We investigated whether group B streptococcal (STREP) infusion impairs the cerebral blood flow (CBF) response to acute hypercarbia in piglets, and whether STREP-induced prostanoids or hemodynamic alterations could account for this impairment. Piglets, 2-3 wk old, were anesthetized, paralyzed, and mechanically ventilated (50% O2; partial pressure of arterial CO2 (PaCO2) approximately 40 torr). CBF was assessed by internal carotid artery blood flow (ICBF). Group 1 (n = 5) received a continuous infusion of STREP for 4 h (2.0-8.0 x 10(7) org/kg-min). Group 2 (n = 5) was pretreated with indomethacin (5 mg/kg), then received the identical STREP infusion. Group 3 (n = 6) did not receive STREP, but cardiac output (CO) and systemic blood pressure (BP) were reduced to levels equal to that of group 1 by incremental inflation of a left atrial balloon (LAB) catheter. Cerebral vascular reactivity to acute hypercarbia (PaCO2 approximately 70 torr for 7.5 min) was assessed at baseline and after each hour of STREP infusion or LAB inflation. We found that 4 h of STREP infusion caused CO to fall significantly (634 +/- 121 to 324 +/- 172 mL/min, group 1; 600 +/- 68 to 291 +/- 80 mL/min, group 2) and BP to fall significantly (104 +/- 20 to 57 +/- 4 mm Hg, group 1; 91 +/- 11 to 53 +/- 16 mm Hg, group 2) By design, in group 3 LAB inflation caused CO (573 +/- 181 to 375 +/- 159 mL/min) and BP (104 +/- 14 to 60 +/- 9 mm Hg) to fall to values not significantly different from septic groups 1 and 2. At 4 h, unilateral ICBF decreased significantly during STREP infusion in group 1 (32.0 +/- 10.8 to 21.0 +/- 7.3 mL/min) and group 2 (22.9 +/- 9.9 to 13.1 +/- 4.3 mL/min), but not in nonseptic group 3 (23.1 +/- 7.4 to 19.6 +/- 6.3 mL/min). At baseline, hypercarbia induced an increase in ICBF (% delta ICBF = 68.7 +/- 13.0% in group 1, 62.2 +/- 15.6% in group 2, and 87.7 +/- 34.0% in group 3). After 4 h of STREP, this response was completely ablated as ICBF fell during hypercarbia by -7.8 +/- 23.2% (group 1). Indomethacin did not protect cerebral vascular reactivity after 4 h of STREP infusion, as % delta ICBF fell during hypercarbia by -10.9 +/- 17.7% (group 2). In contrast, despite equivalent reductions in CO and BP after 4 h of LAB inflation in nonseptic group 3, ICBF rose during hypercarbia by 61.8 +/- 23.2%, not significantly different from baseline, but significantly different from the decrease in % delta ICBF in groups 1 and 2. We conclude that STREP infusion reduces ICBF and cerebral vascular reactivity to acute hypercarbia in piglets. This phenomenon is not accounted for by STREP-induced reduction in CO or BP, and is not mediated by prostanoids.

We tested the effects of nebulized nitroprusside (Neb-NP) on pulmonary and systemic hemodynamics during pulmonary hypertension induced by hypoxia or group B streptococci infusion in piglets. Twenty-three anesthetized and mechanically ventilated piglets received Neb-NP under four experimental conditions: 1) normoxia; 2) 15 and 60 min of pulmonary hypertension induced by hypoxia; 3) after pretreatment with dipyridamole; 4) pulmonary hypertension induced by infusion of group B streptococci. In addition, Neb-NP was contrasted to nebulization of tolazoline. During hypoxia-induced pulmonary hypertension, Neb-NP significantly reduced pulmonary artery pressure [PAP; -8.4+/-0.9 (SEM) mm Hg] and pulmonary vascular resistance (-25+/-2.1%) (both p < 0.001), whereas neither systemic arterial pressure nor cardiac output changed significantly. Selective pulmonary vasodilation began within 2 min of the onset of Neb-NP, and did not wane over 1 h. In contrast, within 5 min after Neb-NP was discontinued while hypoxia persisted, PAP rose significantly. Pretreatment with dipyridamole did not enhance the pulmonary vasodilation induced by Neb-NP, but did reduce systemic arterial pressure. Nebulized tolazoline did not reduce PAP significantly, but did lower systemic arterial pressure. Selective pulmonary vasodilation induced by Neb-NP was significantly smaller during group B streptococci-induced versus hypoxia-induced pulmonary hypertension. In sum, Neb-NP produced prompt, significant, selective reduction of PAP in piglets with pulmonary hypertension. Cautious extrapolation of these findings to selected clinical conditions in human infants may be warranted.

ABSTRACT. The brain is considered an "essential" organ, defined as one whose blood supply is preferentially maintained vis-a-vis other less-essential circulations during periods of reduced systemic cardiac output (CO). We asked whether the actions of either prostaglandins or endothelium-derived relaxation factor might underlie the essential qualities of the cerebral circulation; that is, would the absence of one or the other impair the ability of the brain to preferentially redirect systemic blood flow during a period of reduced systemic CO. We compared hemodynamics in the cerebral and systemic circulations in 33 anesthetized piglets under three conditions that reduced systemic CO equivalently: endothelium-derived relaxation factor inhibition with the substituted L-arginine analog Nnitro-L-arginine (NNLA; 25 mg/kg), prostaglandin inhibition with indomethacin (INDO, 5 mglkg), and inflation of a left atrial balloon (LAB) catheter. NNLA, INDO, and LAB each reduced CO to an equivalent value (-30% from baseline). NNLA and INDO, but not LAB elevated systemic blood pressure, cerebral perfusion pressure (CPP), systemic vascular resistance (SVR), and cerebral vascular resistance (CVR). Cerebral blood flow (CBF) was preserved after NNLA and LAB but fell after INDO (-35%).Despite the equivalent reduction in CO noted during the three experimental protocols, the proportion of systemic blood flow directed toward the brain (CBFICO) rose significantly during LAB and NNLA (+30%) but fell significantly during INDO (-12%). Similarly, relative cerebral vascular resistance (CVRISVR) fell significantly during LAB and NNLA but rose during INDO. Cerebral vascular regulation can be considered along two complementary dimensions. Vascular regulation within the cerebral circulation itself (cerebral autoregulation) is expressed as CBF versus CPP. CBF was unchanged as CPP fell during LAB and as CPP rose after NNLA in piglets. In contrast, after INDO, CBF fell as CPP rose. Vascular regulation of the cerebral circulation vis-a-vis the rest of the body (referred to here as cerebral-specific vascular regulation) can be expressed either in terms of blood flow (CBFICO) or vascular resistance (CVRISVR). After both NNLA and LAB, as CO fell, CBFICO rose and CVRISVR fell, demonstrating preservation of the "essential" status of the cerebral circulation. In contrast, after INDO as systemic CO fell, CBFICO fell and CVRISVR rose. Prostaglandins,

Group B streptococcal sepsis in human newborns and in animal models of human newborns is characterized by a hemodynamic constellation of "cold shock"--increased vascular resistance and reduced systemic blood flow. Endothelium-derived relaxation factor inhibition during group B streptococcal sepsis in piglets exacerbated many of the adverse hemodynamic consequences of group B streptococcal infusion. We speculate that endothelium-derived relaxation factor inhibition has no foreseeable therapeutic role in neonatal septic shock.

Both inhaled nitric oxide and nebulized nitroprusside produced prompt, significant, selective reduction of pulmonary artery pressure and pulmonary vascular resistance in piglets with hypoxia-induced pulmonary hypertension, without apparent effects on systemic hemodynamics or pulmonary gas exchange. The equivalence of the two effects in this animal model suggests that cautious extrapolation of the use of nebulized nitroprusside as a convenient bridge to inhaled nitric oxide in selected clinical contexts for human infants may be warranted.