The diagnostic accuracy of truncated cardiovascular MR protocols for detecting non-ischemic cardiomyopathies.

Cardiovascular magnetic resonance imaging is one of the most important diagnostic modalities in the evaluation of cardiomyopathies. However, significant limitations are the complex and time-consuming workflows and the need of contrast agents. The aim of this multi-center retrospective study was to assess workflows and diagnostic value of a short, contrast agent-free cardiac magnetic resonance protocol. 160 patients from Heidelberg, Germany and 119 patients from Montreal, Canada with suspected cardiomyopathy and 20 healthy volunteers have been enrolled. Scans were performed at a 1.5Tesla or 3Tesla scanner in Heidelberg and at a 3Tesla scanner in Montreal. We used single-slice T1 map only. A stepwise analysis of images has been performed. The possible differential diagnosis after each step has been defined. T1-values and color-encoded T1 maps significantly contributed to the differential diagnosis in 54% of the cases (161/299); the final diagnosis has been done without late gadolinium enhancement images in 83% of healthy individuals, in 99% of patients with dilated cardiomyopathy, in 93% of amyloidosis patients, in 94% of patients with hypertrophic cardiomyopathy and in 85% of patients with hypertensive heart disease, respectively. Comparing the scan time with (48 ± 7 min) vs. without contrast agent (23 ± 5 min), significant time saving could be reached by the short protocol. Subgroup analysis showed the most additional diagnostic value of T1 maps in amyloidosis and hypertrophic cardiomyopathy or in confirmation of normal findings. In patients with unclear left ventricular hypertrophy, a short, non-contrast protocol can be used for diagnostic decision-making, if the quality of the T1 map is diagnostic, even if only one slice is available.

The effects of epidural analgesia on the course and outcome of labour.

The potential effects of epidural analgesia on the progress and outcome of labour have been the subject of lasting controversy. Retrospective reviews indicate that epidurals are associated with longer labours and/or an increase in the incidence of instrumental or operative delivery. Similar results were obtained in non-randomized prospective studies. None of them established a causal relationship, because without randomization the selection bias cannot be ruled out. Other factors, such as premature rupture of membranes and maternal socioeconomic status, may affect the outcome of labour. It was also reported that introduction of the on-demand epidural service did not increase the primary caesarean section rate. The few prospective randomized studies are contradictory and not very reliable owing to small patient populations and high cross-over rates. There is, however, unanimity among the authors regarding the superiority of pain relief provided by epidural blocks over systemically administered opioids.

The effects of bupivacaine, L-nitro-L-arginine-methyl ester, and phenylephrine on cardiovascular adaptations to asphyxia in the preterm fetal lamb.

UNLABELLED: The preterm fetal lamb that is exposed to clinically relevant plasma concentrations of lidocaine loses its cardiovascular adaptations to asphyxia, and its condition deteriorates further. Nitric oxide (NO) is an important regulator of vascular tone, and local anesthetics are known to inhibit endothelium-dependent vasodilation. The purpose of the present study was to determine whether the adverse effects of lidocaine noted in the preterm fetal lamb also occur with bupivacaine and whether the inhibition of NO results in effects similar to those of bupivacaine. Thirty-two chronically prepared pregnant sheep were studied at 117-119 days' gestation. Maternal and fetal blood pressure, heart rate, and acid-base state were evaluated. Fetal organ blood flows were determined using 15-microM diameter dye-labeled microspheres. After a control period, mild to moderate asphyxia (fetal PaO2 15 mm Hg) was induced by partial umbilical cord occlusion and maintained throughout the experiment. Ewes in Group I (n = 13) were given a two-step intravenous infusion of bupivacaine for 180 min. Fetuses in Group II (n = 12) received an intravenous injection of L-nitro-L-arginine-methyl ester (L-NAME) (25 mg/kg), and measurements were taken 10 and 30 min after the injection. A third group (Group III) of fetuses (n = 7) were given an intravenous infusion of phenylephrine to mimic the blood pressure increases noted in L-NAME-treated fetuses. At 90 min of stable asphyxia, there was a significant decrease in fetal PaO2 and pHa and an increase in PaCO2 and mean arterial blood pressure. There was also an increase in blood flow to the adrenals, myocardium, and cerebral cortex, whereas blood flow to the placenta decreased. Administration of bupivacaine during asphyxia did not affect the changes in mean arterial blood pressure and acid-base state but did abolish the increases in blood flows to the myocardium and cerebral cortex. Injection of L-NAME to the asphyxiated fetus resulted in an increase in mean arterial blood pressure above the level noted at 90 min of cord occlusion, and an increase in fetal PaO2 toward control levels. This was accompanied by a reduction in organ blood flows to preasphyxia levels. In asphyxiated Group III fetuses, titration of the phenylephrine infusion to achieve blood pressure increases similar to those noted with L-NAME were also associated with an increase in fetal PaO2. These data indicate that bupivacaine abolishes some of the circulatory adaptations to mild to moderate asphyxia induced by partial cord occlusion in the preterm fetal lamb. It is not clear whether these effects of bupivacaine are due to inhibition of NO. IMPLICATIONS: In the preterm fetal lamb, clinically relevant plasma concentrations of bupivacaine achieved by intravenous infusion to the pregnant ewe (80% gestation) abolished some of the fetal cardiovascular adaptations to asphyxia induced by partial umbilical cord occlusion.

Comparative pharmacokinetics of ropivacaine and bupivacaine in nonpregnant and pregnant ewes.

We determined the pharmacokinetics and protein binding of ropivacaine and bupivacaine after intravenous administration to nonpregnant and pregnant sheep. All animals were in good condition throughout the study. The highest mean total serum drug concentrations were found at the end of infusion. For both drugs, pregnancy was associated with lower volumes of distribution during the terminal phase of drug elimination (V(d)beta) and steady state (V(d)ss), as well as with a lower total body clearance (CL). The relationship between V(d)beta and CL was such that the elimination half-life (T(1/2)beta) was not altered. There were also differences between the two drugs. In all animals, the distribution half-life (T(1/2)alpha), T(1/2)beta, volume of central compartment (V(c)), V(d)beta, V(d)ss, and mean residence times (MRT) were greater and CL lower for bupivacaine than ropivacaine. For both drugs, protein binding was concentration-dependent and greater in pregnant ewes. In conclusion, the pharmacokinetics of ropivacaine and bupivacaine are altered by ovine pregnancy in a similar way. If these data are applicable to humans, an unintended intravascular injection of either drug could be expected to result in higher total serum concentrations in the pregnant than in the nonpregnant patient, but drug levels would decline at similar rates in both groups of individuals. However, differences between the two drugs, particularly in T(1/2)beta and MRT, may make ropivacaine preferable for use in obstetric anesthesia.

Do receptors get pregnant too? Adrenergic receptor alterations in human pregnancy.

In this review we discuss adrenergic receptor number and function during pregnancy, with emphasis on evidence that pregnancy results in specific receptor alterations from the nonpregnant state. Changes in adrenergic receptor function or distribution in vascular smooth muscle may be in part responsible for the decreased vascular responsiveness seen in human pregnancy, and the lack of the normal alterations may be a part of the syndromes of gestational hypertension, including preeclampsia-eclampsia. The onset of labor may be influenced by adrenergic modulation, and receptor or postreceptor level molecular alterations may trigger or facilitate normal or preterm labor. Human studies are emphasized when possible to assess the role of adrenergic signal transduction regulation in the physiology and pathophysiology of normal and complicated human pregnancy.

Comparative systemic toxicity of ropivacaine and bupivacaine in nonpregnant and pregnant ewes.

BACKGROUND: Ropivacaine is a new amide local anesthetic, having therapeutic properties similar to those of bupivacaine but with a wider margin of safety. Bupivacaine is probably the most commonly used drug in obstetric epidural analgesia, even though laboratory studies have suggested that pregnancy increases the cardiotoxicity of bupivacaine but not of other local anesthetics. The current study was designed to reevaluate, in a random and blinded fashion, the systemic toxicity of bupivacaine and ropivacaine in nonpregnant and pregnant sheep. METHODS: Chronically prepared nonpregnant and pregnant ewes were randomized to receive an intravenous infusion of ropivacaine or bupivacaine at a constant rate of 0.5 mg.kg-1.min-1 until circulatory collapse. The investigators were blinded to the identity of local anesthetic. Heart rate, arterial blood pressure, and cardiac rhythm were monitored throughout the study. Arterial blood samples were obtained before infusion and at the onset of toxic manifestations, which appeared in the following sequence: convulsions, hypotension, apnea, and circulatory collapse. Serum drug concentrations and protein binding were determined. Blood pH and gas tensions were measured. RESULTS: There were no significant differences between non-pregnant and pregnant animals in the doses or serum concentrations of either drug required to elicit toxic manifestations. In nonpregnant animals, similar doses and serum concentrations of ropivacaine and bupivacaine were associated with the onset of convulsions and circulatory collapse. In pregnant ewes, greater doses of ropivacaine as compared to bupivacaine were required to produce convulsions (7.5 +/- 0.5 vs. 5.0 +/- 0.6 mg.kg-1) and circulatory collapse (12.9 +/- 0.8 vs. 8.5 +/- 1.2 mg.kg-1). The corresponding serum concentrations of ropivacaine were similar to those of bupivacaine. Pregnancy did not affect the serum protein binding of either drug. The proportion of animals manifesting a malignant ventricular arrhythmia as the terminal event was similar among all groups. CONCLUSIONS: The systemic toxicity of ropivacaine or bupivacaine is not enhanced by gestation in sheep. This is in contrast to an earlier study in which the cardiotoxicity of bupivacaine was enhanced during ovine pregnancy. Greater doses of ropivacaine, as compared to bupivacaine, are needed to produce toxic manifestations in pregnant animals.

Effect of ropivacaine and bupivacaine on uterine blood flow in pregnant ewes.

The effects of ropivacaine, a new amide local anesthetic, on uterine blood flow and fetal well-being were compared with those of bupivacaine in 10 chronically instrumented pregnant ewes. In random sequence, animals received two intravenous infusions of each drug. The low infusion rate regimens were chosen to result in clinically relevant maternal plasma concentrations of local anesthetics, whereas the more rapid rates of infusions were given to assess the safety of higher maternal drug concentrations. An epinephrine infusion was given to demonstrate the appropriateness of the animal model for the measurement of uterine blood flow. Maternal and fetal heart rates, arterial blood pressure, and the ewe's central venous pressure, intraamniotic pressure, and uterine blood flow were recorded continuously. Arterial blood samples were taken from mother and fetus at frequent intervals to determine acid-base status and local anesthetic concentrations. A total of 39 studies were performed. None of the infusions of either local anesthetic resulted in a significant decrease in uterine blood flow or deterioration in fetal condition. The mean maternal plasma concentrations at the end of infusions were as follows: ropivacaine low dose, 1.60 +/- 0.35 micrograms/mL; bupivacaine low dose, 1.55 +/- 0.15 micrograms/mL; ropivacaine high dose, 2.50 +/- 0.37 micrograms/mL; and bupivacaine high dose, 1.83 +/- 0.19 micrograms/mL. Epinephrine infusion resulted in a 25% decrease in uterine blood flow without adverse fetal effects. We conclude that neither ropivacaine nor bupivacaine, as administered in this study, led to any ill effects on uterine artery blood flow or fetal well-being.

The maternal and fetal effects of milrinone and dopamine in normotensive pregnant ewes.

The safety of milrinone, administered during gestation, was evaluated in seven chronically instrumented pregnant ewes and their fetuses. Each of the following six intravenous regimens was administered in random order: milrinone, 75 micrograms.kg-1, over 1 minute, followed by 240-minute infusions of the drug at a rate of 1, 2, or 4 micrograms.kg-1.min-1; dopamine 5 or 10 micrograms.kg-1.min-1 over 60 minutes; or normal saline solution, 0.5 ml.min-1 for 240 minutes. Maternal and fetal acid-base parameters, heart rate, and blood pressure were monitored as were the ewe's venous and intraamniotic pressures and uterine blood flow. Milrinone concentrations determined in maternal arterial blood samples obtained during 1 and 2 micrograms.kg-1.min-1 infusions were found to be within the human therapeutic range. Bolus injection of milrinone, as well as the lowest drug infusion, resulted in no significant changes in uterine blood flow, whereas 2 micrograms.kg-1.min-1 milrinone infusion led to a 14% to 19% increase in uterine blood flow between 120 and 240 minutes. With the highest milrinone infusion, this increase was approximately 20%. In contrast, with both dopamine infusions, a dose-related decrease in uterine blood flow of 15% to 26% occurred between 15 and 60 minutes. No milrinone could be detected in any fetal plasma samples. Fetal arterial pH and blood gas tensions did not change during milrinone infusions. Dopamine 10 micrograms.kg-1.min-1 led to a progressive decrease in fetal arterial pH and an increase in PaCO2, which may have been related to similar changes in the ewe. It is concluded that milrinone has no adverse effects on uterine blood flow and fetal well-being when administered during ovine pregnancy.

Systemic toxicity of ropivacaine during ovine pregnancy.

Ropivacaine is a new amide local anesthetic structurally related to bupivacaine and mepivacaine. Its potency and duration of action are similar to those of bupivacaine but its therapeutic index may be greater. Since pregnancy enhances the cardiotoxicity of bupivacaine, the current study was devised to compare the toxicity of ropivacaine in chronically instrumented nonpregnant and pregnant ewes during continuous intravenous infusion of the drug at the rate of 0.5 mg.kg-1.min-1. In all animals, symptoms of local anesthetic toxicity occurred in the usual order--convulsions, hypotension, apnea, and circulatory collapse. There were no significant differences between the two groups of animals in the doses and plasma concentrations of ropivacaine associated with each toxic manifestations. For example, circulatory collapse occurred at a mean dose of 11.3 +/- 1.1 mg.kg-1 in nonpregnant and 12.4 +/- 0.9 mg.kg-1 in pregnant animals, with corresponding plasma concentrations of 7.3 +/- 0.3 and 9.6 +/- 2.1 micrograms.ml-1 (P = not significant). Protein binding of ropivacaine in the concentration range associated with toxic manifestations was similar in sera obtained from nonpregnant and pregnant ewes. In conclusion, ovine pregnancy does not enhance the systemic toxicity of ropivacaine, possibly because of an absence of gestation-related increase in the availability of free drug.

Pregnancy does not alter lidocaine toxicity.

Pregnant sheep are more vulnerable to the toxic effects of bupivacaine, a potent local anesthetic, than are nonpregnant sheep. In contrast, ovine pregnancy does not enhance the toxicity of mepivacaine, a drug with properties similar to lidocaine. We studied the central nervous and cardiovascular toxicity of lidocaine in pregnant sheep receiving a continuous intravenous drug infusion at the rate of 2 mg/kg/min and compared our results with data previously obtained in nonpregnant ewes. In all animals, toxic manifestations occurred in the following sequence: convulsions, hypotension, respiratory arrest, and circulatory collapse. The doses of lidocaine required to produce these symptoms in pregnant and nonpregnant ewes were similar. Convulsions occurred at 5.9 +/- 0.6 mg/kg (mean +/- SE) in the pregnant ewe and 5.8 +/- 1.8 mg/kg in the nonpregnant ewe, whereas circulatory collapse occurred at 40.7 +/- 2.6 and 36.7 +/- 3.3 mg/kg in the pregnant and nonpregnant animals, respectively. Lidocaine plasma concentrations associated with the onset of convulsions in both pregnant and nonpregnant ewes were almost identical (12.1 +/- 0.7 and 11.7 +/- 2.0 micrograms/ml, respectively). At circulatory collapse, these concentrations were 35.1 +/- 3.2 and 41.2 +/- 6.7 micrograms/ml, respectively. It appears that pregnancy does not enhance the toxic effects of lidocaine. These findings are similar to those for mepivacaine but not for bupivacaine, and may be related in part to differences in the way pregnancy affects serum protein binding of these drugs.

Pharmacokinetics of ropivacaine in nonpregnant and pregnant ewes.

The pharmacokinetics of ropivacaine were studied in chronically instrumented nonpregnant and pregnant ewes. On the day of study, the urinary bladder was catheterized. Ropivacaine (2.5 or 3.0 mg/kg) was administered by intravenous infusion over 2 or 4 min. Serial samples of arterial blood and urine were collected over 5 h, and drug concentrations were determined using a gas chromatographic technique. Total clearance of ropivacaine was lower in the pregnant animals (21.6 +/- 4.5 mL.min-1.kg-1) compared with the nonpregnant animals (45.1 +/- 6.7 mL.min-1.kg-1). There was a tendency toward a decrease in the volume of distribution during the terminal exponential phase of drug elimination of 2.03 +/- 0.36 L/kg in the pregnant and 4.32 +/- 1.03 L/kg in the nonpregnant sheep. Thus the difference in the elimination half-life was only minimal: 74.7 +/- 10.7 min in the pregnant and 64.4 +/- 7.4 min in the nonpregnant animals. It is concluded that ovine pregnancy is accompanied by changes in the pharmacokinetics of ropivacaine. Inadvertent intravenous injections of similar drug doses to pregnant and nonpregnant women might result in higher plasma concentrations of ropivacaine in the former. However, the rate of decline in plasma levels of the drug would be similar in both.

Adverse effects of maternally administered lidocaine on the asphyxiated preterm fetal lamb.

Lidocaine was infused at a constant rate of 0.1 mg.kg-1.min-1 for 180 min into 12 chronically prepared pregnant sheep while asphyxia, induced by partial umbilical cord occlusion, was maintained in the premature fetus (80% of gestation). In five similar preparations saline instead of lidocaine was infused into the mother for 180 min. Maternal and fetal arterial blood pressure, heart rate, pHa, PaCO2, and PaO2 were monitored, and fetal cardiac output and the distribution of blood flow to fetal organs were measured, using labeled microspheres, before and after asphyxia and again after maternal infusion of lidocaine or saline. Maternal and fetal arterial blood and maternal urine were obtained at intervals for determination of lidocaine concentrations and urinary drug clearance. At the end of infusion, these animals were killed and tissues dissected for determination of lidocaine concentrations and organ blood flow. Maternal and fetal lidocaine plasma concentrations at steady state were 2.32 +/- 0.12 and 1.23 +/- 0.17 microgram/ml, respectively, similar to those seen during human epidural anesthesia. Asphyxia resulted in a significant drop in fetal heart rate and increased blood flow to the brain, heart, and adrenals. Asphyxia and saline did not produce additional deterioration of the fetus, but asphyxia and lidocaine led to a significant increase in PaCO2 and decreases in pHa, mean arterial pressure, and blood flows to the brain, heart, and adrenals. It is concluded that the immature fetus loses its cardiovascular adaptation to asphyxia when exposed to clinically acceptable plasma concentrations of lidocaine obtained transplacentally from the mother.

Incidence of visceral pain during cesarean section: the effect of varying doses of spinal bupivacaine.

The safety of 0.5% hyperbaric bupivacaine, as well as the incidence and severity of visceral pain, were evaluated in 36 women undergoing elective cesarean section under spinal anesthesia who, randomly divided into two groups, received different dose ranges according to height, 7.5-10 mg in group A and 10-12.5 mg in group B. When sensory block to at least the fourth thoracic dermatome was established, surgery was begun and the occurrence and severity of visceral pain recorded (visual analog scale) by an observer unaware of patient data. The level of analgesia to pinprick was determined when and if there was onset of pain intraoperatively, and supplementary medication was administered as needed. Hypotension, the incidence of which was similar in both groups, was treated as necessary with ephedrine. No patients experienced pain until after delivery of the infant. Thereafter, moderate to severe pain, in association with peritoneal traction, occurred in 12 patients in group A (70.5%) but only in 6 patients in group B (31.6%). In patients experiencing moderate to severe pain, the mean time between induction of anesthesia and onset of pain was similar in both groups, as was the amount of systemic narcotic given. Total time for regression of sensory analgesia to L5 was longer in patients in group B (243.9 versus 195.4 min), and the incidence of complete motor blockade was greater in group B. Increasing the amount of 0.5% hyperbaric bupivacaine per spinal segment reduces the occurrence of moderate to severe visceral pain during elective cesarean section without jeopardizing mother or fetus.

Does pregnancy alter the systemic toxicity of local anesthetics?

The toxicity of mepivacaine in chronically instrumented nonpregnant and pregnant sheep was evaluated, and compared with data from previous studies of the toxicity of other local anesthetics. Thirteen preparations were studied, seven nonpregnant (NP) and six pregnant (P). Mepivacaine 2 mg.kg-1.min-1 was infused at a constant rate into the femoral vein until toxic manifestations occurred, in the following sequence: convulsions, hypotension, respiratory arrest, and circulatory collapse. The doses and plasma concentrations of mepivacaine necessary to produce toxic symptoms were similar in NP and P animals, whereas, in a previous study, pregnancy enhanced the cardiotoxicity of bupivacaine. No malignant ventricular arrhythmias were observed throughout the study. Protein binding of mepivacaine was also determined in sera from nonpregnant and pregnant ewes and compared with that for bupivacaine. Serum protein binding of mepivacaine was not reduced in pregnancy at the drug concentrations associated with toxic symptoms; at circulatory collapse, it was approximately 22% in NP and P. In contrast, the proportion of bound bupivacaine was 73% in NP and 51% in P, a significant difference. These protein binding data suggest that, although lethal concentrations of bupivacaine, determined in the previous study, were higher in NP than in P animals, concentrations of free drug were similar. Thus, the difference between the two drugs may be related to gestational increases in the availability of free drug in the case of bupivacaine.

Pharmacokinetics of lidocaine in nonpregnant and pregnant ewes.

The pharmacokinetics of lidocaine were studied in nonpregnant and pregnant ewes. The maternal femoral vessels were cannulated and, on the day of study, the urinary bladder was catheterized. Lidocaine HCl, 4-5 mg/kg, was administered by IV injection over 60 seconds. Serial samples of arterial blood and urine were collected over 4 hours, and drug concentrations were determined using a gas chromatographic technique. The volume of the central compartment was greater in pregnant than in nonpregnant ewes (1.51 +/- 0.20 vs. 0.96 +/- 0.16 L/kg) as was the volume of distribution at steady state (Vdss): 3.24 +/- 0.40 vs. 1.88 +/- 0.32 L/kg. The volume of distribution during the terminal exponential phase of drug elimination (Vd beta) and total clearance of lidocaine (Cl) were also higher in pregnant animals: 4.17 +/- 0.50 L/kg and 99.6 +/- 8.5 ml.min-1.kg-1, respectively; compared to 2.46 +/- 0.48 L/kg and 44.1 +/- 6.5 ml.min-1.kg-1, in nonpregnant ewes. However, the balance between these changes in Vd beta and Cl did not result in a significant difference in the elimination half-life of lidocaine (38.1 +/- 2.1 minutes in nonpregnant and 31.9 +/- 3.0 minutes in pregnant ewes). If these data are applicable to humans, the risk of drug accumulation after repeated administration of lidocaine is no greater in pregnant than in nonpregnant patients.