Prolonged Apneas and Hypoxia Mediated by Nicotine and Endotoxin in Piglets

Abstract

Objective: Infections and maternal smoking are risk factors for SIDS, and toxins from common bacteria have been proposed as a causative link between infections and SIDS. Nicotine can be transferred in significant amounts postnatally to the infant through environmental tobacco smoke or maternal smoking before nursing. We investigated the acute effects of nicotine and endotoxin on repeated apnea by laryngeal reflex stimulation and the following autoresuscitation. Design: Thirty-four 1-week-old (± 1 day) piglets were sedated and randomized to 1 of 4 pretreatment groups: (1) 1 µg endotoxin i.v./kg; (2) 5 µg nicotine i.v./kg; (3) 1 µg endotoxin i.v./kg and 5 µg nicotine i.v./kg, and (4) placebo. Apnea was induced by insufflation of 0.1 ml of acidified saline (pH 2) in the subglottic space of the trachea three times with intervals of 2 min. Results: Pretreatment with endotoxin caused a significant increase in plasma TNF-α in the endotoxin groups (mean value ± SEM 953 ± 246 and 980 ± 226 pg/ml, respectively) but no significant change in plasma IL-1β. Blood pressure, respiratory rate or S_aO₂ was not significantly affected before induced apnea. Both pretreatment with nicotine and endotoxin caused prolonged apneas by 35–45%, a complete loss of normal hyperventilation during autoresuscitation, and prolonged hypoxia after apnea. Conclusions: Nicotine and endotoxin interferes with autoresuscitation after apnea. This experimental model on piglets may shed light over important mechanisms involved in the causation of SIDS.

Microglia modulate respiratory rhythm generation and autoresuscitation

“…Finally, both the inhibition and activation of microglia affected the hypoxic response, both in vitro and in vivo , and LPS worsened autoresuscitation in vivo , an effect that was not observed when LPS and MIN were co‐applied. It was reported that peripheral application of LPS affected the acute ventilatory response to mild hypoxia (Ladino et al, ; McDeigan et al, ) as well as the ability to generate gasping in severe hypoxia which, consequently, negatively impacts autoresuscitation (Frøen et al, ; Olsson et al, ). However, in this study we showed that LPS affects gasping generation and autoresuscitation by directly activating microglia in the absence of peripheral inflammation, probably by affecting the preBötC and that this effect is blocked by its co‐application with MIN.…”

“…Although the mechanisms linking these pathological conditions have not been revealed (Huxtable et al, 2011), it is likely that proinflammatory mediators could affect the generation and control of breathing (Herlenius, 2011;Huxtable et al, 2011). For instance, peripheral application of proinflammatory mediators can modulate respiratory centers (Ericsson et al, 1997;Herlenius, 2011) and reduce breathing in animals (Frøen et al, 2000(Frøen et al, , 2002Guerra et al, 1988;Hofstetter and Herlenius, 2005;Hofstetter et al, 2007;Hutchinson et al, 2008;Kitterman et al, 1983;Olsson et al, 2003;Siljehav et al, 2012;Stoltenberg et al, 1994;Tai and Adamson, 2000) and in humans (Hoch and Bernhard, 2000;Preas et al, 2001). Peripheral infection and inflammation can induce central neuroinflammation (Elmore et al, 2014;Henry et al, 2009;Liu et al, 2012), which is produced by microglia (Elmore et al, 2014;Henry et al, 2009;Liu et al, 2012).…”

Detection rate of Helicobacter pylori stool antigen in newborn infants and small children

“…High levels of the nicotine breakdown-product cotinine has been detected in SIDS victims 64 , suggesting that exposure to nicotine has occurred within the last hours prior to death. Nicotine has a direct inhibitory effect on neurologic development and is associated with decreased arousal to hypoxia 65 and alterations in the autonomic control 66 .…”

Prenatal nicotine exposure and development of nicotinic and fast amino acid-mediated neurotransmission in the control of breathing

“…Neonatal mammals that are nicotine exposed in utero show abnormalities in central ventilatory control, such as reduced ventilatory output (Huang et al, 2004; St-John and Leiter, 1999), altered breathing pattern (Fewell et al, 2001; Hafstrom et al, 2002; Huang et al, 2004), increased apnea frequency (Fewell et al, 2001; Huang et al, 2004) and duration (Froen et al, 2002), delayed arousal in response to hypoxia (Hafstrom et al, 2000; Lewis and Bosque, 1995), decreased sensitivity to hypoxia (Bamford and Carroll, 1999; Bamford et al, 1996; Fewell et al, 2001, 2001; Froen et al, 2002; Hafstrom et al, 2005; St-John and Leiter, 1999) and diminished capacity for autoresuscitation following severe hypoxic exposure (Fewell and Smith, 1998; Froen et al, 2000), but we do not understand how prenatal nicotine exposure (PNE) causes these abnormalities. This is despite epidemiological findings showing that exposure to tobacco smoke is now the number one risk factor for the sudden infant death syndrome (SIDS), accounting for approximately one-third of all SIDS deaths (Anderson et al, 2005; Mitchell and Milerad, 2006).…”