David D. Hood

Anesthetic and obstetric outcome in morbidly obese parturients

BackgroundLarge studies reporting anesthetic outcome for morbidly obese parturients are lacking. This study compares the anesthetic and obstetric outcome in morbidly obese parturients and matched control parturients. MethodsAnesthesia records were prospectively collected for all patients delivering between September 1978 and November 1989 whose weight exceeded 136.4 kg (300 pounds) at the time of delivery. A retrospective control patient group was collected by matching the first patient weighing less than 136.4 kg, delivered in the same month by the same obstetrician, to the corresponding morbidly obese parturient. Anesthetic and obstetric outcome variables were extracted from medical records and analyzed. ResultsSixty-two percent of 117 morbidly obese women underwent cesarean section, while only 24% of control patients delivered abdominally (P < 0.05). Forty-eight percent of all laboring morbidly obese parturients required emergency cesarean section, compared with 9% of control laboring parturients (P < 0.05). Epidural anesthesia was used successfully for labor and cesarean delivery in 74 of 79 morbidly obese women and 66 of 67 control patients. When compared with control patients, initial epidural anesthesia failure was significantly more likely in morbidly obese women, requiring epidural catheter replacement. Difficult tracheal intubation occurred in 6 of 17 morbidly obese women, compared with 0 of 8 control women (P = 0.06). Morbidly obese women had increased incidences of antepartum medical disease, prolonged cesarean section operation times, serious postoperative complications, and increased hospital stays. ConclusionsThe high incidences of antepartum medical disease and emergency cesarean section complicate anesthetic care in the morbidly obese parturients. Epidural anesthesia is feasible; however, the high initial failure rate necessitates early catheter placement, critical block assessment and catheter replacement when indicated, and provision for alternative airway management.

phase I Safety Assessment of Intrathecal Neostigmine Methylsulfate in Humans

Background In dogs, sheep, and rats, spinal neostigmine produces analgesia alone and enhances analgesia from alpha2 ‐adrenergic agonists. This study assesses side effects and analgesia from intrathecal neostigmine in healthy volunteers. Methods After institutional review board approval and informed consent, 28 healthy volunteers were studied. The first 14 volunteers received neostigmine (50–750 micro gram) through a #19.5 spinal needle followed by insertion of a spinal catheter. The remaining 14 volunteers received neostigmine through a #25 or #27 spinal needle without a catheter. Safety measurements included blood pressure, heart rate, oxyhemoglobin saturation, end‐tidal carbon dioxide, neurologic evaluation, and computer tests of vigilance and memory. Analgesia in response to ice water immersion was measured. Results Neostigmine (50 micro gram) through the #19.5 needle did not affect any measured variable. Neostigmine (150 micro gram) caused mild nausea, and 500–750 micro gram caused severe nausea and vomiting. Neostigmine (150–750 micro gram) produced subjective leg weakness, decreased deep tendon reflexes, and sedation. The 750‐micro gram dose was associated with anxiety, increased blood pressure and heart rate, and decreased end‐tidal carbon dioxide. Neostigmine (100–200 micro gram) in saline, injected through a #25 or #27 needle, caused protracted, severe nausea, and vomiting. This did not occur when dextrose was added to neostigmine. Neostigmine by either method of administration reduced visual analog pain scores to immersion of the foot in ice water. Conclusions The incidence and severity of these adverse events from intrathecal neostigmine appears to be affected by dose, method of administration, and baricity of solution. These effects in humans are consistent with studies in animals. Because no unexpected or dangerous side effects occurred, cautious examination of intrathecal neostigmine alone and in combination with other agents for analgesia is warranted.

Hemodynamic and Analgesic Actions of Epidurally Administered Clonidine

Background:α2-Adrenergic agonists such as clonidine produce behavioral analgesia and cardiovascular depression in animals, but clonidines site of action in clinical analgesia and cerebrospinal fluid (CSF) pharmacokinetics have not been defined. Methods:Clonidine was administered in the lumbar epidural space to nine volunteers while monitoring blood pressure, heart rate, finger and toe blood flow, and response to cold pain testing, and while sampling CSF and arterial plasma for clonidine analysis. Effects were correlated to plasma and CSF clonidine concentrations. Ten other volunteers received stepped Intravenous infusions of the opioid alfentanil with similar testing. Results:Clonidine decreased pain report in the foot but not the hand, and this effect correlated stronger with CSF than with plasma clonidine, suggesting a spinal site for analgesia. Extrapolation of CSF clonidine pharmacokinetics suggests the minimum effective CSF clonidine concentration for postoperative pain relief is 76 ± 15 ng/ml. Clonidine increased finger and toe blood flow, decreased blood pressure and heart rate, produced sedation, and mildly increased arterial PCO2, in most cases correlating better with plasma than CSF clonidine concentrations, suggesting actions at central sites. In 10 other volunteers, intravenous infusion of the opioid alfentanil produced analgesia of similar intensity to clonidine but was accompanied by significant respiratory depression. Conclusions:These data support previous studies in animals and provide the scientific rationale for this novel analgesic therapy. In comparison to the potent opioid alfentanil, epidural clonidine produces a similar degree of analgesia but less respiratory depression.

Interaction between intrathecal neostigmine and epidural clonidine in human volunteers.

Background alpha2 ‐Adrenergic agonists are thought to produce analgesia, in part, by activating spinal acetylcholine release. The purpose of the current study was to examine the interaction between intrathecal neostigmine and epidural clonidine for analgesia and side effects in humans. Methods A total of 58 volunteers received an intrathecal injection of 5% dextrose in normal saline (D5NS) or neostigmine (50, 100, or 200 micro gram in D5NS), followed in 1 h by epidural saline or clonidine (computer‐controlled infusion targeted to 50, 100, 200, or 400 ng/ml in cerebrospinal fluid) using an isobolographic design. Visual analog scale pain to a noxious cold stimulus, nausea, weakness, sedation, and other safety variables was measured before and at specified intervals after drug administration. Results The first 21 volunteers randomized to receive intrathecal hyperbaric neostigmine rather than D5NS received the drug while in the sitting position, and had none‐to‐minimal analgesia 1 h later. The remaining volunteers received the drug while in the lateral position, and demonstrated dose‐dependent analgesia in the foot 1 h later. Epidural clonidine also caused dose‐dependent analgesia. The combination of neostigmine and clonidine resulted in an additive enhancement for analgesia, but no enhancement of each drugs side effects, and a reduction in clonidine‐induced hypotension. Neostigmine injected into subjects in the lateral position diminished clonidine‐induced reductions in blood pressure and plasma norepinephrine. Conclusion These results support enhancement of alpha2 ‐adrenergic analgesia by intrathecal neostigmine, but do not demonstrate synergy, as observed in animals. Lack of enhancement of side effects suggests this combination may be clinically useful.

Intrathecal, but Not Intravenous, Clonidine Reduces Experimental Thermal or Capsaicin-induced Pain and Hyperalgesia in Normal Volunteers

Clonidine is approved for intraspinal administration in the treatment of neuropathic cancer pain.Some studies have suggested an analgesic effect after systemic clonidine administration. The purpose of this study was to compare the analgesic effects of intrathecal and IV clonidine with acute noxious stimulation and with hyperalgesia from intradermal capsaicin injection in volunteers. Sixteen healthy volunteers received intradermal injections of capsaicin (100 [micro sign]g) before and after the IV or intrathecal injection of clonidine 50 or 150 [micro sign]g in a randomized, double-blind manner. Pain and areas of mechanical hyperalgesia and allodynia were determined at specified intervals. In addition, pain to noxious heat stimulation was determined. The capsaicin injection produced pain, followed by hyperalgesia and allodynia. The intrathecal, but not IV, injection of 150 [micro sign]g of clonidine reduced capsaicin-induced pain and area of hyperalgesia. Intrathecal clonidine (150 [micro sign]g) reduced pain to heat stimulation, whereas IV clonidine did not. The groups did not differ in hemodynamic or sedative effects from clonidine. These data support the value of intraspinal administration of clonidine for the treatment of acute pain and of pain states associated with hyperalgesia. Similarly, they suggest that analgesia from the systemic administration of this [alpha]2-adrenergic agonist, if any, is weak in doses that produce sedation and reduce blood pressure. Implications: To the extent that the experimental pain conditions used in this study reflect those in patients with acute and chronic pain, these data support the spinal rather than IV injection of clonidine for analgesia. (Anesth Analg 1998;87:591-6)

Spinal versus Epidural Anesthesia for Cesarean Section in Severely Preeclamptic Patients A Retrospective Survey

BACKGROUND Selection of spinal anesthesia for severely preeclamptic patients requiring cesarean section is controversial. Significant maternal hypotension is believed to be more likely with spinal compared with epidural anesthesia. The purpose of this study was to assess, in a large retrospective clinical series, the blood pressure effects of spinal and epidural anesthesia in severely preeclamptic patients requiring cesarean section. METHODS The computerized medical records database was reviewed for all preeclamptic patients having cesarean section between January 1, 1989 and December 31, 1996. All nonlaboring severely preeclamptic patients receiving either spinal or epidural anesthesia for cesarean section were included for analysis. The lowest recorded blood pressures were compared for the 20-min period before induction of regional anesthesia, the period from induction of regional anesthesia to delivery, and the period from delivery to the end of operation. RESULTS Study groups included 103 women receiving spinal anesthesia and 35 receiving epidural anesthesia. Changes in the lowest mean blood pressure were similar after epidural or spinal anesthesia. Intraoperative ephedrine use was similar for both groups. Intraoperative crystalloid administration was statistically greater for patients receiving spinal versus epidural anesthesia (1780 +/- 838 vs. 1359 +/- 674 ml, respectively). Neonatal Apgar scores and incidence of maternal intensive care unit admission or postoperative pulmonary edema were also similar. CONCLUSION Although we cannot exclude the possibility that the spinal and epidural anesthesia groups were dissimilar, the magnitudes of maternal blood pressure declines were similar after spinal or epidural anesthesia in this series of severely preeclamptic patients receiving cesarean section. Maternal and fetal outcomes also were similar.

Intrathecal neostigmine for post-cesarean section analgesia: dose response.

Intrathecal (IT) neostigmine produces analgesia in animals and humans and enhances systemic opioid analgesia. To examine the safety of IT neostigmine for eventual use in obstetrics, we studied 24 healthy, term pregnant patients scheduled to receive elective cesarean section using a combined spinal-epidural anesthetic. Using an open-label, dose-ranging design, patients received either IT placebo or neostigmine 10, 30, or 100 microg in a 1-mL solution of 5% glucose in normal saline followed in 15 min by 2% epidural lidocaine for cesarean section. Neostigmine did not affect fetal heart rate tracings or Apgar scores. The women received patient-controlled analgesia intravenous morphine postoperatively. Compared with the glucose control, neostigmine produced a dose-independent reduction in postoperative morphine use. Cumulative average 24-h morphine use was 82 +/- 7 mg for women receiving IT placebo and 50 +/- 8 mg for women receiving IT neostigmine (P < 0.003). Hourly morphine use was significantly reduced in the neostigmine groups for 10 h postoperatively. These data indicate that IT neostigmine can produce 10 h of post-cesarean section analgesia without adverse fetal effects and support cautious further prospective study.

Intravenous opioids stimulate norepinephrine and acetylcholine release in spinal cord dorsal horn. Systematic studies in sheep and an observation in a human.

Background Opioids produce analgesia by direct effects as well as by activating neural pathways that release nonopioid transmitters. This study tested whether systematically administered opioids activate descending spinal noradrenergic and cholinergic pathways. Methods The effect of intravenous morphine on cerebrospinal fluid and dorsal horn microdialysate concentrations of norepinephrine and acetylcholine was examined in 20 sheep. Animals received either intravenous morphine or fentanyl alone, or morphine plus intravenous naloxone or intrathecal idazoxan. Results Intravenous morphine (0, 0.5, 1 mg/kg, intravenous) produced dose‐dependent increases in cerebrospinal fluid norepinephrine and acetylcholine, but not epinephrine or dopamine. Morphines effect was blocked by intravenous naloxone and by intrathecal idazoxan. In microdialysis experiments, intravenous morphine increased the concentration of norepinephrine and acetylcholine, but not epinephrine or dopamine, in the dorsal horn. In contrast, intravenous morphine exerted no effect on any of these monoamines in the ventral horn. Intravenous naloxone and cervical cord transection each blocked morphines effect on dorsal horn norepinephrine. Conclusions These results support functional studies that indicate that systematically administered opioids cause spinal norepinephrine and acetylcholine release by a naloxone‐sensitive mechanism. Idazoxan blockade of morphines effects on cerebrospinal fluid norepinephrine was unexpected, and suggests that both norepinephrine and acetylcholine release in the spinal cord may be regulated by alpha2 ‐adrenoceptors. Microdialysis experiments suggest increased norepinephrine and acetylcholine levels in cerebrospinal fluid resulted from intravenous morphine‐induced activation of bulbospinal pathways.

Sex differences in cholinergic analgesia I: a supplemental nicotinic mechanism in normal females.

BACKGROUND Cholinergic agents produce analgesia after systemic and intrathecal administration. A retrospective review showed that intrathecal neostigmine was more potent in women than in men, suggesting a sex difference in this response. The purpose of this study was to determine whether such a sex difference exists in normal rats and to examine the pharmacologic mechanisms that underlie this difference. METHODS Male and female rats with indwelling intrathecal catheters received injections of neostigmine, bethanechol (muscarinic agonist), or RJR-2403 (neuronal nicotinic agonist) alone or with atropine (muscarinic antagonist), mecamylamine (nicotinic antagonist), or phentolamine alpha-adrenergic antagonist) with antinociception determined to a noxious heat stimulus to the hind paw. Time versus subcutaneous paw temperature relationships were defined for males and females. RESULTS Neostigmine produced dose-dependent antinociception with five times greater potency in female than in male rats. Neostigmine-induced antinociception was reversed in male rats by atropine and unaffected by mecamylamine, whereas it was partially reduced by each antagonist alone in females and completely reversed after injection of both. RJR-2403 was more potent in females than in males, whereas there was no sex difference to bethanechol. Phentolamine partially reversed antinociception from RJR-2403 in females. Paw temperature increased more rapidly in females than in males for the same lamp intensity. CONCLUSIONS These data demonstrate a large sex difference in antinociception to intrathecal neostigmine that is primarily the result of a nicotinic component in females. Phentolamine reversal suggests that part of this nicotinic component may rely on spinal norepinephrine release. A better understanding of this sex difference could lead to development of novel pain therapy for women.

A Multi-center Study of Intrathecal Neostigmine for Analgesia following Vaginal Hysterectomy

Background Intrathecal neostigmine injection produces analgesia in volunteers and reduces hypotension from intrathecal bupivacaine in animals. Initial clinical trials with neostigmine studied doses of more than 100 [micro sign]g, but animal studies suggest that smaller doses may be effective. In addition, all controlled clinical trials of neostigmine have come from one Brazilian university. This multicenter, placebo‐controlled trial investigated the effects of 25‐75 [micro sign]g intrathecal neostigmine on analgesia and blood pressure in women undergoing vaginal hysterectomy. Methods After institutional review board approval was obtained at the three university centers, and after patients gave informed consent, 92 women scheduled for vaginal hysterectomy were randomized to receive an intrathecal injection of 2 ml bupivacaine, 0.75%, in dextrose plus either 1 ml saline or 25, 50, or 75 [micro sign]g neostigmine. Blood pressure, heart rate, pain and nausea (both assessed by visual analog scale), and intravenous morphine use were recorded during surgery and at specified intervals afterward. Results Morphine use was reduced similarly by all doses of neostigmine. Only the 75‐[micro sign]g dose of neostigmine increased the nausea score in the recovery room. The incidence of treatment for nausea was greater in patients receiving neostigmine (61%) than in those receiving saline placebo (29%) and was unaffected by neostigmine dose. Neostigmine did not reduce the incidence of hypotension from bupivacaine. Conclusion These data in patients after vaginal hysterectomy suggest that analgesia from intrathecal neostigmine may occur at doses less than 50 [micro sign]g. In these doses, neostigmine does not reduce spinal bupivacaine‐induced hypotension but may increase the need for treatment of nausea.