The study investigated the safety and efficacy of two antithrombin III (ATIII) products in pediatric patients receiving extracorporeal membrane oxygenation (ECMO) by performing a retrospective analysis of patients who received either recombinant ATIII (rATIII) or human-derived ATIII (hATIII). Twenty-two patients were included in the study from January 2014 to September 2015 and all received unfractionated heparin (UFH) as anticoagulation during ECMO. In total, 86 doses of ATIII were included in the analysis in which 37 doses (43%) were rATIII and 49 doses (57%) were hATIII. Unfractionated heparin rates were also evaluated for all cases (n = 86) at 24 hours post-ATIII supplementation. The UFH rate decreased after the administration of both types of ATIII. However, neither the reduction in UFH rate between the two ATIII products ( p = 0.52) nor the UFH rates pre- and post-ATIII supplementation at 24 hours ( p = 0.08) reached statistical significance. There was a significant difference in cost favoring the rATIII product ( p < 0.0001). An ad-hoc estimation of waste associated with ATIII supplementation showed >$100,000 in financial loss of unused drug. Future studies are warranted to evaluate the efficacy of ATIII supplementation in pediatric ECMO.

Purpose: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is being recognized with increasing frequency among children. Given the paucity of evidence to guide the critical care management of these complex patients, we provide a comprehensive review of the literature with pooled analysis of published case reports and case series. Methods: We performed a comprehensive literature search using PubMed, Scopus, EMBASE, and Web of Science for relevant published studies. The literature search was conducted using the terms NMDA, anti-NMDA, Anti-N-methyl-D-aspartate, pediatric encephalitis, and anti-NMDAR and included articles published between 2005 and May 1, 2016. Results: Forty-eight references met inclusion criteria accounting for 373 cases. For first-line treatments, 335 (89.8%) received high-dose corticosteroids, 296 received intravenous immunoglobulin (79.3%), and 116 (31%) received therapeutic plasma exchange. In these, 187 children (50.1%) had a full recovery with only minor deficits, 174 patients (46.7%) had partial recovery with major deficits, and 12 children died. In addition, 14 patients were reported to require mechanical ventilation. Conclusion: Anti-NMDA encephalitis is a formidable disease with great variation in clinical presentation and response to treatment. With early recognition of this second most common cause of pediatric encephalitis, a multidisciplinary approach by physicians may provide earlier access to first-and second-line therapies. Future studies are needed to examine the efficacy of these current therapeutic strategies on long-term morbidity.

OBJECTIVES:To examine the impact of an ICU bundle on delirium screening and prevalence and describe characteristics of delirium cases.DESIGN:Quality improvement project with prospective observational analysis.SETTING:Nineteen-bed PICU in an urban academic medical center.PATIENTS:All consecutive patients admitted from December 1, 2013, to September 30, 2015.INTERVENTIONS:A multidisciplinary team implemented an ICU bundle consisting of three clinical protocols: delirium, sedation, and early mobilization using the Plan-Do-Study-Act cycles as part of a quality improvement project. The delirium protocol implemented in December 2013 consisted of universal screening with the Cornell Assessment of Pediatric Delirium revised instrument, prevention and treatment strategies, and case conferences. The sedation protocol and early mobilization protocol were implemented in October 2014 and June 2015, respectively.MEASUREMENTS AND MAIN RESULTS:One thousand eight hundred seventy-five patients were screened using the Cornell Assessment of Pediatric Delirium revised tool. One hundred forty patients (17%) had delirium (having Cornell Assessment of Pediatric Delirium revised scores ≥ 9 for 48 hr or longer). Seventy-four percent of delirium positive patients were mechanically ventilated of which 46% were younger than 12 months and 59% had baseline developmental delays. Forty-one patients had emerging delirium (having one Cornell Assessment of Pediatric Delirium revised score ≥ 9). Statistical process control was used to evaluate the impact of three ICU bundle process changes on monthly delirium rates over a 22-month period. The delirium rate decreased with the implementation of each phase of the ICU bundle. Ten months after the delirium protocol was implemented, the mean delirium rate was 19.3%; after the sedation protocol and early mobilization protocols were implemented, the mean delirium rate was 11.84%.CONCLUSIONS:Implementation of an ICU bundle along with staff education and case conferences is effective for improving delirium screening, detection, and treatment and is associated with decreased delirium prevalence.

Purpose Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is being recognized with increasing frequency among children. Given the paucity of evidence to guide the critical care management of these complex patients, we provide a comprehensive review of the literature with pooled analysis of published case reports and case series. Methods We performed a comprehensive literature search using PubMed, Scopus, EMBASE, and Web of Science for relevant published studies. The literature search was conducted using the terms NMDA, anti-NMDA, Anti-N-methyl-d-aspartate, pediatric encephalitis, and anti-NMDAR and included articles published between 2005 and May 1, 2016. Results Forty-eight references met inclusion criteria accounting for 373 cases. For first-line treatments, 335 (89.8%) received high-dose corticosteroids, 296 received intravenous immunoglobulin (79.3%), and 116 (31%) received therapeutic plasma exchange. In these, 187 children (50.1%) had a full recovery with only minor deficits, 174 patients (46.7%) had partial recovery with major deficits, and 12 children died. In addition, 14 patients were reported to require mechanical ventilation. Conclusion Anti-NMDA encephalitis is a formidable disease with great variation in clinical presentation and response to treatment. With early recognition of this second most common cause of pediatric encephalitis, a multidisciplinary approach by physicians may provide earlier access to first- and second-line therapies. Future studies are needed to examine the efficacy of these current therapeutic strategies on long-term morbidity.

Objective Congenital anomalies of the kidney and urinary tract constitute up to 30% of anomalies identified in the neonatal period. In utero oligohydramnios is often associated with pulmonary hypoplasia and respiratory failure in the neonate who may not be responsive to mechanical ventilation. Placement of these neonates on extracorporeal membrane oxygenation (ECMO) remains controversial and is considered in most centers to be a relative contraindication. The objective of this study is to use the Extracorporeal Life Support Organization (ELSO) database to describe the outcomes and complications of patients with congenital renal and urogenital anomalies with pulmonary hypoplasia who underwent ECMO in the neonatal period. Data Sources Data from the ELSO registry were retrospectively reviewed for all patients with congenital renal and urogenital anomalies with pulmonary hypoplasia treated with ECMO support between 1990 and November 2014 using ICD-9 diagnosis codes. Data Synthesis We identified 45 patients. The average age of the patient at the time of ECMO was 1.7 days (range: 0–14 days) and weight was 3.1 kg (interquartile range [IQR]: 2.5–3.3). Patients spent an average of 162 hours on ECMO (IQR: 81–207). The majority of patients were managed with venoarterial ECMO (60%), and the overall survival of this cohort was 42%. Survivors had higher weights (3.4 vs. 2.8 kg; p < 0.019) and were more likely to be male (90 vs. 44%; p < 0.002). Patients with obstructive urogenital lesions had an overall survival of 71 versus 16.6% in patients with a primary intrinsic renal diagnosis (p = 0.004). Renal replacement therapy was required in 51% of the patients during their ECMO support. Conclusion Neonates with renal or urogenital disease and pulmonary hypoplasia have an overall survival rate of 42%. Patients with a diagnosis of urogenital obstruction have much more favorable outcomes when compared with those with intrinsic renal disease such as polycystic kidney disease.

OBJECTIVE To compare withdrawal symptoms among pediatric intensive care patients receiving clonidine to those not receiving clonidine while being weaned from long-term dexmedetomidine. METHODS This retrospective analysis evaluated Withdrawal Assessment Tool-1 (WAT-1) scores and hemodynamic parameters in pediatric patients on dexmedetomidine for 5 days or longer between January 1, 2009, and December 31, 2012. The primary objective was to compare withdrawal symptoms based on the number of elevated WAT-1 scores among patients on clonidine to those not on clonidine, while being weaned from long-term dexmedetomidine. The secondary objective was to describe withdrawal symptoms associated with long-term dexmedetomidine use. RESULTS Nineteen patients (median age, 1.5 years; interquartile range [IQR], 0.67-3.3) received 20 treatment courses of dexmedetomidine for at least 5 days. Clonidine was received by patients during 12 of the treatment courses. The patients in the clonidine group had an average of 0.8 (range, 0-6) elevated WAT-1 scores 24 hours post wean compared to an average of 3.2 (0-8) elevated WAT-1 scores in the no clonidine group (p = 0.49). There were no significant difierences between prewean and postwean systolic or diastolic blood pressures among the 2 groups. The average heart rate during the postwean period was 112 beats per minute (bpm) (range, 88.5-151.5) in the clonidine group compared to 138.4 bpm (range, 117.8-168.3) in the no clonidine group (p = 0.003). In the clonidine group, the mean change in heart rate postwean compared to prewean was an increase of 3.6 bpm (range, -39.6 to 47.5), compared to a mean increase of 29.9 bpm (range, 5.5-74.7) in the no clonidine group (p = 0.042). CONCLUSIONS There was no difierence in WAT-1 scores between groups, with the clonidine group displaying a trend towards fewer elevated WAT-1 scores during the 24 hours post dexmedetomidine wean. Patients who received clonidine had significantly lower heart rates than the no clonidine group.

Society of Critical Care Medicine; 28th Educational and Scientific Symposium; San Francisco, California, USA; January 23-27, 1999: Poster Presentations: Poster Hall

Intratracheal Pulmonary Ventilation vs. Conventional Ventilation in an Oleic Acid Lung Injury Model in the Young Lamb 197

Objective: To study the effects of venovenous extracorporeal membrane oxygenation (ECMO) on cerebral autoregulation in the newborn lamb.Design: Animal studies, using newborn lambs, with comparison of two randomized treatment groups.Subjects: Newborn lambs of mixed breed, 1 to 7 days of age, were randomized into two study groups: control animals, with jugular Vein ligation but no ECMO (n = 6), and ECMO animals placed on venovenous ECMO (n = 6).Setting: Laboratory animal facilities of the Department of Anesthesiology and Critical Care Medicine at The Johns Hopkins Medical Institutions, Baltimore, MD.Interventions: Animals were anesthetized with pentobarbital, intubated, and ventilated, and monitoring catheters were inserted. Control animals had their right jugular vein ligated, and a cerebral autoregulation curve was performed after 1 hr of stabilization. ECMO animals were placed on venovenous ECMO and after 1 hr of stabilization, they had a cerebral autoregulation curve performed. Cerebral autoregulation was examined by increasing intracranial pressure, thereby decreasing cerebral perfusion pressure. Intracranial pressure was increased by infusion of artificial cerebrospinal fluid into the lateral ventricle of the brain.Measurements and Main Results: Four ranges of cerebral perfusion pressure were evaluated: a) baseline (1 hr after initiation of bypass in venovenous ECMO or completion of surgery in controls); b) cerebral perfusion pressure of 55 to 40 mm Hg; c) cerebral perfusion pressure of 39 to 25 mm Hg; and d) cerebral perfusion pressure of < 25 mm Hg. Cerebral blood flow (radiolabeled microspheres), cerebral oxygen consumption, fractional oxygen extraction, and oxygen transport Values were calculated at. each study period.In ECMO animals, cerebral blood flow (cerebral hemispheres) decreased from a baseline measurement of 46 +/- 9 (SD) mL/100 g/min to 29 +/- 12 mL/100 g/min at a cerebral perfusion pressure of < 25 mm Hg. In the control group, cerebral blood flow was unchanged from baseline at any range of cerebral perfusion pressure. Cerebral oxygen consumption was unchanged from baseline as cerebral perfusion pressure decreased in either group. When cerebral oxygen consumption was compared between the two groups, it was lower in the ECMO group at baseline and at a cerebral perfusion pressure of < 25 mm Hg. At a cerebral perfusion pressure of < 25 mm Hg, cerebral blood flow, cerebral oxygen delivery, and metabolic rate were lower in the ECMO group than in the control group, and fractional oxygen extraction and cerebral Vascular resistance were higher, indicating that autoregulation was impaired. There was no difference between blood flow in the right and left cerebral hemispheres when autoregulation was impaired in the ECMO animals.Conclusions: These findings indicate that cerebral autoregulation was altered in animals on venovenous ECMO, with cerebral blood flow decreasing at a cerebral perfusion pressure of (25 mm Hg, compared with control animals which showed no changes at the same cerebral perfusion pressure. This disruption of cerebral autoregulation decreased cerebral oxygen metabolism despite an increased oxygen extraction in ECMO animals.

Objective To determine factors associated with acute respiratory failure after bone marrow transplantation which can be identified before the onset of lung disease. Design Population-based, retrospective study. Setting A referral-based pediatric intensive care unit and bone marrow transplant center. Patients Thirty-nine patients with lung disease (abnormal chest radiograph or a need for supplemental oxygen) were identified from a group of 318 pediatric bone marrow transplant patients from 1978 to 1988. Thirty-four of 39 patients with complete data were further classified into patients with mild lung disease (recovery without needing endotracheal intubation, n = 16) and patients with acute respiratory failure (requirement for endotracheal intubation, n = 18). Interventions Regression analyses were performed to define risk factors for development of respiratory failure (multivariate logistic regression) and for a shortened interval between the identification of lung disease and respiratory failure (Cox proportional hazards analysis). Measurements and Main Results Ninety-three percent (15/16) of patients with mild lung disease survived. Conversely, only 9% (2/23) of patients with respiratory failure survived. Predictors of respiratory failure included graft vs. host disease (odds ratio 28.3, 95% confidence interval 1.9–421, p = .015), a prelung disease (baseline) circulating creatinine concentration of >1.5 mg/dL (>132.6 μmol/L) (odds ratio 28.4, 95% confidence interval 1.4–577, p = .029), and male gender (odds ratio 14.6, 95% confidence interval 1–210, p = .049). Predictors of a shortened time to onset of respiratory failure included baseline serum creatinine value of >1.5 mg/dL (>132.6 μmol/L) (hazard ratio 6.2, 95% confidence interval 1.5–26.5, p = .013) and baseline total bilirubin concentration >1.4 mg/dL (>23.9 μmol/L) (hazard ratio 4.5, 95% confidence interval 0.98–20.7, p = .053). The median time to onset of respiratory failure was 4 days in patients with baseline creatinine values ≥1.5 mg/dL (>132.6 μmol/L) and 5 days in patients with baseline bilirubin concentrations ≥;1.4 mg/dL (>23.9 μmol/L) vs. >26 days in patients with creatinine <1.5 mg/dL (<132.6 μmol/L) and >29 days in patients with bilirubin <1.4 mg/dL (<23.9 μmol/L) (Kaplan-Meier analysis). Conclusions Renal and liver dysfunction preceded clinical evidence of lung disease in bone marrow transplant patients who developed respiratory failure. Lung disease leading to respiratory failure and adult respiratory distress syndrome appears to develop as one component of the multiple organ failure syndrome in pediatric bone marrow transplant patients.

This study was designed to evaluate the effect of ligation of the carotid artery and/or jugular vein, after exposure to prolonged (4 hours) hypoxia, and the effect of acute normalization of PaO2 after prolonged hypoxia with vessel ligation, on the cerebral circulation. Twelve 1- to 7-day-old lambs were anesthetized with pentobarbital. Catheters were placed in the femoral artery and vein, left ventricle, lingual artery, and sagittal sinus. Cerebral blood flow (CBF) was determined using the radiolabeled microsphere technique. After baseline studies, the animals were made hypoxic with a nitrogen/air mixture, to lower PaO2 to 36 +/- 5 mm Hg for 4 hours, followed by 1 hour of normoxia. After four hours of hypoxia, studies were performed. The animals were divided into two groups to evaluate carotid artery and jugular vein ligation separately. In group I, the carotid artery was ligated first, with studies performed after 5 minutes; this was followed by ligation of the jugular vein, with studies after 5 minutes. In group II, the jugular vein was ligated first, with studies after 5 minutes; this was followed by ligation of the carotid artery, with studies after 5 minutes. With regard to physiological variables, there were no differences between the groups. CBF increased 106% (P < .001 compared with the baseline value) after 4 hours of hypoxia, maintaining cerebral oxygen consumption (CMRO2) and oxygen transport (OT) constant in both groups. Ligation of either the carotid artery or jugular vein after 4 hours of hypoxia, did not alter CBF responses to hypoxia.(ABSTRACT TRUNCATED AT 250 WORDS)

ObjectiveTo determine if the institution of extracorporeal membrane oxygenation (ECMO) alters the cerebrovascular response to changes in Paco2. DesignProspective, randomized, controlled animal trial. SubjectsAnesthetized 1− to 7-day-old lambs of mixed breed (n = 16). SettingUniversity research laboratory. InterventionsThe experimental group was placed on ECMO. Both experimental and control groups (n = 8) were exposed to three concentrations of Paco2 (hypocarbia, normocarbia, and hypercarbia) by varying mechanical ventilation and by adding carbon dioxide to the ventilator gases. Measurements and Main ResultsCerebral blood flow was measured by the radiolabeled microsphere method. Arterial blood gases and sagittal sinus blood gases were drawn at the time of cerebral blood flow measurement so that cerebral metabolism, cerebral oxygen transport, and extraction could be calculated. In the control group, as Paco2 increased from 34 ± 2 (SD) to 53 ± 4 torr (4.5 ± 0.3 to 7.1 ± 0.5 kPa), cerebral blood flow increased from 53 ± 12 to 147 ± 50 mL/min/100 g. This increase in cerebral blood flow was not different from that of the ECMO group, where Paco2 increased from 33 ± 2 to 56 ± 3 torr (4.4 ± 0.3 to 7.5 ± 0.4 kPa) and cerebral blood flow increased from 48 ± 17 to 106 ± 38 mL/min/100 g. As Paco2 decreased from 34 ± 2 to 19 ± 2 torr (4.5 ± 0.27 to 2.5 ± 0.27 kPa), cerebral blood flow decreased from 53 ± 12 to 43 ± 8 mL/min/100 g in the control group. This decrease was not different from that of the ECMO group, where cerebral blood flow decreased from 48 ± 17 to 39 ± 10 mL/min/100 g as Paco2 decreased from 33 ± 2 to 22 ± 3 torr (4.4 ± 0.3 to 2.9 ± 0.4 kPa). When regional cerebral blood flow was analyzed, no regional differences in the cerebrovascular responses to Paco2 between ECMO and control groups were found.The cerebral metabolic rate was not different between ECMO and control groups at any level of Paco2, nor was the cerebral metabolic rate affected by changes in Paco2. Oxygen extraction increased with hypocarbia and decreased with hypercarbia in a similar fashion in both ECMO and control groups. ConclusionThe cerebrovascular response to changes in Paco2 was unaffected by ECMO. (Crit Care Med 1994; 22:291–298)

ABSTRACT: This study was designed to evaluate the effect of normothermic partial bypass, or venoarterial extracorporeal membrane oxygenation (ECMO), on cerebral autoregulation. Fourteen newborn lambs, 1–7 d of age, were randomized into two groups: control (ligation of right carotid artery and jugular vein without ECMO; n = 7) and ECMO (ligation with placement on routine venoarterial ECMO at 120–150 mL/kg/min; n = 7). After 1 h of ECMO or stabilization in controls, cerebral autoregulation was evaluated by lowering cerebral perfusion pressure (CPP) by increasing intracranial pressure through infusion of artificial cerebrospinal fluid into the lateral ventricle. Four ranges of CPP were evaluated: 1) baseline, 2) 55–40, 3) 39–25, and 4) < 25 mm Hg. In ECMO animals, cerebral blood flow (CBF) decreased from baseline (39 ± 7 mL/100 g/min) to 23 ± 7 and 12 ± 2 at CPP of 39–25 and < 25 mm Hg. In the control group, CBF was unchanged from baseline (48 ± 11 mL/100 g/min) until CPP was < 25 mm Hg, at which time it decreased to 27 ± 16 mL/100 g/min. Cerebral oxygen consumption decreased from baseline (4.2 ± 1.1 mL/100 g/min) to 4.0 ± 0.7 and 3.2 ± 1.3 mL/100 g/min at CPP of 39–25 and < 25 mm Hg, respectively, in the ECMO group. In the control group, cerebral oxygen consumption was unchanged from baseline (4.2 ± 1.1 mL/100 g/min) until CPP was reduced to < 25 mm Hg (3.2 ± 1.3 mL/100 g/min). When CBF autoregulation was altered, i. e. when total CBF decreased, right-left hemispheric CBF differences were noted in both groups. These findings show that venoarterial ECMO, at flow rates of 120–150 mL/kg/min, alters cerebral autoregulation in healthy newborn lambs and that, if CBF is decreased by an increase in intracranial pressure, carotid artery ligation can result in lower CBF on the ipsilateral side.

ABSTRACT: Extracorporeal membrane oxygenation (ECMO) supplies respiratory support to term or near-term infants with respiratory failure. Although infants requiring this therapy may have already sustained significant hypoxia and/or ischemia predisposing them to neurologic injury, the high incidence of neuroimaging abnormalities in the ECMO population raises concerns about the additional neurologic risk associated with the ECMO procedure itself. Our study was undertaken to evaluate the effects of ECMO on the normal neonatal cerebral circulation. Thirteen newborn lambs (1-7 d of age) were placed on normothermic venoarterial ECMO using a silicone membrane oxygenator and roller occlusion pump. Regional brain blood flows, cerebral oxygen consumption, fractional oxygen extraction, and oxygen transport were determined 30 and 120 min after initiation of ECMO. Neither cerebral blood flow (baseline, 60.2 ± 23.6; 30 min, 56.1 ± 18.1; 120 min 56.1 ± 12.9 mL/100 g/min) nor oxygen metabolism (cerebral oxygen consumption: baseline, 4.48 ± 1.48; 30 min, 3.86 ± 1.53; 120 min, 4.10 ± 1.32 mL/100 g/min and oxygen extraction: baseline, 0.52 ± 0.09; 30 min, 0.47 ± 0.14; 120 min, 0.46 ± 0.14 mL/100 g/min) changed after the initiation of ECMO. Regional and left/right blood flow differences were not noted. These findings suggest that in healthy newborn lambs, initiation of ECMO does not alter cerebral blood flow or oxygen metabolism.