Bedside ultrasound of the neck confirms endotracheal tube position in emergency intubations.

PURPOSE: In controlled environments such as the operating room, bedside ultrasound (BUS) of the neck has shown high accuracy for distinguishing endotracheal (ETI) from esophageal intubations. We sought to determine the accuracy of BUS for endotracheal tube (ETT) position in the emergency department (ED) setting. MATERIALS AND METHODS: We assessed the utility of BUS in a single-center observational study in an ED setting. BUS was performed either simultaneously with ED intubation (S/ED), within < 3 minutes of ED intubation (A/ED), or in < 3 minutes of patient's ED arrival after pre-hospital intubation (A/EMS). Trained ED providers performed BUS; intubators were blinded to ultrasound findings. We used Cormack and Lehane categories (CL) to classify intubation attempts as "easy" (CL-I/II), "moderate" (CL-III) and "difficult" (CL-IV). Additional data included the diagnostic accuracy of the sonographer and intubator compared to the clinical outcome, anatomy identified by sonography and time to diagnosis. RESULTS: During a 10-month period, 89 subjects with 115 intubation attempts were included in the study, and 86 patients/101 attempts with complete data were used in the study (63-easy, 19-moderate, 19-difficult). The sonographers achieved 100 % accuracy with respect to determining the correct ETT position utilizing an anterior neck approach, while the intubators' accuracy in assessing correct tube location was 97 % compared to the clinical outcome. A blinded review of sonography findings confirmed all BUS anatomical findings. A sonographically empty esophagus was 100 % specific for endotracheal intubation, and a "double trachea sign" was 100 % sensitive and 91 % specific for esophageal intubation. The sonographic time to diagnosis was significantly faster than the intubator time to diagnosis ("easy" p < 0.001; n = 47; "moderate" p = 0.001; n = 15; "difficult" p < 0.001; n = 19); Wilcoxon test; A/EMS cases excluded). CONCLUSION: In this emergency setting, ultrasound determined ETT locations rapidly with 100 % accuracy and independently of the CL-category.

Regional tracheal blood flow during conventional and high-frequency jet ventilation in suckling pigs.

OBJECTIVE: To determine whether intubation and ventilation with either conventional mechanical ventilation or high-frequency jet ventilation, using dry or humidified gas, could induce regional tracheal ischemia and serve as a basis for the tracheal necrosis observed clinically during ventilation. DESIGN: Prospective, multiple group, controlled experimental study. SETTING: Medical school research laboratory. SUBJECTS: Twenty, 3- to 5-wk-old suckling pigs. INTERVENTIONS: Anesthetized, closed-chest piglets were intubated and ventilated for 30 mins with conventional mechanical ventilation and then ventilated for 2 additional hrs with either conventional mechanical ventilation or high-frequency jet ventilation. Groups were also ventilated, using both modes of ventilation, with either 37 degrees C humidified gas or 25 degrees C dry gas. MEASUREMENTS AND MAIN RESULTS: Blood flow groups were compared during spontaneous breathing, conventional mechanical ventilation, high-frequency jet ventilation and both ventilation modes, using 37 degrees C humidified or 22 degrees C dry inspired gas. Groups were compared, using an analysis of variance with a Newman-Keul's post-test. Regional tracheal blood flow was measured, using radioactive microspheres. Cardiac output and organ blood flows were also monitored. Tracheal blood flow increased 10.3-fold within 30 mins after intubation, but there were no significant differences in regional or total tracheal blood flow between conventional mechanical ventilation and high-frequency jet ventilation, using 37 degrees C humidified gas. Tracheal blood flow was increased further using high-frequency jet ventilation and 25 degrees C dry gas but not conventional mechanical ventilation with dry gas. Although ventilation reduced cardiac output by approximately 30%, there were no significant differences in organ distribution between modes of ventilation. CONCLUSIONS: Acute tracheal hyperemia occurred with intubation and ventilation with both conventional mechanical ventilation and high-frequency jet ventilation but no differences were observed between ventilation modes. Hyperemia was further increased with cool, dry inspired gas, using high-frequency jet ventilation but not conventional mechanical ventilation. Although acute tracheal ischemia was not produced by high-frequency jet ventilation or conventional mechanical ventilation, factors which alter the balance between arterial supply and metabolic demand or induce inflammation may contribute to the tracheal necrosis reported during sustained ventilation.

The spinal potentiating effect and the supraspinal inhibitory effect of midazolam on opioid-induced analgesia in rats.

The authors investigated the effects of spinal and supraspinal administration of the benzodiazepine receptor agonist midazolam alone and with opioids on tests of nociception (tail-flick and hot-plate tests) and motor function (catalepsy) in rats. At the spinal level, the dose-response curves for peak effect and area under the curve for morphine were shifted to the left (indicating potentiation) by a submaximal dose of intrathecal (i.t.) midazolam (20 micrograms) in both nociceptive tests. Additionally, 2.5 micrograms of i.t. midazolam, a dose having no effect when given alone, increased antinociception in both tests when given with i.t. morphine. Isobolographic analysis confirmed that i.t. injection of midazolam potentiated antinociception induced by i.t. morphine. At the supraspinal level, intracerebroventricular (i.c.v.) injection of 4 micrograms of midazolam inhibited morphine antinociception, i.e., the dose-response curve for morphine in the hot-plate test shifted to the right. Midazolam did not affect morphine antinociception in the tail-flick test. Catalepsy occurred only when the highest doses of i.t. or i.c.v. morphine or midazolam were injected alone. The differing effect of midazolam on morphine-induced antinociception suggests that different mechanisms are involved in the spinal cord and brain.

Mechanisms of the influence of midazolam on morphine antinociception at spinal and supraspinal levels in rats.

The mechanisms for the combined antinociceptive effect of midazolam and morphine administered at spinal (intrathecal, i.t.) and supraspinal (intracerebroventricular, i.c.v.) levels were investigated in rats. Nociceptive test results showed that co-administration of midazolam and morphine at the spinal level potentiated morphine-induced antinociception, and that this interaction was blocked by intraperitoneal (i.p.) naloxone and reversed by i.t. bicuculline and i.p. flumazenil. Also, bicuculline and flumazenil blocked midazolam-induced antinociception at the spinal level, and naloxone completely reversed morphine antinociception. In contrast, when drugs were injected intracerebroventricularly, midazolam inhibited the antinociceptive effect of morphine (as determined by the hot-plate test). The inhibitory effects of i.c.v. midazolam upon i.c.v. morphine antinociception were partly blocked by flumazenil and bicuculline. Midazolam-induced antinociception was increased by bicuculline and decreased by flumazenil; naloxone i.p. blocked both i.c.v. morphine antinociception and i.c.v. morphine-midazolam antinociception. Results after i.t. injection may be due to an interaction between morphine and midazolam/GABAA receptor-activated systems. At the supraspinal level, this interaction may also activate other systems that are distinct from those governing the individual action of each agonist.

Spinal delivery of sufentanil, alfentanil, and morphine in dogs. Physiologic and toxicologic investigations.

BACKGROUND: This study examines the behavioral effects and potential neurotoxicity of sufentanil, alfentanil, and morphine after chronic daily epidural (15-day) and intrathecal (28-day) administration in dogs. METHODS: Dogs were chronically implanted with a lumbar intrathecal or epidural catheter and received daily injections for 28 or 15 days, respectively, of saline or one of three mu agonists: sufentanil (intrathecal 5, 25, or 50 micrograms/0.5 ml; epidural 10, 50, or 100 micrograms/2.0 ml), alfentanil (intrathecal 40 or 400 micrograms/0.5 ml; epidural 80 or 800 micrograms/2.0 ml), or morphine (intrathecal 0.5 or 5 mg/0.5 ml; epidural 1 or 10 mg/2.0 ml). Dogs were examined for antinociception (skin twitch) and neurobehavioral changes. When the animals were killed, cisternal cerebrospinal fluid was taken for clinical chemistry, and after perfusion fixation, spinal cord tissue was taken for histologic analysis. RESULTS: Bolus intrathecal and epidural injections of sufentanil, alfentanil, and morphine produced dose dependent antinociception, bradycardia, an initial tachypnea followed by a decrease in respiratory rate, hypothermia and somnolence. The order of potency was sufentanil > alfentanil > morphine on all measures. Over the extended period of drug delivery, a loss of response (tolerance) was observed on all measures. No abnormal morphologic or histologic effects were found when comparing the drug and dose groups. An inflammatory reaction secondary to the catheter was found in all animals. Intrathecal, but not epidural, catheters resulted in significant increases in cerebrospinal fluid protein and cell counts in vehicle animals. Values in drug treated animals did not differ significantly from the respective vehicle controls. A rapid systemic redistribution of all three drugs was observed. No differences were found in the pharmacokinetic parameters measured at day 1 and at the day of killing for any route. CONCLUSIONS: This large-animal model demonstrates the expected pharmacologic potency of these three agents and tolerance development. Based on cerebrospinal fluid and systematic histopathologic analyses, these three spinally administered agents showed no evidence of neurotoxicity over the range of doses/concentrations employed when given by the intrathecal or epidural route as compared to vehicle controls. Consideration of the toxicokinetics in this canine model suggests that it provides an appropriate test of the safety of these agents in concentrations which exceed those employed for daily intermittent epidural and intrathecal drug delivery in humans.

Patient-controlled analgesia. Pharmacokinetic and therapeutic considerations.

The opioid analgesic agents exhibit relatively large pharmacokinetic differences between drugs, and there is substantial pharmacokinetic and pharmacodynamic variability across subjects or patients with each agent. The advent of patient-controlled analgesic administration techniques and their widespread use in contemporary pain management, especially in postsurgical and cancer patients, has decreased the unfortunate impact of interpatient variability on achieving the optimal balance between pain relief and opioid adverse effect intensity. The improvements in pain management provided by patient-controlled analgesia do not, however, decrease the importance of knowledge of opioid pharmacokinetics towards enlightened use of these drugs and attainment of maximal benefits from them in any patient. Future improvements in patient-controlled analgesia technology will probably be based on the pharmacokinetic behaviour of different opioid analgesic agents in specific receptor-containing regions. Finally, physicochemical and pharmacokinetic characteristics of these agents are important determinants of the speed of onset of effects, duration of action and spinal selectivity of epidurally and intrathecally administered analgesics. Thus, effective patient-controlled analgesia depends on an understanding of the differential pharmacokinetics of opioids self-administered by a variety of possible modes.

Redistribution of sufentanil to cerebrospinal fluid and systemic circulation after epidural administration in dogs.

Due to its higher lipid solubility, sufentanil may be less likely than morphine to migrate rostrally in the cerebral spinal fluid (CSF) and cause delayed respiratory depression following epidural administration. However, early respiratory depression has been reported in patients after relatively large doses of epidural sufentanil. This has been attributed to systemic drug uptake. We used a dog model to investigate the pharmacokinetics and rostral spread of epidural sufentanil in CSF. Sampling catheters were placed in the lumbar subarachnoid space, the cisterna magna, and femoral arteries of six mongrel dogs. Samples of cisternal CSF, lumbar CSF, and blood were drawn at 0, 1, 5, 15, 30, 60, 90, 120, and 180 min after lumbar epidural sufentanil injection. We measured sufentanil concentrations by gas chromatography-mass spectrometry and used the least squares method to a fit tri-exponential function to each sufentanil concentration versus time data set. Paired t-test was used to test for statistical significance. After epidural sufentanil, lumbar CSF concentrations were significantly higher than plasma or cisternal CSF sufentanil concentrations at all assessment times. Sufentanil concentrations were significantly higher in cisternal CSF than in plasma at 30 and 60 min after injection. Sufentanil appeared rapidly in lumbar CSF, reaching a maximum concentration (Cmax) of 57 ng/mL at 6.5 min. In cisternal CSF, a Cmax of 1.2 ng/mL was reached at 21 min, and Cmax in plasma was 0.35 ng/mL at 6 min. The area under the concentration-time curve (AUC) of sufentanil in cisternal CSF was approximately six times higher than the plasma AUC (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment of acute graft-versus-host disease with a nonmitogenic anti-CD3 monoclonal antibody.

Treatment with the monoclonal antibody OKT3 specific for the CD3 complex associated with the T cell antigen receptor can reverse acute rejection of human renal allografts. However, efficacy of anti-CD3 antibodies for treatment of patients with acute graft-versus-host disease after marrow transplantation has not been established. The dose-limiting side effects resulting from T cell activation induced by some anti-CD3 antibodies in vivo have discouraged their use for this application. We now report a phase I-II study of GVHD treatment with the anti-CD3 antibody BC3, a monoclonal murine IgG2b that, unlike OKT3, does not activate T cells. Fourteen patients were treated with BC3 after progression of acute GVHD despite treatment with cyclosporine and corticosteroids, and three patients received BC3 as primary treatment for GVHD. BC3 was administered at a dose of 0.1 or 0.2 mg/kg/day for seven or eight days. Five patients achieved complete resolution of GVHD, eight patients had partial improvement, two patients had no change, and two patients had progression of GVHD on therapy. Responses were sustained in 8 of 13 patients. Mild chills, fever, hypertension, and chest discomfort occurred in various combinations following 6 of 17 (35%) initial infusions of BC3 and following 4 of 99 (4%) subsequent infusions. In each instance it was possible to continue BC3 therapy without adjusting the dose or treatment schedule. In each patient treated, the absolute count of peripheral blood lymphocytes decreased transiently but returned to baseline within 22 hr after the first infusion. Circulating T cells had surface CD3 molecules saturated by the infused antibody in all but one patient. Four patients survived longer than one year after treatment with antibody BC3, and 13 patients died of infection or organ failure. Administration of the nonmitogenic anti-CD3 antibody BC3 was associated with improvement in the clinical manifestations of GVHD with minimal acute toxicity. Efficacy of antibody treatment did not depend on depletion of circulating T cells. Therefore, antibody BC3 may be achieving therapeutic immunosuppression by modulating T cell function. Controlled studies in patients treated earlier in the course of GVHD should determine whether antibody BC3 can improve survival.

Physical and chemical properties of drug molecules governing their diffusion through the spinal meninges.

Drugs administered into the epidural space for selective spinal analgesia must diffuse through the spinal meninges to gain access to their sites of action in the spinal cord. Therefore, knowledge of the physical and chemical properties of drug molecules that govern their diffusion through the meninges is important for understanding the pharmacokinetics of epidural analgesia. To determine the physicochemical properties of drug molecules that govern the rate at which drugs diffuse through the spinal meninges, the authors measured the permeability coefficient of eight different drug molecules through the spinal meninges of the monkey using a previously established in vitro model. We previously reported permeability measurements for four of the molecules used in this study; the other four molecules' permeability measurements are new. The measured permeability coefficient was then correlated with the drugs' molecular weight, molecular surface area, molecular volume, length of the major molecular axis, and octanol:buffer distribution coefficient. We found no relationship between the drugs' permeability coefficients and any measure of drug mass, molecular shape, or molecular size. There was, however, a biphasic relationship between the octanol: buffer distribution coefficient and the drugs' measured permeability coefficients. Drugs that were either very hydrophilic or very hydrophobic had permeability coefficients that were significantly less than drugs of intermediate hydrophobicity. These data suggest that it should be possible to design novel analgesics for which meningeal permeability is maximal.

Liposome encapsulation prolongs alfentanil spinal analgesia and alters systemic redistribution in the rat.

The effect of liposome encapsulation on the analgesia produced by intrathecally administered alfentanil was examined in the rat. In rats prepared with chronic intrathecal catheters, alfentanil in doses of 1-50 micrograms was administered intrathecally in either saline or in multilamellar liposomes (dipalmitoylphosphatidylcholine and cholesterol). Animals were then tested for analgesia by hot-plate and paw-pressure tests. A second group of animals received intrathecal injections of 30 micrograms alfentanil in saline or liposomes, and blood samples were obtained at 5, 15, 45, and 135 min thereafter for measurement of alfentanil plasma concentrations. The liposome preparation markedly prolonged spinal analgesia in the paw-pressure test and to a lesser extent in the hot-plate test. Neither the time to peak analgesia nor the intensity of analgesia differed between the saline and liposome groups. Liposome encapsulation significantly reduced the peak alfentanil plasma concentration at 5 min and prolonged the period in which low but measurable levels of alfentanil could be measured in plasma. These pharmacokinetic data demonstrate that liposome encapsulation resulted in a slow but prolonged appearance of free alfentanil into a diffusible pool available for uptake into the spinal cord. Consistent with the lower peak plasma concentration of alfentanil, the liposome group demonstrated a significantly lower incidence of catalepsy, indicating less systemic redistribution of alfentanil to supraspinal sites. Liposome encapsulation thus appears to produce a significant reduction in peak plasma concentration with a concomitant reduction in systemic side effects and an increase in the duration of action for a given intrathecal dose of the otherwise rapidly cleared alfentanil.

Use of 2-hydroxypropyl-beta-cyclodextrin as an intrathecal drug vehicle with opioids.

2-Hydroxypropyl-beta-cyclodextrin (CDEX), a seven-membered glucose pyranose structure, forms reversible inclusion complexes with the lipophilic portion of a drug molecule by noncovalent bonding. This can increase the water solubility of lipid-soluble drugs and reduce the rate of clearance of such agents from the spinal cord into the vasculature after i.t. administration. In this study, opioids (morphine, lofentanil, alfentanil and sufentanil) with and without CDEX (20, 2, 0.2 and 0.02% w/v in sterile water) were administered spinally in rats prepared with chronic i.t. catheters. CDEX prolonged the duration of analgesia (52.5 degrees C hot plate) and reduced the incidence of catalepsy otherwise produced by a supermaximal i.t. dose of each of the opioids. The magnitude of the potentiating effect of CDEX on opioids was dependent upon concentration of the CDEX and varied with drug lipid partition coefficients. The highest concentration of CDEX alone (20%) had no effect upon the volume-evoked micturition reflex, blood pressure, heart rate, or spinal reflexes. Our data indicate that CDEX may be a useful i.t. vehicle for modifying the redistribution characteristics of highly diffusible molecules after their i.t. administration, and that for each drug there is an optimal CDEX concentration. In the present case, CDEX prolongs the spinal analgesic action and reduces the supraspinal actions of i.t. drugs.

Can midazolam diminish sufentanil analgesia in patients with major trauma? A retrospective study with 43 patients.

Benzodiazepine agonists in combination with opioid analgesics are commonly used for combined analgesia and sedation in intensive care patients as well as for anesthesia. In animals, studies indicate either agonistic or antagonistic interactions of benzodiazepine agonists and opioids. This retrospective study of 43 patients evaluated the possible clinical relevance of benzodiazepine-opioid interactions related to pain management. We observed an increase of greater than 50% of the maximal sufentanil infusion rate in significantly more patients in group 2 (13 patients vs 6 patients; chi 2: p = 0.04) and a decrease of the sufentanil infusion rate in eight group 1 patients, but only in one patient in group 2 (chi 2: p = 0.03). We believe that an interaction between midazolam and sufentanil on nociceptive transmission and/or a rapid development of tolerance to sufentanil may be responsible for the observed difference. Contrary to the common clinical impression that midazolam potentiates opioid analgesia, these results indicate that systemic co-administration of midazolam over a period of more than three days can diminish sufentanil efficacy.

The spinal nerve root sleeve is not a preferred route for redistribution of drugs from the epidural space to the spinal cord.

It has been frequently suggested that the spinal nerve root sleeve is a preferred route for redistribution of drugs from the epidural space to the spinal cord. To determine if this supposition is true, the authors measured the rate at which morphine, fentanyl, and lidocaine diffuse through dog and monkey meningeal specimens with and without a root sleeve. Two meningeal specimens of intact dura-arachnoid-pia mater were removed from each animal and placed in separate temperature-controlled diffusion cells. One specimen included a spinal nerve root sleeve; the other did not. The permeability of the tissues to each drug was then determined by placing the study drug in one of the reservoirs of the diffusion cell and measuring the rate at which the drug diffused through the tissue and accumulated in the second reservoir. There was no difference in permeability between specimens with and without a nerve root sleeve for any drug in either species. Lidocaine was found to diffuse through the tissue significantly faster than fentanyl in both the dog and monkey even though fentanyl is nearly 48 times more lipid soluble than lidocaine. Morphine diffused through the tissue significantly slower than both lidocaine and fentanyl. The authors conclude that the spinal nerve root sleeve is not a preferred route of entry for drugs moving from the epidural space to the spinal cord. In addition, despite hypotheses to the contrary, lipid solubility does not appear to be the overriding determinant of meningeal permeability.

Influence of dexmedetomidine and clonidine on human liver microsomal alfentanil metabolism.

Perioperative administration of the alpha 2 agonist clonidine has been shown to increase plasma alfentanil concentrations; however, the mechanism for this pharmacokinetic drug interaction is unknown. Because alfentanil undergoes extensive hepatic biotransformation, clonidine inhibition of alfentanil metabolism may alter alfentanil disposition. The first purpose of this investigation was to test the hypothesis that clonidine impairs human liver alfentanil metabolism. The new highly selective alpha 2 agonist dexmedetomidine (D-medetomidine) is a substituted imidazole and thus may inhibit hepatic drug biotransformation. The second purpose of this study, therefore, was to assess the effect of D-medetomidine and its levo (L) isomer on alfentanil biotransformation. Human liver microsomal alfentanil metabolism was assessed in vitro using a gas chromatography--mass spectrometry assay. Clonidine, at concentrations as great as 10 microM (far exceeding therapeutic levels), had no significant effect on alfentanil oxidation. In contrast, D-medetomidine and its optical isomer L-medetomidine were potent inhibitors of human liver microsomal alfentanil metabolism. The concentration producing 50% inhibition (IC50) of alfentanil (10 microM) oxidation was 0.7-1.0 and 2.8-4.0 microM for D-medetomidine and L-medetomidine, respectively. Preincubation of D-medetomidine with microsomes did not enhance the inhibition of alfentanil metabolism. These results suggest that the increased alfentanil plasma concentrations and potentiation of alfentanil anesthesia associated with clonidine do not result from clonidine inhibition of alfentanil metabolism. D-medetomidine impairment of alfentanil metabolism, however,if present at therapeutic concentrations, may influence alfentanil disposition.(ABSTRACT TRUNCATED AT 250 WORDS)

A computer-based system for controlling plasma opioid concentration according to patient need for analgesia.

Microprocessor-controlled infusion pumps, which allow a patient to self-administer bolus doses of an analgesic to relieve pain, are becoming commonplace. While these patient-controlled analgesia (PCA) systems overcome the large interpatient variations in pharmacokinetics, they do not provide steady relief from pain since they rely on delivering a drug in small, incremental doses. To overcome this problem, the authors developed an algorithm and computer-pump system that allows patients to control their own plasma concentration of analgesic. This approach uses individually predetermined pharmacokinetic parameters to provide steady plasma opioid concentrations that can be increased or decreased by the patient in line with the need for more pain relief or fewer side effects. The control software uses a novel, recursive algorithm to compute the pump rates necessary to maintain constant plasma drug (e.g. morphine) concentrations at desired values and to reach a new steady concentration in response to patient requests. This report describes the mathematical approach to the problem of control of plasma opioid concentration, the application of this new drug delivery system to management of persistent pain in cancer patients undergoing bone marrow transplantation, and the magnitude of pharmacokinetic variability with morphine in this patient population. Results are presented from individual patients using this adjustable drug delivery system continuously for up to 2 weeks to control pain from oral mucositis.

Multiple-dose evaluation of intravenous hydromorphone pharmacokinetics in normal human subjects.

We measured the pharmacokinetics of hydromorphone in normal volunteers given three doses of the drug (10, 20, and 40 micrograms/kg) as intravenous 45-s injections on different days. Concentrations of hydromorphone in plasma from serial blood samples were measured by a high-performance liquid chromatography method specific for hydromorphone with a detection limit of 0.1 ng/mL. In all cases, plasma hydromorphone concentration versus time data for individual subjects were best described by a triexponential (instead of mono- or biexponential) function. Furthermore, we found that the pharmacokinetics of hydromorphone was independent of dose across the range studied. Averaged across doses, the distribution and terminal elimination half-lives were 1.27 min (t1/2 pi), 14.7 min (t1/2 alpha), and 184 min (t1/2 beta), respectively. Average values for systemic clearance, initial dilution volume, and steady-state volume of distribution were 1.66 L/min (Cl), 24.4 L (Vc), and 295 L (Vdss). Our results indicate that hydromorphone pharmacokinetic parameters are linear across a fourfold range of doses that are usually employed clinically and that previously reported pharmacokinetic values for hydromorphone (based on radioimmunoassay measurements) deserve reconsideration.

Patient-controlled analgesic administration. A comparison of steady-state morphine infusions with bolus doses.

The authors have shown previously that bone marrow transplant (BMT) patients who self-administered bolus doses of morphine gained equal oral mucositis pain relief while using less drug compared with similar patients receiving morphine by staff-controlled continuous infusion. In a follow-up study they compared the efficacy and side effects of morphine in two groups of marrow transplant patients who controlled their own analgesic administration either by conventional bolus-dose, patient-controlled analgesia (PCA) or by adjusting the rate of continuous morphine infusion to increase or decrease their plasma morphine concentration. Patients controlling their morphine infusion rates (pharmacokinetically based patient-controlled analgesia [PKPCA] group) obtained more relief from oral mucositis pain than did patients using conventional PCA. Patients in the PKPCA group used more morphine than PCA patients and achieved superior pain relief without significant increases in side effects (e.g., nausea, mood changes, sedation). The authors conclude that PKPCA improves the management of prolonged, severe pain in marrow transplant patients and that this approach to patient-controlled analgesia may be useful in other types of persistent pain.

Morphine and alfentanil permeability through the spinal dura, arachnoid, and pia mater of dogs and monkeys.

Little information exists about which spinal meninx is the principal permeability barrier between the epidural space and the spinal cord or about what physicochemical properties of drug molecules govern their meningeal permeability. To better understand these aspects of epidural pharmacokinetics, the authors measured the permeability of morphine and alfentanil through the different components of the spinal meninges-dura mater, arachnoid mater, and pia mater-of dogs and monkeys in vitro. Live meningeal tissue from either species (dura mater alone, pia mater alone, or intact dura-arachnoid-pia) was placed between two fluid reservoirs of a temperature-controlled diffusion cell. The permeability of the tissues to each opioid was determined by placing the opioid in one of the reservoirs of the diffusion cell and measuring the rate at which the drug diffused through the tissue and appeared in the second reservoir. The arachnoid mater was found to be the major meningeal diffusion barrier between the epidural space and the spinal cord. Alfentanil was 3.7 times more permeable than morphine through all three meninges, suggesting that increased lipid solubility increases meningeal permeability. However, neither lipid solubility nor molecular weight adequately explained the difference in permeability between morphine and alfentanil. The authors conclude that this in vitro model has significant utility for studies aimed at predicting in vivo meningeal permeability and hence the potency and rapidity of action of any opioid administered by the epidural route.

Steady-state infusions of opioids in human volunteers. I. Pharmacokinetic tailoring.

We report a method for controlling and adjusting plasma opioid concentration to preselected target values in individual human subjects in order to study analgesic and other effects of opioids at steady state. The method employs a computer-controlled infusion pump and an algorithm that utilizes individual subject pharmacokinetic parameters predetermined with tailoring bolus opioid doses. We used this approach to produce 3-step increases in plasma concentrations of alfentanil, fentanyl and morphine in each of 15 subjects. We maintained each plasma concentration plateau for 70 min, measured plasma opioid concentrations achieved during the infusions and analyzed the results for bias and precision of the individually tailored infusions. Our results show that pharmacokinetically tailored opioid infusions produce stable plasma opioid concentrations within 10 min for alfentanil and morphine; with each drug overall prediction error was 20% or less. Fentanyl was somewhat more difficult to control by this method than were the other 2 opioids. We conclude that individual tailoring of opioid infusions minimizes the impact of individual pharmacokinetic differences on achieving preselected plasma opioid concentrations and provides an accurate means of controlling steady-state drug concentrations for studies of concentration-effect relationships and comparisons of side-effect intensities produced by equianalgesic plasma opioid concentrations.