Assessment of hepatic function in cystic fibrosis by lidocaine metabolism.

BACKGROUND: To determine hepatic drug metabolism in patients with cystic fibrosis, as measured by monoethylglycinexylidide formation after lidocaine injection and indocyanine green (ICG) clearance. METHODS: The following study is a case-control study, which included 19 patients with cystic fibrosis and 13 control subjects. Serum monoethylglycinexylidide concentration was measured after intravenous injection of 1 mg/kg (maximum, 50 mg) lidocaine. Indocyanine green (0.5 mg/kg) was injected concomitantly, and absorbance (805 nm) of serum was measured over time to determine its volume of distribution, serum half-life, and hepatic blood flow. RESULTS: Monoethylglycinexylidide formation was decreased in patients with cystic fibrosis compared with controls (39.4+/-16.9 microg/L versus 70.3+/-45.7 microg/L, mean +/- SD, respectively, P < 0.02). Indocyanine green half-life (4.6+/-2.7 min versus 3.0+/-1.0 min), volume of distribution (8.6+/-5.5 L versus 8.3+/-3.4 L), and hepatic blood flow (10.9+/-5.9 ml x kg(-1) x min(-1) versus 7.4+/-2.0 ml x kg(-1) x min(-1)) were similar in both groups. CONCLUSION: Monoethylglycinexylidide formation after lidocaine injection is impaired in patients with cystic fibrosis. This impairment may have clinical implications when using hepatically metabolized medications in patients with cystic fibrosis.

Prednisolone plus albuterol versus albuterol alone in mild to moderate bronchiolitis.

To evaluate combination therapy of mild to moderate bronchiolitis with bronchiodilators and corticosteroids, we treated 51 young children with first-time wheezing and symptoms of respiratory tract infection with albuterol plus either prednisolone or placebo for 5 days. Disease severity was scored on days 0, 2, 3, and 6. On day 2, prednisolone resulted in significantly lower scores (2.7 +/- 1.4 vs. 4.0 +/- 1.5 in all patients evaluated, p < 0.05) than placebo, whereas there was no detectable difference on day 6, suggesting that addition of prednisolone to albuterol transiently accelerates recovery from bronchiolitis. The clinical significance of this effect needs to be evaluated in further studies.

Hepatic function as assessed by lidocaine metabolism in sickle cell disease.

OBJECTIVE: To evaluate hepatic drug metabolism, as determined by the formation of monoethylglycinexylidide (MEGX) after lidocaine injection and indocyanine green (ICG) clearance, in patients with sickle cell disease. STUDY DESIGN: A case-control study including 19 patients with homozygous hemoglobin S, and 13 age- and sex-matched black control subjects. Serum MEGX concentration was measured after intravenous injection of 1 mg/kg (maximum 50 mg) lidocaine. ICG (0.5 mg/kg) was injected concomitantly and absorbance (805 nm) of serum was measured over time to determine its volume of distribution, serum half-life, and hepatic blood flow. RESULTS: MEGX formation at 15 minutes was decreased in patients with sickle cell disease compared with formation in the control subjects (39.9 +/- 18.0 vs 65.6 +/- 50.0 micrograms/L, respectively, p < 0.02). The volume of distribution of ICG was increased in patients with sickle cell disease compared with that in the control subjects (0.21 +/- 0.09 vs 0.11 +/- 0.03 L/kg, p < 0.01). This partly accounts for the decreased MEGX formation. The ICG half-life was similar in both groups (3.8 +/- 1.5 vs 3.1 +/- 1.0 min). Hepatic blood flow, derived from ICG clearance, was increased in sickle cell patients compared with that of the control subjects (12.2 +/- 4.5 vs 8.1 +/- 2.1 ml/kg/min, p < 0.01). CONCLUSION: Hepatic drug metabolism, as assessed by MEGX formation after lidocaine injection, is impaired in patients with sickle cell disease. This impairment may have clinical implications when using hepatically metabolized medications in patients with sickle cell disease.

Management of children with hypertension from reflux or obstructive nephropathy.

During a ten-year period, 35 children presenting with vesicoureteral reflux, ureteropelvic junction obstruction, or a "small kidney" were found to be hypertensive. Of these, 15 subsequently underwent surgical procedures for relief of hypertension. Seven were "cured," six were "improved," and two were "unchanged." The severity of hypertension could not be correlated with the degree of reflux nor with the degree of obstructive uropathy. However, all children with reflux in our study who were hypertensive had some degree of calicectasis noted preoperatively on intravenous pyelogram. Also it was noted that hypertension may occur several years after successful anti-reflux surgery. Children with vesicoureteral reflux, ureteropelvic junction obstruction, or a small kidney need to have blood pressure determinations at regular intervals, even if all previous readings had been in the normotensive range and whether or not they were followed up medically or post surgically. We suggest that blood pressure determinations be made every three months for the first year after diagnosis of reflux or ureteropelvic junction obstruction, and at least once a year thereafter.

Ibuprofen in experimental group B streptococcal shock.

A rabbit model was used to characterize the effects of high (Group II, 100 mg/kg) and low (Group III, 10 mg/kg) dose ibuprofen in modulating the hemodynamic and hematologic manifestations of group B streptococcal shock. Short-term survival was significantly increased with ibuprofen pretreatment. Ibuprofen failed to prevent GBS-induced shock, although shock was favorably modified in a dose dependent manner. Likewise, GBS-induced increases in 6KPGF1a and TxB2 were not prevented but were modified in Group II at 120 min. However, neutropenia, thrombocytopenia, and acidosis were not prevented by pretreatment with ibuprofen and may have been exacerbated. Thus, ibuprofen modifies but does not prevent GBS-induced hemodynamic and hematologic manifestation.

Characterization of polymorphonuclear leukocyte aggregation in vitro induced by heat-inactivated group B streptococcus.

We studied the aggregatory characteristics of human polymorphonuclear leukocytes (PMNs) in response to heat-inactivated group B streptococcus. PMNs suspended in physiologic salt solution do not aggregate to heat-inactivated group B streptococcus (GBS) unless the GBS is previously opsonized in autologous plasma. The aggregating activity of both opsonized GBS and activated plasma are reduced if the plasma is decomplemented before incubation with GBS. Pretreatment of PMNs with pronase inhibited opsonized GBS-induced aggregation, suggesting aggregation via cell membrane receptors for opsonic fragments of C3. Pronase pretreatment had no significant effect on aggregation induced by activated plasma or arachidonic acid. Unlike PMNs in physiologic salt solution, PMNs suspended in plasma aggregate when stimulated by unopsonized GBS. GBS aggregates PMNs via complement cascade activation, opsonization, and interaction with cell membrane receptors to stimulate cellular mechanisms resulting in PMN aggregation.

The comparison of myocardial dysfunction in three forms of experimental septic shock.

A rabbit model of septic shock was used to determine if myocardial dysfunction is a common component of shock due to diverse neonatal pathogens, and prostaglandins modulate septic myocardial dysfunction. The infusion of heat-killed Escherichia coli (group I), Haemophilus influenzae (group II), or Staphylococcus epidermidis (group III) produced significant decreases in the first derivative of left ventricular pressure with respect to time (p less than 0.05). Each organism also produced significant changes in mean arterial pressure, cardiac output, and heart rate, while pulmonary artery pressure was altered in groups I and III. Saline-infused control animals (group IV) exhibited no significant changes in any hemodynamic variable. Blood gas variables were not significantly changed in any group. These cardiovascular changes appeared dependent on arachidonic acid metabolism since indomethacin pretreatment prevented the cardiovascular changes induced by bacterial infusion. These results suggest that septic myocardial dysfunction is a common component of gram-negative and gram-positive septic shock, and that myocardial dysfunction is modulated by prostaglandin products.

Prostaglandin synthetase inhibition in group B streptococcal shock: hematologic and hemodynamic effects.

A rabbit model of group B Streptococcal (GBS) shock was used to study the effects of prostaglandin synthetase inhibition on the hemodynamic and hematologic response to GBS shock. The infusion of heat-killed GBS in groups I and II produced significant decreases in mean arterial pressure, neutrophil counts, and platelet counts (p less than 0.05), and significant rises in concentrations of thromboxane B2 and 6-Keto-PGF1 alpha, the stable metabolites of thromboxane A2 and prostacyclin (p less than 0.05). Administration of indomethacin (4 mg/kg) after GBS infusion (group II) was associated with a significant rise in mean arterial pressure and a significant decline in thromboxane B2 and 6-Keto-PGF1 alpha concentrations (p less than 0.05) but had no effect on GBS-induced hematologic alterations. Indomethacin administration before GBS infusion (group III) prevented alterations in mean arterial pressure and was associated with a decrease in thromboxane B2 and 6-Keto-PGF1 alpha concentrations. Indomethacin in group III did not prevent neutropenia and thrombocytopenia and may have exacerbated neutropenia. Alteration of experimental GBS shock with prostaglandin synthetase inhibition produces disparate hemodynamic and hematologic response.

Effects of endotoxin on coronary vascular resistance in the isolated blood-perfused rabbit heart.

Rabbit hearts were excised and perfused with blood pumped through a cannula placed in the aortic root. A fluid-filled balloon-tipped catheter was positioned in the left ventricle for the measurement of left ventricular pressure and dP/dt. Total coronary vascular resistance (CVR) was calculated by dividing the coronary perfusion pressure by the rate of coronary blood flow. Following stabilization, coronary blood flow was held at a constant rate. Compared to control hearts, endotoxin (E. coli) added directly to the blood perfusate (6 mg/80 ml of circulating blood) had no effect on CVR or left ventricular dP/dt. In contrast, changing the perfusate to blood obtained from rabbits previously given endotoxin (LD100; 6 mg/kg IV) resulted in significantly higher CVR, without depression of left ventricular dP/dt. This increase in CVR was observed not only when the endotoxemic donor rabbits were hypotensive at the time the blood was obtained (4-6 hours following endotoxin administration), but also when the endotoxemic donors remained normotensive (blood withdrawn 30 minutes following endotoxin administration). A pathologic increase in CVR might contribute to the myocardial ischemia and contractile dysfunction observed in endotoxin shock.

Myocardial dysfunction in group B streptococcal shock.

A rabbit model of group B Streptococcal (GBS) shock was used to determine if myocardial dysfunction contributes to GBS shock and, if so, to ascertain if prostaglandins modulate this dysfunction. The infusion of heat-killed GBS (group I) produced a dramatic decrease in the first derivative of left ventricular pressure with respect to time (LVdP/dt) from baseline values (p less than 0.05). LVdP/dt remained stable in rabbits pretreated with indomethacin (group II) and in saline-infused control rabbits (group III), and was significantly different at 30 min from LVdP/dt in group I (p less than 0.05). Values for group I mean arterial pressure, cardiac output, pulmonary vascular resistance, and heart rate and for pH and pO2 after GBS infusion were all significantly different from baseline values and from postinfusion values for groups II and III (p less than 0.05). Systemic vascular resistance and left ventricular end diastolic pressure did not change significantly in any group at any time interval. These results indicate a primary role for myocardial dysfunction in the pathogenesis of GBS shock, and suggest strongly that prostaglandins modulate GBS-induced myocardial dysfunction.

Efficacy of sulfhydryl compounds as inhibitors of iron-dependent doxorubicin-enhanced lipid peroxidation.

The ability of sulfhydryl compounds to inhibit doxorubicin enhanced lipid peroxidation in the presence of added iron was evaluated. Optimal conditions for doxorubicin-enhanced lipid peroxidation were 25 microM doxorubicin, 2 mM ADP and 250 microM ferric chloride at pH 8.0. Lipid peroxidation was inhibited by EDTA (500 microM), SKF 525 A (100 microM) and vitamin E (0.1 unit/ml). Cysteamine (1 mM) stimulated basal lipid peroxidation but produced net inhibition of lipid peroxidation with doxorubicin. Cysteamine (10 mM) was more efficacious at inhibiting lipid peroxidation. N-acetylcysteine at 1 and 10 mM was a potent stimulator of lipid peroxidation and was ineffective at inhibiting lipid peroxidation in the presence of doxorubicin either at optimal or suboptimal concentrations of iron. In contrast, glutathione (1 mM) was a potent inhibitor of lipid peroxidation. The data suggests that N-acetylcysteine protects against doxorubicin by prior conversion to glutathione.

Myocardial dysfunction in children with acute meningococcemia.

Acute meningococcemia is frequently associated with cardiovascular collapse of uncertain cause. Review of the records of 12 consecutive children revealed clinical evidence of myocardial dysfunction in six (50%). Subsequently myocardial function was prospectively assessed clinically and echocardiographically in 12 children. Seven (58%) of the 12 children had echocardiographic evidence of myocardial dysfunction as defined by a depressed left ventricular shortening fraction (LVSF). The mean LVSF in these seven children was 0.25 +/- 0.03, as compared with the mean LVSF of 0.39 +/- 0.7 in the remaining children. The LVSF estimate of myocardial function strongly correlated with cardiac output as measured by standard thermodilution (r = 0.98, P less than 0.01). Acute meningococcemia was not fatal in those children without evidence of myocardial dysfunction. In contrast, three of the seven children with evidence of myocardial dysfunction died. In four children, echocardiographic evidence of left ventricular dysfunction preceded cardiovascular collapse and clinical recognition of myocardial dysfunction. In children with an initially low LVSF, recovery of LVSF was associated with survival. Children with acute meningococcemia may have impaired myocardial function as indicated by depressed LVSF, resulting in low cardiac output despite normal intravascular volume. Thus, in addition to restoring intravascular volume, knowledge of the status of myocardial function may help direct therapy toward optimizing myocardial contractility.

Short-term hemodynamic effects of hydralazine in infants with complete atrioventricular canal defects.

We evaluated the acute hemodynamic responses to hydralazine during cardiac catheterization in eight infants (ages 1.0 to 5.5 months) with congestive heart failure due to complete atrioventricular canal defect. Hydralazine administered intravenously (0.5 to 1.0 mg/kg body weight) increased heart rate and systemic blood flow and decreased mean right atrial pressure, systemic and pulmonic arterial pressures, systemic arteriolar resistance, and the ratio of pulmonary to systemic blood flow (p less than .05). The percentage of pulmonary flow contributed by shunted blood (percent left-to-right shunt; measured by indicator dilution) was decreased by hydralazine in six (mean = 85% before to 64% after hydralazine; p less than .01), but remained unchanged (79%) in two infants. The two infants with no change in percent left-to-right shunt had higher pulmonary arteriolar resistances (Rp) before hydralazine (mean = 12.8 vs 3.2 U/m2) and had greater declines in Rp (mean change = -5.1 vs + 0.3 U/m2) in response to hydralazine. Thus, if Rp does not fall, hydralazine reduces the percentage of left-to-right shunt over the short term and therefore might be useful for managing congestive heart failure in these infants. However, because the response varies, an evaluation of the short-term hemodynamic effects of hydralazine may be warranted in an attempt to select those infants who might respond favorably to long-term hydralazine therapy.

Depression of contractility in isolated rabbit myocardium following exposure to iron: role of free radicals.

The mechanism of acute iron cardiotoxicity was investigated in isometrically contracting left atrial strips and right ventricular papillary muscles isolated from rabbit hearts. A 90-min exposure to iron (1.8 mM; as ferrous sulfate) reduced the peak-developed tension and the maximal rate of tension development. The presence of either N-acetylcysteine (20 mM), superoxide dismutase (2000 units/ml), or mannitol (5 mM) prevented this depression of contractility. Catalase (30,000 units/ml) was not protective against the effects of iron. Iron did not decrease myocardial adenosine triphosphate or creatine phosphate contents. The force-frequency relationship (positive staircase phenomenon) was examined in the absence and presence of iron. Iron did not reduce the positive inotropic response evoked by increasing the stimulation frequency, but at higher frequencies iron prolonged the time from peak tension to 90% relaxation. We conclude that acute iron cardiotoxicity may be mediated by free radical generation and does not involve impairment of myocardial high energy phosphate production.

Acute effects of iron on contractile function in isolated rabbit myocardium.

Changes in contractile function following exposure to iron (Fe) salts were evaluated in isolated isometrically contracting rabbit left atrial strips and right ventricular papillary muscles. Fe acutely depressed myocardial contractility as evidenced by dose-related declines in developed force and maximal rate of force development. There were no significant changes in duration of contraction or resting force. The tissue Fe content was increased nearly 3-fold after a 60 min exposure to Fe and subsequently was not decreased by repeated washing or by treatment with deferoxamine. Isoproterenol, but not deferoxamine, reversed the Fe-mediated impairment of myocardial contractility. These findings suggest that in cases of severe acute iron poisoning, depression of cardiac contractility might occur which may be improved by treatment with isoproterenol.

Relationship between the in-situ activity of ornithine decarboxylase and contractile function of the rabbit papillary muscle.

The relationship between isometric contraction and myocardial ornithine decarboxylase (ODC; EC.4.1.1.17) activity was studied in right ventricular papillary muscles isolated from rabbits. ODC specific activity and polyamine content were significantly increased in papillary muscles contracting isometrically 90 times per minute at the apex of the length-tension relationship for 4 to 5 hours when compared with paired non-contracting muscles or isometrically contracting muscles stimulated at 30 times per min. The increase in ODC activity appeared to be due to new protein synthesis since cycloheximide blocked the increase in ODC activity without affecting isometric function. Thus, the present results suggest that increased contractile demands of the heart may stimulate the synthesis of myocardial ODC, increase ODC activity and polyamine content.