Immediate Effects of Use of Recombinant Bone Morphogenetic Protein in Children Having Spinal Fusion and Refusion Procedures in United States.

STUDY DESIGN: Retrospective study of Nationwide Inpatient Sample (NIS). OBJECTIVE: The objective of this study is to estimate the prevalence of complications in children who had insertion of recombinant human bone morphogenetic protein (rhBMP) at the time of spinal fusion procedures (SFP) and to examine if the use of rhBMP is associated with an increased risk of complications. SUMMARY OF BACKGROUND DATA: Use of rhBMP for SFP has been associated with conflicting safety profile reports in adults. METHODS: NIS (years 2004-2010) was used. All patients with age  < 18 years who had a SFP during hospitalization with or without insertion of rhBMP were selected. Complications were selected based on a literature review of studies examining outcomes of SFP. Association between insertion of rhBMP and occurrence of complications was examined by multivariable logistic regression models. RESULTS: Of the 72,898 children who underwent SFP, 7.1% children had insertion of rhBMP. Overall complication rate was 14.34% (15.2% in rhBMP group and 14.3% in no-rhBMP group). There was no statistically significant difference in the overall complication rate [odds ratio (OR) = 1.08, 95% confidence intervals (CI) = 0.89-1.30] or among 14 different complications between rhBMP and no-rhBMP groups. Children who had rhBMP were associated with higher odds for "other infections" (OR = 2.09, 95% CI = 1.26-3.48, P = 0.004) when compared with their counterparts. CONCLUSION: Despite the lack of Food and Drug Administration approval, rhBMP was not infrequently used in pediatric SFP. In this large retrospective study using administrative data, the use of rhBMP in children during SFP was not associated with higher risks for majority of assessed complications with the exception of "other infections". Future studies must examine the long-term impact of use of rhBMP in children with SFP. LEVEL OF EVIDENCE: 3.

Outcomes of stem cell transplant patients with acute respiratory failure requiring mechanical ventilation in the United States.

SCT indications and procedures are increasing worldwide. We sought to estimate the prevalence of acute respiratory failure (ARF) of any cause in hospitalized SCT patients, and assess the impact of invasive mechanical ventilation (IMV) on outcomes. We hypothesize that duration of IMV in such patients is an independent predictor of higher mortality. We performed a retrospective analysis of the largest all-payer hospitalization data set in the United States, Nationwide In-patient Sample for years 2004-2010. Of the 101 462 SCT hospitalizations, 6074 (6%) developed ARF and were the final cohort. Type of SCT with ARF included autologous 1987 (32.7%), allogeneic 3467 (57.1%) and cord blood 655 (10.8%). Duration of IMV included <96 h (17.1%) and ⩾96 h (41.1%). Overall in-hospital mortality (IHM) was 50.6% (3075). Predictors of IHM were IMV <96 h (odds ratio=3.42 (2.44-4.79), P<0.0001) or IMV ⩾96 h (OR=4.61 (3.17-6.70), P<0.0001). Type of SCT, comorbid burden, gender, hospital-teaching status/bed size or insurance did not influence IHM. IMV ⩾96 h was associated with higher hospital charges (mean $762 515, 95% estimate 0.3991 (0.3123-0.4859), increase of $304 474, P<0.0001) and higher length of stay (mean 61.5 days, 95% estimate 0.2198 (0.1531-0.2866), increase of 13 days, P<0.0001). In conclusion, ARF in hospitalized SCT patients is not an uncommon occurrence and is associated with 50% mortality. Duration of IMV (⩾96 h) was an independent predictor of higher mortality rates. Hospital resource utilization was significant.

Comparison of lung protective ventilation strategies in a rabbit model of acute lung injury.

OBJECTIVE: To determine the impact of different protective and nonprotective mechanical ventilation strategies on the degree of pulmonary inflammation, oxidative damage, and hemodynamic stability in a saline lavage model of acute lung injury. DESIGN: A prospective, randomized, controlled, in vivo animal laboratory study. SETTING: Animal research facility of a health sciences university. SUBJECTS: Forty-six New Zealand White rabbits. INTERVENTIONS: Mature rabbits were instrumented with a tracheostomy and vascular catheters. Lavage-injured rabbits were randomized to receive conventional ventilation with either a) low peak end-expiratory pressure (PEEP; tidal volume of 10 mL/kg, PEEP of 2 cm H2O); b) high PEEP (tidal volume of 10 mL/kg, PEEP of 10 cm H2O); c) low tidal volume with PEEP above Pflex (open lung strategy, tidal volume of 6 mL/kg, PEEP set 2 cm H2O > Pflex); or d) high-frequency oscillatory ventilation. Animals were ventilated for 4 hrs. Lung lavage fluid and tissue samples were obtained immediately after animals were killed. Lung lavage fluid was assayed for measurements of total protein, elastase activity, tumor necrosis factor-alpha, and malondialdehyde. Lung tissue homogenates were assayed for measurements of myeloperoxidase activity and malondialdehyde. The need for inotropic support was recorded. MEASUREMENTS AND MAIN RESULTS: Animals that received a lung protective strategy (open lung or high-frequency oscillatory ventilation) exhibited more favorable oxygenation and lung mechanics compared with the low PEEP and high PEEP groups. Animals ventilated by a lung protective strategy also showed attenuation of inflammation (reduced tracheal fluid protein, tracheal fluid elastase, tracheal fluid tumor necrosis factor-alpha, and pulmonary leukostasis). Animals treated with high-frequency oscillatory ventilation had attenuated oxidative injury to the lung and greater hemodynamic stability compared with the other experimental groups. CONCLUSIONS: Both lung protective strategies were associated with improved oxygenation, attenuated inflammation, and decreased lung damage. However, in this small-animal model of acute lung injury, an open lung strategy with deliberate hypercapnia was associated with significant hemodynamic instability.

Use of a physiologic scoring system during interhospital transport of pediatric patients.

OBJECTIVE: To determine the incidence of physiologic deterioration in critically ill and injured pediatric patients during interhospital transport with air and ground ambulance DESIGN: Prospective, descriptive study SETTING: All children were treated in regional hospitals and then transported to a pediatric tertiary care center. PATIENTS: Children (n = 100) with a median age of 1.4 years (range 1 week to 18 years) MAIN RESULTS: Three sets of physiologic scores were calculated: at the time of referral, on departure from the referring hospital, and arrival at the tertiary care center. The incidence of significant physiologic deterioration based on the calculated physiologic scores was 5.6% (n = 4) during ground and 3.4% (n = 1) during air ambulance transports. Critical events occurred in 15% of ground and 31% of air ambulance transports. CONCLUSION: No difference existed in the incidence of adverse events or physiologic deterioration when air ambulance transports were compared with ground ambulance transports for critically ill children by our team. The physiologic scoring system we chose is simple and easy to use for quality assurance.

Partial liquid ventilation with perflubron attenuates in vivo oxidative damage to proteins and lipids.

OBJECTIVE: To determine the impact of partial liquid ventilation on the degree of pulmonary damage by reactive oxygen species in a model of acute lung injury caused by systemic endotoxemia. DESIGN: A prospective, controlled, in vivo, animal laboratory study. SETTING: Animal research facility of a health sciences university. SUBJECTS: Forty New Zealand White rabbits. INTERVENTIONS: Mature rabbits were anesthetized and instrumented with a tracheostomy and vascular catheters. Animals were assigned to receive either partial liquid ventilation (n = 16) with perflubron (18 mL/kg via endotracheal tube) or conventional mechanical ventilation (n = 16). Both groups were ventilated using similar strategies, with an Fio2 of 1.0 and tidal volume as required to obtain a normal Paco2. Animals were then given 0.9 mg/kg Escherichia coli endotoxin intravenously over 30 mins. Eight uninjured instrumented and mechanically ventilated animals served as controls. Partial liquid ventilation or conventional ventilation was continued for 4 hrs before the animals were killed. Lung homogenates were analyzed for malondialdehyde (MDA) and 4-hydroxy-2(E)-nonenal (4-HNE) concentrations using a colorimetric assay. To assess protein oxidative damage, carbonyl groups in protein side chains were derivatized with 2,4-dinitrophenylhydrazine followed by Western blotting with a dinitrophenylated-specific primary antibody. MEASUREMENTS AND MAIN RESULTS: MDA (713.42+/-662 vs. 1601.4+/-1156 nmol/g protein; p = .023) and MDA plus 4-HNE (1480.24+/-788 vs. 2675.2+/-1628 nmol/g protein; p = .038) concentrations were lower in animals treated with partial liquid ventilation compared with conventionally ventilated animals, respectively. Animals treated with partial liquid ventilation exhibited attenuation of dinitrophenylated-derivatized protein bands by Western blotting, indicating a reduction in protein oxidative damage. The presence of perfluorocarbon did not interfere with the MDA assay when assessed by independent analysis in vitro. Perflubron did not serve as a sink for peroxyl radicals produced in the aqueous phase during separate in vitro oxidation experiments. CONCLUSIONS: Partial liquid ventilation attenuates oxidative damage to lipids and proteins during experimental acute lung injury. This finding is not caused by binding of lipid peroxidation products to perflubron or by the peroxyl radical scavenging properties of perflubron.

Pathophysiology of cardiac extracorporeal membrane oxygenation.

The treatment of cardiogenic shock using inotropic agents and vascular volume expansion places an added burden on the heart. The resultant increase in cardiac work may cause myocardial ischemia and lead to cardiac arrest. Extracorporeal membrane oxygenation (ECMO) may be used to treat cardiogenic shock. It supports systemic circulation, assures diastolic perfusion of the myocardium, and reduces cardiac workload. The rise in blood pressure associated with restoring systemic circulation afterloads the heart and can cause left atrial hypertension and pulmonary edema. ECMO does not automatically reduce cardiac work, especially in the presence of residual shunts. Left atrial drainage or decompression may be essential in certain patients both to avert pulmonary edema and to reduce cardiac work.

Partial liquid ventilation influences pulmonary histopathology in an animal model of acute lung injury.

PURPOSE: The aim of this study was to assess the effect of partial liquid ventilation (PLV) and conventional mechanical ventilation (CMV) in the pattern of distribution of lung injury in a rabbit model of acute lung injury. MATERIALS AND METHODS: Animals (1.5 to 3.5 kg) were assigned to receive CMV (tidal volume of 10 mL/kg and a PEEP of 5 cm H2O) or PLV with 18 mL/kg of intratracheal perflubron (tidal volume of 10 mL/kg and a PEEP of 5 cm H2O). Lung injury was elicited by intravenous administration of Escherichia coliendotoxin. Uninjured animals ventilated as the CMV group served as controls. After 4 hours of mechanical ventilation, the lungs were removed and tissue injury was assessed by light microscopy using a scoring system. RESULTS: Animals in the CMV group had higher lung injury scores in comparison to the PLV group (10+/-4.5 vs. 5+/-3.3, respectively, P < .05). The injury scores were similar for nondependent lung regions (CMV: 8+/-4.3, PLV: 6+/-2.9) but significantly different for the dependent regions (CMV: 12+/-4.6, PLV: 5+/-3.8, P< .05). CONCLUSIONS: PLV is associated with significant attenuation of lung injury, in comparison to CMV. This effect is predominantly due to attenuation of injury in the dependent region of the lung.

Liquid ventilation attenuates pulmonary oxidative damage.

PURPOSE: Liquid perfluorochemicals reduce the production of reaction oxygen species by alveolar macrophages. We sought to determine whether the use of liquid perfluorochemicals in vivo during liquid ventilation would attenuate oxidative damage to the lung. MATERIALS AND METHODS: Healthy infant piglets (n = 16) were instrumented for mechanical ventilation and received intravenous oleic acid to create an acute lung injury. The animals were assigned to a nontreatment group receiving conventional mechanical ventilation or a treatment group receiving partial liquid ventilation with a liquid perfluorochemical. Following sacrifice, the bronchoalveolar lavage and lung parenchyma were analyzed for evidence of oxidative damage to lipids and proteins by determination of TBARS and carbonylated protein residues, respectively. RESULTS: Mortality in the control group was 50% at the completion of the study compared with no deaths in the partial liquid ventilation group (P = .025). The alveolar-arterial oxygen difference was more favorable following injury in the partial liquid ventilation group. The liquid ventilation group demonstrated a 32% reduction in TBARS (P = .043) and a 14% reduction in carbonylated protein residues (P = .061). CONCLUSION: These data suggest that partial liquid ventilation supports gas exchange and reduces mortality in association with a reduction in the production of reactive oxygen species and the concomitant attenuation of tissue damage during the early phase of acute lung injury.

Lipid peroxidation during initiation of extracorporeal membrane oxygenation after hypoxia in endotoxemic rabbits.

Initiation of extracorporeal membrane oxygenation (ECMO) in septic children with severe respiratory failure often improves oxygenation but not pulmonary function. The factors affecting pulmonary function following onset of ECMO are not completely understood, but are thought to involve injury mediated, in part, by reactive oxygen species. We hypothesized that induction of ECMO using 100% oxygen as the sweep gas through the oxygenator would increase lipid peroxidation in endotoxin-primed animals after severe hypoxia. We further speculated that provision of oxygenated blood to the pulmonary circulation via venovenous ECMO would promote a greater degree of oxidative damage to the lung as compared to venoarterial ECMO. Eighteen New Zealand White rabbits were assigned to a control group (control) or two intervention groups subjected to 60 min of venoarterial or venovenous ECMO. ECMO was initiated following an intravenous challenge with 0.5 mg/kg of E. coli endotoxin and a period of global hypoxia leading to an arterial pH of 6.99 +/- 0.09, PaCO2 of 103 +/- 31 mmHg and PaO2 of 27 +/- 5 mmHg. Malondialdehyde (MDA), a marker of lipid peroxidation, was measured in lung tissue homogenates and in arterial plasma. Lung tissue MDA demonstrated a strong trend towards an increase in the venoarterial group (1884 +/- 945 nmol/g protein) and in the venovenous group (1905 +/- 758 nmol/g protein) in comparison to the control group (644 +/- 71 nmol/g protein) (p = 0.1; significance at 95% in Scheffe test). Lung tissue MDA in the venovenous group had a significant correlation with mean PaO2 during ECMO by regression analysis (r2 = 0.678, p = 0.044). The change in blood MDA concentration between pre-ECMO and post-ECMO values was greater in the venovenous group (pre 1.62 +/- 0.61 versus post 5.12 +/- 0.2.07 mumol/l, p = 0.043) compared with that seen in the venoarterial group (pre 1.46 +/- 0.38 versus post 3.9 +/- 0.93 mumol/l). Our data support the hypothesis that initiation of ECMO with a circuit gas oxygen concentration of 100% after global hypoxia enhances oxidative damage to lipids in endotoxin-challenged animals. During venovenous ECMO this finding is dependent on PaO2.

Partial liquid ventilation reduces pulmonary neutrophil accumulation in an experimental model of systemic endotoxemia and acute lung injury.

OBJECTIVE: To determine whether pulmonary neutrophil sequestration and lung injury are affected by partial liquid ventilation with perfluorocarbon in a model of acute lung injury (ALI). DESIGN: A prospective, controlled, in vivo animal laboratory study. SETTING: An animal research facility of a health sciences university. SUBJECTS: Forty-one New Zealand White rabbits. INTERVENTIONS: Mature New Zealand White rabbits were anesthetized and instrumented with a tracheostomy and vascular catheters. Animals were assigned to receive partial liquid ventilation (PLV, n = 15) with perflubron (18 mL/kg via endotracheal tube), conventional mechanical ventilation (CMV, n = 15) or high-frequency oscillatory ventilation (HFOV, n = 5). Animals were ventilated, using an FIO2 of 1.0, and ventilatory settings were required to achieve a normal PaCO2. Animals were then given 0.9 mg/kg of Escherichia coli endotoxin intravenously over 30 mins. Partial liquid ventilation, conventional mechanical ventilation, or high-frequency oscillatory ventilation was continued for an additional 4 hrs before the animals were killed. A group of animals not challenged with endotoxin underwent conventional ventilation for 4.5 hrs, serving as the control group (control, n = 6). Lungs were removed and samples were frozen at -70 degrees C. Representative samples were stained for histology. A visual count of neutrophils per high-power field (hpf) was performed in five randomly selected fields per sample in a blinded fashion by light microscopy. Lung samples were homogenized in triplicate in phosphate buffer, ultrasonified, freeze-thawed, and clarified by centrifugation. Supernatants were analyzed for myeloperoxidase (MPO) activity by spectrophotometry with o-dianisidine dihydrochloride and hydrogen peroxide at 460 nm. MEASUREMENTS AND MAIN RESULTS: Histologic analysis of lung tissue obtained from control animals showed normal lung architecture. Specimens from the PLV and HFOV groups showed a marked decrease in alveolar proteinaceous fluid, pulmonary vascular congestion, edema, necrotic cell debris, and gross inflammatory infiltration when compared with the CMV group. Light microscopy of lung samples of animals supported with PLV and HFOV had significantly lower neutrophil counts when compared with CMV (PLV, 4 +/- 0.3 neutrophils/hpf; HFOV, 4 +/- 0.5 neutrophils/hpf; CMV, 10 +/- 0.9 neutrophils/hpf; p < .01). In addition, MPO activity from lung extracts of PLV and HFOV animals was significantly lower than that of CMV animals (PLV, 61 +/- 13.3 units of MPO activity/lung/kg; HFOV, 43.3 +/- 6.8 units of MPO activity/lung/kg; CMV, 140 +/- 28.5 units of MPO activity/lung/kg; p < .01). MPO activity from lungs of uninjured control animals was significantly lower than that of animals in the PLV, HFOV, and CMV groups (control, 2.2 +/- 2 units of MPO activity/lung/kg; p < .001). CONCLUSIONS: Partial liquid ventilation decreases pulmonary neutrophil accumulation, as shown by decreased neutrophil counts and MPO activity, in an experimental animal model of ALI induced by systemic endotoxemia. The attenuation in pulmonary leukostasis in animals treated with PLV is equivalent to that obtained by a ventilation strategy that targets lung recruitment, such as HFOV.

Purine nucleotides contribute to pulmonary vasodilation caused by birth-related stimuli in the ovine fetus.

We investigated the hypothesis that the purine nucleotides ATP and adenosine mediate the pulmonary vasodilation that occurs at birth in fetal lambs. We instrumented 44 fetal lambs to measure left pulmonary arterial pressure and flow. In control studies, we investigated the effects of sequential ventilation with 10, 50, and 100% O2 on fetal pulmonary arterial pressure and flow and pulmonary vascular resistance (PVR). We also measured the blood and plasma ATP levels in the pulmonary artery and left atrium in the control studies. In three separate groups of studies, we investigated the effects of 8-phenyltheophylline, an adenosine-receptor antagonist, and cibacron blue, an inhibitor of ATP-sensitive P2y receptors, given alone or in combination, on the response of PVR to sequential ventilation. Fetal arterial PO2 increased during ventilation with 50 and 100% O2 but not with 10% O2. Ventilation with 10% O2 caused a 4-fold increase in pulmonary blood flow and a 10-fold decrease in PVR. Ventilation with 50 and 100% O2 caused a 7-fold increase in pulmonary blood flow and a 20-fold decrease in PVR. Blood and plasma ATP levels in the pulmonary artery and blood ATP levels in the left atrium increased significantly during ventilation with 50 and 100% O2 but not with 10% O2. Pretreatment of animals with 8-phenyltheophylline attenuated the increase in pulmonary flow and decrease in PVR caused by ventilation at all fractions of inspired O2 (FIO2 levels). Pretreatment of animals with cibacron blue attenuated pulmonary vasodilation at 50 and 100% FIO2. Combined treatment with 8-phenyltheophylline and cibacron blue caused complete inhibition of the decrease in PVR in response to ventilation at the three FIO2 levels. Incubation of fetal red blood cells in vitro with 100% O2 caused an increase in ATP production. An increase in arterial PO2 in the fetus causes an increase in blood ATP levels, and an inhibition of ATP receptors attenuates the O2-induced decrease in PVR. Adenosine-receptor inhibition attenuates both ventilation- and O2-induced changes in PVR. Increased synthesis and release of ATP plays a major role in causing pulmonary vasodilation in response to birth-related stimuli in the ovine fetus.

Shock of birth. Evaluation of neurologic status of term newborn in the first 48 hours of life.

The shock of birth is a transient depression of muscle tone and deep tendon reflexes seen in newborn babies shortly after birth. We evaluated the shock of birth in a sample of 313 consecutive term newborns at 4, 24 and 48 hours of life. We correlated neurologic findings on examination with maternal, obstetric and perinatal data. Special attention was given to the relationship between the mode of delivery and shock of birth. Of the maternal data, factors associated with the shock of birth were obstetric gestational age, previous gestations, abortion or previous vaginal deliveries. Presence of stained amniotic fluid at birth was associated with the shock of birth. There was also a correlation between shock of birth and newborn sex, birth weight, thoracic circumference and the Battaglia and Lubchenco classification. The shock of birth lasted less than 24 hours in 70% of the newborns and less than 48 hours in 84.3%. We conclude that the mode of delivery, vaginal or cesarean section, did not influence the shock of birth. We also established the duration and factors associated with this phenomenon.

Moraxella catarrhalis bacteremia and preseptal cellulitis.

Invasive disease due to Moraxella catarrhalis is rare and has been associated mostly with immune deficiency conditions. We describe the first case of M catarrhalis bacteremia and preseptal cellulitis in an immunocompetent infant. This organism may be evolving from one with low pathogenicity to one with increased pathogenicity.