Brian Rudinsky

Correlation of Flow Probe Determinations of Common Carotid Artery Blood Flow and Internal Carotid Artery Blood Flow with Microsphere Determinations of Cerebral Blood Flow in Piglets

We investigated whether blood flow determined by a flow probe situated on one common carotid artery provided an accurate estimation of unilateral cerebral blood flow (CBF) in piglets. In eight anesthetized, mechanically ventilated piglets, blood flow determined by an ultrasonic flow probe placed on the right common carotid artery was correlated with CBF determined by microspheres under two experimental conditions: 1) before ligation of the right external carotid artery with both the right external and internal carotid circulations intact [common carotid artery blood flow (CCABF) condition], and 2) after ligation of the right external carotid artery (ipsilateral to the flow probe) with all residual right-sided carotid artery blood flow directed through the right internal carotid artery [internal carotid artery blood flow (ICABF) condition]. The left carotid artery was not manipulated in any way in either protocol. Independent correlations of unilateral CCABF and ICABF with microsphere-determined unilateral CBF were highly significant over a 5-fold range of CBF induced by hypercarbia or hypoxia (r = 0.94 and 0.92, respectively; both p < 0.001). The slope of the correlation of unilateral CCABF versus unilateral CBF was 1.68 ± 0.19 (SEM), suggesting that CCABF overestimated CBF by 68%. The slope of the correlation of unilateral ICABF versus unilateral CBF did not differ significantly from unit (1.06 ± 0.15), and the y intercept did not differ significantly from zero [-1.3 ± 5.2 (SEM) mL]. Consequently, unilateral ICABF determined by flow probe accurately reflected unilateral CBF determined by microspheres under these conditions. Flow probe assessments of CCABF and ICABF in piglets may provide information about dynamic aspects of vascular control in the cerebral circulation that has heretofore been unavailable.

Effects of Nebulized Nitroprusside on Pulmonary and Systemic Hemodynamics during Pulmonary Hypertension in Piglets

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 reduced 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.

The role of prostaglandins and endothelium-derived relaxation factor in the regulation of cerebral blood flow and cerebral oxygen utilization in the piglet: operationalizing the concept of an essential circulation.

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 N-nitro-L-arginine (NNLA; 25 mg/kg), prostaglandin inhibition with indomethacin (INDO; 5 mg/kg), 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 (CBF/CO) rose significantly during LAB and NNLA (+30%) but fell significantly during INDO (-12%). Similarly, relative cerebral vascular resistance (CVR/SVR) 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 (CBF/CO) or vascular resistance (CVR/SVR). After both NNLA and LAB, as CO fell, CBF/CO rose and CVR/SVR fell, demonstrating preservation of the “essential” status of the cerebral circulation. In contrast, after INDO as systemic CO fell, CBF/CO fell and CVR/SVR rose. Prostaglandins, but not endothelium-derived relaxation factor seem critical both for cerebral autoregulation and for preservation of the essential hemodynamic status of the brain vis-a-vis the rest of the body in piglets.

Group B Streptococcal Sepsis Impairs Cerebral Vascular Reactivity to Acute Hypercarbia in Piglets

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) ≈ 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 × 107 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 ≈ 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 (%ΔICBF = 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%ΔICBF 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%ΔICBF 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.

Selective elevation of systemic blood pressure by epinephrine during sepsis-induced pulmonary hypertension in piglets.

ABSTRACT. In a piglet model of group B β Streptococci (GBS)-induced pulmonary hypertension, we have determined hemodynamic responses to epinephrine (EPI) infusion in both the systemic and pulmonary circulations. Three groups of piglets (GBS + EPI, n = 6; GBS + placebo, n = 6; placebo, n = 6) were studied. GBS, infused intravenously at ã 5 × 107 organisms/kg/min, reduced cardiac index and stroke volume index while elevating pulmonary artery pressure and pulmonary vascular resistance index. Systemic vascular resistance index, heart rate and aortic pressure did not change during GBS infusion. Six piglets received intravenous EPI after cardiac index had fallen by 30% during GBS infusion. At 3.5, 7.0, and 15 μ/kg/min, respectively, EPI raised aortic pressure by 18.5, 31.0, and 45.0 mm Hg while EPI reduced pulmonary artery pressure by 5.2, 6.3, and 8.2 mm Hg. At each dose, EPI elevated systemic vascular resistance index and lowered pulmonary vascular resistance index. At 3.5 μg/kg/min, the elevation of aortic pressure was associated with an increase in both cardiac index and systemic vascular resistance index. At higher EPI doses, the rise in aortic pressure was accounted for entirely by an increase in systemic vascular resistance index. Systemic acid/base status and PaO2 did not differ among piglets who received GBS + EPI, GBS alone, or placebo. Extrapolation of these data to human infants must be approached with extreme caution. However, selective elevation of systemic blood pressure may be a feasible strategy for some infants to impede right-to-left shunting of blood often associated with sepsis-induced pulmonary hypertension.

Relationship between oxygen delivery and metabolic acidosis during sepsis in piglets.

Objective:To determine if the preservation of oxygen delivery (Do2) ameliorates the development of metabolic acidosis during group B streptococcal infusion. Methods:We examined 22 piglets (2 to 4 wks of age) that were anesthetized, intubated, and mechanically ventilated. Three groups of piglets were studied: group 1 (n = 6), in which Do2 was reduced progressively over 4 hrs by infusion of group B streptococci; group 2 piglets (n = 6) received a similar infusion of streptococci, but Do2 was preserved at presepsis levels by the infusion of dextran and exogenous porcine RBCs; group 3 piglets (n = 6) received no bacteria, but did receive a continuous infusion of 0.9% sodium chloride to maintain cardiac output, and thus, Do2, at baseline levels. To correlate arterial lactate concentrations with metabolic acidosis, four additional piglets received the continuous infusion of streptococci. Results:Do2 decreased significantly in group 1 (14.2 to 5.7 ml oxygen/kg/min) but not in either group 2 or 3. The arterial pH decreased significantly in both septic groups, groups 1 and 2 (7.47 to 7.20; 7.45 to 7.36, respectively), but not in the uninfected group 3. The pH was significantly lower for group 1 vs. group 2 piglets at 210 and 240 mins of streptococcal infusion. Base excess decreased significantly for group 1 and group 2 piglets (+1.5 to −13.9; −0.1 to −5.8 mM/L, respectively) but not in group 3. Base excess was significantly lower for group 1 vs. group 2 piglets at 210 and 240 mins of streptococcal infusion. Oxygen extraction increased significantly for only the low Do2 group 1 piglets (32% to 73%), and did not differ comparing group 2 vs. group 3. In both groups of septic piglets, metabolic acidosis developed before any detectable reduction in oxygen consumption. The increase in circulating lactate concentration (1.0 to 4.6 mM/L) was correlated with the decrease in base excess (-1.0 to −9.7 mM/L) in the four additional piglets that received an infusion of streptococci. Conclusions:Maintaining Do2 at presepsis levels ameliorated the development of metabolic acidosis during streptococcal infusion. Nevertheless, a significant degree of metabolic acidosis developed despite the preservation of Do2.

Oxygen Delivery, Oxygen Consumption, and Metabolic Acidosis during Group B Streptococcal Sepsis in Piglets

ABSTRACT. The development of metabolic acidosis during neonatal sepsis with group B streptococci (GBS) has been attributed to progressive tissue ischemia resulting from reduced oxygen delivery (QO2). Using an animal model of GBS disease, we attempted to test this hypothesis by comparing the development of metabolic acidosis in two groups of piglets with comparably diminished systemic QO2, one septic and one not. Eighteen anaesthetized piglets were instrumented to observe aortic pressure, cardiac output, arterial and mixed venous blood gases, oxygen content, and hemoglobin concentration. QO2, oxygen consumption, and oxygen extraction ratio were calculated. Six piglets (group 1) received continuous infusion of live GBS organisms; six piglets (group 2) received continuous infusion of phenylephrine (PE), beginning with 10-μg/kg/min and increasing as required to match the PE-induced reduction in QO2 to the fall observed in the group 1 (GBS) piglets at each 30-min interval. Group 3 piglets (n = 6) received 0.9% saline and served as controls. No differences in either cardiac output or QO2 were noted comparing GBS and PE piglets at any time interval from 0 - 180 minutes. At 120, 150, and 180 minutes, both QO2 and cardiac output were lower in GBS and PE piglets compared to controls. Despite equivalent reductions in cardiac output and QO2, only GBS piglets developed significant metabolic acidosis, while pH and base deficit for PE piglets did not differ from controls. Oxygen consumption did not differ significantly among the three experimental groups at any observation time. Oxygen extraction ratio did not differ comparing PE and GBS piglets at any observation time. We conclude that the reduction of QO2 effected by GBS infusion in piglets is not, in itself, sufficient to account for the development of metabolic acidosis during these experiments.

The effects of intravenous l-arginine supplementation on systemic and pulmonary hemodynamics and oxygen utilization during group B streptococcal sepsis in piglets

PURPOSE In these investigations, three questions were addressed. First, to what extent did inhibition of endothelium-derived relaxation factor (EDRF) mimic the hemodynamic disturbances noted in a piglet model of neonatal group B streptococcal (GBS) sepsis? Second, to what extent would an attempt to augment EDRF production reverse the hemodynamic effects of continued GBS infusion in septic piglets? Third, to what extent would an attempt to augment EDRF production affect hemodynamics in piglets who were not septic. METHODS Six experimental protocols were studied in a total of 25 piglets. The extent to which inhibition of EDRF resembled GBS sepsis was determined by comparing hemodynamic observations during (1) EDRF inhibition (using a competitive inhibitor of nitric oxide synthase, N-nitro-L-arginine [NNLA], 80 mg/kg) with (2) GBS infusion. Next, the extent to which an attempt to augment EDRF production would reverse hemodynamic effects of neonatal GBS sepsis was addressed by comparing hemodynamic observations during (3) administration of pharmacological doses (300 mg/kg) of the EDRF precursor L-arginine (L-ARG) in piglets receiving continuous GBS infusion with (4) continuous GBS infusion in piglets who did not receive L-ARG. Finally, to provide an additional comparison for the protocols described above, the effects of (5) L-ARG in piglets pretreated with NNLA were compared with (6) L-ARG infusion in normal piglets, who had received neither GBS nor NNLA. RESULTS Both NNLA and GBS increased systemic and pulmonary vascular resistance and decreased systemic cardiac output. For equivalent reductions in cardiac output, GBS preferentially vasoconstricted the pulmonary versus systemic circulation, whereas NNLA produced equivalent vasoconstriction in both circulations. During continuous GBS infusion, L-ARG attenuated the progressive increase in systemic and pulmonary vascular resistance, pulmonary artery pressure, and pulmonary vascular resistance/systemic vascular resistance. L-ARG infusion in nonseptic, non-NNLA-treated piglets had no significant effect on any hemodynamic variable. L-ARG infusion in piglets pretreated with NNLA restored hemodynamic values towards those of piglets treated with L-ARG alone. CONCLUSIONS EDRF inhibition with NNLA appeared to model GBS infusion partially but not completely. L-ARG appeared to produce desirable hemodynamic effects during GBS sepsis when compared with the consequences of ongoing GBS infusion without L-ARG. Given the constellation of increased pulmonary and systemic vascular resistance often observed during neonatal GBS sepsis in human infants, all these effects of L-ARG, if extrapolated from our piglets to the clinical arena, would appear to be beneficial. Particularly in the context of deleterious consequences resulting shunting or right ventricular decompensation from increased afterload), L-ARG administration might prove clinically useful.

Neither nitroglycerin nor nitroprusside selectively reduces sepsis-induced pulmonary hypertension in piglets

No therapeutic agent consistently decreases pulmonary arterial pressure (PAP) more than aortic pressure in neonates with persistent pulmonary hypertension of the newborn. We have investigated whether nitroglycerin (NG) or nitroprusside (NP) selectively decreases PAP in an animal model of sepsis-induced pulmonary hypertension. Piglets were anesthetized, intubated, and ventilated. Pulmonary hypertension was induced by an iv infusion of group B Streptococci. Piglets were then divided into three groups with group B Streptococci infusion ongoing. Neither PAP nor the pulmonary vascular resistance index was decreased significantly by either NP or NG. NP decreased significantly both mean aortic pressure and the systemic vascular resistance index. Cardiac index decreased significantly during both NG and placebo infusion. These data suggest that neither NP nor NG is likely to be beneficial in sepsis-induced pulmonary hypertension in newborns.

Internal jugular venous oxygen saturation does not reflect sagittal sinus oxygen saturation in piglets.

Can blood samples from the internal jugular vein (IJ) be used reliably in place of sagittal sinus (SS) samples in the calculation of cerebral oxygen extraction? To test this question we compared the O2 saturation (Sat) of blood samples drawn from SS, IJ vein, and pulmonary artery (MV) during hypercarbia, eucarbia and hypocarbia in 7 paralyzed, ventilated piglets. Cerebral blood flow was assessed by measuring unilateral internal carotic artery blood flow (ICABF), determined by an electromagnetic flow probe placed around the common carotid artery after ligation of the external carotid artery. During hypocarbia, eucarbia and hypercarbia SatSS (37.3 +/- 9.3, 48.9 +/- 10.2, 70.8 +/- 11.8%, respectively) was significantly different from SatIJ (54.8 +/- 8.9, 54.5 +/- 9.0, 62.0 +/- 15.1%) and SatMV (55.9 +/- 5.5, 58.7 +/- 5.3, 53.5 +/- 11.2%). The mean slope of the SatSS vs. PaCO2 regression lines was +0.583 +/- 0.303%/mm Hg, significantly greater than the mean slope of the regression lines for SatIJ vs. PaCO2 (+0.087 +/- 0.310%/mm Hg) or SatMV vs. PaCO2 (-0.112 +/- 0.230%/mm Hg). The relationship of ICABF vs. PaCO2 (mean slope = 0.444 +/- 0.294 ml/min/mm Hg) was statistically significant, while the relationship of cardiac output (determined by an electromagnetic flow probe placed around the pulmonary artery) vs. PaCO2 (mean slope = 0.470 +/- 1.617 ml/min/mm Hg) was not. We conclude that blood samples from the IJ do not reliably reflect cerebral venous blood and cannot be substituted for SS samples in piglets. It is most probable that the substitution of IJ for SS blood is not valid in piglets because the IJ receives venous effluent from noncerebral tissue.