Carlo Pancaro

Nocebo-induced hyperalgesia during local anesthetic injection.

Common practice during local anesthetic injection is to warn the patient using words such as: “You will feel a big bee sting; this is the worst part.” Our hypothesis was that using gentler words for administration of the local anesthetic improves pain perception and patient comfort. One hundred forty healthy women at term gestation requesting neuraxial analgesia were randomized to either a “placebo” (“We are going to give you a local anesthetic that will numb the area and you will be comfortable during the procedure”) or “nocebo” (“You are going to feel a big bee sting; this is the worst part of the procedure”) group. Pain was assessed immediately after the local anesthetic skin injection using verbal analog scale scores of 0 to 10. Median verbal analog scale pain scores were lower when reassuring words were used compared with the harsher nocebo words (3 [2–4] vs 5 [3–6]; P < 0.001). Our data suggest that using gentler, more reassuring words improves the subjective experience during invasive procedures.

Prolonged Suppression of Postincisional Pain by a Slow-release Formulation of Lidocaine

Background: Postoperative pain can occur despite nerve blocks during the surgical period. Here we tested Xybrex (Orthocon, Inc., Irvington, NY), a slow-release formulation of lidocaine that blocks rat sciatic nerve for 1–2 days, for its ability to suppress postincisional pain. Methods: A plantar paw incision was made in rats, either along the midline (Brennan model) or at the lateral edge, 30 min after different treatment groups received either lidocaine (0.2 ml, 2%) or Xybrex implant at the ipsilateral sciatic nerve or Xybrex at the contralateral sciatic nerve. Behavioral testing by von Frey filaments occurred at 2 and 6 h postoperatively and for the next 10 postoperative days. The fractional response (paw withdrawal responses per 10 pokes) was scored at each time. Results: Mechanosensitivity from the Brennan paw incision was reduced throughout the postoperative period by ipsilateral Xybrex, although lidocaine injection almost had no effect. Contralateral Xybrex had a weaker but still significant antihyperalgesic effect, converging to that from ipsilateral Xybrex at postoperative day 2. Xybrex at the nuchal midline reduced allodynia for only postoperative days 1–3, whereas hyperalgesia was reduced continuously after postoperative day 2. Hyperalgesia from the lateral incision was also reduced by ipsilateral Xybrex but not by contralateral Xybrex. Conclusions: Implants of slow-release lidocaine formulations are most effective against postincisional pain when placed at the ipsilateral nerve innervating the area of incision. Contralateral nerve implants are somewhat less effective, probably acting by releasing lidocaine into the systemic circulation. There appears to be a differential role of central sensitization between postincisional allodynia and hyperalgesia.

Scopolamine Prevents Dreams during General Anesthesia

Background:Dreaming during anesthesia is not a well-understood phenomenon. Anticholinergic drugs are used in anesthesia as premedication, but their use to decrease the incidence of dreams and psychological adverse reactions after anesthesia is not well established. The authors therefore studied the efficacy of intramuscular atropine and scopolamine for the prevention of dreams during general anesthesia with propofol and nitrous oxide. Methods:Healthy women undergoing minor gynecologic surgery were randomly assigned to receive 2.5 &mgr;g/kg scopolamine or 10 &mgr;g/kg atropine intramuscularly (n = 50/group). In both groups, anesthesia was induced and maintained with propofol as a 2.5-mg/kg bolus, followed by 12 mg · kg−1 · h−1 as a continuous infusion and 70% nitrous oxide in oxygen. Two interviews regarding dreaming activity and characteristics were conducted at 20 min and 6 h after surgery. Results:None of the patients in the scopolamine group and 47% of the patients in the atropine group reported the occurrence of dreams 20 min after recovery. The results were similar at 6 h: 6% of the scopolamine group and 43% of the atropine group reported dream activity. No differences in sedation or anesthetic requirements were found. Conclusions:Previous studies in animals and humans suggest that dreams are affected by drugs acting on the central cholinergic system. The current results suggest that intramuscular scopolamine prevents dreams or dream recall in healthy young women undergoing short elective surgery with propofol-nitrous oxide anesthesia.

Low-dose systemic bupivacaine prevents the development of allodynia after thoracotomy in rats.

BACKGROUND: Chronic pain after thoracotomy has been recently reproduced in a rat model that allows investigation of the effect of drugs that might reduce the incidence of allodynia after thoracotomy. Previous studies suggest that intrathecal or systemic morphine, clonidine, neostigmine, and gabapentin reduce the incidence of allodynia in the rat postthoracotomy pain model. Our purpose was to test whether intercostal and systemic injection of bupivacaine prevented the development of allodynia in an animal model of chronic intercostal neuropathic pain. METHODS: Male Sprague-Dawley rats were anesthetized and the right 4th and 5th ribs surgically exposed. The pleura were opened and the ribs were retracted for 1 h. Intercostal or systemic bupivacaine 1 mg (0.2 mL at 0.5%) was injected before and after surgery, or before surgery; a control group underwent rib retraction and did not receive any drug. Rats were tested for mechanical allodynia at a predetermined area around the incision site during the 3 wk after surgery. RESULTS: Allodynia developed in 43% of the animals that did not receive bupivacaine (control group); in contrast, allodynia developed in only 6%, 12%, and 12% of those animals that received intercostal bupivacaine before surgery, after surgery, or systemically before surgery, respectively. DISCUSSION: Previous studies suggest that allodynia after rib retraction can be prevented by opioids, α2-adrenergic agonists, neostigmine, and gabapentin. The current results suggest that bupivacaine is effective in preventing mechanical allodynia, whether given by intercostal injection before or after surgery, or systemically before surgery.

Dexmedetomidine and ketamine show distinct patterns of cell degeneration and apoptosis in the developing rat neonatal brain

Abstract Objective: Early exposure to common anesthetic and sedative agents causes widespread brain cell degeneration and apoptosis in the developing rat brain, associated with persistent learning deficits in rats. This study was designed to determine whether the α2 adrenergic receptor agonist, dexmedetomidine, produces brain cell degeneration and apoptosis in postnatal day-7 rats in the same brain areas when compared to ketamine. Methods: Systemic saline, ketamine 20 mg/kg, or dexmedetomidine at 30 or 45 μg/kg were given six times to postnatal day 7 rats (n  =  6/group) every 90 min. Twenty-four hours after the initial injection, brain regions were processed and analyzed for cell degeneration using the silver stain and for apoptosis using activated caspase-3 immunohistochemistry. Results: Exposure to ketamine resulted in significant cellular degeneration and apoptosis in limbic brain regions, but nonsignificant changes in primary sensory brain regions. In contrast, dexmedetomidine produced significant cellular degeneration and apoptosis in primary sensory brain regions, but nonsignificant changes in limbic regions. Conclusions: These data show that ketamine and dexmedetomidine result in anatomically distinct patterns of cell degeneration and apoptosis in the brains of 7-day-old rat pups. The meaning and the clinical significance of these findings remain to be established.

The Effects of Resiniferatoxin in an Experimental Rat Thoracotomy Model

BACKGROUND: Chronic pain after thoracotomy has been reproduced in a rat model that allows investigation of drugs that might reduce the incidence of allodynia after thoracotomy. Previous studies suggest that morphine, clonidine, neostigmine, gabapentin, and bupivacaine reduce the incidence of allodynia in the rat postthoracotomy pain model. One purpose of this study was to test whether intercostal injection of resiniferatoxin (RTX) decreased the amount of allodynia in an animal model of chronic postthoracotomy pain. We also tested whether RTX induced a transient mechanical hyperalgesic response in uninjured animals. METHODS: Male Sprague-Dawley rats were anesthetized, and the right fourth and fifth ribs were surgically exposed. The pleura was opened, and the ribs were retracted. Intercostal RTX 0.8 or 8 μg was injected in animals that developed allodynia after surgery; a control group underwent rib retraction and received vehicle only. An additional group of uninjured animals received RTX. Rats were tested for mechanical allodynia at a predetermined area around the incision site for 3 wk. RESULTS: Allodynia developed in 42% of the animals that underwent thoracotomy. A transient hyperalgesic response was noted in the uninjured group that underwent drug injections. Intercostal RTX did not modify the course of allodynia in injured rats. DISCUSSION: The current results suggest that intercostal RTX causes a transient hyperalgesic response in uninjured animals and is ineffective in reducing the mechanical allodynia after thoracotomy.

Noninfectious Fever in the Near-Term Pregnant Rat Induces Fetal Brain Inflammation: A Model for the Consequences of Epidural-Associated Maternal Fever.

BACKGROUND: Women laboring with epidural analgesia experience fever much more frequently than do women who chose other forms of analgesia, and maternal intrapartum fever is associated with numerous adverse consequences, including brain injury in the fetus. We developed a model of noninfectious inflammatory fever in the near-term pregnant rat to simulate the pathophysiology of epidural-associated fever and hypothesized that it would produce fetal brain inflammation. METHODS: Twenty-four pregnant Sprague-Dawley rats were studied at 20 days gestation (term: 22 days). Dams were treated by injection of rat recombinant interleukin (IL)-6 or vehicle at 90-minute intervals, and temperature was monitored every 30 minutes. Eight hours after the first treatment, dams were delivered of fetuses and then killed. Maternal IL-6 was measured at delivery. Fetal brains (n = 24) were processed and stained for ED-1/CD68, a marker for activated microglia, and cell counts in the lateral septal and hippocampal brain regions were measured. Fetal brains were also stained for cyclooxygenase-2 (COX-2), a downstream marker of neuroinflammation. Eight fetal brains were further analyzed for quantitative forebrain COX-2 by Western blotting compared to a &bgr;-actin standard. Maternal temperature and IL-6 levels were compared between treatments, as were cell counts, COX-2 staining, and COX-2 levels by Mann-Whitney U test, repeated-measures analysis of variance, or Fisher exact test, as appropriate. RESULTS: Injection of rat IL-6 at 90-minute intervals produced an elevation of maternal temperature compared to vehicle (P < .0001). IL-6 levels were elevated to clinically relevant levels at delivery in IL-6 compared to vehicle-treated animals (mean ± standard deviation: 923 ± 97 vs 143 ± 94 pg/mL, P = .0006). ED-1–stained cells were present in significantly higher numbers in fetal brains from IL-6 compared to saline-treated dams (median [interquartile range]: caudal hippocampus, 99 [94–104] and 64 [57–68], respectively, P = .002; lateral septum, 102 [96–111] and 68 [65–69], respectively, P = .002), as well as COX-2 immunostaining (lateral septum, 22 [20–26] and 17 [15–18], respectively, P = .005; dorsal hippocampus, 27 [22–32] and 16 [14–19], respectively, P = .013) and quantitative COX-2 Western blotting activity (mean ± standard error of the mean: vehicle, 0% of &bgr;-actin intensity versus IL-6, 41.5% ± 24%, P < .001). CONCLUSIONS: Noninfectious inflammatory fever is inducible in the near-term pregnant rat by injection of IL-6 at levels comparable to those observed during human epidural labor analgesia. Maternal IL-6 injection causes neuroinflammation in the fetus.

Phenylephrine as a simulated intravascular epidural test dose in pediatrics: A pilot study

A test dose is used to detect intravascular injection during neuraxial block in pediatrics. Accidental intravascular epidural local anesthetic injection might be unrecognized in anesthetized children leading to potential life‐threatening complications. In children, sevoflurane anesthesia blunts the hemodynamic response when intravascular cathecolamines are administered. No studies have explored the hemodynamics and the criteria for a positive test dose result following phenylephrine in sevoflurane anesthetized children.

Obstetric analgesia: back to the future?

One hundred and fifty years ago, on 7 April 1853, John Snow administered chloroform to Victoria, Queen of England, for childbirth. The Queen ‘blessed the chloroform’ after a happy delivery and began the age of analgesia for women in labor. In 1858, in his fundamental book On Chloroform, Snow wrote of the differences beween analgesia and anesthesia, showing profound knowledge of the concentrations of delivered anesthetics and the resultant effects on the uterus and the newborn. During the birth of her ninth child, Queen Victoria accepted chloroform again. This action aided the acceptance and respectability of labor analgesia; in 1847 James Simpson, Professor of Midwifery in Edinburgh, Scotland, introduced ether for vaginal delivery despite the considerable resistance of church leaders. Use of nitrous oxide dates from 1881, when Stanislav Klikovich, a Polish physician living in Russia, found that it was a safe and effective anesthetic, with no interference with uterine contraction. Although a mixture of nitrous oxide and oxygen was re-introduced in the 1940s and 1950s, it was not until 1961 that Tunstall described the use of premixed nitrous oxide–oxygen for labor. In the UK the adoption of nitrous oxide and oxygen in a premixed form began in 1963. Now, nitrous oxide is the world’s most commonly used inhaled agent during labor and delivery. During the decade 1975–85 in the USA, nitrous oxide was used for 6% of deliveries, while, in the UK, Finland, Canada, Australia and New Zealand, it is used by 50–80% of women1. Unfortunately, only a few studies have proved the efficacy of nitrous oxide during labor2,3, and others have shown no advantages of nitrous oxide over placebo4. For this reason, inhaled anesthetics have seldom been considered an option for the parturient. To date, epidural and combined spinal and epidural analgesics are the gold standard during labor. ‘First-class delivery’, that is labor that is pain-free, is produced by a combination of the skills of the anesthesiologist, the availability of specific equipment and personnel, and acceptance among physicians. Many researchers have attempted to demonstrate that epidural analgesia did not raise the incidence of Cesarean section, but none have studied the incidence of an avoided surgical procedure because of epidural analgesia. The development of regional anesthetic techniques, along with new drugs and advanced devices, offers the opportunity of a serene delivery in an equipped environment. However, despite the efforts made to improve the techniques, it is not certain that epidural and combined spinal–epidural analgesia present no risk to the parturient. Scott and Hibbard reported a rate of permanent major neurological damage of around 1/125 000 after epidural analgesia for labor and delivery5. Are these numbers acceptable? The majority of parturients, if properly informed, would not accept even a small risk for their labor and delivery6. They would probably prefer a safer, but less effective, alternative for preventing pain during uterine contractions and cervical dilatation than a ‘first-class delivery’ technique. The complications of epidural analgesia are acceptable for surgical procedures in ill subjects, but they are not adequate for physiological delivery. Labor is not an illness, and every woman shows a variable acceptance of pain, because she knows that, in a brief time, she will embrace her baby. The ideal inhalational anesthetic agent must display a non-pungent smell and adequate potency for keeping the patient awake, with intact laryngeal reflexes. In clinical practice, the introduction of more potent anesthetics, characterized by fast onset and offset, could open new perspectives in the search for a valid alternative to invasive techniques. Intermittent administration of sevoflurane, an ether introduced in operative theaters since 1993, was successful in 50 parturients without major or minor complications7. Although these numbers are inconclusive regarding efficacy, potential adverse outcomes and safety, these results are being confirmed by other promising research in progress. Inhaled analgesia could constitute an effective technique. It is easy to administer even without special training and, with some precautions, without the continuous presence of an anesthesiologist. Sevoflurane The Journal of Maternal–Fetal and Neonatal Medicine 2003;14:6–7

Temperature probe used as a flexible stylet for unexpected difficult laryngoscopy in an infant

To the Editor: A 5 month old male infant presented for laparoscopic fundoplication. General anesthesia was induced via inhalation of sevoflurane 8% in oxygen. Intravenous access was obtained after induction. Blankets supporting the patients shoulders and a foam pad under the patients head were used to optimize airway manipulation. Easy mask ventilation was established before neuromuscular relaxation. Three laryngoscopies were performed and a Cormack-Lehane grade 2 view was obtained during all attempts. When a regularly styletted endotracheal tube (ETT; size 4.0 cuffed; Mallinckrodt, Athlone, Ireland) was introduced through the oral cavity, the small mouth opening partly or entirely obscured the laryngoscopic views. In addition, the proximal part of the ETT touched the upper lip at all times, limiting fine distal ETT bevel movements. On the fourth attempt, a temperature probe was cut between the rubber and the wire junction and used as a flexible bougie to aid in obtaining a successful laryngoscopic view and endotracheal intubation (Fig. 1). The Miller laryngoscope was left in place as the ETT was threaded over the flexible stylet so as to counteract the hypopharyngeal wall collapse that is often associated with general anesthesia. Capnography and auscultation confirmed correct ETT positioning. The external diameter of the temperature probe (Vital Signs, Inc., Totowa, NJ, USA) is 9-French, and the smallest ETT size that may be threaded is a 3.5mm (internal diameter). The length of the temperature probe after being cut at the junction measures 45 cm. A selection of stylets, bougies, and videoor light-assisted intubating tools [1] are currently available for management of the pediatric difficult airway. When a laryngoscopic grade 2 view is obtained and only a small area is available for insertion of the airway, a modified temperature probe may be used as a soft stylet with minimal risk of airway trauma and bleeding. This arrangement would be unlikely to compromise any further attempts of video or fiberoptic-assisted laryngoscopy or mask ventilation.