A randomized, observer-blind comparison between the Neurotip mounted Neuropen and a disposable plastic neurological wheel for assessing the level of spinal blockade at cesarean section.

BACKGROUND: Various methods are used to assess the height of sensory block to touch under spinal anesthesia for cesarean section. We tested a novel, inexpensive, miniature, user-dependent plastic neurological wheel against the user-independent Neurotip mounted Neuropen. METHODS: Patients received either spinal or combined spinal-epidural anesthesia. For each patient assessment, the devices were randomly assigned to one of two independent investigators. The order of device application was randomly permuted. Neither researcher was involved with anesthetic care. At 5-min intervals for 20 min after spinal injection, and again at the end of the operation, the levels of block to loss-of-touch sensation were assessed. While one investigator evaluated the block, the other left the operating room and vice versa. Mixed-effects regression and Bland-Altman analysis were used to weigh agreement between devices. RESULTS: The mean difference in level-to-touch was 0.04 (95% CI -0.18, 0.27) dermatome levels. Measurement error standard deviation associated with the Neurotip mounted Neuropen and plastic neurological wheel was 1.36 (95% CI 1.26, 1.41) and 1.33 (95% CI 1.26, 1.46) dermatome levels, respectively. The difference in measurement error standard deviation was -0.03 (95% CI -0.16, 0.24). This evidence excludes the possibility, with 95% confidence, of clinically significant bias or measurement error differences between methods. Occasional wide variances in dermatome level were observed with both instruments at the initial assessment only. CONCLUSION: The compact plastic neurological wheel is as clinically reliable as the Neurotip mounted Neuropen.

Hypothesis: selective phosphodiesterase-5 inhibition improves outcome in preeclampsia.

The pathogenesis of preeclampsia stems from aberrant changes at the placental interface. The trophoblastic endovascular invasion of tonic spiral arteries that converts them to passive conduits falters. Uteroplacental insufficiency and fetoplacental hypoxemia result. Secondary maternal oxidative stress and an excessive inflammatory response to pregnancy generate the clinical syndrome of preeclampsia. Current treatment focuses on preventing seizures, controlling hypertension, preserving renal function and delivering the baby. We propose that the pathophysiological changes induced by preeclampsia in the placenta parallel those caused by persistent hypoxemia in the lungs at high altitude or with chronic obstructive pulmonary disease. Unrelenting pulmonary hypoxic vasoconstriction induces pulmonary hypertension and cor pulmonale. Inhalation of nitric oxide and phosphodiesterase-5 inhibitors opposes pulmonary hypoxic vasoconstriction, alleviates pulmonary hypertension and improves systemic oxygenation. Notably nitric oxide donor therapy also counters hypoxemic fetoplacental vasoconstriction, a biological response analogous to pulmonary hypoxic vasoconstriction. Fetal oxygenation and nutrition improve. Placental upstream resistance to umbilical arterial blood flow decreases. Fetal right ventricular impedance falls. Heart failure (cor placentale) is avoided. Emergency preterm delivery can be postponed. Other than low dose aspirin and antioxidants vitamins C and E no available therapy specifically targets the underlying disease profile. We hypothesize that, like nitric oxide donation, pharmacological inhibition of placental phosphodiesterase-5 will also protect the fetus but for a longer time. Biological availability of guanosine 3'5'-cyclic monophosphate is boosted due to slowed hydrolysis. Adenosine 3'5'-cyclic monphosphate levels increase in parallel. Cyclic nucleotide accumulation dilates intact tonic spiral arteries and counters hypoxemic fetoplacental vasoconstriction. Intervillous and intravillous perfusion pick up. Maternal to fetal placental circulatory matching improves. Enhanced placental oxygen uptake alleviates hypoxemic fetal stress. Appropriate fetal nutrition resumes. Cor placentale and severe intrauterine growth restriction are averted. Increased maternal cyclic nucleotide concentrations promote systemic vasodilatation so that blood pressures fall. Preemption of oxidative stress initiated by "consumptive" oxidation of nitric oxide stabilizes the vascular endothelium and corrects coagulopathy. Anti-inflammatory and immunosuppressant adenosine 3'5'-cyclic monphosphate offsets the extreme gestational inflammatory response. Cellular injury and multi-organ damage are prevented. One tablet a day of the new long acting phosphodiesterase-5 inhibitor, tadalafil (half life of 17.5 h) theoretically should allow a preterm pregnancy affected by preeclampsia to continue safely. Selective monitoring of vital organ functions guards against life-threatening maternal complications. Regular biophysical profiling warns the obstetrician of impending fetal compromise. Fetal growth and vital organ maturation can continue. As a result workloads imposed upon neonatal intensivists will lighten. Parental anxiety and concern will be allayed. The cost of treating preeclamptic mothers and their extremely low birth weight infants will decrease. Money saved by midwifery services in poorer states can be used to pay for better prenatal care. Severe preeclampsia/eclampsia will be less common. Maternal and perinatal morbidity and mortality will be reduced. Because the human immunodeficiency virus often infects individuals at a workforce eligible age, the global acquired immunodeficiency syndrome pandemic has already brought many nations to the brink of economic ruin. Potentially productive lives saved for the future will help restore them fiscally.

Transfer of methohexital across the perfused human placenta.

STUDY OBJECTIVES: To evaluate the transfer properties of methohexital and the influence of protein binding using the in vitro human placental perfusion model. DESIGN: Fresh term human placentae from healthy parturients were perfused bidirectionally via a cannulated fetal chorionic artery and vein and needles placed into the maternal intervillous space. Maternal-to-fetal (M-->F) and fetal-to-maternal (F-->M) transfer and ultimate distribution of methohexital was investigated using a closed (recirculating) placental perfusion model. SETTING: Obstetric anesthesia laboratories of two university medical centers. PATIENTS: No patient participation occurred as placentae were obtained after delivery. INTERVENTION: M-->F and F-->M transfer of methohexital was compared in vitro in perfusates with equal protein concentrations (2 g/100 mL in both perfusates) or albumin-simulated physiologic protein binding concentrations (maternal 8 g/100 mL; fetal 4 g/100 mL). MEASUREMENTS AND MAIN RESULTS: Data obtained consisted of measurements of methohexital and antipyrine concentrations by high-performance liquid chromatography. Glucose and lactate concentrations and perfusate loss were measured to assess placental viability. Methohexital protein binding was assessed at 2, 4, and 8 g/100 mL of albumin by equilibrium dialysis. The transfer index of 0.83 +/- 0.11 for the M-->F perfusions was significantly greater (p < or = 0.05) than in the F-->M direction (0.61 +/- 0.04) when albumin concentration was equal in both perfusates. This transfer asymmetry disappeared when albumin concentrations simulating maternal (8 g/100 mL) versus fetal (4 g/100 mL) protein concentrations in the perfusate were used (M-->F 0.87 +/- 0.12 and F-->M 0.95 +/- 0.11). CONCLUSION: Methohexital readily crosses the placenta in both directions. Protein binding has significant effects on the degree of transfer of methohexital at any time when compared with antipyrine and its ultimate fetal/maternal distribution.

A comparison of the placental transfer of ropivacaine versus bupivacaine.

UNLABELLED: This study compares the placental transfer of ropivacaine and bupivacaine using the dual perfused, single cotyledon human placental model. We studied the effects of maternal/fetal protein binding, maternal ropivacaine concentration, and fetal pH on ropivacaine transfer. At a clinically relevant maternal concentration (1 microg/mL), the calculated transfer ratios (local anesthetic percent transfer/antipyrine percent transfer) of ropivacaine (0.82 +/- 0.03) and bupivacaine (0.74 +/- 0.01) were comparable at the completion of the perfusion experiment (120 min). When the perfusates were modified to simulate actual in vivo plasma protein binding values, the maternal-to-fetal transfer of ropivacaine and bupivacaine decreased significantly (P < 0.05) as indicated by transfer ratios of 0.42% +/- 0.07% and 0.40% +/- 0.03%, respectively. No saturation of the transfer process was observed for either drug at the maternal concentrations investigated. The placental transfer of both local anesthetic agents increased significantly as the fetal pH decreased. This investigation shows that ropivacaine and bupivacaine cross the human placenta at a similar rate, despite their differences in lipophilicity and stereochemistry. Placental transfer of both compounds is highly influenced by maternal and fetal protein concentration and the fetal pH. IMPLICATIONS: The placental transfer of ropivacaine was shown to be similar to that of bupivacaine, and is thus highly influenced by the degree of maternal and fetal protein binding and fetal pH.

Transfer of lidocaine across the dual perfused human placental cotyledon.

Factors affecting lidocaine transfer across the normal term human placenta were studied using the dual perfused isolated single cotyledon. Experiments were performed using perfusates which provided equal protein binding in both the maternal and fetal circuits as well as perfusates that approached the actual in vivo maternal/fetal protein binding gradient. Additional experiments were performed to investigate the effects of increasing maternal lidocaine concentration (5, 10, 40, 80 microg/mL) on maternal to fetal (M-->F) lidocaine transfer across the human placenta. Lidocaine crossed the placenta rapidly in both the M-->F and fetal to maternal (F-->M) directions. When protein binding was similar in the two circuits, M-->F transfer ratios (lidocaine transfer/antipyrine transfer) were significantly lower than the transfer ratios seen in the F-->M direction (0.59+/-0.04 versus 0.84+/-0.06, P<0.05). Transfer ratios (M-->F: 0.83+/-0.06, F-->M: 0.96+/-0.06) were not reduced when the physiological maternal/fetal protein binding gradient was present. Lidocaine transfer was not diminished by increasing maternal concentrations and, in contrast to bupivacaine, was not significantly affected by its binding.

The placental transfer of sufentanil: effects of fetal pH, protein binding, and sufentanil concentration.

This study investigated factors that influence the placental transfer of sufentanil using the dual-perfused, single-cotyledon human placental model. Placentas were collected from healthy women. Experiments were designed to elucidate the effects of maternal protein binding, changing maternal sufentanil concentration (1, 10, 20, and 100 ng/mL) and decreasing fetal pH (fetal acidemia 7.2, 7.0, 6.8) on the placental transfer of sufentanil. Sufentanil crossed the placenta rapidly at a rate two-thirds that of the transfer marker, antipyrine. Sufentanil transfer increased linearly with the maternal concentration (r = 0.999). Sufentanil/antipyrine maternal to fetal (M-->F) transfer ratios were significantly reduced (0.66 +/- 0.05 vs 0.40 +/- 0.04, P < 0.05) when fresh frozen plasma was added to the maternal circuit to enhance protein binding. Fetal pH and sufentanil transfer were related because sufentanil M-->F clearance increased significantly as the fetal pH decreased (r = 0.973, P < 0.05). Sufentanil appears to cross the placenta by passive diffusion but is modulated by the degree of maternal protein binding. Sufentanil M-->F transfer is enhanced by fetal acidemia.

A comparison of catheter vs needle injection of local anesthetic for induction of epidural anesthesia for cesarean section.

It is generally believed that bolus injections of local anesthetic through an epidural needle produce a more rapid onset of blockade, but at the expense of an increased incidence and severity of hypotension, whereas intermittent injections through a catheter take longer to achieve adequate anesthesia but with a lower risk of hypotension. The present study investigated two commonly used needle and catheter epidural injection techniques for differences in speed of onset of surgical anesthesia and incidence and severity of hypotension. Term parturients scheduled for elective cesarean section were randomized into two groups to receive epidural anesthesia with intermittent injection either through the epidural needle (n = 44) or via a previously placed catheter (n = 44). The incidence and severity of hypotension was similar in the two groups. No significant difference was found for the time to onset of surgical anesthesia. In the absence of benefits of needle injection, incremental catheter administration of local anesthetic with its multiple safety advantages is the technique of choice for induction of epidural anesthesia for cesarean section.

The pharmacokinetics of epidural lidocaine and bupivacaine during cesarean section.

We studied the maternal pharmacokinetics of epidural lidocaine and bupivacaine in 20 healthy parturients with institutional review board approval and written, informed consent. Epidural anesthesia was induced using either 2% lidocaine with epinephrine 1:200,000, n = 10, or 0.5% plain bupivacaine, n = 10. Maternal arterial (Ma) blood was sampled at regular intervals and umbilical venous (Uv) blood at delivery. Results for lidocaine and bupivacaine, respectively, were (mean +/- SEM): age 30.4 +/- 1.5 and 24.7 +/- 1.6 yr; weight 74.0 +/- 4.2 and 74.9 +/- 4.5 kg; duration of surgery 55.5 +/- 4.3 and 53.1 +/- 3.5 min; epidural dosage 6.1 +/- 0.6 and 1.5 +/- 0.2 mg/kg; elimination half-life 113.9 +/- 5.6 and 110.4 +/- 20.4 min; plasma clearance 6.1 +/- 0.4 and 13.6 +/- 1.3 mL.kg-1.min-1; volume of distribution 0.98 +/- 0.1 and 1.67 +/- 0.3 L/kg; time to peak concentration 31 +/- 2.3 and 40.5 +/- 1.7 min; peak Ma concentration 6.4 +/- 0.65 and 0.8 +/- 0.1 microgram/mL; and Uv/Ma gradient 0.43 +/- 0.05 and 0.26 +/- 0.1. Peak Ma lidocaine concentrations in 2 of 10 patients reached potentially toxic levels without producing clinical toxicity, whereas peak bupivacaine Ma concentrations never approached levels considered unsafe. The results suggest that epidural bupivacaine reliably produces acceptable Ma concentrations below the toxic range.

Effects of fetal pH on local anesthetic transfer across the human placenta.

BACKGROUND: Fetal acidemia increases umbilical venous bupivacaine concentrations in the in situ rabbit model. The authors studied the effects of decreasing fetal pH on the rate of maternal to fetal (M-->F) clearances of lidocaine, bupivacaine, 2-chloroprocaine, and antipyrine (a nonionic marker of placental transfer) across the isolated, dual perfused, human placental cotyledon. METHODS: Maternal to fetal clearances of bupivacaine, lidocaine, 2-chloroprocaine, and antipyrine were determined at fetal pH (7.4), during progressive fetal acidemia (pH 7.2-->7.0-->6.8), and after recovery to fetal pH 7.4 in experiments with both low protein state and in those with in vivo maternal and fetal protein-binding potentials. RESULTS: Placental transfer of all three agents increased linearly as the fetal pH decreased. Antipyrine transfer was unaffected. Clearance of lidocaine and bupivacaine, but not 2-chloroprocaine, returned to baseline when fetal pH was restored to 7.4. When maternal and fetal protein-binding potentials were increased, clearance at fetal pH 7.4 of bupivacaine, but not lidocaine, decreased significantly. During fetal acidemia, the transfer of both agents increased, but to a lesser extent than in the low protein concentration experiments. CONCLUSIONS: Increasing the pH difference between maternal and fetal perfusates promotes M-->F passage of unionized lidocaine, bupivacaine, and 2-chloroprocaine. This likely results from an increased proportion of ionized local anesthetic in the acidemic fetal perfusate and consequent widening of the M-->F concentration gradient of the unionized form. Transfer of lidocaine and bupivacaine was limited by the maternal protein binding.

Bupivacaine transfer across the human term placenta. A study using the dual perfused human placental model.

BACKGROUND: Bupivacaine is widely used for obstetric analgesia, yet published information on the mechanism of human placental bupivacaine transfer is sparse. The dual perfused human placental model was used to elucidate the factors governing the placental transfer of bupivacaine. METHODS: Bupivacaine transfer was studied using the recirculating (closed) model and the single pass (open) model. Single placental cotyledons were perfused with either heparinized Krebs-Ringer's buffer (KRB) supplemented with human albumin (fetal and maternal circuits) or 100% fresh frozen plasma (maternal circuit) to control the bupivacaine protein binding in those circuits. In the open model, bupivacaine clearance was compared before and after being subjected to either increasing concentrations of bupivacaine or its structural analog, mepivacaine. RESULTS: For those studies in which the maternal and fetal protein binding was equal, the maternal to fetal (M-->F) transfer was significantly greater (P < 0.05) than that in the fetal to maternal (F-->M) direction. When the perfusates were modified to simulate actual in vivo plasma protein concentrations, bupivacaine transfer was shown to be related to the degree of protein binding found in the two circuits. In the open studies, bupivacaine transfer was similar at all concentrations investigated, unaffected by mepivacaine, and related to the pH of the fetal perfusate. A concentration effect was seen within the placental tissue at the end of the experiment. CONCLUSIONS: Bupivacaine placental transfer characteristics suggest passive diffusion rather than active drug transport and appear to be influenced by the maternal and fetal plasma protein binding, fetal pH, and placental uptake.

The transfer of cocaine and its metabolites across the term human placenta.

This study defines human placental transport of cocaine and its two minor, but pharmacologically active, metabolites--norcocaine and cocaethylene. The experimental system was the single, isolated perfused cotyledon of a normal term human placenta, and antipyrine served as a freely diffusible marker. Cocaine was transferred rapidly by the placenta at a rate about 80% that of antipyrine. The transfer had characteristics of passive transport consistent with the high lipid solubility of the drug. We found no evidence of significant placental metabolism of cocaine during its rapid placental transfer. Ethanol did not alter the cocaine transfer rate. Norcocaine and cocaethylene were equally as rapidly transferred. Thus the placenta is no barrier to the transfer of cocaine and its derivatives to the fetus.

Incidence of venous air embolism during cesarean section is unchanged by the use of a 5 to 10 degree head-up tilt.

One hundred healthy parturients were divided at random into two demographically similar groups and were positioned for cesarean section either horizontally or flexed 5 to 10 degrees head up, with a 15 degrees lateral tilt. A Doppler ultrasound transducer was positioned over the fourth intercostal space parasternally. Initially, two patients received spinal, three general, and 95 epidural anesthesia. Two patients subsequently needed general for failed epidural anesthesia. Changes in Doppler heart tones (greater than 15 sec duration) indicative of venous air embolism (VAE) were identified 15 times in 11 patients--seven in supine and four in head-up patients (no statistically significant difference). Six awake patients (three horizontal, three head-up) developed chest tightness or pain during surgery, but only one episode correlated with VAE. No patient developed breathlessness. Moderate hypotension (greater than 10% decrease in systolic arterial pressure [SAP]) occurred in seven of 11 (63.6%) patients with, and in 26 (29.2%) of 89 patients without, VAE (P less than 0.001). More severe hypotension (SAP less than 90 mm Hg) due to bleeding occurred once. We conclude that a modest (5-10 degrees) head-up position does not influence the occurrence of VAE in patients having cesarean section. An 11% incidence of clinically insignificant VAE, although low, is still worrisome, as even small air bubbles in the circulation are potentially harmful, especially if the foramen ovale is patent. VAE during cesarean section should be anticipated and the anesthetic management planned accordingly.