %). The highest mortality risk was observed within the first months after ECMO. We conclude that both short and long-term survival is high in all age categories, especially considering the high mortality risk of the patients eligible for ECMO treatment. More studies are needed to evaluate long term prognostic markers, cognitive functions and quality of life, especially in the adult.