Hakan Sundell

Effect of Epidermal Growth Factor on Lung Maturation in Fetal Rabbits

Summary: Injection of epidermal growth factor (EGF) into 24-day rabbit fetuses (5 μg, im or ip) induced accelerated maturation of the lung. On sacrifice at day 27, there was greater distensibility and stability on deflation associated with the appearance of a complement of type II cells approaching that of the rabbit at term. EGF treatment had no demonstrable effect on body weight or lung weight in this group of animals. Saline-injected control fetuses were not affected significantly.Speculation: EGF is capable not only of promoting epithelial cell growth but also differentiation in the fetal rabbit lung. It may be an important hormone in the maturation of the lung and capable of protecting the prematurely delivered fetus against the development of hyaline membrane disease.

Effects of two rescue doses of a synthetic surfactant on mortality rate and survival without bronchopulmonary dysplasia in 700- to 1350-gram infants with respiratory distress syndrome

In a multicenter, double-blind, placebo-controlled rescue trial conducted at 21 American hospitals, two 5 ml/kg doses of a synthetic surfactant (Exosurf Neonatal) or air were administered to 419 infants weighing 700 to 1350 gm who had respiratory distress syndrome and an arterial/alveolar oxygen pressure ratio less than 0.22. The first dose was given between 2 and 24 hours of age; the second dose was given 12 hours later to those infants remaining on ventilatory support. Infants were stratified at entry by birth weight and gender. Among infants receiving synthetic surfactant, improvements in alveolar-arterial oxygen pressure gradient, arterial/alveolar oxygen pressure ratio, and oxygen and ventilator needs through 7 days of age were apparent. Death from respiratory distress syndrome was reduced by two thirds (21 vs 7; p = 0.007), and the overall neonatal mortality rate was reduced by half (50 vs 23; p = 0.001). Although there was no significant reduction in the incidence of bronchopulmonary dysplasia (39 vs 31; p = 0.107), the hypothesis that survival through 28 days without bronchopulmonary dysplasia would be enhanced by two rescue doses of synthetic surfactant was proved true (21% improvement, from 132 to 156 patients; p = 0.001). In addition, the incidence of pneumothorax was reduced by one third (62 vs 40; p = 0.022), and the incidence of pulmonary interstitial emphysema was reduced by half (102 vs 51; p = 0.001). The only side effect identified was an increase in the incidence of apnea (102 vs 134; p = 0.001). These findings indicate that rescue use of a synthetic surfactant can improve the morbidity and mortality rates for premature infants with respiratory distress syndrome.

Intracranial hemorrhage in the prematurely born infant. Timing of clots and evaluation of clinical signs and symptoms

Intraventricular hemorrhage is a frequent postmortem finding in the preterm infant with severe perinatal problems, often with respiratory distress. It is a late event, most probably secondary to perinatal circulatory disturbances related to central cerebral infarction. The bleeding occurs generally during the second or third day of life. Except for characteristic seizures, individual clinical signs and symptoms are of limited value for the timing of the bleeding, although in most instances the general clinical picture may accurately indicate the diagnosis of intraventricular hemorrhage.

Cardiorespiratory effects of nicotine exposure during development.

Exposure to tobacco smoke is a major risk factor for the sudden infant death syndrome. Nicotine is thought to be the ingredient in tobacco smoke that is responsible for a multitude of cardiorespiratory effects during development, and pre- rather than postnatal exposure is considered to be most detrimental. Nicotine interacts with endogenous acetylcholine receptors in the brain and lung, and developmental exposure produces structural changes as well as alterations in neuroregulation. Abnormalities have been described in sympathicovagal balance, arousal threshold and latency, breathing pattern at rest and apnea frequency, ventilatory response to hyperoxia or hypoxia, heart rate regulation and ability to autoresuscitate during severe hypoxia. This review discusses studies performed on infants of smoking mothers and nicotine-exposed animals yielding varying and sometimes inconsistent results that may be due to differences in experimental design, species and the dose of exposure. Taken together however, developmental nicotine exposure appears to induce vulnerability during hypoxia and a potential inability to survive severe asphyxia.

Nicotine attenuates the ventilatory response to hypoxia in the developing lamb.

ABSTRACT: Decreased ability to generate a hyperventilatory response to hypoxemia is believed to be an important mechanism in the pathophysiology of sudden infant death syndrome, and maternal smoking is a leading risk factor. To investigate whether there may be a link between these two observations, we studied five lambs at mean ages of 7,17, and 27 d to determine the effects of an i.v. infusion of nicotine (0.5 μg/kg/min) on ventilation when peripheral chemoreceptor activity was stimulated by hypoxia (0.1 FiO2) or briefly inhibited by hyperoxia. Ventilatory measurements were performed using a computer-aided occlusion valve device which permitted breath-by-breath determinations of inspiratory occlusion pressures (P0.1) and minute ventilation. Nicotine attenuated the early ventilatory response to hypoxia (min 1, 2, and 3 of the test) by 8, 26, and 37%, respectively, at the age of 7 d (analysis of variance overall, p < 0.05), by 23%, 23 and 37% at 17 d (p = NS) and by 40, 45, and 37% at 27 d (p < 0.05). The decrease in ventilation in response to hyperoxia during the control study without nicotine was 18, 35, and 34% at 7, 17, and 27 d, respectively. Nicotine caused a greater decrease in the response: 31, 45, and 46%, respectively, (p < 0.05 at 27 d). The paradoxical effects of nicotine, attenuation of the ventilatory response to hypoxia and augmentation of the response to hyperoxia, suggest that nicotine altered peripheral chemoreceptor oxygen sensitivity and most likely also affected central processing of the chemoreceptor input. It is hypothesized that the association between parental smoking and sudden infant death syndrome is related to the adverse effects of nicotine on central control of breathing.

The Physiologic Effects of Surfactant Treatment on Gas Exchange in Newborn Premature Infants with Hyaline Membrane Disease

ABSTRACT: To describe the physiologic effects of surfactant treatment on gas exchange in human premature infants with hyaline membrane disease, functional residual capacity (FRC), tidal volume (VT), the alveolar portion of tidal volume (VA), alveolar ventilation (VA), nitrogen clearance index, effective breath fraction calculated as VA/VT, compliance of the respiratory system, and arterial oxygen and carbon dioxide tensions were measured in 17 patients before and 0.5, 2, and 6 h after the administration of a single dose of either a synthetic surfactant (SS), Exosurf (n = 10), or a bovine surfactant (BS), Survanta (n = 7). By 2 h, treatment with either BS or SS was followed by an increase in the arterial/alveolar ratio of Po2 (a/A) and in FRC (p < 0.01 for both a/A and FRC). The a/A and FRC improved sooner (p < 0.001) and to a greater extent (p < 0.01) after BS than after SS. Compliance of the respiratory system and VT were decreased after either BS or SS at 0.5 h (p < 0.01) and remained decreased after SS at 2 h (p < 0.01). There was no significant change in VA or VA after either BS or SS. Because FRC and a/A increased without an accompanying increase in VA, VA, or compliance of the respiratory system, we believe that the immediate increase in FRC in this study was caused by stabilization of gas exchange units already being ventilated in addition to recruitment of new units. Nitrogen clearance index decreased and effective breath fraction increased after treatment, indicating an improved efficiency in gas mixing also thought to result from stabilization and maintenance of patency of distal airways by surfactant.

Laryngeal chemoreflex in newborn lambs: respiratory and swallowing response to salts, acids, and sugars.

Summary: The laryngeal chemoreflex was tested in a standardized manner in eighteen 1- to 6-day-old lambs. The respiratory and swallowing components of the reflex response to chemical solutions introduced to the larynx were quantified to characterize the function of the receptors and to elucidate what kind of receptors most likely are involved. A relationship between the strength of the stimulus and the respiratory response was found. The response was suppressed with the addition of small amounts of CaCl2, NaCl, and LiCl. NaCl, 0.3-0.6 M, 0.15 M NaCl titrated to a pH of 3-5 with hydrochloric or acetic acid, and 0.25-1.0 M glucose in 0.15 M NaCl elicited the reflex response.A quantitative separation was seen in the respiratory response to equimolar concentrations of the salt solutions as well as to the acid solutions in normal saline with equal pH. The response to glucose was significantly reduced after application of potassium gymnemate (P < 0.001). A direct relationship between the amount of swallowing and the respiratory response was found (r = 0.83). The laryngeal chemoreflex responses to the stimuli used have certain functional characteristics that are similar to taste receptor responses. This would suggest that the taste bud-like structures present in the laryngeal area are likely receptors for mediation of the reflex.Speculation: Laryngeal chemoreflex apnea was elicited in newborn lambs with weak salt, acid, and sugar solutions applied to the larynx. The concentrations of these stimuli were similar to those which can be present in regurgitated stomach contents of human infants. If such regurgitated material comes in contact with laryngeal chemoreceptors, apnea, and Sudden Infant Death Syndrome (SIDS) might be elicited.

Nicotine Delays Arousal during Hypoxemia in Lambs

A decreased ability to arouse from sleep in response to arterial hypoxemia may lead to severe asphyxia and has been proposed as a mechanism of sudden infant death syndrome. Based on previous observations that nicotine exposure, a major environmental risk factor for sudden infant death syndrome, may impair hypoxic defense in neonates, we hypothesized that a short-term infusion of nicotine could impair hypoxic arousal through interference with oxygen-sensing mechanisms. Seven chronically instrumented unanesthetized lambs were studied at the age of 4.6 ± 1.3 d during normoxia and acute hypoxia (0.1 fraction of inspired oxygen) for 5 min. Ventilation, transcutaneous Hb oxygen saturation, blood pressure, heart rate, and time to arousal were compared during a control saline infusion and during a 0.5 μg·kg−1·min−1 nicotine infusion. Activity states, i.e. wakefulness and quiet sleep as well as arousal, were defined by EEG, nuchal electromyogram, and electrooculogram. Each lamb acted as its own control. Arousal from quiet sleep occurred significantly later during nicotine infusion compared with control (177 ± 93 versus 57 ± 41 s, p < 0.01) and at a lower transcutaneous Hb oxygen saturation (60 ± 12 versus 79 ± 12%, p < 0.01) (paired t test). The ventilatory response to hypoxia in wakefulness was similar during both conditions but was significantly attenuated in quiet sleep during nicotine infusion (p < 0.001, 2-way ANOVA repeated-measures design). Blood pressure and heart rate responses were similar during both conditions. These results suggest that a brief nicotine exposure blunts oxygen sensitivity in young lambs, a finding of potential relevance for sudden infant death syndrome.

Reflex apnea from laryngeal chemo-stimulation in the sleeping premature newborn lamb.

Summary: The laryngeal chemoreflex was studied during quiet and REM sleep and wakefulness in premature newborn lambs. The response to reflex stimulation with a 5 sec-water infusion was evaluated during 30 sec, as % change in ventilation, heart rate and blood pressure. Apnea, hypertension and bradoardia were more pronounced during sleep than during walleffilhess, when arousal was not associated with the stimulation. The response was similar during quiet and REM sleep. Arousal, which occurred in 24 and 31% of the tests respectively, resulted in a response comparable to that seen during wakefulness. The respiratory drive was evaluated by measurement of the mean inspiratory flow and was found to be decreased during both sleep states when compared to wakefulness. We propose that during sleep in the newborn period there is a decreased ability to respond to asphyxia possibly due to a functional immaturity of the arterial chemoreceptors. This results in a low incidence of arousal and a delayed termination of the pronounced poststimulus apnea resulting from laryngeal chemoreflex stimulation.Speculation: In the newborn lamb, quiet and REM sleep have been shown to be more vulnerable states than wakefulness to reflex apnea elicited by laryngeal chemoreflex stimulation with water, probably as a reflection of decreased respiratory drive and a failure to arouse. It is possible that reflex apnea during sleep triggered by a variety of mechanisms may play a role in the pathogenesis of Sudden Infant Death Syndrome (SIDS).

Antitumor effects of GBS toxin: a polysaccharide exotoxin from group B beta-hemolytic streptococcus.

A group B streptococcus (GBS) isolated from human neonates diagnosed with sepsis and respiratory distress (“early-onset disease”) produces a polysaccharide exotoxin (GBS toxin) that, when infused in sheep, causes lung pathophysiology similar to that seen in humans. Histological studies have demonstrated that GBS toxin induces a strong inflammatory response in the lung, with pulmonary sequestration of granulocytes and extensive capillary endothelial damage. The susceptibility of humans to GBS toxin is age-dependent and limited to about 4 days after birth. It is rarely evident thereafter. This suggests that the binding of GBS toxin to the target endothelium occurs via specific components in the developing lung endothelial cells of the newborn that are later lost. We report here that GBS toxin can also bind to developing endothelium associated with neoplasia and induce an inflammatory response. GBS toxin was shown by immunohistochemistry to bind to capillary endothelium of human large-cell carcinomas. In nude mice bearing human tumor xenografts, intravenously administered GBS toxin caused tumor necrosis and hemorrhagic lesions, and substantially inhibited the rate of growth of the tumors. In BALB/c mice bearing Madison lung tumors, GBS toxin induced an inflammatory response resulting in marked changes in tumor morphology, including vasodilation, endothelial and tumor cell necrosis, invasion of lymphocytes and macrophages, and capillary thrombosis. In these tumor models, no evidence of toxicity to the vasculature of other tissues was observed. The reported pathophysiology of GBS in human neonates, the lack of disease in non-neonates colonized with GBS, and these results suggest that GBS toxin may have potential as a well tolerated agent in cancer therapy of some human tumors.