Respiratory arrest following intrathecal injection of sufentanil and bupivacaine in a parturient

PURPOSE: To present a case of respiratory arrest following the use of intrathecal sufentanil and bupivacaine for combined spinal-epidural anaesthesia in a healthy labouring parturient. CLINICAL FEATURES: A 20-yr-old term parturient received 10 micrograms sufentanil and 2.5 mg bupivacaine intrathecally as part of a combined spinal-epidural technique for labour analgesia. She had received no previous analgesics. Twenty-three minutes after the intrathecal injection she became unresponsive and suffered a respiratory arrest. Resuscitation included manual bag/mask ventilation with oxygen and intravenous naloxone. CONCLUSION: Respiratory arrest is a rare but potentially life-threatening complication associated with the use of intrathecal opioids for labour analgesia. Vigilance in post-procedure patient monitoring is imperative.     

An intravenous fluid bolus is not necessary before administration of intrathecal fentanyl for labor analgesia

The acute phase response to inflammation is mediated in part by the endogenous production of pro-inflammatory cytokines. Interleukin 6 (IL-6) and members of its superfamily, including ciliary neurotrophic factor (CNTF) and leukaemia inhibitory factor (LIF) have been implicated as primary mediators of the hepatic acute phase response. In the present report, mice suffering a turpentine-induced myositis were passively immunized with antibodies against either IL-6, CNTF or LIF. Passive immunization against IL-6 attenuated the anorexia and completely prevented the hypoalbuminaemia, and increases in the serum concentration of the acute phase reactants, amyloid P, amyloid A and seromucoid. In contrast, passive immunization against either CNTF or LIF failed to modulate the anorexia, weight loss or hepatic acute phase protein responses. The findings suggest that IL-6, but not other members of its superfamily, is primarily responsible for the hepatic acute phase response, and contributes to the anorexia, associated with turpentine-induced myositis.     

Prevention of neonatal respiratory distress syndrome through the administration of prednisolone in the fetal period

The clinical effectiveness of antenatal prednisolone medication (prednisolone hemisuccinate) for the prophylaxis of idiopathic respiratory distress syndrome (IRDS) was studied in 114 premature infants with a gestational age between 28 and 36 weeks. There was a statistically significant difference (chi2 - test, p less than 0,01) between the frequency of IRDS in this group and in another one consisting of 137 premature babies with a nearly identical distribution of gestational age, whose mothers did not get prednisolone before delivery. It could be shown that the time interval between medical induction and delivery should not exceed 2 weeks, since the effect decreases with time. At present prednisolone medication during the fetal period may serve as useful prophylactic measure for IRDS in cases of premature birth. As there are a lot of contraindication against prednisolone and as we do know very much about side effects, it seems necessary to seek for other, less dangerous inductors.     

Comparison of pre- versus post-incision administration of intrathecal bupivacaine and intrathecal morphine in a rat model of postoperative pain

BACKGROUND: Preclinical studies in experimental animals suggest that preemptive analgesia may improve postoperative pain management. The beneficial effects of preemptive analgesia appear less remarkable clinically. The purpose of this study is to examine the effect of pre- and post-incision administration of intrathecal bupivacaine and intrathecal morphine in a rat model for postoperative pain. METHODS: Rats with intrathecal catheters were anesthetized with halothane, and the surgical field was prepared. A saline vehicle or the test drug was administered 15 min before an incision was made in the plantar aspect of the hindpaw or after the incision was completed. After recovery, mechanical hyperalgesia to punctate and nonpunctate stimuli was measured. Rats were tested on the day of surgery for the first 5 h and each day for 6 days. RESULTS: In saline vehicle-treated rats, the median withdrawal threshold decreased from 522 mN to 54 mN or less, and the response frequency to pressure from application of the plastic disc increased from 0 +/- 0% to 96 +/- 12% or greater after incision. Hyperalgesia was persistent through 2 days after surgery and then gradually returned toward preincision values over the next 4 days. Pre- or postincision administration of either intrathecal morphine or intrathecal bupivacaine reduced hyperalgesia on the day of surgery; at all subsequent times, there were no differences between the saline vehicle groups and the drug treatment groups. There were never any significant differences between pre- and postincision treatments. CONCLUSIONS: Early reduction in pain behaviors either by pre- or postincision management had no impact on subsequent measures of hyperalgesia in this model. These results agree with a number of clinical studies and suggest that incisional pain may be initiated and maintained differently than pain in other models.     

Obstetric analgesia using continuous epidural perfusion of bupivacaine, adrenaline, and fentanyl

OBJECTIVES: To determine the efficacy and complications of continuous epidural perfusion of bupivacaine, adrenaline and fentanyl in the relief of pain during first and second stage labour during vaginal birth. PATIENTS AND METHODS: Between January 1990 and March 1993 we used continuous epidural perfusion for control of pain during labor in 1307 women. The solution administered through an epidural catheter and maintained until expulsion was one 10 ml bolus of bupivacaine 0.25% with adrenaline 1:200,000 and fentanyl 25 micrograms followed by continuous perfusion of bupivacaine 0.0625% with adrenaline 1:200,000 and fentanyl 2 micrograms/ml at an infusion rate of 12 ml/h. When analgesia was insufficient, a bolus of local anesthetic was administered or a pudendal block was carried out. RESULTS: Ninety-two percent of the birthing women reported good analgesic effect during the first stage; for 7% the effect was fair and for 0.55% it was poor. During the second stage 88% reported satisfactory analgesia, and 8% fair or poor. Assessment was not possible for the remaining women, who underwent cesarean sections. Complications were few and easily controllable. CONCLUSIONS: Maintenance of epidural perfusion with 0.0625% bupivacaine with adrenaline 1:200,000 and fentanyl 2 micrograms/ml provides sufficient analgesia during all stages of childbirth.     

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 prospective randomized comparison of epidural infusion of fentanyl and intravenous administration of morphine by patient-controlled analgesia after radical retropubic prostatectomy

In a prospective, randomized study, continuous infusion of epidural fentanyl citrate (group E) was compared with patient-controlled intravenously administered morphine sulfate (group P) for analgesia in 66 men after radical retropubic prostatectomy. Although both methods provided satisfactory analgesia, the mean comfort level scores were lower (that is, greater comfort) in group E than in group P at all observation times. The difference in mean resting comfort level scores between groups E and P was statistically significant (P < or = 0.05) at 9 of the 11 observation times. In addition, significant differences in comfort level scores were noted at 8 of the 11 observation times during deep breathing, 5 of 11 during coughing, and 3 of 9 during ambulation. Maximal and minimal comfort level scores recorded by each patient during the course of the study were significantly lower (that is, less pain) in group E than in group P for all four categories of activity. The percentage of patients who reported no pain was significantly higher in group E than in group P at 9 of 11 observation times during resting and 5 of 11 observation times during deep breathing. No significant differences were noted in side effect profiles or duration of hospital stay. In summary, when two effective methods of analgesia used after radical retropubic prostatectomy were compared prospectively, patients who received epidural infusion of fentanyl were more comfortable than those with patient-controlled intravenous administration of morphine, as evidenced by lower mean, maximal, and minimal comfort level scores and a greater proportion of patients with complete relief of pain.     

Disposition of phenol in rat after oral, dermal, intravenous, and intratracheal administration

The absorption and elimination of [14C]-phenol (63.5 nmol) after oral, dermal, intratracheal, or intravenous administration in rat was rapid and extensive. Urinary elimination of radioactivity predominated, with a range of 75-95% of the dose detected in urine by 72 h post-exposure. Washing the dermal site 72 h post-exposure removed 14% of the dose. Two per cent of the dose was detected in the skin. The urinary metabolites at 4 and 8 h after administration by the four routes included phenyl sulphate and lower amounts of phenyl glucuronide. Phenol was poorly retained in the body after administration by the four routes. Phenol remaining in the body was widely distributed, with accumulation primarily in the liver, lung, and kidney.     

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)     

Pharmacokinetics of clentiazem after intravenous and oral administration in healthy subjects

This study characterized the pharmacokinetics of clentiazem (CLZ) after a single intravenous bolus (IV) and oral (PO) dose in humans. Twenty-four healthy male subjects (28.5 +/- 5.2 years; 77 +/- 8.2 kg) received IV (20 mg) and PO (80 mg) doses of CLZ as part of a four-way, randomized, complete crossover study. Serial blood samples were drawn up to 48 hours after administration of the drug. Plasma samples were analyzed for CLZ and three metabolites by a high-pressure liquid chromatography method. The values (mean [CV, %]) for systemic clearance, volume of distribution at steady-state, and half-life of CLZ were 63.6 L/hour (23.5), 756.1 L (19.1), and 10.6 hours (33.1), respectively, after IV administration. The peak plasma CLZ concentration (Cmax) and time to Cmax were 37.0 ng/mL (38.7) and 3.7 hours (22.9), respectively, with a lag time after PO administration. The absolute bioavailability of PO CLZ was 45% (30.7). The ratio of area under the curve of N-desmethyl CLZ to that of CLZ increased from 0.15 (57.0) after IV to 0.60 (21.4) after PO administration, suggesting a significant first-pass effect. The mean residence time and mean absorption time of CLZ were 12.3 hours (24.3) and 3.1 hours (88.1), respectively. The plasma concentration-time data of CLZ can be described by either a one- or two-compartment pharmacokinetic model.     

Disposition of methyl ethyl ketoxime in the rat after oral, intravenous and dermal administration

1. The disposition of 14C-methyl ethyl ketoxime (MEKO) was determined in the male F344 rat following oral, intravenous (i.v.) and dermal administration. 2. Oral doses of 2.7, 27 and 270 mg/kg were primarily excreted as CO2 (71-49%) in decreasing percentage as the dose increased. Excretion in urine (13-26%) and as volatiles (5-18%) increased as the dose increased. Five to 6% of the dose remained in the major tissues after 72 h. 3. An i.v. dose of 2.7 mg/kg was also principally excreted as CO2 (48.8%) with excretion in urine and as expired volatiles accounting for 21.4 and 11.4%, respectively. About 7% of the administered radioactivity remained in the tissues after 72 h. 4. Following dermal administration, 13 and 26% of a 2.7 and 270 mg/kg dose, respectively, were absorbed. Volatilization from the dose site prior to placement in the metabolism cage may account for the low absorption. 5. MEKO was biotransformed to at least five polar metabolites that could only be partially resolved by anion exchange chromatography. Incubation with glucuronidase, but not sulphatase, changed the urinary metabolic profile. Methyl ethyl ketone was a major component in the volatiles.     

Cytokine patterns in patients after major vascular surgery, hemorrhagic shock, and severe blunt trauma. Relation with subsequent adult respiratory distress syndrome and multiple organ failure

OBJECTIVE: This study investigates the course of serum cytokine levels in patients with multiple trauma, patients with a ruptured abdominal aortic aneurysm (AAA), and patients undergoing elective AAA repair and the relationship of these cytokines to the development of adult respiratory distress syndrome (ARDS) and multiple organ failure (MOF). SUMMARY BACKGROUND DATA: Severe tissue trauma, hemorrhagic shock, and ischemia-reperfusion injury are pathophysiologic mechanisms that may result in an excessive uncontrolled activation of inflammatory cells and mediators. This inflammatory response is thought to play a key role in the development of (remote) cell and organ dysfunction, which is the basis of ARDS and MOF. METHODS: The study concerns 28 patients with multiple trauma, 20 patients admitted in shock because of a ruptured AAA, and 18 patients undergoing elective AAA repair. Arterial blood was serially sampled from admission (or at the start of elective operation) to day 13 in the intensive care unit, and the serum concentrations of tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1 beta, and IL-6 were determined. RESULTS: Twenty-two patients died, 15 within 48 hours and 7 after several weeks, as a result of ARDS/MOF. At hospital admission and after 6 hours, these nonsurvivors had significantly higher plasma TNF-alpha and IL-1 beta levels than did the survivors. At the same measuring points, TNF-alpha and IL-1 beta were significantly more elevated in patients with ruptured AAA than in traumatized patients. However, IL-6 was significantly higher in the traumatized patients. In 10 patients, ARDS/MOF developed, and 41 had an uncomplicated course in this respect. Those with ARDS/MOF exhibited significantly different cytokine patterns in the early postinjury phase. TNF-alpha and IL-1 beta levels were higher mainly on the first day of admission; IL-6 concentrations were significantly elevated in patients with ARDS/MOF from the second day onward. The latter cytokine showed a good correlation with the daily MOF score during the whole 2-week observation period. CONCLUSIONS: In the early postinjury phase, higher concentrations of these cytokines are associated, not only with an increased mortality rate, but also with an increased risk for subsequent ARDS and MOF. These data therefore support the concept that these syndromes are caused by an overwhelming autodestructive inflammatory response.     

Development of a gas chromatographic-mass spectrometric drug screening method for the N-dealkylated metabolites of fentanyl, sufentanil, and alfentanil

A sensitive, specific urinary assay for fentanyl, sufentanil, and alfentanil based on their N-dealkylated metabolites is described. Norfentanyl, norsufentanil-noralfentanil, and 2H5-norfentanyl are synthesized and characterized by standard analytical techniques. Derivatization of these secondary amines to yield the pentafluorobenzamides produces stable products with good gas chromatographic properties and unique, high-mass fragments in their mass spectra. These properties are utilized to develop a drug screening procedure based on gas chromatography-mass spectrometry to detect these major metabolites in human urine. The metabolites are isolated from urine samples by a liquid-liquid extraction procedure. The method allows for detection of metabolite concentrations as low as 0.3 ng/mL.     

Stereoselective pharmacokinetics of bisoprolol after intravenous and oral administration in beagle dogs

We report 81 of 107 cases of hemolytic uremic syndrome (HUS), admitted between July 1994 and February 1996, following an outbreak of Shigella dysenteriae type 1 dysentery in Kwazulu/Natal. All patients, excluding 1, were black with a mean age of 38 months (range 1-121); 50 (61.7%) were males. The mean duration of dysentery was 11.3 days (range 1-41) and HUS 15 days (range 1-91). Most patients had acute oliguric renal failure (90.1%), 42 (51.6%) required peritoneal dialysis. Complications included encephalopathy 30 (37.0%), convulsions 12 (14.8%) and hemiplegia 2 (2.3%), gastrointestinal perforation 8 (9.9%), protein losing enteropathy 26 (32.1%), toxic megacolon 4 (4.9%), rectal prolapse 5 (6.2%), hepatitis 11 (13.6%), myocarditis 5 (6.2%), congestive cardiac failure 3 (3.7%), cardiomyopathy 3 (3.7%), infective endocarditis 1 (1.2%), septicemia 15 (18.5%), disseminated intravascular coagulation 17 (21%). Leukemoid reactions were found in 74 (91.3%) patients, hyponatremia in 56 (69.1%), and hypoalbuminemia in 67 (82.7%). Stool culture for Shigella dysenteriae type I was positive in only 7 (8.6%) patients; Shiga toxin assays were not performed. Outcome was as follows: recovery 32 (39.5%), impaired renal function 8 (9.9%), chronic renal failure 26 (32.1%), end-stage renal disease 1 (1.2%), and death 14 (17.3%) patients.