George F. Rich

Inhaled nitric oxide: Selective pulmonary vasodilation in cardiac surgical patients

Background:Inhaled nitric oxide (NO), an endothellum-derlved relaxing factor, is a selective pulmonary vasodilator. The authors investigated whether the pulmonary vasodilation resulting from 20 ppm inhaled NO is related to the degree of pulmonary hypertension or affected by cardiopulmonary bypass (CPB) or the presence of intravenous nitrates. Methods:In patients undergoing cardiac surgery (n=20) or in whom the circulation was supported with a ventricular assist device (VAD; n=5), the lungs were ventilated with 80% O2 and 20% N2 followed by the same gas concentrations containing 20 ppm NO for 6 min. Results:Inhaled NO decreased (P<0.05) the pulmonary artery pressure from 36 ± 3 to 29 ± 2 mmHg and 32 ± 2 to 27 ± 1 mmHg, before and after CPB, respectively, and from 68 ± 12 to 55 ± 9 mmHg in patients with a VAD. Similarly, the pulmonary vascular resistance (PVR) decreased (P<0.05) from 387 ± 44 to 253 ± 26 dyne·cm·s-5 and 260 ± 27 to 182 ±18 dyne·cm·s-5, before and after CPB, respectively, and from 1,085 ± 229 to 752 ± 130 dyne·cm·s-5 in patients with a VAD. Central venous pressure, cardiac output, systemic hemodynamics, and blood gases did not change after inhalation of NO before or after CPB, whereas arterial oxygen tension, mixed venous hemoglobin saturation, and mean arterial pressure increased (P<0.05) in patients supported with a VAD. All hemodynamic and laboratory data returned to control 6 min after discontinuation of NO. The decrease in PVR was proportional to baseline PVR ( PVR=-0.45 PVRb + 39.9) before CPB. The pre- and post-CPB slopes were identical despite possible damage to the endothelium resulting from CPB and the post-CPB presence of intravenous nitroglycerin (17 of 20 patients). Conclusions:This study demonstrates that 20 ppm inhaled NO is a selective pulmonary vasodilator in cardiac surgical patients before and after CPB and in patients in whom the circulation is supported with a VAD. Furthermore, NO-induced pulmonary vasodilation is proportional to PVRb and does not appear to be altered by CPB, the presence of a VAD, or infusion of nitrates.

The Response to Varying Concentrations of Inhaled Nitric Oxide in Patients with Acute Respiratory Distress Syndrome

We investigated the response to varying concentrations of inhaled nitric oxide (NO) in 18 patients with acute respiratory distress syndrome (ARDS).The study was divided into two parts. In Part 1, 5-40 ppm of inhaled NO was evaluated in 10 patients with ARDS. In Part 2, 0.1-10 ppm of inhaled NO was evaluated in eight patients with ARDS. Inhaled NO significantly (P < 0.05) decreased the mean pulmonary artery pressure (MPAP) and pulmonary vascular resistance index (PVRI), and increased the arterial oxygenation (PaO2) at concentrations of 0.1 to 40 ppm. No dose response was detectable for the pulmonary artery pressure (PAP) or PVRI over this dose range. The increase in PaO2 at 10 ppm of NO was significantly greater than that at 0.1 ppm but not 1 ppm. The decrease in PVRI and the increase in PaO2 were both significantly correlated with the baseline PVRI. While the maximum hemodynamic and oxygenation responses to inhaled NO are achieved at approximately 1 ppm, it appears that the maximum hemodynamic response is observed at lower concentrations (0.1 ppm) of inhaled NO than the improvement in oxygenation (1-10 ppm). Higher concentrations of NO do not produce any further change in these variables. It appears that the baseline PVRI may be the best marker predicting a beneficial response to NO. (Anesth Analg 1996;82:574-81)

Inhaled nitric oxide selectively decreases pulmonary vascular resistance without impairing oxygenation during one-lung ventilation in patients undergoing cardiac surgery

BackgroundInhaled nitric oxide (NO), an endothelium-derived relaxing factor, is a selective pulmonary vasodilator. The authors investigated whether inhaled NO decreases pulmonary vascular resistance (PVR) while preserving hypoxic pulmonary vasoconstriction and whether it maintains or improves oxygenation in patients during one-lung ventilation. MethodsIn supine cardiac surgical patients with a normal mean pulmonary artery pressure (PAP) (< 25 mmHg, n = 10) or a moderately elevated PAP (25–35 mmHg, n = 10), one-lung ventilation was established with 80% oxygen and 20% nitrogen followed by the same gas mixture containing 20 ppm NO for 6 min. ResultsInhaled NO decreased (P < 0.05) PAP from 30 ± 2 to 27 ± 2 mmHg in the patients with moderate pulmonary hypertension. Likewise, PVR decreased (P < 0.05) from 266 ± 10 to 205 ± 8 dyn.s.cm–5. The PAP and PVR did not change significantly after NO inhalation in the patients without pulmonary hypertension. All other hemodynamic variables remained unchanged after inhalation of NO in both groups. In the patients with pulmonary hypertension, the PAP and PVR returned to baseline after discontinuation of inhaled NO. Inhaled NO did not significantly change the arterial oxygen tension or venous admixture in either group of patients. Ventilation, airway pressure, tidal volume, and lung compliance also were unaffected by inhaled NO. ConclusionsThis study demonstrates that 20 ppm inhaled NO is a selective pulmonary vasodilator in patients with moderate pulmonary hypertension secondary to cardiac disease who are undergoing one-lung ventilation. In contrast to what would be expected with intravenous vasodilators that inhibit hypoxic pulmonary vasoconstriction, inhaled NO does not increase the venous admixture or impair oxygenation.

Isoflurane Pretreatment Inhibits Lipopolysaccharide-induced Inflammation in Rats

Background Previous studies have indicated that volatile anesthetic pretreatment protects cells from inflammation in vitro; therefore, the authors hypothesized that pretreatment with isoflurane may attenuate the hemodynamic and pathologic changes to the vasculature that are associated with inflammation in vivo. Methods Rats received intravenous lipopolysaccharide or saline placebo with and without pretreatment with isoflurane (1.4% for 30 min immediately before lipopolysaccharide). Mean arterial pressure (MAP) and response to endothelium-dependent (acetylcholine) and -independent (sodium nitroprusside) vasodilators were assessed hourly for 6 h. Tumor necrosis factor-&agr; concentrations, arterial blood gases, and vascular histology were also determined. Results Lipopolysaccharide decreased MAP and vasodilation to acetylcholine and sodium nitroprusside. Lipopolysaccharide also caused acidosis, endothelial swelling, and endothelial detachment from the smooth muscle. Isoflurane pretreatment prevented the decrease in MAP for 5 h and attenuated the decrease at 6 h. Pretreatment increased the vasodilation to acetylcholine in lipopolysaccharide rats to control concentrations but had no effect on sodium nitroprusside. In control rats, isoflurane pretreatment increased the response to acetylcholine and sodium nitroprusside but had no effect on MAP. Isoflurane pretreatment prevented the acidosis and endothelial damage to mesenteric and aortic vessels, and attenuated the increase in tumor necrosis factor-&agr; associated with lipopolysaccharide-induced inflammation. Conclusion Pretreatment with 30 min of isoflurane attenuated the decrease in MAP and endothelium-dependent vasodilation, the acidosis, the increase in tumor necrosis factor-&agr;, and the damage to the vascular endothelium associated with lipopolysaccharide-induced inflammation in rats. This study suggests that isoflurane pretreatment may protect the vasculature during inflammation.

Isoflurane pretreatment inhibits cytokine-induced cell death in cultured rat smooth muscle cells and human endothelial cells.

Background Anesthetics are protective during ischemic–reperfusion injury and associated inflammation; therefore, the authors hypothesized that anesthetic pretreatment may provide protection in culture from cytokine-induced cell death. Methods Rat vascular smooth muscle (VSM) cell and human umbilical vascular endothelial cell (HUVEC) cultures were used to determine whether pretreatment with 30 min of isoflurane decreases cell death from tumor necrosis factor &agr; (TNF-&agr;), interleukin 1 (IL-1&bgr;), and interferon (IFN-&ggr;) alone or in combination. Cell survival and viability were determined by trypan blue staining and cell proliferation assay, as well as by DNA fragmentation assays. The roles of protein kinase C (PKC) and adenosine triphosphate–sensitive potassium (KATP) channels in mediating isoflurane (and halothane) protection were evaluated with the antagonists staurosporine or glibenclamide in cytokine- and also hydrogen peroxide (H2O2)–induced cell death. Results Pretreatment with 1.5% isoflurane immediately prior to cytokine exposure increased cell survival and viability from cytokines by 10–60% for 24, 48, 72, and 96 h in VSMs and up to 72 h in HUVECs. DNA fragmentation (TUNEL) was also attenuated by isoflurane. Isoflurane was equally effective in VSMs at 0.75, 1.5, and 2.5%, whereas in HUVECs, 1.5 and 2.5% were more effective than 0.75%. In VSMs, isoflurane administered 1 h prior to or simultaneously with cytokines was also effective, whereas isoflurane 2 h prior to cytokines was less effective, and either 4 h prior to or 30 min after cytokines was not effective. In both cytokine- and H2O2-induced cell death, isoflurane and halothane pretreatment were equally protective, and staurosporine and glibenclamide attenuated the protective effect. Conclusions Thirty minutes of isoflurane attenuates cytokine-induced cell death and increases cell viability in VSMs for 96 h and in HUVECs for 72 h. Isoflurane must be administered less than 2 h prior to or simultaneously with the cytokines to be protective. These initial inhibitor studies suggest involvement of PKC and KATP channels in isoflurane and halothane protection against both cytokine- and H2O2-induced cell death of VSMs and HUVECs.

Selective iNOS inhibition prevents hypotension in septic rats while preserving endothelium-dependent vasodilation.

UNLABELLED Nitric oxide (NO) derived from inducible nitric oxide synthase (iNOS) mediates hypotension and metabolic derangements in sepsis. We hypothesized that selective iNOS-inhibition would prevent hypotension in septic rats without inhibiting endothelium-dependent vasodilation caused by the physiologically important endothelial NOS. Rats were exposed to lipopolysaccharide (LPS) for 6 h and the selective iNOS-inhibitor L-N6-(1-iminoethyl)-lysine (L-NIL), the nonselective NOS-inhibitor N:(G)-nitro-L-arginine methyl ester (L-NAME), or control. Mean arterial pressure (MAP) and vasodilation to acetylcholine (ACh, endothelium-dependent), sodium nitroprusside (SNP, endothelium-independent), and isoproterenol (ISO, endothelium-independent beta agonist) were determined. Exhaled NO, nitrate/nitrite-(NOx) levels, metabolic data, and immunohistochemical staining for nitrotyrosine, a tracer of peroxynitrite-formation were also determined. In control rats, L-NAME increased MAP, decreased the response to ACh, and increased the response to SNP, whereas L-NIL did not alter these variables. LPS decreased MAP by 18% +/- 1%, decreased vasodilation (ACh, SNP, and ISO), increased exhaled NO, NOx, nitrotyrosine staining, and caused acidosis and hypoglycemia. L-NIL restored MAP and vasodilation (ACh, SNP, and ISO) to baseline and prevented the changes in exhaled NO, NOx, pH, and glucose levels. In contrast, L-NAME restored MAP and SNP vasodilation, but did not alter the decreased response to ACh and ISO or prevent the changes in exhaled NO and glucose levels. Finally, L-NIL but not L-NAME decreased nitrotyrosine staining in LPS rats. In conclusion, L-NIL prevents hypotension and metabolic derangements in septic rats without affecting endothelium-dependent vasodilation whereas L-NAME does not. IMPLICATIONS Sepsis causes hypotension and metabolic derangements partly because of increased nitric oxide. Selective inhibition of nitric oxide produced by the inducible nitric oxide synthase enzyme prevents hypotension and attenuates metabolic derangements while preserving the important vascular function associated with endothelium-dependent vasodilation in septic rats.

Differences between aortic and radial artery pressure associated with cardiopulmonary bypass.

Previous investigators have identified an aortic-to-radial artery pressure gradient thought to develop during rewarming and discontinuation of cardiopulmonary bypass. The authors measured mean aortic and radial artery pressures before, during, and after cardiopulmonary bypass in 30 patients, to determine when the pressure gradient develops. The pressure gradient was also measured before and after intravenous injections of sodium nitroprusside (1 microgram/kg) and phenylephrine (7 micrograms/kg) to determine the effect of changes in systemic vascular resistance. A significant (P less than 0.05) pressure gradient (mean +/- SEM = 4.9 +/- 0.7 mmHg) developed upon initiation of cardiopulmonary bypass. This gradient did not change significantly during the middle of bypass (4.2 +/- 0.5 mmHg), with rewarming (4.8 +/- 0.7 mmHg), immediately prior to discontinuation of bypass (4.6 +/- 0.7), or 5 and 10 min following bypass (4.9 +/- 0.9 and 4.8 +/- 0.7 mmHg). Sodium nitroprusside significantly decreased systemic vascular resistance, by 15 +/- 2%, during the middle of bypass but did not affect the pressure gradient. Likewise, phenylephrine increased the systemic vascular resistance by 52 +/- 6% and 34 +/- 4% during the middle of bypass and rewarming, respectively, without affecting the pressure gradient. Although the exact mechanisms responsible for the pressure gradient remain unknown, these results suggest its etiology is associated with events occurring during initiation of cardiopulmonary bypass rather than with rewarming or discontinuation of cardiopulmonary bypass.

Direct effects of intravenous anesthetics on pulmonary vascular resistance in the isolated rat lung.

We determined the direct effects of thiopental, ket-amine, midazolam, etomidate, and propofol on pulmonary vascular resistance (PVR), the relationship of the direct effects to the baseline PVR, and the possible interaction with functional endothelium. The intravenous anesthetics were injected randomly into 1) endothelium-intact isolated rat lungs which were either unconstricted or constricted with angiotensin II (n = 10), and 2) lungs with endothelial injury produced by electrolysis (n = 10). In endothelium-intact lungs thiopental (0.5 and 5.0 mg/kg) and etomidate (3.0 mg/ kg) significantly (P < 0.05) increased PVR by 3% ± 1%, 30% ± 7%, and 29% ± 5%, respectively. Ketamine (3.0 and 100 mg/kg) and propofol (20 mg/kg) significantly (P < 0.05) decreased the PVR by 6% ± 1%, 15% ± 1%, and 8% ± 1%, respectively. Midazolam (0.3 and 3.0 mg/kg) and smaller doses of etomidate (0.3 mg/kg) and propofol (2.0 mg/kg) did not affect PVR. These responses did not vary with the baseline PVR over a twofold range. The effects of thiopental, ketamine, etomidate, and midazolam were not altered by endothelial injury. In contrast to the vasodilation produced by propofol in normal lungs, propofol (20 mg/kg) significantly (P < 0.05) increased the PVR by 8% ± 2% after endothelial injury. In conclusion, this study demonstrates that thiopental and etomidate are direct pulmonary vasoconstrictors, ketamine and propofol are direct pulmonary vasodilators, and midazolam has no direct effects in the isolated rat lung. Further, these effects on pulmonary vasculature do not vary with baseline PVR, and only propofol appears to have endothelium-dependent effects.

Lidocaine attenuates cytokine-induced cell injury in endothelial and vascular smooth muscle cells.

Local anesthetics have been reported to attenuate the inflammatory response and ischemia/reperfusion injury. Therefore, we hypothesized that pretreatment with local anesthetics may protect endothelial and vascular smooth muscle (VSM) cells from cytokine-induced injury. Human microvascular endothelial cells and rat VSM cells were pretreated with lidocaine or tetracaine (5–100 &mgr;M for 30 min) and then exposed to the cytokines tumor necrosis factor-&agr;, interferon-&ggr;, and interleukin-1&bgr; for 72 h. Cell survival and integrity were evaluated by trypan blue exclusion and lactate dehydrogenase release. The role of adenosine triphosphate-sensitive potassium (KATP) channels, protein kinase C, or both in modulating local anesthetic-induced protection was evaluated with the mitochondrial KATP antagonist 5-hydroxydecanoate, the cell-surface KATP antagonist 1-[5-[2-(5-chloro-o-anisamido)ethyl]-2-methoxyphenyl]sulfonyl-3-methylthiourea (HMR-1098), and the protein kinase C inhibitor staurosporine. Lidocaine attenuated cytokine-induced cell injury in a dose-dependent manner. Lidocaine (5 &mgr;M) increased cell survival by approximately 10%, whereas lidocaine (100 &mgr;M) increased cell survival by approximately 60% and induced a threefold decrease in lactate dehydrogenase release in both cell types. In contrast, tetracaine did not attenuate cytokine-induced cell injury. 5-hydroxydecanoate abolished the protective effects of lidocaine, but staurosporine and HMR-1098 had no effect on the lidocaine-induced protection. This study showed that lidocaine, but not tetracaine, attenuates cytokine-induced injury in endothelial and VSM cells. Lidocaine-induced protection appears to be modulated by mitochondrial KATP channels.

Use of inhaled nitric oxide perioperatively and in intensive care patients.

NITRIC oxide (NO) is an endogenous molecule that has important physiologic functions. In blood vessels, NO produced in the endothelium causes vasodilation by increasing cyclic guanosine 3 ’ , 5’-monophosphate (cGMP) in the vascular smooth muscle. The NO-cGMP pathway plays a significant role in the modulation of vascular tone, and, in disease states, a dysfunctional endothelium may result in altered flow or hypertension. The understanding of the endogenous NOcGMP pathway led to the idea of using exogenous inhaled gaseous NO as a therapeutic vasodilator. It was hypothesized that inhaled NO would act like endothelial NO to cause pulmonary vasodilation. Because ’ NO rapidly binds to pulmonary artery pressure and pulmonary vascular resistance (PVR) in patients with primary pulmonary hypertension (fig. 1). The vasodilation occurred within minutes of delivery of inhaled NO and was reversible within minutes of its discontinuation, and there was no systemic vasodilation. These studies triggered an intensive international investigation of the potential therapeutic role of inhaled NO in virtually all diseases associated with pulmonary hypertension.