Eichi Narimatsu

Experimental incision-induced pain in human skin: effects of systemic lidocaine on flare formation and hyperalgesia

&NA; In order to try to gain a better understanding of the mechanisms of post‐operative pain, this study was designed to psychophysically determine physiological and pharmacological characteristics of experimental pain induced by a 4‐mm‐long incision through the skin, fascia and muscle in the volar forearm of humans. In experiment 1, the subjects (n=8) were administered lidocaine systemically (a bolus injection of 2 mg/kg for a period of 5 min followed by an intravenous infusion of 2 mg/kg/h for another 40 min), and then the incision was made. In experiment 2, cumulative doses of lidocaine (0.5–2 mg/kg) were systemically injected in the subjects (n=8) 30 min after the incision had been made, when primary and secondary hyperalgesia had fully developed. Spontaneous pain was assessed using the visual analog scale (VAS). Primary hyperalgesia was defined as mechanical pain thresholds to von Frey hair stimuli (from 7 to 151 mN) in the injured area. The area of secondary hyperalgesia to punctate mechanical stimuli was assessed using a rigid von Frey hair (151 mN). Flare formation was assessed in the first experiment using a laser doppler imager (LDI). Pain perception was maximal when the incision was made and then rapidly disappeared within 30 min after the incision had been made. Primary hyperalgesia was apparent at 15 min after the incision had been made and remained for 2 days. The incision resulted in a relatively large area of flare formation immediately after the incision had been made. The area of flare began to shrink within 15 min and was limited to a small area around the injured area at 30 min after incision. Secondary hyperalgesia was apparent at 30 min after incision and persisted for 3 h after incision and then gradually disappeared over the next 3 h. In experiment 1, pre‐traumatic treatment with systemic lidocaine suppressed primary hyperalgesia only during the first 1 h after the incision had been made. The lidocaine suppressed the development of flare formation without affecting the pain rating when the incision was made. The development of secondary hyperalgesia continued to be suppressed after completion of the lidocaine infusion. In experiment 2, post‐traumatic treatment with lidocaine temporarily suppressed primary as well as secondary hyperalgesia that had fully developed; however, the primary and secondary hyperalgesia again became apparent after completion of the lidocaine administration. These findings suggest that pre‐traumatic treatment with lidocaine reduces the excessive inputs from the injured peripheral nerves, thus suppressing development of flare formation and secondary hyperalgesia through peripheral and central mechanisms, respectively. Pre‐traumatic treatment with lidocaine would temporarily stabilize the sensitized nerves in the injured area, but the nerves would be sensitized after completion of the administration. Post‐traumatic treatment with lidocaine reduced primary and secondary hyperalgesia that had fully developed. However, the finding that the suppressive effect of lidocaine on secondary hyperalgesia was temporary suggests that the development and maintenance of secondary hyperalgesia are caused by different mechanisms.

Emergency Endovascular Stent-Grafting for Infected Pseudoaneurysm of Brachial Artery

Abstract.The use of covered stents in an infected field is controversial. It is generally recommended that infected aneurysms be treated using autografts or allografts. We report a case of infected brachial pseudoaneurysms that developed after medical debridement of a methicillinresistant Staphylococcus aureus (MRSA)-infected wound of the right arm and emergency brachial artery bypass-grafting using the saphenous vein, which was successfully treated by endovascular stent-grafting followed by antibiotic administration. The present case suggests that endovascular stent-grafting prevents rupture and occlusion of infected aneurysms and enables the continued administration of antibiotics.

Changes in Response Properties and Receptive Fields of Spinal Dorsal Horn Neurons in Rats after Surgical Incision in Hairy Skin

Background: Mechanical hyperalgesia and allodynia associated with chemical irritant application are mediated by spinal high-threshold (HT) as well as wide-dynamic-range neurons as a result of “central sensitization.” Because the pathophysiology of pain is thought to differ depending on the type of injury and may vary between hairy and glabrous skin, the authors examined changes in properties of spinal dorsal horn neurons after surgical incisions in hairy skin of rats to obtain insights into the mechanisms of postoperative pain. Methods: Withdrawal responses to punctate mechanical stimulation and gentle brushing were measured in awake rats in an area adjacent to the injured site (primary area) and in an area 2 cm from the injured site (secondary area) after 1-cm longitudinal incisions through the hairy skin, fascia, and muscle had been made in the hindquarters. In a separate study, responses of spinal wide-dynamic-range, HT, and low-threshold neurons to nonnoxious and noxious stimuli were recorded before and after similar incisions had been made in the centers of their receptive fields. Effects of spinal application of the &ggr;-aminobutyric acid A receptor antagonist bicuculline (15 &mgr;g) on responses of HT neurons were then studied. Results: Awake rats showed primary and secondary hyperalgesia to punctate mechanical stimulation 30 min after the incision and thereafter for 4 days and 1 day, respectively. Mechanical allodynia associated with brush stimulation was only seen in the primary area 30 min after the incision and thereafter for 1 day. The incision resulted in increases in activity of wide-dynamic-range neurons (receptive field sizes and responses to both innocuous and noxious stimuli). HT neurons did not respond to innocuous stimulation and showed very small increases or no changes in receptive field size and responses to noxious stimuli after the incision. However, the majority of HT neurons began to respond to innocuous stimuli after application of bicuculline (15 &mgr;g/50 &mgr;l) to the spinal cord. Conclusions: The results suggest that wide-dynamic-range neurons are responsible for behavioral hyperexcitability after surgical incision but that HT neurons are not involved in the hyperexcitability, despite the fact that HT neurons are capable of responding to innocuous stimuli by reversal of &ggr;-aminobutyric acid–mediated inhibition.

Alteration in diaphragmatic contractility during septic peritonitis in rats: effect of polyethylene glycol-absorbed superoxide dismutase.

Objectives To assess the alterations in diaphragmatic contractility measured in vitro during experimental septic peritonitis and to evaluate the effect of polyethylene glycol-absorbed superoxide dismutase (PEG-SOD) on the alterations in contractility. Design Prospective, randomized, controlled animal trial. Setting Research laboratory. Subjects A total of 321 male Wistar rats, weighing 250–300 g. Interventions Rats were treated with cecal ligation and puncture (CLP). In the first experiment, diaphragmatic contractility was measured at 4, 10, 12, and 16 hrs after CLP. In the second experiment, PEG-SOD (4000 units/kg) was administered intraperitoneally, and then diaphragmatic contractility was measured at 10 and 16 hrs after CLP. Levels of lipid peroxides and antioxidant enzymes in the diaphragm tissue were measured at 10 and 16 hrs after CLP. Measurements and Main Results In experiment 1, diaphragmatic twitch characteristics and force-frequency relationships were determined at 4, 10, 12, and 16 hrs after CLP. In experiment 2, the effects of administration of PEG-SOD on twitch characteristics and force-frequency relationships were determined at 10 and 16 hrs after CLP. The levels of diaphragmatic thiobarbituric acid reactive substances and superoxide dismutase (SOD) and glutathione peroxidase activities were measured at 10 and 16 hrs after CLP. Twitch tension and force-frequency curves were significantly lower in the CLP groups than in the sham-operated group. Administration of PEG-SOD attenuated the reduction in twitch tension and the downward shift of force-frequency curves after CLP. Diaphragmatic levels of thiobarbituric acid reactive substances increased after CLP. However, the administration of PEG-SOD prevented increases in levels of diaphragmatic thiobarbituric acid reactive substances after CLP. Diaphragmatic SOD activity, but not glutathione peroxidase activity, was increased after CLP. Conclusions Intra-abdominal sepsis (CLP) induced a marked reduction in diaphragmatic contractility, but PEG-SOD attenuated this reduction. Therefore, we conclude that oxygen-derived free radicals play an important role in the alterations in diaphragmatic contractility during intra-abdominal sepsis.

Outcome from severe accidental hypothermia with cardiac arrest resuscitated with extracorporeal cardiopulmonary resuscitation

PURPOSE This study aimed to identify factors of neurologic prognosis in severe accidental hypothermic patients with cardiac arrest. BASIC PROCEDURES This retrospective observational study was performed in a tertiary care university hospital in Sapporo, Japan (January 1994 to December 2012). We investigated 26 patients with accidental hypothermic cardiac arrest resuscitated with extracorporeal cardiopulmonary resuscitation (ECPR). We evaluated the neurologic outcome in patients who were resuscitated with ECPR at discharge from hospital. MAIN FINDINGS In those 26 patients, their median age was 50.5 years; and 69.2% were male. The cause of hypothermia was exposure to cold air in 46.1%, submersion in 46.1%, and avalanche in 7.8%. Ten (38.5%) of these patients survived to favorable neurological outcome at discharge. Factors associated with favorable neurological outcome were a cardiac rhythm other than asystole (P = .009), nonasphyxial hypothermia (P = .006), higher pH (P = .01), and lower serum lactate (P = .01). In subgroup analyses, the patients with hypothermic cardiac arrest due to submersion or avalanche (asphyxia group) showed no factors associated with good neurological outcome, whereas the nonasphyxia group showed a significantly lower core temperature (P = .02) and a trend towards a lower serum lactate (P = .09). PRINCIPAL CONCLUSIONS Patients with hypothermic cardiac arrest due to nonasphyxial hypothermia have improved neurologic outcomes when treated with ECPR compared to patients with asphyxial hypothermic cardiac arrest. Further investigation is needed to develop a prediction rule for patients with nonasphyxial hypothermic cardiac arrest to determine which patients would benefit from treatment with ECPR.

Effects of systemic administration of lidocaine and QX-314 on hyperexcitability of spinal dorsal horn neurons after incision in the rat.

Abstract Although systemic lidocaine has been shown to suppress postoperative pain in a clinical setting, the mechanisms of action of lidocaine have not been elucidated. The present study was therefore designed to determine the relative contribution of central and peripheral sites to the action of lidocaine on incision‐induced hyperexcitation of spinal dorsal horn (SDH) neurons in the rat. Receptive field (RF) areas, spontaneous activities, and responses of single wide‐dynamic‐range (WDR) neurons of the SDH to nonnoxious and noxious stimuli were recorded before and after longitudinal incisions of 1 cm through the skin, fascia, and muscle had been made in the center of their RFs of the hindquarters. Significant increases in spontaneous activities, RF sizes, and responses of WDR neurons to both nonnoxious and noxious stimuli were observed at 30 min after the incision (P < 0.001). Systemic administration of lidocaine (1 mg/kg bolus plus 0.5 mg/kg/h and 2 mg/kg bolus plus 1 mg/kg/h) and QX‐314 (1 mg/kg bolus plus 0.5 mg/kg/h and 2 mg/kg bolus plus 1 mg/kg/h) significantly but temporarily suppressed and reversed the increases in spontaneous activity, responses to nonnoxious, and noxious stimuli and RF sizes (P < 0.01). Systemic administration of the same doses of lidocaine and QX‐314 did not affect responses of WDR neurons to nonnoxious or noxious stimuli or their RF sizes in sham‐operated animals in which an incision had not been made. The results suggest that systemic administration of lidocaine has suppressive effects on postoperative pain mainly through peripheral sites of action.

Sepsis attenuates the intensity of the neuromuscular blocking effect of d-tubocurarine and the antagonistic actions of neostigmine and edrophonium accompanying depression of muscle contractility of the diaphragm.

Background: Prolonged effects of non‐depolarizing muscle relaxants in septic patients have been reported, although the influence of sepsis on neuromuscular transmission has not yet been clarified satisfactorily. These studies were intended to elucidate the influence of sepsis on neuromuscular transmission and on the action of drugs being utilized for regulation of muscle tone (a neuromuscular blocker and anti‐cholinesterase (anti‐ChE) drugs).

A comparison of the effect of halothane on N-methyl-D-aspartate and non-N-methyl-D-aspartate receptor-mediated excitatory synaptic transmission in the hippocampus

Halothane depresses synaptic transmission in the rat brain.First we determined the concentration of halothane which decreased the amplitude of the population spike recorded in the CA1 region of the hippocampus to 50% of the control value (105 +/- 4.9 micro gram/mL [0.53 mM] halothane). Hippocampal glutamate receptors are divided into N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionate (AMPA) and kainate (non-NMDA) subtypes. The NMDA and non-NMDA receptors were blocked with (+/-)-2-amino-5-phosphonopentanoic acid (AP5) (30 micro Meter) and 6,7-dinitroquinoxaline-2,3-dione (DNQX) (10 micro Meter), respectively, to allow observation of the effects of halothane on the NMDA and non-NMDA receptors, respectively. gamma-Aminobutyric acid type A (GABAA) receptors were blocked in all studies with picrotoxin (PTX) (40 micro Meter). When the non-NMDA receptors were blocked a halothane concentration of 38.1 +/- 5.6 mg/mL was required to produce a further 50% decrease in population spike amplitude. When NMDA receptors were blocked with AP5 or only GABAA receptors were blocked the halothane concentrations needed to produce 50% block were higher than needed for the control (160.8 +/- 17.8 and 190.2 +/- 12.1 micro gram/mL, respectively). These studies indicate that the NMDA receptors are more sensitive to the effects of halothane than the non-NMDA receptors. (Anesth Analg 1996;82:843-7)

Sepsis stage dependently and differentially attenuates the effects of nondepolarizing neuromuscular blockers on the rat diaphragm in vitro.

We investigated the effects of early and late sepsis on the actions of nondepolarizing neuromuscular blockers by using a rat sepsis model induced by cecal ligation and puncture. Isometric twitch tensions of nerve-hemidiaphragm preparations elicited by indirect (phrenic nerve) supramaximal stimulation at 0.1 Hz were evaluated. Rocuronium, pancuronium, and d-tubocurarine dose-dependently decreased the twitch tensions of the nonseptic, early septic, and late septic diaphragms (P < 0.01 each by analysis of variance [ANOVA]). Late sepsis shifted the concentration-twitch tension curves rightward from those of nonsepsis to larger degrees than did early sepsis, as indicated by increases in 50% inhibitory concentration (IC50) values (P < 0.01 each by ANOVA and P < 0.01 or 0.05 by the Scheffé F test). The standardized rightward shifts in early and late sepsis were largest for pancuronium, second largest for rocuronium, and smallest for d-tubocurarine (5.741, 2.979, and 1.660 times in late sepsis, respectively; P < 0.01 each by ANOVA and the Scheffé F test). Sepsis-induced increases in IC50 values did not accompany the decreases in slopes. The results indicate that sepsis induces hyposensitivities to nondepolarizing neuromuscular blockers, the degree of which depends on the stage of sepsis and on the kind of neuromuscular blocker.

Transient depression of excitatory synaptic transmission induced by adenosine uptake inhibition in rat hippocampal slices

The transient property of the dipyridamole-induced depression of excitatory synaptic transmission was analyzed using field EPSPs (fEPSPs) recorded from the CA1 region in rat hippocampal slices. The fEPSPs were depressed by 1 microM dipyridamole and then gradually recovered to the control level. The depression was antagonized by aminophylline or DPCPX, although it was not significantly affected by DMPX. The results suggest that the fEPSP depression is induced by a mechanism through the A(1) receptor.