Damian J. Horstman

Variability of Target-controlled Infusion Is Less Than the Variability after Bolus Injection

Background:Target-controlled infusion (TCI) drug delivery systems deliver intravenous drugs based on pharmacokinetic models. TCI devices administer a bolus, followed by exponentially declining infusions, to rapidly achieve and maintain pseudo–steady state drug concentrations in the plasma or at the site of drug effect. Many studies have documented the prediction accuracy of TCI devices. The authors’ goal was to apply linear systems theory to characterize the relation between the variability in concentrations achieved with TCI devices and the variability in concentrations after intravenous bolus injection. Methods:The authors developed a mathematical model of the variability of any arbitrary method of drug delivery, based on the variability with intravenous bolus injection or the variability with an arbitrary infusion regimen. They tested the model in a simulation of 1,000 patients receiving propofol by simple bolus injection, conventional infusion, or a TCI device. The authors then examined an experimental data set for the same behavior. Results:The variability of any arbitrary infusion regimen, including TCI, is bounded by the variability after bolus injection. This is observed in the simulation and experimental data sets as well. Conclusion:TCI devices neither create nor eliminate biologic variability. For any drug described by linear pharmacokinetic models, no infusion regimen, including TCI, can have higher variability than that observed after bolus injection. The median performance of TCI devices should be reasonably close to the prediction of the device. However, the overall spread of the observations is an intrinsic property of the drug, not the TCI delivery system.

Selective iNOS Inhibition Attenuates Acetylcholine- and Bradykinin-induced Vasoconstriction in Lipopolysaccharide-exposed Rat Lungs

BACKGROUND Nonselective nitric oxide synthase (NOS) inhibition has detrimental effects in sepsis because of inhibition of the physiologically important endothelial NOS (eNOS). The authors hypothesized that selective inducible NOS (iNOS) inhibition would maintain eNOS vasodilation but prevent acetylcholine- and bradykinin-mediated vasoconstriction caused by lipopolysaccharide-induced endothelial dysfunction. METHODS Rats were administered intraperitoneal lipopolysaccharide (15 mg/kg) with and without the selective iNOS inhibitors L-N6-(1-iminoethyl)-lysine (L-NIL, 3 mg/kg), dexamethasone (1 mg/kg), or the nonselective NOS inhibitor Nomega-nitro-L-arginine methylester (L-NAME, 5 mg/kg). Six hours later, the lungs were isolated and pulmonary vasoreactivity was assessed with hypoxic vasoconstrictions (3% O2), acetylcholine (1 microg), Biochemical Engineering, and bradykinin (3 microg). In additional lipopolysaccharide experiments, L-NIL (10 microM) or 4-Diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP, 100 microM), a selective muscarinic M3 antagonist, was added into the perfusate. RESULTS Exhaled nitric oxide was higher in the lipopolysaccharide group (37.7+/-17.8 ppb) compared with the control group (0.4+/-0.7 ppb). L-NIL and dexamethasone decreased exhaled nitric oxide in lipopolysaccharide rats by 83 and 79%, respectively, whereas L-NAME had no effect. In control lungs, L-NAME significantly decreased acetylcholine- and bradykinin-induced vasodilation by 75% and increased hypoxic vasoconstrictions, whereas L-NIL and dexamethasone had no effect. In lipopolysaccharide lungs, acetylcholine and bradykinin both transiently increased the pulmonary artery pressure by 8.4+/-2.0 mmHg and 35.3+/-11.7 mmHg, respectively, immediately after vasodilation. L-NIL and dexamethasone both attenuated this vasoconstriction by 70%, whereas L-NAME did not. The acetylcholine vasoconstriction was dose-dependent (0.01-1.0 microg), unaffected by L-NIL added to the perfusate, and abolished by 4-DAMP. CONCLUSIONS In isolated perfused lungs, acetylcholine and bradykinin caused vasoconstriction in lipopolysaccharide-treated rats. This vasoconstriction was attenuated by administration of the iNOS inhibitor L-NIL but not with L-NAME. Furthermore, L-NIL administered with lipopolysaccharide preserved endothelium nitric oxide-dependent vasodilation, whereas L-NAME did not.

Prolonged Inhaled No Attenuates Hypoxic, but Not Monocrotaline-induced, Pulmonary Vascular Remodeling in Rats

In concentrations of 10-20 ppm, inhaled nitric oxide (NO) decreases pulmonary artery pressure and attenuates vascular remodeling in pulmonary hypertensive rats. Because NO is potentially toxic, it is important to know whether lower concentrations attenuate vascular remodeling produced by different etiologies. Therefore, we determined the effects of prolonged, small-dose inhaled NO administration on hypoxic and monocrotaline (MCT)-induced pulmonary vascular remodeling. Rats were subjected to normoxia, hypoxia (normobaric 10% oxygen), or hypoxia plus NO in concentrations of 50 ppb, 200 ppb, 2 ppm, 20 ppm, and 100 ppm for 3 wk. A second group of normoxic rats was given MCT (60 mg/kg intraperitoneally) alone or in the presence of 2, 20, and 100 ppm of NO. Subsequently, pulmonary artery smooth muscle thickness and the number of muscular arteries (percentage of total arteries) were determined. Right ventricular hypertrophy was determined by right to left ventricle plus septum weight ratio (RV/LV + S). Pulmonary artery smooth muscle thickness and the percent muscular arteries were increased by hypoxia and MCT. The hypoxic increase in thickness was attenuated by all concentrations of NO, with 100 ppm being greatest, whereas NO had no effect on MCT rats. NO attenuated the increase in percent muscular arteries in hypoxic but not MCT rats. The RV/LV + S was increased by hypoxia and MCT compared with normoxia. Hypoxia-induced RV hypertrophy was decreased by all concentrations of inhaled NO, although attenuation with 50 ppb was less than with 200 ppb, 20 ppm, and 100 ppm. In MCT rats 2 and 100 ppm NO increased RV hypertrophy, whereas 20 ppm had no effect. In conclusion, inhaled NO in concentrations as low as 50 ppb attenuates the pulmonary vascular remodeling and RV hypertrophy secondary to hypoxia. In contrast, concentrations as high as 100 ppm do not attenuate MCT-induced pulmonary remodeling. These results demonstrate that extremely low concentrations of NO may attenuate remodeling but that the effectiveness is dependent on the mechanism inducing pulmonary remodeling. Implications: The authors determined whether inhaled NO, a selective pulmonary vasodilator, attenuates pulmonary vascular remodeling caused by two models of pulmonary hypertension: chronic hypoxia and monocrotaline injection. Analysis of pulmonary vascular morphology suggests that very low concentrations of NO effectively attenuate hypoxic remodeling but that NO is not effective in monocrotaline-induced pulmonary remodeling.

Cyclooxygenase inhibitors attenuate bradykinin-induced vasoconstriction in septic isolated rat lungs.

Cyclooxygenase (COX) products play an important role in modulating sepsis and subsequent endothelial injury. We hypothesized that COX inhibitors may attenuate endothelial dysfunction during sepsis, as measured by receptor-mediated bradykinin (BK)-induced vasoconstriction and/or receptor-independent hypoxic pulmonary vasoconstriction (HPV). Rats were administered intraperitoneally a nonselective COX inhibitor (indomethacin, 5 or 10 mg/kg) or a selective COX-2 inhibitor (NS-398, 4 or 8 mg/kg) 1 h before lipopolysaccharide (LPS, 15 mg/kg), or saline (control). Three hours later, the rats were anesthetized, the lungs were isolated, and pulmonary vasoreactivity was assessed with BK (0.3, 1.0, and 3.0 &mgr;g) and HPV (3% O2). Perfusion pressure was monitored as an index of vasoconstriction. To investigate what receptor-subtype is mediating BK responses, the BK1-receptor antagonist des-Arg9-[Leu8]-BK, the BK2-receptor antagonist HOE-140, or the thromboxane A2-receptor antagonist SQ 29548 (all at 1 &mgr;M) were added to the perfusate. BK-induced vasoconstriction was significantly increased in LPS lungs (1.4–5.2 mm Hg) compared with control (0.1–1.1 mm Hg). In LPS lungs, indomethacin 10 mg/kg significantly decreased BK vasoconstriction by 78% ± 9%, whereas 5 mg/kg did not. NS-398, 4 mg/kg, significantly attenuated BK vasoconstriction at 0.3 &mgr;g (71% ± 7%) and 1.0 &mgr;g (56% ± 12%), whereas 8 mg/kg attenuated 0.3 &mgr;g BK (57% ± 14%), compared with LPS lungs. HPV was increased in LPS lungs (21.5 ± 2 mm Hg) compared with control lungs (9.8 ± 0.6 mm Hg). Indomethacin 5 mg/kg increased HPV in LPS lungs; otherwise, HPV was not altered by COX inhibition. BK-induced vasoconstriction was prevented by BK2, but not BK1 or thromboxane A2-receptor antagonism. This study suggests that nonselective COX inhibition, and possibly inhibition of the inducible isoform COX-2, may attenuate sepsis-induced, receptor-mediated vasoconstriction in rats. Implications: This study demonstrated that, in an isolated rat lung model, nonselective inhibition of the cyclooxygenase pathway, and possibly selective inhibition of the inducible cyclooxygenase-2 isoform, may attenuate sepsis-induced endothelial dysfunction.

Inhaled nitric oxide and nifedipine have similar effects on lung cGMP levels in rats

UNLABELLED Inhaled nitric oxide (NO) may downregulate the endogenous NO/cyclic guanosine monophosphate (cGMP) pathway, potentially explaining clinical rebound pulmonary hypertension. We determined if inhaled NO decreases pulmonary cGMP levels, if the possible down-regulation is the same as with nifedipine, and if regulation also occurs with the cyclic adenosine monophosphate (cAMP) pathway. Rats were exposed to 3 wk of normoxia, hypoxia (10% O2), or monocrotaline (MCT; single dose = 60 mg/kg) and treated with either nothing (control), inhaled NO (20 ppm), or nifedipine (10 mg x kg(-1) x day(-1). The lungs were then isolated and perfused with physiologic saline. Perfusate cGMP, prostacyclin, and cAMP levels were measured. Perfusate cGMP was not altered by inhaled NO or nifedipine in normoxic or MCT rats. Although hypoxia significantly increased cGMP by 128%, both inhaled NO and nifedipine equally prevented the hypoxic increase. Inhibition of the NO/cGMP pathway with N(G)-nitro-L-arginine methyl ester (L-NAME) decreased cGMP by 72% and 88% in normoxic and hypoxic lungs. Prostacyclin and cAMP levels were not altered by inhaled NO or nifedipine. L-NAME significantly decreased cGMP levels, whereas inhaled NO had no effect on cGMP in normoxic or MCT lungs, suggesting that inhaled NO does not inhibit the NO/cGMP pathway. Inhaled NO decreased cGMP in hypoxic lungs, however, nifedipine had the same effect, which indicates the decrease is not specific to inhaled NO. IMPLICATIONS High pulmonary pressure after discontinuation of inhaled nitric oxide (NO) may be secondary to a decrease in the natural endogenous NO vasodilator. This rat study suggests that inhaled NO either does not alter endogenous NO or that it has similar effects as nifedipine.

Nitric Oxide Synthase Inhibitors Alter Ventilation in Isoflurane Anesthetized Rats

Background Nitric oxide (NO) is present in medullary structures and can modulate respiratory rhythm. The authors determined if spontaneous ventilation at rest and in response to increased carbon dioxide is altered by selective neuronal NO synthase (NOS; 7‐nitro‐indazole, 7‐NI) or nonselective (neuronal plus endothelial) NOS (NG ‐L‐arginine methyl ester [L‐NAME] and NG ‐monomethyl L‐arginine [L‐NMMA]) inhibitors in rats anesthetized with isoflurane. Methods Fifty‐four rats received either L‐NAME or L‐NMMA (1, 10, and 30 mg/kg) or 7‐NI (20, 80, and 400 mg/kg) and were compared with time controls (isoflurane = 1.4%), with isoflurane concentrations (1.6%, 1.8%, and 2%) increased consistent with the increased anesthetic depth caused by NOS inhibitors, or with L‐arginine (300 mg/kg). Tidal volume (VT), respiratory frequency (f), minute ventilation (V with dotE), and ventilatory responses to increasing carbon dioxide were determined. Results L‐NAME and L‐NMMA decreased resting VT and V with dot (E), whereas 7‐NI had no effect. Increasing concentrations of isoflurane decreased resting f, VT, and V with dotE. L‐NAME and L‐NMMA decreased VT and V with dotE, whereas 7‐NI had no effect at 8%, 9%, and 10% end‐tidal carbon dioxide (ETCO2). Increasing concentrations of isoflurane decreased f, VT, and V with dotE at 8%, 9%, and 10% ETCO2. The slope of V with dotE versus ETCO2 was decreased by isoflurane but was unaffected by L‐NAME, L‐NMMA, or 7‐NI. L‐arginine alone had no effect on ventilation. Conclusions Nonselective NOS inhibitors decreased VT and V with dotE at rest and at increased carbon dioxide levels but did not alter the slope of the carbon dioxide response. Selective neuronal NOS inhibition had no effect, suggesting that endothelial NOS may be the isoform responsible for altering ventilation. Finally, the cause of the decreased ventilation is not a result of the enhanced anesthetic depth caused by NOS inhibitors.

The effect of prolonged inhaled nitric oxide on pulmonary vasoconstriction in rats.

Down-regulation of the endogenous nitric oxide (NO) pathway may explain rebound pulmonary hypertension after discontinuation of inhaled NO. We determined whether the prolonged administration of inhaled NO increases pulmonary vasoconstriction, which may occur from decreased endogenous NO. Rats were placed in normoxic (N; 21% O2) or hypoxic (H; 10% O2) chambers with or without inhaled NO (20 ppm) for 1 or 3 wk. Immediately after or 24 h after discontinuation of NO, vasoconstrictive responses were determined in isolated lungs to acute hypoxia (HPV; 0% O2 for 6 min), angiotensin II (0.05 [micro sign]g), and the thromboxane analog U-46619 in the presence and absence of the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 100 [micro sign]M). Inhaled NO did not alter HPV or angiotensin II vasoconstriction in the N group immediately after or 24 h after discontinuation of NO. In the H group, inhaled NO decreased HPV but had no effect on the angiotensin II vasoconstriction compared with H alone. Inhaled NO did not alter the response to L-NAME. Inhaled NO did not alter, whereas L-NAME significantly decreased, the dose of U-46619 required to increase the pulmonary pressure by 10 mm Hg. In conclusion, prolonged inhaled NO decreased or did not alter HPV and did not alter vasoconstriction secondary to angiotensin II, U-46619, or L-NAME in N and H rats. These results suggest that prolonged inhaled NO does not increase pulmonary vasoconstriction, as would be expected from down-regulation of endogenous NO. Implications: High pulmonary pressure has been observed clinically after discontinuation of inhaled NO. This rat study suggests that 1-3 wk of inhaled NO does not increase pulmonary vasoconstriction, as would be expected from decreasing the endogenous vasodilator NO. (Anesth Analg 1998;87:1285-90)