Detrimental effects of nicotine and endotoxin in the newborn piglet brain during severe hypoxemia.
Hypoxia-ischemia is a major cause of perinatal brain damage, but evidence shows that brain injury also is associated with intrauterine infections and maternal smoking. The mechanisms are not known, and we therefore explored the effects of experimental inflammation or nicotine on perinatal brain metabolism and injury during severe hypoxemia. Twenty-eight 1-week-old piglets were anesthetized and instrumented with microdialysis probes in the striatum and brainstem. We studied three pretreatment groups: (1) 20 microg/kg i.v. nicotine (n = 9); (2) 1 microg/kg i.v. endotoxin from Escherichia coli (n = 11), or (3) control (n = 8). The piglets were subsequently exposed to 30 min of hypoxemia (6% O(2)). In order to minimize any ischemic component and increase survival, this was abrupted for 1 min if blood pressure fell to 30 mm Hg. During hypoxemia, both the pretreatment with endotoxin and nicotine induced higher levels of extracellular lactate and peak lactate/pyruvate ratio compared with controls (54.7 +/- 9.6 (p < 0.01) and 65.2 +/- 13.1 (p < 0.02) vs. 15.9 +/- 7.4, respectively), reflecting a deterioration of the metabolic status in these groups. The two pretreated groups reached significantly higher peak levels of extracellular glycerol (30.9 +/- 4.1 vs. 77.9 +/- 12.7 and 89.4 +/- 14.2 micromol/l, respectively, p = 0.01), indicating a higher level of cellular membrane disintegration or leakage. In addition, 3 endotoxin piglets and 4 nicotine piglets died during reoxygenation, while all controls survived (p = 0.13 and p < 0.04, respectively). Mortality was associated with a rise in extracellular glutamate at the end of hypoxemia/start reoxygenation (p = 0.02). These findings contribute in explaining how nicotine and inflammatory response to bacterial toxins could act as cofactors for hypoxic-ischemic neurologic injury in the immature brain.
Frøen
J Frederik
JF
Department of Pediatric Research, The National Hospital, University of Oslo, Norway. j.f.froen@klinmed.uio.no
Amerio
Giulia
G
Stray-Pedersen
Babill
B
Saugstad
Ola Didrik
OD
D000818:Animals; D000831:Animals, Newborn; D001794:Blood Pressure; D001927:Brain Diseases / Q000209:etiology* / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D004731:Endotoxins / Q000008:administration & dosage / Q000633:toxicity*; D004926:Escherichia coli; D018698:Glutamic Acid / Q000032:analysis; D005990:Glycerol / Q000032:analysis; D006863:Hydrogen-Ion Concentration; D000860:Hypoxia / Q000150:complications*; D019344:Lactic Acid / Q000032:analysis; D017551:Microdialysis; D009538:Nicotine / Q000008:administration & dosage / Q000633:toxicity*; D010100:Oxygen / Q000008:administration & dosage; D019289:Pyruvic Acid / Q000032:analysis; D013552:Swine; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000134:cerebrospinal fluid
D004731:Endotoxins; D014409:Tumor Necrosis Factor-alpha; D019344:Lactic Acid; D018698:Glutamic Acid; D009538:Nicotine; D019289:Pyruvic Acid; D005990:Glycerol; D010100:Oxygen