Robert Hipps

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.

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.

Relative contribution of endothelium-derived relaxation factor to vascular tone in the systemic, pulmonary, and cerebral circulations of piglets

UNLABELLED We determined the contribution of endothelium-derived relaxation factor (EDRF) to vascular tone in the systemic, pulmonary, and cerebral circulations of piglets. METHODS 11 piglets were anesthetized and mechanically ventilated. Systemic cardiac output was determined by an electromagnetic flow probe placed on the main pulmonary artery. Cerebral blood flow was assessed by determining unilateral internal carotid artery blood flow (ICBF) using a flow probe placed on the common carotid artery after ligation of the ipsilateral external carotid circulation. Progressive inhibition of EDRF was achieved by continuous infusion of the substituted L-arginine analog N-nitro-L-arginine (NNLA). Hemodynamic observations were compared at 0, 0.1, 1.0, 10, 30, and 80 mg/kg cumulative dose of NNLA. RESULTS At all NNLA doses > or = 1 mg/kg, both systemic blood pressure and systemic vascular resistance were elevated. At all NNLA doses > or = 10 mg/kg, systemic cardiac output was reduced. At all NNLA doses > or = 10 mg/kg, pulmonary artery pressure and pulmonary vascular resistance were elevated. Although cerebral vascular resistance was elevated at all NNLA doses > or = 10 mg/kg, ICBF was maintained at or near baseline values up to a dose of 80 mg/kg. At all levels of EDRF inhibition, both the pulmonary and systemic circulations demonstrated approximately equal magnitudes of vasoconstriction. In contrast, at 30 and 80 mg/kg cumulative dose of NNLA, the cerebral circulation was relatively less constricted by NNLA than was the systemic circulation. Systemic VO2 was significantly reduced at 30 mg/kg and 80 mg/kg cumulative NNLA dose, while cerebral VO2 was preserved at both NNLA doses. CONCLUSIONS EDRF contributes to resting vasodilator tone in the systemic, pulmonary, and cerebral circulations in piglets. Progressive inhibition of EDRF constricts the systemic and pulmonary circulation equally. Inhibition of EDRF does not impair the ability of the brain to vary cerebral vascular resistance in order to redistribute blood flow towards itself during a period of reduced cardiac output.

Hemodynamic Homeostasis during Acute Hypoxia in Septic and Nonseptic Piglets: Differential Role of Prostaglandins and Nitric Oxide

We studied the hemodynamic responses of 29 anesthetized and mechanically ventilated piglets to acute hypoxia [reduction of Pao2 from 130 to 38 mm Hg induced by inhalation of 7% fraction of inspired oxygen (Fio2) for 7.5 min] before and during group B β-hemolytic streptococci (GBS) sepsis. During hypoxia, nonseptic piglets maintained stable systemic blood pressure [105 ± 9 (SD) to 97 ± 14 mm Hg] and cardiac output (CO) (667 ± 72 to 685 ± 113 mL/min). However, during GBS/hypoxia, systemic blood pressure fell from 94 ± 17 to 49 ± 25 mm Hg, CO fell from 397 ± 146 to 223 ± 142 mL/min (both p < 0.001 versus pre-GBS), and cardiac arrest often ensued. We tested three hypotheses that might underlie GBS-induced intolerance to systemic hypoxia:1) GBS-induced reduction of systemic CO/systemic oxygen delivery (QO2) below a critical QO2 beyond which the superimposition of hypoxia becomes intolerable; this mechanism is unlikely as nonseptic piglets with comparable reductions in CO/QO2 (induced by inflation of a left atrial balloon) tolerated hypoxia well;2) GBS-induced inhibition of nitric oxide (NO) synthesis that is vital to tolerance of hypoxia; this mechanism is unlikely as infusion of the NO substrate l-arginine did not restore tolerance to hypoxia during GBS infusion (as it did after inhibition of NO synthesis during infusion of N-nitro-l-arginine in nonseptic piglets); and 3) GBS-induced production of pathologic prostaglandins that impaired the piglets capacity to tolerate hypoxia; this mechanism finds support in the observation that inhibition of prostaglandins with the cyclooxygenase inhibitor indomethacin completely restored the ability of septic piglets to tolerate hypoxia. Further evaluation of GBS-induced intolerance to systemic hypoxia may provide insight into the incompletely understood mechanisms by which sepsis induces circulatory collapse in experimental animals and in humans.

Cerebrovascular effects of nebulized nitroprusside (Neb-NP) during hypoxia-induced pulmonary hypertension in piglets |[diams]| 336

Intra-pulmonary administration of nitric oxide (iNO) or nitric oxide analogs such as nitroprusside produces selective pulmonary vasodilation. However, nitric oxide has been implicated in control of the cerebral as well as the pulmonary circulation. We tested the hypothesis that Neb-NP (a user-friendly analog of iNO) would adversely affect the cerebral circulation while improving pulmonary artery pressure (PAP) during hypoxia-induced pulmonary hypertension in piglets.

Effects of nebulized nitroprusside (Neb-NP) during hypoxia-induced pulmonary hypertension in piglets: tachyphylaxis, rebound, effect of pre-administration with Dipyridamole (Dip), and comparison with nebulized tolazoline (Tz) |[dagger]| 213

Inhaled nitric oxide (iNO) has been shown to selectively reduce pulmonary hypertension in several biologic models. However, iNO is not as convenient as one might wish. We tested the effects of Neb-NP (a user-friendly analog of inhaled nitric oxide) on pulmonary and systemic hemodynamics during pulmonary hypertension induced by hypoxia in piglets.

Hemodynamic Effects of Nebulized Sodium Nitroprusside and Inhaled Nitric Oxide on Hypoxic Pulmonary Vasoconstriction in Piglets

Hemodynamic Effects of Nebulized Sodium Nitroprusside and Inhaled Nitric Oxide on Hypoxic Pulmonary Vasoconstriction in Piglets

Do We Still Need Bicarb? 329

Sodium bicarbonate (Bicarb) therapy for metabolic acidosis is a mainstay of current NICU care. Why? Bicarb undoubtedly raises pH -- so what? Specifically, does Bicarb produce any beneficial hemodynamic changes in either the systemic or pulmonary circulations in either healthy or ill organisms?