Adverse effects of nicotine and interleukin-1 beta on autoresuscitation after apnea in piglets: Implications for sudden infant death syndrome

Objectives. Maternal cigarette smoking is established as a major dose-depen dent risk factor for sudden infant death syndrome (SIDS). Both prenatal and postnatal exposures to constituents of tobacco smoke are associated with S IDS, but no mechanism of death attributable to nicotine has been found. Bre astfeeding gives a substantial increase in absorbed nicotine compared with only environmental tobacco smoke when the mother smokes, because the milk:p lasma concentration ratio of nicotine is 2.9 in smoking mothers. Furthermor e, many SIDS victims have a slight infection and a triggered immune system before their death, thus experiencing a release of cytokines like interleuk in-1 beta (IL-1 beta) that may depress respiration. Because apneas in infan cy are associated with SIDS, we have tested the hypothesis that postnatal e xposure to tobacco constituents and infections might adversely affect an in fant's ability to cope with an apneic episode. This is performed by investi gating the acute effects of nicotine and IL-1 beta on apnea by laryngeal re flex stimulation and on the subsequent autoresuscitation. Design. Thirty 1-week-old piglets (+/-1 day) were sedated with azaperone. A tracheal and an arterial catheter were inserted during a short halothane a nesthesia. The piglets were allowed a 30-minute stabilization period before baseline values were recorded and they were randomized to 4 pretreatment g roups (avoiding siblings in the same group): 1) immediate infusion of 10 pm ol IL-1 beta intravenously/kg (IL-1 beta group; n = 8); 2) slow infusion of 5 mu g nicotine intravenously/kg 5 minutes later (NIC group; n = 8); 3) bo th IL-1 beta and NIC combined (NIC + IL-1 beta group; n = 6); or 4) placebo by infusion of 1 mi .9% NaCl (CTR group; n = 8). Fifteen minutes later, ap nea was induced by insufflation of .1 mi of acidified saline (pH = 2) in th e subglottic space 5 times with 5-minute intervals, and variables of respir ation, heart rate, blood pressure, and blood gasses were recorded. Results. Stimulation of the laryngeal chemoreflex by insufflation of acidif ied saline in the subglottic space produced apneas, primarily of central or igin. This was followed by a decrease in heart rate, a fall in blood pressu re, swallowing, occasional coughs, and finally autoresuscitation with gaspi ng followed by rapid increase in heart rate, rise in blood pressure, and ti n the CTR group) an increase of respiratory rate. Piglets pretreated with n icotine had more spontaneous apneas, and repeated spontaneous apneas caused an inability to perform a compensatory increase of the respiratory rate af ter induced apnea. This resulted in a lower Sao(2) than did CTR at 2 minute s after apnea (data shown as median [interquartile range]: 91% [91-94] vs 9 7% [94-98]). The pretreatment with IL-1 beta caused prolonged apneas in pig lets and an inability to hyperventilate causing a postapneic respiratory ra te similar to the NIC. When nicotine and IL-1 beta were combined, additive adverse effects on respiratory control and autoresuscitation compared with CTR were observed: NIC + IL-1 beta had significantly more spontaneous apnea s the last 5 minutes before induction of apnea (2 [.3-3] vs 0 [0-0]). Apnea s were prolonged (46 seconds [39-51] vs 26 seconds [22-31]) and followed by far more spontaneous apneas the following 5 minutes (6.6 [4.0-7.9] vs .5 [ .2-.9]). Instead of normal hyperventilation after apnea, a dramatic decreas e in respiratory rate was seen (at 20 seconds: -45% [-28 to -53] vs +29% [24-+50], and at 60 seconds: -27% [-23 to -32] vs +3% [-2-+6), leading to Sa o(2) below 90% 3 minutes after end of apnea: 89% (87-93) versus 97% (95-98) . These prolonged adverse effects on ventilation were reflected in lowered Pao(2) elevated Paco(2) and lowered pH 2 minutes, and even 5 minutes, after induction of apnea. Conclusions. Nicotine interferes with normal autoresuscitation after apnea when given in doses within the range of what the child of a smoking mother could receive through environmental tobacco smoke and breast milk. This is seriously aggravated when combined with the presence of IL-1 beta that is r eleased during infections. This experimental model with piglets may shed li ght on important mechanisms involved in the cause of SIDS.