A clinical inflammatory syndrome attributable to aerosolized lipid-DNA administration in cystic fibrosis.

Immunologic reactivity to lipid-DNA conjugates has traditionally been viewed as less of an issue than with viral vectors. We performed a dose escalation safety trial of aerosolized cystic fibrosis transmembrane conductance regulator (CFTR) cDNA to the lower airways of eight adult cystic fibrosis patients, and monitored expression by RT-PCR. The cDNA was complexed to a cationic lipid amphiphile (GL-67) consisting of a cholesterol anchor linked to a spermine head group. CFTR transgene was detected in three patients at 2-7 days after gene administration. Four of the eight patients developed a pronounced clinical syndrome of fever (maximum of 103.3EF), myalgias, and arthralgia beginning within 6 hr of gene administration. Serum IL-6 but not levels of IL-8, IL-1, TNF-alpha, or IFN-gamma became elevated within 1-3 hr of gene administration. No antibodies to the cationic liposome or plasmid DNA were detected. We found that plasmid DNA by itself elicited minimal proliferation of peripheral blood mononuclear cells taken from study patients, but led to brisk immune cell proliferation when complexed to a cationic lipid. Lipid and DNA were synergistic in causing this response. Cellular proliferation was also seen with eukaryotic DNA, suggesting that at least part of the immunologic response to lipid-DNA conjugates is independent of unmethylated (E. coli-derived) CpG sequences that have previously been associated with innate inflammatory changes in the lung.

Chronic aspiration in children: evaluation of the lipid-laden macrophage index.

Chronic pulmonary aspiration (CPA) causes significant morbidity, but is underdiagnosed because of difficulties in establishing a diagnosis. The lipid-laden macrophage index (LLMI) is said to differentiate between those with and without CPA. Records of 113 patients were reviewed to determine specificity and sensitivity of the LLMI for CPA. Diagnostic accuracy was inferred from treatment outcome. Mean LLMI for aspirators was 104 +/- 62 (range, 20-233), and for nonaspirators, 44 +/- 39 (range, 0-170) (P < 0.05). Sensitivity and specificity were 0.69 and 0.79, respectively. While the LLMI provides clinically helpful information, it does not stand alone as the gold standard for the diagnosis of CPA. Failure to thrive and neurological impairment correlated with CPA, using Fisher's exact test. CPA was not diagnosed in any patient with normal growth, normal neurological development, and an LLMI <86. No other clinical observation (cough, wheeze, vomiting, difficulty feeding, choking with feeding, recurrent pneumonia, bronchopulmonary dysplasia, chronic chest X-ray changes, endotracheal tube, tracheostomy tube, nasogastric feeding tube, or transpyloric feeding tube) or diagnostic study (upper gastrointestinal series, gastroesophageal scintigraphy, modified barium swallow, or pH probe) correlated with the diagnosis of CPA.

Hemodynamic responses of chronically instrumented piglets to bolus injections of group B streptococci.

Group B beta-hemolytic Streptotocci cause pulmonary hypertension when injected into animals and may precipitate the persistent pulmonary hypertension syndrome in infected human neonates. We used chronically instrumented piglets to study the effects of repeated injections of heat-killed group B Streptococcus (GBS) type III. Daily exposure to GBS was associated with a 2-fold or greater potentiation of pulmonary and systemic hypertensive responses after 1 wk. Throughout experimentation, pulmonary pressure changes were more marked than systemic changes. After establishing a dose-response relationship, we chose a control dose that produced intermediate hypertensive responses. We then evaluated the effects of antibody and various drugs on the hypertensive responses. Preincubation of organisms with rabbit antiserum containing type-specific antibody enhanced the responses. Beta endorphin blockade with naloxone had little or no effect; leukotriene synthesis inhibition also did not affect responses. Both indomethacin, a cyclooxygenase inhibitor, and dazmegrel, a specific thromboxane synthesis inhibitor, blocked the hypertensive responses to GBS. It appears that repeated doses of GBS potentiate the hypertensive responses, a process that we hypothesize may be mediated by development of type-specific antibody as type-specific antibody levels rose during potentiation. It is likely that thromboxane A2 is the effector of the pulmonary and systemic hypertensive responses to GBS injection, because thromboxane inhibition by dazmegrel was as effective as indomethacin in blocking these effects. Thromboxane synthesis blockade may prove useful in management of hemodynamic disturbances accompanying severe bacterial infections in humans.

Thromboxane synthesis inhibition reverses group B Streptococcus-induced pulmonary hypertension.

Group B Streptococcus (GBS) sepsis in humans may cause the persistent pulmonary hypertension syndrome. Infusions of GBS in animals elevate pulmonary artery pressure (PAP) and resistance and are associated with elevated thromboxane levels. We investigated the hemodynamic effects of the specific thromboxane synthesis inhibitor, dazmegrel, in a piglet model of GBS-induced pulmonary hypertension. PAP rose from 22 +/- 6 to 42 +/- 11 (SD) mm Hg during infusion of heat-killed GBS; pulmonary vascular resistance increased from 1440 +/- 400 to 4000 +/- 1040 dyne X sec/cm5. No significant changes in cardiac output, mean arterial pressure, or left atrial pressure were noted. Treatment with 1 mg/kg of dazmegrel resulted in a rapid return of PAP and resistance to control values. No other hemodynamic effects of either bacteria or drug were observed despite continued infusion of GBS.

Influence of prostaglandin D2 on hemodynamic effects of group B streptococcus in neonatal lambs.

Infusions of group B streptococci cause pulmonary hypertension in several neonatal animal models. A continuous infusion of prostaglandin D2 reduced the magnitude of this pulmonary hypertensive response; indomethacin completely blocked the response. Prostaglandin D2 or cyclooxygenase inhibitors may be important therapeutic agents for infants with group B streptococcal sepsis who manifest pulmonary hypertension.

Alkalosis attenuates hypoxic pulmonary vasoconstriction in neonatal lambs.

Hyperventilation (respiratory alkalosis) is an important treatment for persistent pulmonary hypertension in neonates. The precise way that hyperventilation attenuates hypoxic pulmonary vasoconstriction is unclear. We studied the effect of alkalosis on hypoxia-induced pulmonary vasoconstriction in 13 acutely instrumented, pentobarbital anesthetized, neonatal lambs. We specifically examined the relative effects of a metabolic alkalosis versus a respiratory alkalosis on hypoxic pulmonary vasoconstriction and compared these results to the control response to hypoxia without alkalosis. Hypoxic pulmonary vasoconstriction was significantly milder whenever the animal was alkalotic, regardless of whether the alkalosis was respiratory of metabolic. Thus, the elevated pHa rather than decreased PaCO2 during hyperventilation appears to be the major factor in moderating the response of the pulmonary vessels to acute hypoxia in this neonatal lamb model.

Hemodynamic effects of nifedipine in normoxic and hypoxic newborn lambs.

We studied the effects of nifedipine, a calcium-channel blocker, in two acutely instrumented groups of newborn lambs during normoxic and hypoxic conditions. Nifedipine at 10 or more micrograms/kg reduced systemic, but not pulmonary artery pressure and resistance in normoxic lambs. When acute hypoxia was produced in these animals, 50 or more micrograms/kg reduced, but did not prevent, the expected rise in pulmonary pressure and resistance. When infused into already hypoxic lambs, nifedipine in doses of 50 micrograms/kg or more reduced both systemic and pulmonary pressures and resistances equally. Thus, nifedipine is a nonspecific vasodilator in newborn lambs.

Control of pulmonary vascular resistance in the fetus and newborn.

This article describes the anatomy and physiology of the fetal, transitional, and neonatal circulations and then reviews our current state of knowledge about the many factors that work in concert to govern pulmonary vascular resistance.

Prostaglandins, related compounds, and the perinatal pulmonary circulation.

It is clear that prostaglandins and related compounds are important in the physiology and pathophysiology of the perinatal pulmonary circulation. This article focuses on what is known about prostaglandin-related compounds (PRC) in the pulmonary circulation of the developing and newly born mammal. Also included is a discussion of the effects of PRC on the ductus arteriosus and on the systemic circulation.

Prostaglandin D2 inhibits hypoxic pulmonary vasoconstriction in neonatal lambs.

Intrapulmonary injections of prostaglandin D2 (PGD2) reduce pulmonary arterial pressure and resistance in fetal and hypoxic neonatal lambs without affecting systemic arterial pressure. This apparently specific pulmonary effect of PGD2 could be explained by inactivation of the agent during passage through the pulmonary capillary bed. We therefore studied the effects of both pulmonary and systemic infusions of PGD2 on the acute vascular response to a 1-min episode of hypoxia in newborn lambs. Since PGD2 has been reported to be a pulmonary vasoconstrictor in normoxic lambs, we also evaluated its effects during normoxemia. Pulmonary vascular pressures were not affected by either 1- or 10-micrograms . kg-1 . min-1 infusions into the left atrium or inferior vena cava during normoxia. Infusion of 1 microgram . kg-1 . min-1 PGD2 into the inferior vena cava decreased pulmonary vascular resistance and increased systemic arterial pressure. These two parameters were unchanged with the other three infusion regimens. Mean pulmonary vascular resistance rose 83% with hypoxia and no PGD2. PGD2 prevented any change in pulmonary vascular resistance with hypoxia, while systemic arterial pressure increased (1-microgram . kg-1 . min-1 doses) or was unchanged. Thus PGD2 specifically prevents hypoxic pulmonary vasoconstriction while maintaining systemic pressures, regardless of infusion site. PGD2 may be indicated in treatment of persistent pulmonary hypertension of the newborn and other pulmonary hypertensive disorders.

Effects of PEEP and tolazoline infusion on respiratory and inert gas exchange in experimental meconium aspiration.

Meconium aspiration syndrome often produces respiratory failure in the neonate. We utilized the multiple inert gas elimination technique to study the effects on respiratory and inert gas exchange of the application of positive end expiratory pressure or continuous infusion of tolazoline HCl. The application of PEEP, with the optimal level of PEEP defined for each animal, produced a decrease in AaDO2 and pulmonary shunt, without an increase in blood flow to low VA/Q areas, or an increase in dead space. Tolazoline infusion, at 2 mg/kg/hour, had no apparent effect on AaDO2 or shunt, or magnitude of low VA/Q regions. Tolazoline therapy was associated with an increase in heart rate and a decrease in systemic blood pressure. We conclude that immediate postaspiration application of PEEP, but not of tolazoline, will diminish pulmonary shunt without creating low VA/Q areas, and therefore will improve gas exchange in MAS.

Adult respiratory distress syndrome in a pediatric intensive care unit: predisposing conditions, clinical course, and outcome.

Adult respiratory distress syndrome, commonly seen in adults, is not well recognized in children. A retrospective chart review was carried out to determine the relative incidence, predisposing conditions, clinical course, and outcome of children with adult respiratory distress syndrome. fifteen patients were identified. The most common predisposing conditions were near-drowning and near-strangulation with a noticeable absence of major trauma. Mortality was 60%. Death was most often secondary to central nervous system complications. Air leak was the most common complication of treatment. Two of six survivors suffered major neurologic handicaps. Long-term pulmonary sequelae were minimal.

Ventilation by high-frequency oscillation in rabbits with oleic acid lung disease.

The feasibility and efficiency of ventilation by high-frequency oscillation (HFO) were examined in animals with diffuse hemorrhagic lung disease. Twenty-four hours after injection with 0.12 ml/kg oleic acid, 11 spontaneously breathing rabbits had a mean (+/- SD) arterial O2 partial pressure (PaO2) of 65 +/- 16 Torr and arterial CO2 partial pressure (PaCO2) of 38 +/- 7 Torr [inspired fractional O2 concentration (FIO2) of 0.21]. Following paralysis animals were ventilated using a high-frequency oscillator for periods of 20 min followed by three successive hyperinflations to prevent atelectasis. Maintaining a constant mean airway pressure (MAP) of 6 cmH2O and fresh gas flow (FGF) of 2 1/min (FIO2 = 0.21), all combinations of frequency (5, 10, 20, and 30 Hz) and stroke volume (Vs) 2.6, 5.0, and 8.9 ml) were tested. At each frequency, an increase in Vs tended to lower mean PaCO2. At each Vs, CO2 elimination appeared maximal at 20 Hz, an effect attributable to decreasing effective Vs with increasing frequency. With constant Vs, MAP, and frequency, increasing FGF from 1 to 2 or 61/min decreased mean PaCO2 (P less than 0.05). With constant Vs, frequency, and FGF, increases in MAP from 2 to 10 cmH2O increased mean PaO2 (P less than 0.05). HFO, coupled with periodic hyperinflation, supports satisfactory gas exchange in rabbits with oleic acid lung injury. The efficiency of gas exchange is improved by independent increases in Vs, FGF, MAP, or frequency.