Joseph Milerad

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.

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.

Heart rate response profiles during head upright tilt test in infants with apparent life threatening events

Sympatheticovagal imbalance causing episodes of severe bradycardia has been suggested as a cause of apparent life threatening events (ALTEs). The autonomic control of the heart rate in 18 infants with ALTEs and 12 controls was evaluated by the head upright tilt test. Five different heart rate response profiles (compared with the baseline) were observed during the tilt: (1) increase followed by a decrease and return to baseline; (2) sustained increase; (3) decrease followed by an increase and return to baseline; (4) sustained decrease; (5) no change. Eighty eight per cent of controls responded with heart rate increase followed by decrease or sustained increase compared with 55% of infants with an ALTE; a significantly greater proportion of infants with ALTEs than controls responded with heart rate decrease or no change in rate (45% v 8%). This altered reaction during a head upright tilt test may be an expression of an underlying autonomic dysfunction in infants who have experienced an ALTE.

Heart rate variability in infants with apparent life-threatening events.

Heart rate variability (HRV) is often used as an index of sympatho‐vagal balance. A decreased HRV has been observed in patients with central hypoventilation and in infants who have later succumbed to sudden infant death syndrome (SIDS). The aim of the present study was to investigate whether HRV is altered in infants with apparent life‐threatening events (ALTE), a group with an increased risk of SIDS. Fifty infants with ALTE were compared with 50 age‐ and sex‐matched controls. ECG was recorded overnight in all infants. Two sequences of RR intervals free of artefacts were selected from each sleep state and spectral analysis of RR variability was performed. The mean and SD of RR and the low (LFPow) and high (HFPow) frequency power were analysed. In active sleep (AS) the LF/HF ratio was lower in ALTE infants, but no differences were seen in either the LFPow or the HFPow. In quiet sleep (QS), however, ALTE infants had higher SD‐RR (p= 0.006), greater HFPow (p= 0.02) and VLFPow (very low frequency power, p= 0.02) than the control infants. The same results were seen when the two sleep states were combined for analysis, ALTE infants had higher SD‐RR (p= 0.004), HFPow (p= 0.006) and VLFPow (p= 0.04).

Impaired Cardiorespiratory Recovery after Laryngeal Stimulation in Nicotine-Exposed Young Lambs

The hypothesis that postnatal nicotine exposure weakens cardiorespiratory recovery from reflex apnea and bradycardia was tested in eight lambs continuously infused with nicotine from the day of birth at a dose of 1 to 2 mg·kg−1·d−1. Eight age-matched lambs infused with saline served as controls. Apnea and bradycardia were elicited by laryngeal stimulation with 1 mL of water (laryngeal chemoreflex) both during air breathing [0.21 fraction of inspired oxygen (Fio2)] and mild hypoxia (0.10 Fio2) at a mean postnatal age of 5 ± 1, 14 ± 1, and 28 ± 1 d. Ventilation, heart rate, and blood pressure were similar in the two groups at rest. In response to laryngeal chemoreflex stimulation, nicotine-treated lambs had a more pronounced decrease in ventilation (p < 0.05), longer reflex apnea (p < 0.001 in 0.21 Fio2;p < 0.01 in 0.10 Fio2), and greater reflex bradycardia (p < 0.01). During reflex apnea, sighs were less efficient in restoring heart rate to prestimulation level, and a greater decrease in heart rate was observed before sighs in nicotine-treated lambs. These effects were most apparent at 5 d of age, when nicotine-treated lambs also had lower ventilation during hypoxia (p < 0.05). The response to hyperoxia was comparable in the two groups at all ages. The ability to terminate laryngeal chemoreflex-induced apnea is attenuated in young lambs continuously exposed to nicotine. This attenuation is present both in normoxia and in hypoxia and is accompanied by reduced effects from sighing on cardiac autoresuscitation.

The divergent ventilatory and heart rate response to moderate hypercapnia in infants with apnoea of infancy

BACKGROUND Inspired CO2 is a potent ventilatory stimulant exhibiting a paradoxical inhibitory effect on breathing at high concentrations. Severe respiratory depression as a result of CO2rebreathing during sleep has been implicated as a possible trigger factor in sudden infant death syndrome (SIDS). OBJECTIVE To investigate the ventilatory and heart rate (HR) responses to inhaled CO2 in infants with apnoea of infancy, a group believed to be at increased risk of SIDS. STUDY DESIGN Thirty one infants with severe sleep related apnoea, 31 infants with mild recurrent apnoea, and 31 age and sex matched controls for the infants with severe sleep related apnoea were studied. HR was computed from digitised RR intervals, “ventilation” was recorded by inductance plethysmography, and Pco 2 and Po 2 were monitored by transcutaneous electrodes. The ventilatory and HR responses to CO2 were expressed as percentage increase in ventilation and change in HR/unit change in transcutaneous Pco 2. RESULTS The mean increase in transcutaneous Pco 2 during CO2 challenge (0.45 kPa = 3.4 mm Hg) resulted in a mean increase in ventilation of 291%/1 kPa (7.3 mm Hg) increase in transcutaneous Pco 2, with no difference between the groups. A significant difference between infants with severe sleep related apnoea and mild recurrent apnoea versus controls (p < 0.02, p < 0.01, respectively) was found in their HR response to CO2 challenge: HR decreased in 12 severe sleep related apnoea infants and 10 infants with mild recurrent apnoea, but only in two controls. CONCLUSION Infants with apnoea of infancy frequently show a paradoxical decrease in HR during CO2 challenge, possibly because of an insufficient ability to mobilise cardiovascular defence mechanisms when challenged with hypercapnia.

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.

Breath-by-breath determinations of airway occlusion pressure in the developing lamb

The ventilatory effects of breath-by-breath measurements of airway occlusion pressure, i.e., airway pressure determined 100 ms after initiation of inspiration (P0. 1) were evaluated in seven lambs studied sequentially between 7 and 28 days after birth. P0.1 was determined by computer-aided, on-line regression analysis of the inspiratory pressure versus time (dP/dt) by means of a pneumatic occlusion valve that allowed occlusion times to vary in proportion to respiratory rate. No significant changes were found in minute ventilation, tidal volume, respiratory rate or end-tidal CO2 concentration when the valve was operating as a one-way valve (opening pressure 0.02 kPa or 0.2 cm H20) compared to when in occlusion mode [opening pressure 0.18–0.2 kPa or 1.8–2.0 cmH20, mean occlusion time 44 (25) ms]. The calculated P0.1 values correlated well with those obtained from manual occlusions (r = 0.87, P < 0.0001). This new technique, which detects and discards irregular or non-linear (r < 0.95) inspiratory pressure profiles, enables breath-by-breath determinations of inspiratory drive in rapidly breathing lambs with minimal impact on respiratory pattern and ventilation.

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.