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This study describes the utility of overnight sleep studies in children with early onset scoliosis (EOS). Children with EOS have diminished respiratory reserve which is associated with abnormal breathing and sleep quality in children. Currently, there are no criteria for referral of these children to evaluate breathing during sleep or data on the use of sleep treatments as part of their supportive care. A review of the 159 patients with EOS who were followed at a single institution from 2003 to 2016 identified 68 who underwent overnight polysomnograms (PSGs). Sixty-five of 68 (96%) had elevated apnea–hypopnea index (AHI) and a majority (56%) were prescribed nighttime respiratory support. A majority of young children (< 5 years) with PSG were referred for a history of snoring, apnea, or restless sleep; all 30 had abnormal PSGs. Twenty-seven (90%) had nighttime hypoxemia (nadir oxygen saturation values < 92%). Eighteen (60%) were referred to otolaryngology, of whom 11 (37%) subsequently underwent tonsil and/or adenoid removal. In older children (≥ 5 years), those referred for PSGs had more severe restrictive chest wall disease [lower forced vital capacity (FVC) values] than those who were not sent for PSG. Correlation between FVC and apnea–hypopnea index, however, was not significant. Pre-operative coronal curve magnitude did not strongly correlate with nadir SaO2or AHI in either age group. These results suggest that sleep studies are underutilized in the management of children with EOS. Inadequate and poor-quality sleep adversely affects growth, behavior, and cognitive function in children. This study suggests that screening for sleep abnormalities should be incorporated into assessment and treatment of more patients with EOS.

We determined whether a @b-lactam and an aminoglycoside have efficacy greater than a @b-lactam alone in the management of a pulmonary exacerbation in patients with cystic fibrosis. Study design: Azlocillin and placebo or azlocillin and tobramycin were administered to 76 patients with a pulmonary exacerbation caused by Pseudomonas aeruginosa in a randomized double-blind, third-party monitored protocol. Improvement was assessed by standardized clinical evaluation, pulmonary function testing, sputum bacterial density, sputum DNA content, and time to the next pulmonary exacerbation requiring hospitalization. Results: No significant difference was seen between the 2 treatment groups in clinical evaluation, sputum DNA concentration, forced vital capacity, forced expiratory volume in second 1, or peak expiratory flow rate at the end of treatment (33 receiving azlocillin alone and 43 both antibiotics); adverse reactions were equivalent in each group. Sputum P. aeruginosa density decreased more with combination therapy (P = .034). On follow-up evaluation, an average of 26 days after the end of treatment, all outcome indicators had worsened in both groups. Time to readmission for a new pulmonary exacerbation was significantly longer in the group receiving azlocillin plus tobramycin (P < .001). Treatment-emergent tobramycin resistance occurred in both groups and was more frequent with combination therapy. Conclusion: We conclude that the combination of a @b-lactam and an aminoglycoside produces a longer clinical remission than a @b-lactam alone and slightly better initial improvement. (J Pediatr 1999;134:413-21)

Neonatal group B streptococcal (GBS) sepsis produces pulmonary arterial hypertension and hypoxemia that are preventable by pretreatment with the selective thromboxane A2synthase inhibitor, dazmegrel. In the present experiment we administered dazmegrel (8 mg/kg) 2 h after the initiation of a 2 h infusion of 5 × 108GBS/kg/h in ten 2− to 3-wk-old piglets. The multiple inert gas elimination technique was used to measure intrapulmonary shunt and alveolar ventilation to pulmonary perfusion mismatching. Thromboxane B2, the stable metabolite of thromboxane A2, and 6-keto-prostaglandin F1α, the stable metabolite of prostacyclin, were assayed in arterial blood. Pulmonary arterial pressure increased immediately after initiation of the GBS infusion, rising from 12 ± 2 to 34 ± 4 torr (p< 0.02); pulmonary vascular resistance increased by 400 (p< 0.01). Arterial hypoxemia developed (p< 0.02) in association with an increase in the low ventilation-perfusion ratio index but without a significant increase in intrapulmonary shunt. Thromboxane B2levels increased 10-fold. Infusion of the carrier substance for dazmegrel after 2 h of GBS infusion produced no change in any variables. In contrast, infusion of the drug resulted in the return to pre-GBS infusion baseline values for both pulmonary arterial pressure and pulmonary vascular resistance. However, no improvement in arterial pO2or in the low ventilation-perfusion ratio index occurred. Both pulmonary vascular resistance and pulmonary arterial pressure remained normal for 0.5 h after dazmegrel administration despite continued GBS infusion. Thromboxane B2levels were decreased 30 min after dazmegrel (p< 0.02), but remained greater than pre-GBS levels. Dazmegrel reversed pulmonary hypertension and elevated pulmonary vascular resistance, but did so without concomitant improvement in pulmonary gas exchange, when administered after 2 h of GBS infusion.

Acute hypoxic pulmonary vasoconstriction is attenuated by respiratory alkalosis. It is unknown if alkalosis similarly reduces pulmonary vasoconstriction produced by thromboxane A2. Respiratory alkalosis does not always attenuate persistent pulmonary hypertension in newborns, some of whom have elevated serum thromboxane B2 levels. We hypothesized that alkalosis attenuates thromboxane-induced pulmonary vasoconstriction less than it does hypoxic pulmonary vasoconstriction in infants. Hemodynamic responses to respiratory alkalosis during pulmonary vasoconstriction produced in random order by breathing 12 inspired oxygen and by infusing 0.1 μg/kg/ min of the thromboxane-mimetic U46,619 were compared in eight 2-wk-old piglets. Hypoxia increased mean pulmonary artery pressure from 12 ± 3 to 29 ± 2 mm Hg and pulmonary vascular resistance (PVR) from 11 ± 4 to 25 ± 8 mmHg/L/min; U46,619 increased pulmonary artery pressure from 16 ± 5 to 37 ± 6 mm Hg and PVR from 14 ± 5 to 51 ± 17 mm Hg/liter/min. U46,619 also decreased cardiac output accounting in part for the greater increase in PVR compared to hypoxia-induced vasoconstriction. Respiratory alkalosis decreased PVR to 14 ± 6 mm Hg/ liter/min during exposure to hypoxia and to 28 ± 9 mm Hg/liter/min during infusion of U46,619. In six additional piglets with U46,619-induced pulmonary vasoconstriction, the effects of lung stretch and hypocapnic alkalosis were separated by doubling tidal volume and then adding inspired CO2to return PaCO2to prehyperventilation levels. Respiratory alkalosis decreased PVR from 52 ± 36 to 35 ± 21 mm Hg/liter/min. Despite the increased tidal volume, PVR increased to 53 ± 35 Hg/liter/min when PaCO2returned to 44 ± 5 mm Hg. Respiratory alkalosis rather than lung stretch reduces thromboxane-induced and hypoxia-induced pulmonary vasoconstriction by equal proportions.

ABSTRACT. Group B streptococcal (GBS) sepsis produces arterial hypoxemia in newborns. In piglets we previously found that hypoxemia develops because of increased ventilation perfusion heterogeneity, and reduced mixed venous pO2occurring in association with decreased pulmonary blood flow. We hypothesize that increased thromboxane A2(TxA2) synthesis mediates the immediate alterations in gas exchange found in GBS sepsis. We studied 18 anesthetized, ventilated piglets before, during, and after a 30-min infusion of 2 × 109colony forming units/kg of GBS. Nine piglets were pretreated with 8 mg/ kg of dazmegrel (DAZ), a TxA2synthetase inhibitor, and nine animals received GBS without DAZ pretreatment. Pulmonary and systemic arterial pressures, pulmonary vascular resistance, pulmonary blood flow, respiratory gas tensions, intrapulmonary shunt, and SD of pulmonary blood flow, an index of ventilation perfusion mismatching, were measured. Systemic and pulmonary arterial levels of thromboxane B2and 6-keto-PGF1αwere also measured. The sham-treated animals showed the expected rise in pulmonary arterial pressure from 12 ± 3 to 29 ± 7 torr, (p<0.02). By comparison, the animals pretreated with DAZ did not demonstrate pulmonary arterial hypertension and had a delay in the fall in pulmonary blood flow until 2 h postinfusion. Arterial PO2did not decline significantly after the GBS infusion in the DAZ-pretreated animals; the untreated animals showed a significant fall in pO2from baseline. There was no significant change in intrapulmonary shunt or SD of pulmonary blood flow compared to baseline in the DAZ-pretreated animals. The elevation in thromboxane B2occurring with GBS sepsis did not occur in the DAZ-pretreated animals. We conclude that TxA2in part mediates the immediate gas exchange and pulmonary hemodynamic abnormalities during GBS sepsis. Inhibition of TxA2synthetase results in preservation of normal pulmonary gas exchange and a delay in the fall in Qp following GBS infusion.

The endogenously produced cytokine, tumor necrosis factor-α (TNF-α), has been shown in adult animal models to be associated with many of the pathophysiologic effects of sepsis, including systemic hypotension and hemorrhagic necrosis. TNF-α can induce the release of various vasoactive arachidonic acid metabolites, suggesting that TNF-α may act either directly or via intermediary substances in producing its effects. The pathophysiologic role of TNF-α in neonatal sepsis, especially its potential effect on pulmonary vascular tone, is presently unknown. To assess the role of TNF-α in neonatal sepsis, 19 piglets (19 ± 5 d old) were anesthetized, intubated, paralyzed, mechanically ventilated, and catheterized to assess pulmonary and systemic vascular hemodynamics and pulmonary gas exchange. The multiple inert gas elimination technique was used to assess ventilation perfusion matching. A 30-min infusion of human recombinant TNF-α (250 μg/kg total dose) was administered to animals pretreated with either 10 mg/kg dazmegrel, a thromboxane synthase inhibitor (n9) or placebo (n10). TNF-α alone induced a prompt and sustained rise in pulmonary arterial pressure and pulmonary vascular resistance that continued at least for 2 h after onset of the infusion. In contrast, the animals pretreated with dazmegrel demonstrated no rise in pulmonary vascular resistance until 2 h after the onset of the infusion. Neither group of animals demonstrated a significant decline in arterial PaCO2or evidence from inert gas analysis of A/ mismatching or increase in intrapulmonary shunt. We conclude that human recombinant TNF-α induces an acute and sustained elevation in Ppa and PVR without the concomitant development of hypoxemia or intrapulmonary shunt. The pulmonary hypertension is blocked acutely by the putative TxA2synthase inhibitor, dazmegrel.

Group B ß-hemolytic streptococcus (GBS) causes thromboxane (Tx)-associated pulmonary hypertension and hypoxemia in neonatal animals and human infants. The components of GBS that induce these features of sepsis are incompletely characterized. The capsular polysaccharide has been implicated based on the effects of GBS extracts. We used isogenic mutants of a parent GBS strain (COH 31 rs) devoid of capsular polysaccharide or ß- hemolysin to determine if these components caused the acute features of GBS bacteremia. In neonatal piglets, we observed a similar increase in pulmonary vascular resistance (PVR, mm HgLmin) during a 1 h infusion at 5 x 108colony-forming unitkgh of COH 31 rs (n5, 11.6 ± 1.4 to 67.1 ± 17.9), an isogenic GBS mutant devoid of type III CP (n5, 12.5 ± 1.4 to 56.9 ± 5.0), and an isogenic GBS mutant devoid of ß-hemolysin (n4, 11.0 ± 1.9 to 51.9 ± 7.9). All three GBS strains caused increases in blood TxB2levels, mild arterial hypoxemia, mild reduction in mixed venous PO2and a 30-40 reduction in cardiac output after a 1 h infusion. The Tx-synthase inhibitor, dazmegrel, completely reversed pulmonary hypertension, and partially reversed arterial hypoxemia and TxB2levels to baseline values for all GBS strains. In six additional piglets, infusion of polystyrene beads of similar size to GBS at a dose of 5 x 108beadskgh caused no changes in gas exchange or blood TxB2levels, but a mild increase in PVR (13.3 ± 2.0 to 17.7 ± 3.5). This suggests a nonspecific response to circulating particulates is not the major cause of the acute features of GBS bacteremia in piglets. We conclude that type III capsular polysaccharide and ß-hemolysin are not essential for type III GBS to cause acute Tx-associated pulmonary hypertension and hypoxemia in piglets.

ABSTRACT: Acute hypoxic pulmonary vasoconstriction is attenuated by respiratory alkalosis. It is unknown if alkalosis similarly reduces pulmonary vasoconstriction produced by thromboxane A2. Respiratory alkalosis does not always attenuate persistent pulmonary hypertension in newborns, some of whom have elevated serum thromboxane B2 levels. We hypothesized that alkalosis attenuates thromboxane-induced pulmonary vasoconstriction less than it does hypoxic pulmonary vasoconstriction in infants. Hemodynamic responses to respiratory alkalosis during pulmonary vasoconstriction produced in random order by breathing 12% inspired oxygen and by infusing 0.1 µg/kg/min of the thromboxane-mimetic U46,619 were compared in eight 2-wk-old piglets. Hypoxia increased mean pulmonary artery pressure from 12 ± 3 to 29 ± 2 mm Hg and pulmonary vascular resistance (PVR) from 11 ± 4 to 25 ± 8 mmHg/L/min; U46,619 increased pulmonary artery pressure from 16 ± 5 to 37 ± 6 mm Hg and PVR from 14 ± 5 to 51 ± 17 mm Hg/liter/min. U46,619 also decreased cardiac output accounting in part for the greater increase in PVR compared to hypoxia-induced vasoconstriction. Respiratory alkalosis decreased PVR to 14 ± 6 mm Hg/liter/min during exposure to hypoxia and to 28 ± 9 mm Hg/liter/min during infusion of U46,619. In six additional piglets with U46,619-induced pulmonary vasoconstriction, the effects of lung stretch and hypocapnic alkalosis were separated by doubling tidal volume and then adding inspired CO2to return PaCO2to prehyperventilation levels. Respiratory alkalosis decreased PVR from 52 ± 36 to 35 ± 21 mm Hg/liter/min. Despite the increased tidal volume, PVR increased to 53 ± 35 Hg/liter/min when PaCO2returned to 44 ± 5 mm Hg. Respiratory alkalosis rather than lung stretch reduces thromboxane-induced and hypoxia-induced pulmonary vasoconstriction by equal proportions.

Helium atoms have been injected into copper by alpha-particle bombardment in a cyclotron. On subsequent heating, the helium precipitates out as small gas bubbles in those parts of the metal where the helium atoms receive vacancies from nearby sources. From the distribution of the gas bubbles it is concluded that grain boundaries are effective sources of vacancies, but twin boundaries are not. Isolated sources of vacancies exist within the crystals, but there is no evidence that the dislocation network generates appreciable numbers of vacancies.

Hypoxemia is common in newborns with Group B Streptococcal (GBS) sepsis, yet the mechanism of abnormal gas exchange in this disease is unknown. We studied ventilation-perfusion matching (VA/Q) and shunt fraction using the multiple inert gas elimination in 7 newborn piglets receiving live GBS. Measurements were made in anesthetized animals ventilated with room air before, during, and after a 30 min intravenous infusion of 2×109colony forming units/kg of GBS. Shunt fraction was measured by sulfur hexafluoride retention and standard deviation of distribution of pulmonary blood flow (sdPBF) was used as an index of VA/Q heterogeneity. Changes are depicted below; * denotes p < .05.PaO2, CO and PvO2fell while Ppa and sdPBF increased significantly during GBS infusion. Shunt increased to >6% in only 2 of the animals. We conclude that arterial hypoxemia during GBS sepsis in newborn piglets results primarily from diminished cardiac output with resultant fall in mixed venous oxygen tension along with an increase in VA/Q heterogeneity within the lungs.