piperidines and Burns

This study aims to evaluate the feasibility of intraoperative composite target-controlled infusion (TCI) anesthesia application using remifentanil hydrochloride with etomidate in patients with severe burns, as monitored by Narcotrend.. A total of 40 patients with severe burns with eschar excisions and skin grafts were randomly and equally grouped into the etomidate (E) and the propofol groups (P). Anesthesia was induced and maintained by a remifentanil hydrochloride TCI combined with etomidate or propofol. The depth of anesthesia and other relevant indicators were recorded through intraoperative electroencephalogram monitoring using a Narcotrend monitor.. No statistically significant differences were observed between the drug withdrawal times, eye opening requirements, or orientation recoveries of the two groups (P>0.05). The cortisol and aldosterone levels in group E were significantly lower than those in group P 24h post operation (P<0.05). No significant differences between the number of operations, hospitalization duration, mean arterial pressure, heart rate, and postoperative adverse reaction incidence of the two groups were observed at each time point (P>0.05).. The application of a composite remifentanil hydrochloride combined with etomidate TCI is feasible for the early eschar excision in patients with severe burns.

Topics: Adult; Anesthesia Recovery Period; Anesthesia, General; Anesthetics, Intravenous; Burns; Electroencephalography; Etomidate; Feasibility Studies; Female; Humans; Infusions, Intravenous; Intraoperative Care; Male; Middle Aged; Monitoring, Intraoperative; Piperidines; Propofol; Remifentanil; Skin Transplantation; Young Adult

In this study, we compared the propofol-ketamine and propofol-remifentanil combinations for deep sedation and analgesia during pediatric burn wound dressing changes.. Fifty pediatric patients aged 12-36 months, undergoing burn wound dressing changes, were randomly assigned to receive propofol-remifentanil (group PR) or propofol-ketamine (group PK) for deep sedation and analgesia. Patients in the group PR received 2 mg·kg(-1) propofol and 0.1 μg·kg(-1) remifentanil, and 0.05 μg·kg(-1) ·min(-1) remifentanil was infused continuously until the end of the procedure. Patients in the group PK received 2 mg·kg(-1) propofol and 1 mg·kg(-1) ketamine, and the same volume of isotonic saline was infused continuously until the end of the procedure. Additional propofol with remifentanil or ketamine was administered when required. Hemodynamic variables, drug requirements, occurrence of patient movement, surgeon's satisfaction score, recovery time, and the incidence of adverse events were recorded throughout the procedure and recovery.. Recovery time was significantly shorter in the group PR compared to that in the group PK (10.3 [9.1-11.5] min vs 22.5 [20.3-25.6] min, median [interquartile range], respectively; P < 0.001). No significant hypotension or bradycardia occurred throughout the procedure. No significant differences were observed in terms of drug requirements, occurrence of patient movement, surgeon's satisfaction, incidence of respiratory depression, hypoxia, or nausea and vomiting. The combinations of propofol-ketamine and propofol-remifentanil were effective for sedation and analgesia in pediatric patients undergoing burn dressing changes, but the propofol-remifentanil combination provided faster recovery compared to the propofol-ketamine combination.

Topics: Analgesia; Anesthesia Recovery Period; Anesthetics, Dissociative; Anesthetics, Intravenous; Bandages; Burns; Child, Preschool; Deep Sedation; Drug Therapy, Combination; Female; Humans; Hypnotics and Sedatives; Infant; Ketamine; Male; Pain; Pain Management; Piperidines; Propofol; Remifentanil; Treatment Outcome

This study evaluated the feasibility and effectiveness of using the bispectral index (BIS) to monitor anesthetic depth in patients with severe burns receiving intravenous target-controlled infusion (TCI) of remifentanil and propofol. We randomly assigned 80 patients undergoing elective escharectomy (<1 week) to BIS (A) and control (B) groups. All patients received remifentanil and propofol as intravenous TCI anesthesia. Clinical data were recorded at different time points. The time from drug withdrawal to eye opening upon the patient hearing his/her name called and upon reaching an Aldrete score of 9 points was also recorded. During anesthesia maintenance, the target concentrations of remifentanil and propofol in group A were significantly lower than that in group B (2.12 ± 0.35 vs 2.50 ± 0.21 ng/mL and 2.54 ± 0.22 vs 2.86 ± 0.31 μg/mL, respectively; P < 0.01). The time from drug withdrawal to eye opening upon the patient hearing his/her name called and reaching an Aldrete score of 9 points in group A was considerably shorter than that in group B (7.90 ± 0.58 vs 8.35 ± 0.66 min and 9.15 ± 0.69 vs 11.13 ± 0.96 min, respectively; P < 0.01). In both groups, mean arterial pressure and heart rate values at each time point after loss of consciousness were significantly lower than the baseline values (P < 0.05), with the exception of 2 min after intubation. The use of BIS to monitor anesthetic depth in patients with severe burns receiving TCI of remifentanil and propofol during the perioperative period reduces propofol consumption and shortens the consciousness recovery time in patients.

Topics: Adult; Anesthesia; Anesthesia Recovery Period; Blood Pressure; Burns; Consciousness Monitors; Female; Heart Rate; Humans; Infusions, Intravenous; Male; Perioperative Care; Piperidines; Propofol; Remifentanil; Wakefulness

To evaluate the feasibility and efficacy of Narcotrend (NT) monitor in monitoring the depth of anesthesia in severely burned patients with target-controlled infusion (TCI) of remifentanil hydrochloride and propofol during perioperative period.. Eighty patients with severe burn hospitalized from February to November 2011, to whom eschar excision was performed within one week after injury, were enrolled. They were classified into II to III grade according to the American Society of Anesthetists classification, and their total burn area ranged from 31% to 50%TBSA, or full-thickness burn area from 11% to 20% TBSA. Patients were divided into trial group (monitoring depth of anesthesia with routine method and NT monitor) and control group (monitoring depth of anesthesia with routine method) according to the random number table, with 40 cases in each group. All patients received TCI of remifentanil hydrochloride and propofol to induce and maintain anesthesia. During the operation, the anesthesia level of NT monitor used in the trial group was maintained from grade D1 to E0, while the fluctuation of mean arterial pressure (MAP) and heart rate of patients in control group was maintained around the basic values within a range of 20%, and on the basis of which, concentrations of two narcotics were adjusted. Concentrations of remifentanil hydrochloride and propofol during maintenance of anesthesia were recorded. The duration from drug withdrawal to waking from anesthesia (including the duration from drug withdrawal to eye opening by calling and the duration from drug withdrawal to orientation recovery) of patients was recorded. Values of MAP and heart rate at admission into the operation room, loss of consciousness, 2 min after intubation, before operation, 2, 15, and 30 min after the beginning of operation, and the end of operation were recorded. The prediction probability (P(k)) of NT stage (NTS) and NT index (NTI) in trial group, and that of MAP and heart rate in control group for two durations from drug withdrawal to waking form anesthesia were recorded. The administration of vasoactive drugs and intraoperative awareness of patients in two groups were recorded. Data were processed with t test, analysis of variance, and chi-square test, and the relationship between NTS, NTI, MAP, heart rate and their corresponding P(k) for the duration from drug withdrawal to orientation recovery was processed with Spearman correlation analysis.. Maintained target effect-site concentration of remifentanil hydrochloride and target plasma concentration of propofol of patients were obviously lower in trial group [(2.62 ± 0.35) ng/mL, (3.84 ± 0.22) µg/mL] than in control group [(2.95 ± 0.21) ng/mL, (4.16 ± 0.31) µg/mL, with t values respectively -5.113 and -5.324, P values all below 0.01]. The duration from drug withdrawal to eye opening by calling and the duration from drug withdrawal to orientation recovery were obviously shorter in trial group [(10.2 ± 0.7) min, (11.1 ± 1.0) min] than in control group [(11.3 ± 1.0) min, (13.1 ± 0.7) min, with t values respectively -5.740 and -10.806, P values all below 0.01]. The MAP (except for 2 min after intubation) and the heart rate of patients in both groups were lower at the time points from loss of consciousness to the end of operation than at the time of entering operation room (with F values respectively 12.074, 36.425, P values all below 0.01 in trial group and F values respectively 21.776, 35.759, P values all below 0.01 in control group). The statistically significant difference between two groups in MAP level was only observed at the time of loss of consciousness (t = 3.985, P < 0.01). MAP level was close in two groups at other time points. Heart rates of patients in two groups were close during perioperative period. P(k) values of NTS and NTI for the duration from drug withdrawal to eye opening by calling (0.937 ± 0.025, 0.899 ± 0.049) were obviously higher than those of MAP and heart rate for this duration (0.579 ± 0.057, 0.536 ± 0.039, F = 900.337, P < 0.01). P(k) values of NTS and NTI for the duration from drug withdrawal to the orientation recovery (0.901 ± 0.031, 0.868 ± 0.046) were significantly higher than those of MAP and heart rate for this duration (0.532 ± 0.060, 0.483 ± 0.044, F = 890.895, P < 0.01). NTS, NTI, MAP, and heart rate were respectively negative, positive, positive and positive in correlation with their P(k) values for the duration from drug withdrawal to the orientation recovery (with r values from -0.734 to 0.682, P values all below 0.01). There was no statistically significant difference between two groups in administration of vasoactive drugs. No intraoperative awareness occurred.. Application of Narcotrend monitor in monitoring the depth of anesthesia in severely burned patients during perioperative period with TCI of remifentanil hydrochloride and propofol is beneficial to reducing dosage of narcotics and shortening duration of recovery from anesthesia, and it can accurately predict the level of consciousness of patients at the time of withdrawal of anesthesia.

Topics: Adolescent; Adult; Aged; Anesthesia, Intravenous; Burns; Female; Humans; Male; Middle Aged; Monitoring, Intraoperative; Piperidines; Propofol; Remifentanil; Skin Transplantation; Young Adult

Fatty acid composition in the Western diet has shifted from saturated to polyunsaturated fatty acids (PUFAs), and specifically to linoleic acid (LA, 18:2), which has gradually increased in the diet over the past 50 y to become the most abundant dietary fatty acid in human adipose tissue. PUFA-derived oxylipins regulate a variety of biological functions. The cytochrome P450 (CYP450)–formed epoxy fatty acid metabolites of LA (EpOMEs) are hydrolyzed by the soluble epoxide hydrolase enzyme (sEH) to dihydroxyoctadecenoic acids (DiHOMEs). DiHOMEs are considered cardioprotective at low concentrations but at higher levels have been implicated as vascular permeability and cytotoxic agents and are associated with acute respiratory distress syndrome in severe COVID-19 patients. High EpOME levels have also correlated with sepsis-related fatalities; however, those studies failed to monitor DiHOME levels. Considering the overlap of burn pathophysiology with these pathologies, the role of DiHOMEs in the immune response to burn injury was investigated. 12,13-DiHOME was found to facilitate the maturation and activation of stimulated neutrophils, while impeding monocyte and macrophage functionality and cytokine generation. In addition, DiHOME serum concentrations were significantly elevated in burn-injured mice and these increases were ablated by administration of 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), a sEH inhibitor. TPPU also reduced necrosis of innate and adaptive immune cells in burned mice, in a dose-dependent manner. The findings suggest DiHOMEs are a key driver of immune cell dysfunction in severe burn injury through hyperinflammatory neutrophilic and impaired monocytic actions, and inhibition of sEH might be a promising therapeutic strategy to mitigate deleterious outcomes in burn patients.

Topics: Animals; Burns; Epoxide Hydrolases; Humans; Immunity, Innate; Inflammation; Linoleic Acid; Mice; Mice, Inbred C57BL; Phenylurea Compounds; Piperidines; Sepsis

Imbalance of oxidants/antioxidants results in heart failure, contributing to mortality after burn injury. Cardiac mitochondria are a prime source of reactive oxygen species (ROS), and a mitochondrial-specific antioxidant may improve burn-induced cardiomyopathy. We hypothesize that the mitochondrial-specific antioxidant, Triphenylphosphonium chloride (Mito-TEMPO), could protect cardiac function after burn.. Male rats had a 60% total body surface area (TBSA) scald burn injury and were treated with/without Mito-TEMPO (7 mg/kg-1, intraperitoneal) and harvested at 24 hours post-burn. Echocardiography (ECHO) was used for measurement of heart function. Masson Trichrome and hematoxylin and eosin (H & E) staining were used for cardiac fibrosis and immune response. Qualitative polymerase chain reaction (qPCR) was used for mitochondrial DNA replication and gene expression.. Burn-induced cardiac dysfunction, fibrosis, and mitochondrial damage were assessed by measurement of mitochondrial function, DNA replication, and DNA-encoded electron transport chain-related gene expression. Mito-TEMPO partially improved the abnormal parameters. Burn-induced cardiac dysfunction was associated with crosstalk between the NFE2L2-ARE pathway, PDE5A-PKG pathway, PARP1-POLG-mtDNA replication pathway, and mitochondrial SIRT signaling.. Mito-TEMPO reversed burn-induced cardiac dysfunction by rescuing cardiac mitochondrial dysfunction. Mitochondria-targeted antioxidants may be an effective therapy for burn-induced cardiac dysfunction.

Topics: Animals; Antioxidants; Burns; Disease Models, Animal; Echocardiography; Heart; Heart Failure; Humans; Injections, Intraperitoneal; Male; Mitochondria; Myocardium; Organophosphorus Compounds; Piperidines; Rats; Reactive Oxygen Species

Oxylipins modulate the behavior of immune cells in inflammation. Soluble epoxide hydrolase (sEH) converts anti-inflammatory epoxyeicosatrienoic acid (EET) to dihydroxyeicosatrienoic acid (DHET). An sEH-inhibitor, TPPU, has been demonstrated to ameliorate lipopolysaccharide (LPS)- and sepsis-induced inflammation via EETs. The immunomodulatory role of DHET is not well characterized. We hypothesized that TPPU dampens inflammation and that sEH-derived DHET alters neutrophil functionality in burn induced inflammation. Outbred mice were treated with vehicle, TPPU or 14,15-DHET and immediately subjected to either sham or dorsal scald 28% total body surface area burn injury. After 6 and 24 h, interleukin 6 (IL-6) serum levels and neutrophil activation were analyzed. For in vitro analyses, bone marrow derived neutrophil functionality and mRNA expression were examined. In vivo, 14,15-DHET and IL-6 serum concentrations were decreased after burn injury with TPPU administration. In vitro, 14,15-DHET impaired neutrophil chemotaxis, acidification, CXCR1/CXCR2 expression and reactive oxygen species (ROS) production, the latter independent from p38MAPK and PI3K signaling. We conclude that TPPU administration decreases DHET post-burn. Furthermore, DHET downregulates key neutrophil immune functions and mRNA expression. Altogether, these data reveal that TPPU not only increases anti-inflammatory and inflammation resolving EET levels, but also prevents potential impairment of neutrophils by DHET in trauma.

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Anti-Inflammatory Agents; Burns; Cytokines; Epoxide Hydrolases; Female; Lipopolysaccharides; Male; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; NADPH Oxidases; Neutrophils; p38 Mitogen-Activated Protein Kinases; Phagocytosis; Phenylurea Compounds; Phosphatidylinositol 3-Kinases; Piperidines; Reactive Oxygen Species; Receptors, Chemokine; Respiratory Burst; Transcription, Genetic

Topics: Anticholinergic Syndrome; Antiparkinson Agents; Antipsychotic Agents; Biperiden; Burns; Cholinesterase Inhibitors; Delirium; Diagnosis, Differential; Donepezil; Drug Administration Routes; Drug Synergism; Humans; Indans; Male; Middle Aged; Muscle Rigidity; Physostigmine; Piperidines; Risperidone; Treatment Outcome

Topics: Animals; Burns; Cicatrix, Hypertrophic; Coated Materials, Biocompatible; Humans; Piperidines; Quinazolinones; Silicone Gels; Skin Transplantation

Burn injury causes nociceptive behaviors, and inflammation-related pathologic pain can lead to glial cell activation. This study tested the hypothesis that burn injury activates glial cells, and cannabinoid receptor 1 (CB1R) antagonist, AM251, will decrease burn pain.. Anesthetized rats received 0.75-cm third-degree burn on dorsal hind paw. Vehicle or AM251 30 μg intrathecally (older rats, n=6 per group) or, either vehicle, 0.1 or 1.0 mg/kg intraperitoneally (younger rats, n=6 per group), started immediate postburn, was administered for 7 days. Mechanical allodynia and thermal hyperalgesia were tested on ventral paw for 14 days. Microglial and astroglial activity was assessed by immunocytochemistry.. Allodynia, observed on burn side from day 1 to 14, was significantly (P<0.05) attenuated by intrathecal and intraperitoneal AM251 (1 mg/kg) starting from 3 to 14 days. Hyperalgesia, observed from day 3 to 12, was completely (P<0.05) reversed by intrathecal and intraperitoneal AM251 (1 mg/kg). AM251 0.1 mg/kg had no effect. Microglial activity (n=3 per time point) increased (P<0.05) 18.5±7.5 and 12.3±1.6 (mean±SD) fold at 7 and 14 days, respectively. Astroglial activity (n=4 per time point) increased 2.9±0.3 fold at day 7 only. Glial activities were unaltered by AM251.. AM251 inhibited nociceptive behaviors after burn even beyond 7-day period of administration. Although many studies have documented the utility of CB1R agonists, this study indicates that endogenous cannabinoids may have an unexpected pronociceptive effect during development of burn pain, explaining why CB1R antagonist, AM251, improves nociceptive behaviors. The decreased nociception with AM251 without altering glial activity indicates that AM251 acts further downstream of activated glial cells.

Topics: Aging; Analgesics, Non-Narcotic; Animals; Burns; Hyperalgesia; Injections, Spinal; Male; Neuroglia; Pain Measurement; Physical Stimulation; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Spinal Cord

Burn scar formations can cause disfiguration and loss of dermal function. The purpose of this study was to examine whether application of modified silicone gel sheets with an antifibrotic drug halofuginone-eluting hybrid surface produce an effect on scar development. There were a total of 2 animal groups. The athymic nude mice (nu/nu) of both groups underwent transplantation of full-thickness human skin grafts onto their backs and setting of partial thickness burn injury. The status of local scar development was observed over a period of 3 months after the application of silicone gel sheets and also after application of surface-modified halofuginone-eluting silicone gel sheets. Subsequently, via real-time polymerase chain reaction, the cDNA levels from key mediators of scar formation (transforming growth factor beta, COL1A1, connective tissue growth factor, fibroblast growth factor 2, matrix metalloproteinase 2, matrix metalloproteinase 9) were established and statistically evaluated. In comparison with uncoated silicone gel sheets, the application of halofuginone-eluting silicone gel sheets lead to a significant difference in gene expression activity in scar tissue. Halofuginone-eluting hybrid surface silicone gel sheets significantly increase the antiscarring effect of adhesive silicone gel sheets by deceleration and downregulation of scar development by normalization of the expression activity.

Topics: Animals; Burns; Cicatrix, Hypertrophic; Coated Materials, Biocompatible; Humans; Mice; Mice, Nude; Piperidines; Protein Synthesis Inhibitors; Quinazolinones; Silicone Gels; Skin Transplantation

Three 13-year-olds with burns on 30%, 70%, and 75% of their body surface areas and with related respiratory tract lesions underwent multiple surgical interventions for debridement, graft placement, and topical treatments. Balanced general anesthesia was provided with sevoflurane and an infusion of remifentanil and cisatracurium. Each patient underwent 41 procedures over a period of 6 months. All interventions were carried out without complications other than the difficulty of establishing an access to veins and monitoring because of the scarcity of intact surfaces. Remifentanil is an effective analgesic for meeting the needs of patients with severe burns. The combination of remifentanil, sevoflurane, and cisatracurium provides good hemodynamic stability and is very appropriate for patients who must undergo a large number of surgical interventions.

Topics: Adolescent; Anesthesia, General; Anesthetics, Intravenous; Burns; Debridement; Humans; Infusions, Intravenous; Injury Severity Score; Male; Piperidines; Remifentanil; Skin Transplantation

Accumulating evidence suggests that cannabinoids can produce antinociception through peripheral mechanisms. In the present study, we determined whether cannabinoids attenuated existing hyperalgesia produced by a mild heat injury to the glabrous hindpaw and whether the antihyperalgesia was receptor-mediated. Anesthetized rats received a mild heat injury (55 degrees C for 30 s) to one hindpaw. Fifteen minutes after injury, animals exhibited hyperalgesia as evidenced by lowered withdrawal latency to radiant heat and increased withdrawal frequency to a von Frey monofilament (200 mN force) delivered to the injured hindpaw. Separate groups of animals were then treated with an intraplantar (i.pl.) injection of vehicle or the cannabinoid receptor agonist WIN 55,212-2 at doses of 1, 10, or 30 microg in 100 microl. WIN 55,212-2 attenuated both heat and mechanical hyperalgesia dose-dependently. The inactive enantiomer WIN 55,212-3 did not alter mechanical or heat hyperalgesia, suggesting the effects of WIN 55,212-2 were receptor-mediated. The CB1 receptor antagonist AM 251 (30 microg) co-injected with WIN 55,212-2 (30 microg) attenuated the antihyperalgesic effects of WIN 55,212-2. The CB2 receptor antagonist AM 630 (30 microg) co-injected with WIN 55,212-2 attenuated only the early antihyperalgesic effects of WIN 55,212-2. I.pl. injection of WIN 55,212-2 into the contralateral paw did not alter the heat-injury induced hyperalgesia, suggesting that the antihyperalgesia occurred through a peripheral mechanism. These data demonstrate that cannabinoids primarily activate peripheral CB1 receptors to attenuate hyperalgesia. Activation of this receptor in the periphery may attenuate pain without causing unwanted side effects mediated by central CB1 receptors.

Topics: Animals; Benzoxazines; Burns; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Disease Models, Animal; Hot Temperature; Hyperalgesia; Indoles; Male; Morpholines; Naphthalenes; Nerve Fibers, Myelinated; Nerve Fibers, Unmyelinated; Nociceptors; Pain; Pain Measurement; Physical Stimulation; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Receptors, Cannabinoid; Reflex; Skin

Despite histamine being a potent endogenous vasoactive agent released in increasing amounts postburn, its role in postburn oedema formation has been controversial and its effect on burn circulation poorly investigated. The present study investigated the involvement of H(1), H(2) and H(3) receptors in postburn edema in rats exposed to skin and muscle burns and their influence on skin circulation postburn. We used the selective antagonists clemastine (H(1)), ranitidine (H(2)), thioperamide (H(3)) and the selective H(3) receptor agonist, imetit. Results showed that none of the antagonists or the H(3) agonist had significant effect on postburn edema measured by quantitative spectrophotometric analysis of extravasated Evans blue-albumin in the full-thickness burned skin or muscle. Clemastine and thioperamide failed to induce significant effect on blood flow in the partial- or full-thickness skin burn injury as measured by laser Doppler flowmetry, while ranitidine significantly (P<0.01) reduced blood flow in the full-thickness burn. In contrast, the H(3) receptor agonist, imetit, significantly increased blood flow, both in the partial-thickness burn injury (P<0.05) and in the full-thickness burn (P<0.01). Moreover, imetit significantly (P<0.01) increased mean arterial pressure while thioperamide significantly (P<0.01) reduced systemic pressure. In conclusion, H(1), H(2) and H(3) receptors are not important actors in the regulation of vascular patency permeability, whereas H(3) receptors play an important role by increasing skin circulation postburn, presumably by relaxation of vascular smooth muscle and/or by interacting with other inflammatory neurotransmitters. Data also suggest that H(2) receptor blockers may not be best choice for stress ulcer prophylaxis in burn patients.

Topics: Animals; Burns; Clemastine; Edema; Histamine Agonists; Histamine H1 Antagonists; Histamine H2 Antagonists; Imidazoles; Male; Piperidines; Ranitidine; Rats; Rats, Sprague-Dawley; Receptors, Histamine; Receptors, Histamine H3; Regional Blood Flow; Skin; Statistics, Nonparametric; Thiourea

Local thermal injury to the paw leads to an increased sensitivity to a noxious stimulus applied to the site (primary thermal hyperalgesia) and an increased sensitivity to tactile stimuli in skin sites adjacent to the primary injury (secondary tactile allodynia; 2 degrees TA). We sought to define the peripheral and spinal actions of mu opioids in regulating 2 degrees TA. First, a mild thermal injury was induced on one heel, producing 2 degrees TA. This 2 degrees TA was blocked by pretreatment, but not posttreatment, with a topical mu-opioid agonist, loperamide (1.7%-5%). Second, 2 degrees TA was blocked by intrathecal morphine (0.1-10 microg) pre- and postinjury. 2 degrees TA reappeared when systemic naloxone was given before, but not after, injury in intrathecal morphine-pretreated rats. Intrathecal remifentanil, a short-lasting mu-opioid agonist, infused periinjury (3 microg/min), did not block subsequent primary thermal hyperalgesia, but it produced a dose-dependent (0.3-3 microg/min) abolition of 2 degrees TA. Local tissue injury leads to 2 degrees TA by the activation of opiate-sensitive afferents and the initiation of a cascade that persists in the absence of that initiating injury-induced stimulus.. Sensitivity to touch observed in areas adjacent to injury is blocked by opioids applied before, but not after, injury. This suggests that injury-activated opioid-sensitive fibers are responsible for sensitization and reveals a cascade that is diminished by pretreatment but not posttreatment, providing a rationale for adequate analgesia before injury (surgery) has occurred.

Topics: Administration, Topical; Analgesics, Opioid; Animals; Burns; Hindlimb; Hyperalgesia; Injections, Spinal; Loperamide; Male; Morphine; Naloxone; Narcotic Antagonists; Neural Pathways; Neurons, Afferent; Pain Threshold; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu; Remifentanil; Spinal Cord; Touch

1. Scald injury in Sv129+C57BL/6 mice induced a temperature and time dependent oedema formation as calculated by the extravascular accumulation of [(125)I]-albumin. Oedema formation was suppressed in NK(1) knockout mice compared to wildtypes at 10 (P<0.01) and 30 min (P<0.001). However, at 60 min a similar degree of extravasation was observed in the two groups. 2. Kinin B(1) (des-Arg(10) Hoe 140; 1 micromol kg(-1)) and B(2) (Hoe 140; 100 nmol kg(-1)) antagonists caused an inhibition of oedema in wildtype mice at 10 and 30 min (P<0.001), but not at 60 min or at 30 min in NK(1) receptor knockout mice. 3. The inhibition of thermic oedema by des-Arg(10) Hoe 140 was reversed by des-Arg(9) bradykinin (0.1 micromol kg(-1); P<0.01) and also observed with a second B(1) receptor antagonist (des-Arg(9) Leu(8) bradykinin; 3 micromol kg(-1); P<0.01). Furthermore des-Arg(10) Hoe 140 had no effect on capsaicin (200 microg ear(-1)) ear oedema, but this was significantly reduced with Hoe 140 (P<0.05). 4. Scalding induced a large neutrophil accumulation at 4 h, as assessed by myeloperoxidase assay (P<0.001). This was not suppressed by NK(1) receptor deletion or kinin antagonists. 5. These results confirm an essential role for the NK(1) receptor in mediating the early, but not the delayed phase of oedema formation or neutrophil accumulation in response to scalding. The results also demonstrate a pivotal link between the kinins and sensory nerves in the microvascular response to burn injury, and for the first time show a rapid involvement of the B(1) receptor in murine skin.

Topics: Administration, Topical; Animals; Bradykinin; Bradykinin Receptor Antagonists; Burns; Capsaicin; Cell Movement; Dermatitis; Edema; Hot Temperature; Injections, Intravenous; Mice; Mice, Inbred C57BL; Mice, Knockout; Neutrophils; Piperidines; Quinuclidines; Receptor, Bradykinin B1; Receptor, Bradykinin B2; Receptors, Bradykinin; Receptors, Neurokinin-1; Tachykinins; Time Factors

The effect of the non-peptide selective tachykinin NK1 receptor antagonist SR140333 has been investigated on oedema formation and neutrophil accumulation induced by thermal injury (50 degrees C for 5 min), mustard oil, substance P, the tachykinin NK1 agonist GR73632, and interleukin-1beta in the abdominal skin of the anaesthetised rat. SR140333 significantly inhibited (120 nmol/kg i.v.) or prevented (240 nmol/kg i.v.) the early oedema formation (0-10 min) induced by thermal injury. However, a dosing strategy which blocked NK1 receptors for 5 h (SR140333, 240 nmol/kg i.v. + 240 nmol/kg s.c.) failed to influence neutrophil accumulation measured 5 h after thermal injury. Thus, the neurogenic component mediated by NK1 receptors is important to elicit the early oedema formation, but does not influence subsequent neutrophil accumulation. Topical application of mustard oil (2%), a neurogenic inflammation stimulant, caused NK1 receptor-mediated early neurogenic plasma extravasation, but did not induce cutaneous neutrophil accumulation over 5 h. Substance P and GR73632 at high doses (1 nmol/site) also failed to elicit neutrophil accumulation. Neutrophil accumulation induced by interleukin-1beta (0.03-3 pmol i.d.) was not affected by SR140333 pretreatment. In conclusion, despite an early pronounced tachykinin NK1 receptor-dependent oedema response after thermal injury, the results suggest that subsequent neutrophil accumulation is not mediated by NK1 receptors. Furthermore, we have not obtained any evidence to suggest that either endogenous or exogenous tachykinins can directly induce neutrophil accumulation in the rat cutaneous microvasculature.

Topics: Abdomen; Animals; Bradykinin; Burns; Dose-Response Relationship, Drug; Edema; Hindlimb; Histamine; Inflammation; Interleukin-1; Male; Microcirculation; Mustard Plant; Neurokinin-1 Receptor Antagonists; Neutrophils; Peptide Fragments; Piperidines; Plant Extracts; Plant Oils; Quinuclidines; Rats; Rats, Wistar; Receptors, Neurokinin-1; Skin; Substance P; Time Factors

1. The involvement of the neuropeptides, substance P (SP) and calcitonin gene-related peptide (CGRP) in plasma extravasation following thermal injury of rat dorsal skin was investigated. 2. Heat applied to the dorsal skin of anaesthetized rats by a temperature-controlled skin heater (1 cm diameter) for 5 min induced temperature-dependent plasma protein extravasation at 46 degrees C to 50 degrees C measured over the 20 min following initiation of heat. 3. The NK1-receptor antagonist, SR140333, at doses above 36 nmol kg-1, significantly (P < 0.05) inhibited plasma extravasation by up to 79 +/- 3% (120 nmol kg-1) after heat application at 48 degrees C and by up to 53 +/- 10% (120 nmol kg-1) after heat application at 50 degrees C. 4. The CGRP1-receptor antagonist, CGRP8-37, at doses of 200 and 400 nmol kg-1, significantly inhibited (P < 0.01) plasma extravasation by 55 +/- 9 and 60 +/- 12%, respectively, after heat application at 48 degrees C. At a dose of 200 nmol kg-1 CGRP8-37 inhibited plasma extravasation by 41 +/- 8% after heat application at 50 degrees C. 5. SR140333, 120 nmol kg-1, and CGRP8-37, 200 nmol kg-1 together significantly (P < 0.01) inhibited plasma extravasation by 84 +/- 15% after heating at 48 degrees C for 5 min. 6. In experiments where the response was measured for 0-5, 5-10, 10-15 or 15-20 min, SR140333, 120 nmol kg-1, significantly (P < 0.05) inhibited plasma extravasation which had accumulated during all the time periods measured. In comparison, CGRP8-37, 200 nmol kg-1, was significantly (P < 0.05) effective at time-points up to 15 min after initiation of injury. 7. In longer term experiments plasma protein extravasation continued for at least 95 min after initiation of thermal injury. SR140333, at a dose of 120 nmol kg-1, significantly inhibited plasma extravasation for up to 65 min after initiation of injury. 8. In conclusion, the data from the present study demonstrate that both SP and CGRP are likely to have a role in the acute plasma extravasation after thermal injury. In addition, evidence suggests SP may have a role in plasma extravasation for up to 65 min.

Topics: Animals; Burns; Calcitonin Gene-Related Peptide; Edema; Male; Peptide Fragments; Piperidines; Quinuclidines; Rats; Rats, Wistar; Skin; Substance P

The synthetic immunomodulators muramyl dipeptide (MDP), thymopoietin pentapeptide (TP5), and CP-46,665 were examined for their effects on wound healing in mice. We found no differences in wound disruption strength between immunomodulator-treated animals and saline controls on days 11, 14, and 21. The only exception was with high-dose CP-46,665, which produced weakened wounds on day 14 (p less than 0.05) and 21 (p less than 0.01). CP-46,665 was further studied by injecting high and low doses 48 hours before or after wounding. No differences were seen for these groups compared to controls at 11 and 21 days. Finally, to simulate a common clinical situation, mice were subjected to a 10% total body surface area (TBSA) burn to the right paraspinal region. Twenty-four hours later, a left paraspinal incision was performed with simultaneous injection of saline, Corynebacterium parvum (C. parvum), or low-dose TP-5, MDP, or CP-46,665. At 11 days, no detriment in wound healing was found for burned control or any of the immunomodulator-treated animals except in the C. parvum-treated mice, with significantly weakened skin strips (p less than 0.001). While C. parvum may be detrimental to wound healing, the synthetic modulators tested appear to have little effect on wound healing.

Topics: Acetylmuramyl-Alanyl-Isoglutamine; Adjuvants, Immunologic; Animals; Burns; Male; Mice; Mice, Inbred Strains; Peptide Fragments; Piperidines; Propionibacterium acnes; Skin; Thymopentin; Thymopoietins; Wound Healing; Wounds, Penetrating

Despite antibiotics, infection remains a significant problem in surgical patients. The reasons are multiple, and include acquired immunologic deficiencies that are seen in malnutrition, sepsis, trauma, and burns. Two immunomodulators, thymopentin (TP-5) and CP-46,665, have been shown to improve survival in infectious animal models of such deficiencies. We investigated the mechanism of action in guinea pigs subjected to a burn of 30% of the total body surface area. These animals received 0.3 mg/kg of thymopentin, 0.3 mg/kg of CP-46,665, or saline solution. Neutrophils, macrophages, and serum samples were obtained from the animals and tested for their ability to phagocytose and kill Pseudomonas aeruginosa. The serum was tested for its ability to opsonize Escherichia coli. Thymopentin was found to improve neutrophil function on postburn days 2 and 4 and to improve macrophage function on postburn day 4. CP-46,665 was found to improve both macrophage function and opsonization on postburn day 2.

Topics: Adjuvants, Immunologic; Animals; Burns; Disease Models, Animal; Female; Guinea Pigs; Immunologic Deficiency Syndromes; Macrophages; Neutrophils; Opsonin Proteins; Peptide Fragments; Phagocytosis; Piperidines; Pseudomonas aeruginosa; Thymopentin; Thymopoietins; Thymus Hormones; Time Factors

Deficiencies in the immune system that lead to increased morbidity and mortality from infectious complications have been well documented in patients suffering from trauma, malnutrition, sepsis, and thermal injuries. We investigated the potential benefit of immune stimulation for preventing infection in such conditions in an animal model by evaluating three drugs: Corynebacterium parvum, thymopentin (TP-5), and CP-46,665. One-hundred eighty female guinea pigs were rendered immunodeficient by first inflicting a 30% total body surface burn and then placing the animals on diets with calories inadequate to maintain body weight. One half of the animals were then given one of the three immunomodulators on the first, third, and fifth days after burn injury, to try to reverse immunodeficiency. The remaining animals received saline solution injections. Animal responses were evaluated by inserting a clot containing Escherichia coli and Bacillus fragilis into their peritoneal cavity 6 days after burn injury. The animals were followed for 21 days after burn injury. Autopsies on those that died revealed peritonitis and/or pneumonia; autopsies on these that survived showed no pneumonia and there was consistent resolution of peritonitis. TP-5 and CP-46,665, but not C. parvum, significantly improved survival rates and mean survival time in those animals receiving 100 kcal/kg/day. TP-5 and CP-46,665 may be of benefit to the severely stressed, malnourished surgical patient who is at risk of bacterial infection.

Topics: Adjuvants, Immunologic; Animals; Bacterial Vaccines; Burns; Female; Guinea Pigs; Nutrition Disorders; Peptide Fragments; Peritonitis; Piperidines; Pneumonia; Propionibacterium acnes; Thymopentin; Thymopoietins

Topics: Adjuvants, Immunologic; Animals; Antibodies, Monoclonal; Antibody Formation; Bacillus; Burns; Humans; Immunity, Cellular; Immunity, Innate; Interleukin-1; Interleukin-2; Neisseria; Peptide Fragments; Piperidines; Pyridines; Staphylococcus; Streptococcus; Sulfhydryl Compounds; Thiazoles; Thymopentin; Thymopoietins; Viruses; Wound Infection

Individuals who have suffered severe trauma, such as burns, have a high incidence of infection associated with impaired host resistance. Nonspecific stimulators of host defense mechanisms, i.e., immunomodulators, may be of benefit in such situations. A small animal model (guinea pigs) was developed to study the efficacy of immunomodulators in burns. Anesthetized animals received a 20% total body surface area, full-thickness, scald burn. There was no mortality associated with this injury, but these animals were highly susceptible to challenge with Pseudomonas aeruginosa strain 1244 by direct injection into the burn wound within 24 hours of injury. This susceptibility persisted about 7 days. The standard model adopted was to injure animals, then challenge with 1 median lethal dose (LD50) of P. aeruginosa 96 hours after injury. Using this model, six synthetic immunomodulators were tested: CP-20,961, CP-46,665, muramyl dipeptide, thymopoietin pentapeptide (TP-5), levamisole, and lithium. Drug administration began 24 hours after injury and ended prior to challenge with P. aeruginosa at 96 hours. CP-20,961, muramyl dipeptide, levamisole, and lithium all had no beneficial effect on survival. A single dosage (0.3 mg/kg, I.V.) of CP-46,665, administered 24 hours postinjury, increased the survival rate from 50% to 85% and mean survival time (MST) from 8.2 days to 12.4 days. TP-5, given in four doses (0.1 mg/kg, I.V. each) every 24 hours, increased the survival rate from 40% to 80% and MST from 6.9 days to 11.6 days. These data show that immunomodulators could be of benefit in burns, but also that not all agents are effective in this particular situation.

Topics: Acetylmuramyl-Alanyl-Isoglutamine; Adjuvants, Immunologic; Animals; Burns; Diamines; Evaluation Studies as Topic; Female; Guinea Pigs; Lethal Dose 50; Levamisole; Lithium; Peptide Fragments; Piperidines; Pseudomonas aeruginosa; Pseudomonas Infections; Thymopentin; Thymopoietins; Time Factors

A number of vasoactive substances, including serotonin, have been implicated in the pathophysiology of burn shock. Ketanserin, a specific serotonin antagonist, was investigated in a porcine burn shock model. Fifteen swine were given a mean 44% total body surface area full-thickness scald burn and received fluid resuscitation with Ringer's lactate for 24 hours postburn. The swine were divided into three groups: Group I (control group) received no ketanserin; Group II received ketanserin as a single intramuscular dose preburn and continuously via intravenous drip postburn; and Group III received ketanserin continuously via intravenous drip postburn only. The ketanserin-treated groups demonstrated improved cardiac index, decreased pulmonary artery pressures, and smaller arteriovenous oxygen content differences compared to the control group in the early postburn period. Ketanserin should be investigated further as a possible adjunctive therapeutic agent during burn shock resuscitation.

Topics: Animals; Blood Pressure; Body Temperature; Burns; Disease Models, Animal; Heart Rate; Hemodynamics; Ketanserin; Piperidines; Serotonin Antagonists; Shock, Traumatic; Swine

Topics: Animals; Benzocycloheptenes; Burns; Cyproheptadine; Exudates and Transudates; Histamine H1 Antagonists; Piperidines; Rats; Skin; Thiophenes; Tissue Extracts

Topics: Adolescent; Adult; Amines; Analgesics; Burns; Child, Preschool; Cyclohexanecarboxylic Acids; Female; Humans; Isonipecotic Acids; Male; Nitriles; Pentazocine; Piperidines

Topics: Adolescent; Anesthesia, Inhalation; Anesthetics; Attitude to Health; Burns; Child; Child, Hospitalized; Child, Preschool; Debridement; Female; Humans; Infant; Intubation, Gastrointestinal; Male; Phencyclidine; Piperidines; Postoperative Care; Skin Transplantation; Transplantation, Autologous

Topics: Animals; Benzoates; Body Weight; Burns; Calcium; Ergoloid Mesylates; Female; Piperidines; Rats; Solutions

Topics: Adult; Alkaloids; Anti-Bacterial Agents; Anti-Infective Agents, Local; Bandages; Burns; Burns, Chemical; Burns, Electric; Child; Electrolytes; Eye Injuries; Facial Injuries; First Aid; Humans; Pain; Piperidines; Plasma Substitutes; Pyrazoles; Respiratory System; Shock; Tetanus; Transportation of Patients; Wounds and Injuries

Topics: Analgesics; Animals; Burns; Chemical Phenomena; Chemistry, Physical; Infrared Rays; Magnetic Resonance Spectroscopy; Optical Rotatory Dispersion; Piperidines; Spectrophotometry