Mark I. Zakowski

Prolongation of epidural anesthesia using a lipid drug carrier with procaine, lidocaine, and tetracaine

This study evaluated the effect of a lipid drug carrier (iophendylate) on epidural anesthesia. The intensity and duration of motor blockade produced by aqueous and lipid preparations of local anesthetics were assessed in rabbits with long-term indwelling catheters in the epidural space. Motor blockades produced by procaine (1%, 2%, and 4%), lidocaine (1%, 2%, and 4%), and tetracaine (0.5%, 1%, and 2%) in normal saline solution were compared with the effects produced by equimolar amounts of the drug solutions in iophendylate. Procaine (4%) in aqueous solution produced motor blockade lasting 30 +/- 3.54 min (mean +/- SD) versus 84 +/- 4.18 min in lipid solution. Lidocaine (2% and 4%) in aqueous solution produced motor blockade lasting 41 +/- 4.18 and 65 +/- 6.12 min versus 39 +/- 4.18 and 118 +/- 10.1 min, respectively, in lipid solution. Aqueous tetracaine (0.5%, 1%, and 2%) produced motor blockade of 106 +/- 9.62, 189 +/- 6.52, and 273 +/- 26.8 min versus 284 +/- 14.7, 335 +/- 15.8, and 365 +/- 26.9 min, respectively, in their lipid counterparts. A control group of animals that received normal saline solution or iophendylate alone did not exhibit motor blockade. These results may be attributed to sustained release of local anesthetics from the lipid vehicle. Hence, lipid drug carriers may be effective in prolonging epidural anesthesia.

Electrocardiographic changes during cesarean section: a cause for concern?

A Holter monitor was used to record ST segment changes during cesarean section in 170 consecutive healthy parturients starting 2 h before and ending 3 h after surgery. Lumbar epidural anesthesia (LEA, n = 120) or subarachnoid anesthesia (SA, n = 50) was used. Transthoracic 2-D echocardiograms were obtained in 30 patients from the LEA group. ST depression or elevation occurred 160 times in 44 patients from both groups. Ninety-eight percent of these changes occurred between induction of anesthesia and the end of surgery, with 78% of the episodes registering -1 mV. In the LEA group, the number of episodes tended to increase after delivery, but in the SA group, the frequency remained constant. ST segment depression was recorded in 38% and 14% of patients in the LEA and SA groups, respectively (P < 0.05, x2 analysis). No wall motion abnormality was noted in the echocardiogram during ST segment depression. Neither the 12-lead electrocardiogram nor plasma myocardial specific creatine kinase suggested myocardial damage. The operative events, alone or in combination, including hypertension, tachycardia, hypotension, bradycardia, air embolism (precordial Doppler) were neither specific nor sensitive as predictors of ST segment change (stepwise logistic regression). Tachycardia was associated with ST segment changes in 10% of time epochs (5 min) (P = 0.05, x2 analysis). Thus, ST segment changes during cesarean section are not caused by myocardial ischemia and are not of any clinical consequence.

Prolonged analgesia and decreased toxicity with liposomal morphine in a mouse model.

Inadequate control of postoperative pain remains a major clinical problem. A reliable method of providing long-lasting postoperative analgesia with a single dose would be very useful. We synthesized a liposomal morphine formulation and compared it to free morphine with regard to duration of analgesia in the mouse. Analgesia was assessed after intraperitoneal injection using the tail-flick test. The systemic toxicity after administration of liposomal and free morphine was compared. The release rate of morphine from liposomes in vitro was also evaluated. The lethal intraperitoneal dose of free morphine in 50% of mice (LD50) was 400 mg/kg. The maximum safe (non-lethal) dose of free morphine was 130 mg/kg. The highest dose of liposomal morphine administered (1650 mg/kg) did not cause death in any animal. Duration of analgesia was significantly prolonged with the highest dose of liposomal morphine (21.5 +/- 5.3 h) compared to the maximum safe dose of free morphine (3.7 +/- 0.75 h), P < 0.01. In vitro experiments showed a slow release rate of morphine from the liposome depot. Prolonged analgesia and decreased systemic toxicity for liposomal morphine are explained by sustained release of morphine from the liposomal depot. These results suggest that liposomal narcotic formulations may provide prolonged analgesia with single-dose administration.

A rat sciatic nerve model for independent assessment of sensory and motor block induced by local anesthetics.

The purpose of this study was to develop a reliable model to independently quantify motor and sensory block produced by local anesthetics. The sciatic nerve was blocked in 52 rats by injecting 0.2 mL of 0.125%, 0.25%, 0.5%, or 0.75% bupivacaine (n = 13 for each concentration). Accurate needle placement was achieved using a nerve stimulator at 0.2 mA and 1 Hz. Ten control rats received 0.9% saline (n = 5) or sham nerve stimulation (n = 5). Motor block was assessed by measuring hindpaw grip strength with a dynamometer. Sensory block was determined by measuring hindpaw withdrawal latency from radiant heat. The intensity of both motor and sensory block measured at 30-min intervals was plotted against time until full recovery to obtain the area under the curve. Intergroup comparisons using analysis of variance showed increasing area under the curve with increasing concentrations of bupivacaine for motor blocks (P < 0.05 for all intergroup comparisons except 0.5% vs 0.75%) and sensory blocks (P < 0.05 for all intergroup comparisons). Normal saline or sham nerve stimulation did not result in any motor or sensory block.

Transfer and Uptake of Alfentanil in the Human Placenta During in Vitro Perfusion

Alfentanil, a short-acting lipophilic opioid, is used for labor analgesia and cesarean section and may cause neonatal depression. However, direct placental alfentanil transfer has not been studied. We measured placental alfentanil transfer and uptake during in vitro perfusion. Placenta lobules from healthy parturients were perfused with biophase at pH 7.4, 95%:5% O2:CO2. Maternal to fetal (MTF, n = 10) and fetal to maternal (FTM, n = 10) transfer were examined during perfusion with alfentanil 10 ng/mL, antipyrine, and creatinine for 1 h. Thereafter, both MTF and FTM placentas were assayed for alfentanil content (n = 3), or perfused with biophase for 1 h to determine drug washout and then assayed for alfentanil content (n = 3). After the 1 h washout, the remaining MTF placentas (n = 4) were then perfused MTF with high-dose alfentanil 1000 ng/mL to assess saturability of placental transfer. The remaining FTM placentas (n = 4) were then perfused with alfentanil 10 ng/mL in the MTF direction to verify that the same alfentanil transfer characteristics found between placentas were valid when the direction of drug transfer was reversed in the same placenta. Alfentanil was rapidly transferred (< 5 min) across the placenta both MTF and FTM. During MTF transfer, fetal effluent reached a plateau at 2.2 ng/mL between 35 and 55 min, and was unmeasurable 30 min into washout. During FTM transfer, maternal effluent reached a plateau at 1.9 ng/mL at 25-45 min, and was absent after 20-45 min of washout.(ABSTRACT TRUNCATED AT 250 WORDS)

Sufentanil transfer in the human placenta during in vitro perfusion

PurposeSufentanil, a lipophilic opioid, is used to provide analgesia for labour and Caesarean section, but may cause neonatal depression. Factors affecting placental transfer of sufentanil were investigated using human placentas.Study designTransfer and uptake of sufentanil by the human placenta were studied using a single pass (open)in vitro perfusion model. The effects of change in sufentanil concentration (1–100 ng· ml−1) and change in fetal pH (range 7.4–6.8) on placental transfer were studied. Placental metabolism of sufentanil and the effects of maternal protein content (fresh human plasma, albumin 4%, Media 199) on placental transfer were also investigated utilizing a closed (recirculated)in vitro perfusion system.ResultsSufentanil transfer was 2% at five minutes and plateaued at 12% by 45 min. The clearance index (Cl =sufentanil clearance/antipyrine clearance) was 0.56 ± 0.2 for maternal to fetal (MTF) and 0.44 ± 0.2 in the fetal to maternal (FTM) directions (P=NS). The Cl was 0.5 ± 0.2 for 1 ng· ml−1 and 0.61 ± 0.3 for 100 ng· ml−1 sufentanil concentration (P=N.S.). The placenta contained 7.1 ± 2 and 9.8 ± 3 ng· g−1 sufentanil following MTF and FTM perfusions for 90 min at 1 ng· ml−1. The placenta did not metabolize sufentanil. After one hour MTF washout, placental sufentanil content was 2.3 ±.5 ng· g−1 with 0.08 ng· ml−1 sufentanil in the umbilical vein. Maternal plasma decreased MTF Cl from 0.41 ± 0.1 for albumin and 0.4 ± 0.1 for Media 199 to 0.17 ±.06 for plasma (P < 0.05). Decreasing fetal pH increased MTF Cl from 0.57 ±.13 at pH 7.4 to 1.6 ±.4 at pH 6.8 (P < 0.05).ConclusionSufentanil crossed the placenta by passive diffusion and accumulated in placental tissue, which acted as a drug depot, slowing the initial transfer. Placental transfer was decreased by maternal plasma proteins, but not by albumin. Fetal acidosis increased placental transfer. Due to its low initial umbilical vein concentration, sufentanil may be the opioid of choice when delivery is imminent (< 45 min).RésuméObjectifLe sufentanil, un morphinique utilisé pour procurer l’analgésie pendant le travail et l’accouchement par césarienne, peut causer une dépression chez le nouveau-né. Cette étude réalisée sur placentas humains s’intéresse aux facteurs qui influencent le transfert placentaire du sufentanil.Type d’étudeUn modèlein vitro (ouvert) de perfusion à un passage a servi à l’étude du transfert et du captage du sufentanil par le plasma humain. On a recherché tes effets du changement de la concentration du sufentanil (1–100 ng· ml−1) et du pH foetal (écart de 7,4 à 6,8) sur le transfert placentaire. Le métabolisme placentaire du sufentanil et l’influence de la concentration matemelle en proteines (plasma humain frais, albumine 4%, Media 199) ont aussi été étudiés a l’aide d’un système de perfusionin vitro fermé.RésultatsLe transfert du sufentanil était de 2% après cinq minutes et a atteint un plateau de 12 % après 45 min. L’index de clairance (IC = clairance du sufentanil/clairance de l’antipyrine) était 0,56 ± 0,2 en direction materno-foetale (MF) et de 0,44 ± 0,2 en direction foeto-maternellle (FM) (P = NS). L’IC était 0,5 ± 0,2 et 0,61 ± 0,3 pour des concentrations de sufentanil de 1 ng· ml−1 et de 100 ng· ml−1. Le placenta contenait 7,1 ± 2 et 9,8 ± 3 ng· g−1 de sufentanil après des perfusions MF et FM de 90 min à I ng· ml−1. Le placenta n’a pas métabolisé le sufentanil. Après une heure de rinçage MF, le contenu placentaire de sufentanil était 2,3 ± 0,5 ng· g−1 dont 0,08 ng· ml−1 dans la veine ombilicale. Le plasma matemel a diminué l’IC MF de 0,41 ± 0,1 pour l’albumine et de 0,4 ± 0,1 pour le Media 199 à 0,17 ±0,06 pour le plasma (P < 0,05). La baisse du pH foetal a fait augmenter l’IC MF de 0,57 ± 0,13 au pH 7.4 à 11,6 ±0,4 au pH 6,8 (P < 0,05).ConclusionLe sufentanil traverse le placenta par diffusion passive et s’accumule dans le tissu placentaire qui agit comme un réservoir et ralentit ainsi le transfert initial. Les protéines plasmatiques maternelles réduisent le transfert placentaire mais non l’albumine. L’acidose foetale accentue le transfert placentaire. À cause de sa faible concentration ombilicale veineuse initiale, le sufentanit pourrait s’avérer le morphinique de choix lorsque l’accouchement est imminent (< 45 min).

Perineural antinociceptive effect of opioids in a rat model

Background: The research on conductive analgesia induced by perineural opioids generated a large body of conflicting data. In this study we reassessed the antinociceptive response to perineural administration of morphine, fentanyl or meperidine in a rat model.

Intrathecal administration of liposomal morphine in a mouse model

The authors determined the duration of analgesia, toxicity, and neuraxial distribution of liposomal morphine after intrathecal administration in the mouse.Analgesic duration was determined using the tail-flick test after intrathecal injection of 12.5, 25, or 50 micro gram of plain or liposomal morphine (n = 6 mice/dose/formulation). Toxicity of the formulations was compared by estimating LD50. Neuraxial morphine distribution was determined after 20 micro gram of plain or liposomal morphine. The excised spinal cord and brain were divided into five segments at 1 min, and at 1, 4, and 8 h after injection for both formulations. In addition, for the liposomal morphine, similar sections were obtained at 24 h (n = 6 mice/formulation/time point). Segmental morphine concentration was quantified using radioimmunoassay. Liposomal encapsulation significantly prolonged duration of analgesia for the 25-micro gram (13.4 +/- 1.64 [SE] vs 4.1 +/- 0.5 h) and 50-micro gram doses (16.8 +/- 4.0 vs 4.6 +/- 1.0 h). The estimated LD50 was 200 (confidence interval 151-257 micro gram) for plain morphine, but was not determinable for the liposomal formulation, since no deaths occurred at the largest dose level which could be tested (371 micro gram). For plain morphine, the drug was not confined to a specific neuraxial segment, and segmental levels declined rapidly. After liposomal morphine, the most morphine was concentrated and persisted in the low spinal cord segment at each time interval. These results show that a single dose of liposomal morphine produces prolonged analgesia with decreased toxicity compared to the plain formulation. (Anesth Analg 1995;81:514-8)

Uptake and distribution of bupivacaine and morphine after intrathecal administration in parturients : effects of epinephrine

This study examines the plasma pharmacokinetics of bupivacaine and morphine and the urinary excretion of morphine administered for spinal anesthesia for cesarean section. Patients received 12 mg of hyperbaric bupivacaine and 0.6 mg of morphine with either 0.2 mL of normal saline (plain, n = 15) or 0.2 mg of epinephrine (n = 15). Venous blood and urine were collected at 0, 0.25, 0.5, 1, 2, 3, 6, 12, and 24 h. Total and unconjugated morphine (UCM) in plasma and urine were measured using radioimmunoassay, and plasma bupivacaine was measured by gas chromatography. Results were expressed as mean +/- SE and analyzed using Students t-test at P less than 0.05. In the epinephrine group, plasma bupivacaine peaked at 15 min and remained approximately 30% higher (P less than 0.05) at 0.25, 0.5, and 1 h than in the plain group, which peaked at 30 min. Although UCM peaked at 3 h in both groups, the plasma levels remained approximately 66% lower in the epinephrine group. In the epinephrine group, bupivacaine had a smaller volume of distribution at steady state, and morphine had a more rapid clearance, shorter t1/2 beta, and smaller area under the curve compared with the plain group (P less than 0.05). Only 45% +/- 5% and 31% +/- 3% of morphine was recovered in the urine in the plain and epinephrine group, respectively (P less than 0.05). In conclusion, epinephrine added to a bupivacaine-morphine mixture increases the initial systemic uptake of bupivacaine and decreases the absorption and urinary excretion of morphine from the intrathecal space.

Zika virus: review and obstetric anesthetic clinical considerations

STUDY OBJECTIVES To review the clinical and basic science literature regarding Zika viral illness and highlight relevant findings for obstetric anesthesiologists. This review provides a global review of Zika viral illness, transmission patterns, pathophysiology of disease, and anesthetic management of the parturient with Zika viral illness and associated comorbidities. DESIGN Systematic review. SETTING Large academic hospital. SUBJECTS None. INTERVENTIONS None. MEASUREMENTS None. MAIN RESULTS None. CONCLUSION With the rapid spread of Zika virus and expected increase of spread in the summer of 2016, this review provides anesthesiologists with current recommendations, physiologic alterations, and anesthetic considerations in regard to the parturient with Zika viral illness and associated diseases.