The Effect of Escherichia coli Endotoxin Infusion on the Ventilatory Response to Hypoxia in Unanesthetized Newborn Piglets

Abstract

To determine the effects of endotoxemia on the neonatal ventilatory response to hypoxia, 17 chronically instrumented and unanesthetized newborn piglets (Յ7 d) were studied before and 30 min after the administration of Escherichia coli O55:B5 endotoxin (n ϭ 8) or normal saline (n ϭ 9). Minute ventilation, oxygen consumption, heart rate, arterial blood pressure, and blood gases were measured during normoxia and 10 min of hypoxia (fraction of inspired oxygen, 0.10). Basal ventilation was not modified by E. coli endotoxin infusion (mean Ϯ SE, 516 Ϯ 49 versus 539 Ϯ 56 mL/min/kg), but the ventilatory response to hypoxia was markedly attenuated at 1 min (955 Ϯ 57 versus 718 Ϯ 97 mL/min/kg, p Ͻ 0.002, saline versus endotoxin) and at 10 min (788 Ϯ 51 versus 624 Ϯ 66 mL/min/kg, p Ͻ 0.002). A larger decrease in oxygen consumption was observed during hypoxia and endotoxemia (6.3 Ϯ 2.8 versus 18.3 Ϯ 2.7%, p Ͻ 0.03, pre-versus post-endotoxin). A significant correlation was demonstrated between the changes in minute ventilation and oxygen consumption with hypoxia during endotoxemia (r ϭ 0.9, p Ͻ 0.002). The ventilatory response to hypoxia was not modified by the saline infusion. These data show a significant attenuation in the ventilatory response to hypoxia during E. coli endotoxemia. This decrease in ventilation was associated with a significant decrease in the metabolic rate during hypoxia and endotoxemia. Changes in the breathing pattern and apnea episodes are frequently associated with neonatal sepsis, especially in the preterm infant (1). It has also been observed that the administration of Escherichia coli endotoxin to anesthetized adult cats produced an abrupt apnea followed by transient rapid and shallow breathing (2). However, the mechanisms explaining these changes in breathing pattern are not clearly understood. Respiratory muscle fatigue, a decrease in lung compliance, and an increase in pulmonary resistance have been cited as possible mechanisms for the ventilatory changes observed during Gram-positive and -negative septicemia (3-6).It is well known that a variety of inflammatory mediators such as cytokines, prostaglandins, leukotrienes, and NO are released during sepsis or endotoxemia (3, 6, 7). Furthermore, the changes in the breathing pattern observed during E. coli infusion to adult cats were eliminated in the animals pretreated with indomethacin or thromboxane A 2 receptor antagonist (2). On the other hand, it has been demonstrated that prostaglandins and NO may mediate the ventilatory depression observed during hypoxia in newborn animals (8, 9). Therefore, the increased release of these inflammatory mediators may further depress the ventilatory response to hypoxia during E. coli endotoxemia.The increased circulating cytokines during sepsis or endotoxemia can induce a systemic inflammatory response involving the microvascular system and trigger hemodynamic changes (7, 10, 11). These changes result in maldistribution of blood flow to different organs, which may be accompanied by January 31, 2002; accepted Dec...

Ventilatory Response to Hypoxia during Endotoxemia in Young Rats: Role of Nitric Oxide

“…In adult humans, endotoxin administration results in changes in the basal respiratory pattern and dyspnea (2). We previously demonstrated that endotoxin infusion in newborn piglets produced attenuation of the VRH (3). In a pilot study, we also observed similar respiratory behavior in 4-to 6-wkold rats.…”

“…Respiratory muscle fatigue or alterations in lung mechanics and metabolic rate have been associated with the respiratory changes observed during Gram-positive and negative septicemia in piglets (3,5,6). Particularly, the attenuation in the VRH observed after endotoxin administration to unanesthetized newborn piglets was associated with a significant decrease in VO 2 (3).…”

Acute on chronic exposure to endotoxin is associated with enhanced chemoreflex responses in preterm fetal sheep

“…Indeed, HR fell more quickly in the LPS-treated group at the onset of occlusion, consistent with an enhanced reflex. This finding is in contrast with previous clinical studies of severe sepsis (29,30) and acute LPS injection in animal models (11,23). Similarly, we found no effect of acute on chronic LPS infusion on peripheral vasoconstriction as measured in the femoral vascular bed or on the initial increase in BP, relative to baseline values, in contrast with a previous report of blunted vasoconstriction during occlusion 1 h after LPS injection in the carcass and liver of preterm fetal sheep (12).…”

“…Supporting a direct effect, there is evidence of impaired chemoreflex responses in adult patients with sepsis and multiple organ failure (29,30) and after acute LPS injection in anesthetized adult cats and neonatal piglets (11,23). In contrast, in adult rats there was marked RSNA activation during acute LPS exposure, with no evidence of inhibition of either the baroreflex or chemoreflex (31).…”

Neural Reflex Control of Inflammation During Sepsis Syndromes

“…In addition, LPS enhances tonic CB chemosensory activity (measured by recording the frequency of chemosensory discharges) but reduces its responsiveness to transient excitatory (hypoxia and nicotine) or depressant (pure oxygen) stimuli. Diminished ventilatory responses to moderate and severe hypoxia in cats reproduces the diminished ventilatory responses to hypoxia observed in unanesthetized newborn piglets subjected to Escherichia coli endotoxin infusion (McDeigan et al, 2003), as well as in rats, in a process that is in part mediated by an inhibitory effect of endothelial nitric oxide on the respiratory control mechanisms (Ladino et al, 2007). Apoptosis studies carried out in CB excised from endotoxemic cats discard that CB diminished chemosensory activity observed in LPS-treated animals resulted from a reduction of functional tissue , and suggest the participation of systemic soluble factors (e.g., cytokines), or locally produced by either resident monocytes/macrophages (Dvorakova et al, 2000), or parenchyma cells.…”