Ola Hafström

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 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.

Postnatal nicotine exposure does not further compromise hypoxia defense mechanisms in prenatally nicotine‐exposed lambs

Aims: To determine whether combined pre‐ and postnatal nicotine exposure compared with prenatal exposure alone results in more compromised postnatal hypoxia defense mechanisms and further alteration of the postnatal breathing pattern (reduced tidal volume and increased respiratory rate). Methods: Seven lambs exposed to nicotine prenatally (pN) (approximate maternal dose: 0.5 mg/kg/d) and seven lambs exposed to nicotine pre‐ and postnatally (ppN) (postnatal dose: 1.6–2 mg/kg/d) were studied without sedation at an average age of 5 d and 21 d during resting (room air) conditions, during exposure to 10% O2 and during a brief exposure to 100% O2. Results: Resting minute ventilation, occlusion pressure, effective impedance, heart rate and mean arterial blood pressure were similar in the two groups during wakefulness and quiet sleep. Resting tidal volume was significantly higher in ppN than in pN lambs during wakefulness (9.4 ±; 0.7 vs 7.7 ±; 1.4 ml/kg, p > 0.05) and quiet sleep (9.8 ±; 0.6 vs 7.6 ±; 1.5 ml/kg, p > 0.01) at 5 d and also at 21 d during wakefulness (7.7 ±; 1.0 vs 6.2 ±; 1.1 ml/kg, p > 0.05). The ventilatory, heart rate and blood pressure responses to hypoxia were comparable in the two groups during both activity states. Time to arousal from quiet sleep in response to hypoxia was equivalent in the two groups. The ventilatory response to hyperoxia was not significantly different in the two groups during either activity state.

NICOTINE DELAYS AROUSAL DURING HYPOXEMIA IN SLEEPING LAMBS. |[dagger]| 2302

Hypoxic arousal is thought to be mediated through activation of peripheral chemoreceptors. Decreased ability to arouse in response to hypoxemia and maternal smoking are two factors believed to play a significant role in SIDS. The aim of this study was to determine if nicotine affects the arousal response to acute hypoxemia and whether this effect is associated with an altered cardiorespiratory response to decreased oxygen saturation.

Dopaminergic Mediation of Delayed Hypoxic Arousal From Quiet Sleep in Young Lambs Exposed to Nicotine In Utero ♦ 1950

Decreased ability to arouse in response to hypoxemia and maternal smoking are major risk factors for SIDS. Hypoxic arousal is thought to be mediated by stimulation of peripheral chemoreceptors. In young lambs, acute postnatal nicotine exposure impairs the ventilatory response to acute hypoxia and delays arousal in quiet sleep (QS) (Pediatr Res 39:386A, 1996). The aim of this study was to determine whether prenatal nicotine exposure alters postnatal hypoxic arousal and to ascertain whether this effect is mediated by dopamine.

Prenatal nicotine exposure impairs the cardiorespiratory response to acute hypoxemia in sleeping lambs. |[bull]| 1798

Maternal smoking is a major risk factor for SIDS. The mechanism of action may be a nicotine mediated attenuation of the hypoxic defense as evidenced by impaired arousal and blunted ventilatory response to acute hypoxemia in young lambs exposed to an acute nicotine infusion (Hafstrom et al, Pediatr Res 39:386A, 1996). The aim of this study was to determine whether prenatal nicotine exposure alters the cardiorespiratory response to hypoxia after birth.

The impaired ventilatory response to acute hypoxemia in sleeping lambs exposed to nicotine prenatally is mediated by a dopaminergic mechanism. ♦ 1949

Maternal smoking is a major risk factor for SIDS. We have previously shown that prenatal nicotine exposure impairs the cardiorespiratory response to acute hypoxemia in sleeping young lambs (Pediatr Res 41:302A, 1997). The aim of this study was to determine whether this effect is mediated by a dopaminergic mechanism.

Attenuated oxygen sensifitivy after prenatal nicotine exposure-evidence for a dopaminergic mechanism. † 1797

Maternal smoking is associated with the sudden infant death syndrome. Exposure to nicotine or tobacco smoke impairs hypoxic defense mechanisms in young animals and human infants. Nicotine enhances the release of the neuromodulator dopamine (DA) in the brain. Increased DA content in the carotid bodies (CB), and in the brain stem (BS) attenuates the ventilatory responses to changes in FiO2. The study hypothesis was that antenatal nicotine exposure during the last trimester decreases ventilatory responses to changes in FiO2 through a dopaminergic mechanism in CB or BS. Subjects& Methods: Hyperoxic tests (change in minute ventilation (Vdot1) to FiO2 1.0 for 10 sec or 5 breaths) were performed in 3 groups of awake, 3-14 d old lambs: 8 controls (CTRL), 6 prenatally nicotine treated (PT) and 6 pre- and postnatally treated (PPT) by implanted minipumps. Hyperoxic tests were performed during infusion of a) saline, b) domperidone (domp), a DA2 receptor blocker in CB or c) SCH 23390, a DA1 receptor blocker in the BS.

Postnatal Nicotine Exposure Does Not Further Enhance Breathing Pattern Alterations Suggestive of Impaired Lung Function in Prenatally Nicotine-Exposed Lambs

Postnatal Nicotine Exposure Does Not Further Enhance Breathing Pattern Alterations Suggestive of Impaired Lung Function in Prenatally Nicotine-Exposed Lambs