RESUMEN
AIM: Patients with severe burns typically undergo multiple surgeries, and ketamine is often used as part of the multimodal anesthetic regimen during such surgeries. The anesthetic ketamine is an N-methyl-D-aspartate receptor antagonist that also provides analgesia at subanesthetic doses, but the psychoactive side effects of ketamine have caused concern about its potential psychological effects on a combat-wounded population. Post-traumatic stress disorder (PTSD) affects approximately 30% of burned U.S. service members injured in Operation Iraqi Freedom/Operation Enduring Freedom. A preliminary analysis by our research group reported that patients who received perioperative ketamine had a significantly lower prevalence of PTSD than those injured service members who did not receive ketamine. We have now expanded this research to examine the relationship between ketamine and PTSD development in a much larger population. METHODS: A retrospective analysis on data from service members being treated for burns at the San Antonio Military Medical Center was conducted. Collected data included drugs received, injury severity score (ISS), total body surface area (TBSA) burned, length of hospital stay (LOS), number of intensive care unit days, number of surgeries, and PTSD Checklist-Military (PCL-M) scores and administration dates. Subjects were grouped based on intraoperative receipt of ketamine, and the groups were compared. The groups were binary for ketamine (yes or no), and dose of ketamine administered was not included in data analyses. Propensity score matching based on ISS and TBSA was performed to control for individual differences in burn severity. RESULTS: Two hundred eighty-nine burned U.S. service members received the PCL-M at least 30 days after injury. Of these subjects, 189 received intraoperative ketamine, and 100 did not. Despite significantly greater injuries, as evidenced by significantly higher TBSA burned and ISS (p < 0.01), patients who received ketamine did not screen positive for PTSD at a different rate than those patients who did not (24% vs. 26.98%, p = 0.582). Patients receiving intraoperative ketamine also underwent a significantly greater number of surgeries, spent more time in the hospital, spent more days in the ICU, and received more morphine equivalent units (p < 0.0001). Propensity score matching based on ISS and TBSA resulted in a total subject number of 130. In the matched samples, subjects who received ketamine still underwent significantly more surgeries and experienced longer hospital stays (p < 0.0001). Again, there was no statistically significant difference in the incidence of a positive screen for PTSD based upon the receipt of ketamine (28% vs. 26.15%, p = 0.843). CONCLUSIONS: Ketamine is often used in burn patients to reduce opioid usage and decrease the hemodynamic and respiratory side effects. Although this study does not show a benefit of ketamine on PTSD development that was identified in previous work with a smaller sample number, it does support the conclusion that ketamine does not increase PTSD development in burned service members.
Asunto(s)
Anestésicos Disociativos/administración & dosificación , Quemaduras/cirugía , Ketamina/administración & dosificación , Personal Militar/psicología , Trastornos por Estrés Postraumático/epidemiología , Adolescente , Adulto , Humanos , Incidencia , Puntaje de Gravedad del Traumatismo , Cuidados Intraoperatorios , Estudios Retrospectivos , Trastornos por Estrés Postraumático/etiología , Estados Unidos/epidemiología , Adulto JovenRESUMEN
Opioid-related side effects are problematic for burn patients. Dual mechanism therapeutics targeting opioid and non-opioid mechanisms may have reduced side effects with similar analgesic efficacy. Tramadol combines mu opioid receptor agonism with norepinephrine reuptake inhibition and has been effective in treating some types of pain. The effectiveness of tramadol in treating pain associated with burns is unclear. We hypothesized that tramadol is effective in reducing thermal injury-evoked pain behaviors in a rat model. Rats were anesthetized and a 100°C metal probe was placed on the hindpaw for 30 s to induce a full thickness thermal injury. A subset of rats was perfusion fixed and hindpaw tissue and spinal cord collected for anatomical analysis. Rats received morphine (5 mg/kg; i.p.), tramadol (10-30 mg/kg; i.p.) or vehicle and latency to paw withdrawal from a noxious thermal or non-noxious mechanical stimulus was recorded every 10 min over 70 min and again at 2 h. We report that pain behaviors developed within 48 h and peaked at 1 week; paralleled by enhanced expression of pronociceptive neuropeptides in the spinal cord. Morphine and tramadol significantly attenuated hyperalgesia and allodynia, while not significantly altering motor coordination/sedation. These data indicate dual mechanism therapeutics may be effective for treating pain associated with burns.
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Analgésicos Opioides/farmacología , Quemaduras/metabolismo , Péptido Relacionado con Gen de Calcitonina/metabolismo , Hiperalgesia/metabolismo , Morfina/farmacología , Nocicepción/efectos de los fármacos , Médula Espinal/metabolismo , Sustancia P/metabolismo , Tramadol/farmacología , Animales , Conducta Animal , Quemaduras/complicaciones , Quemaduras/patología , Modelos Animales de Enfermedad , Hiperalgesia/etiología , Masculino , Dolor Nociceptivo/etiología , Dolor Nociceptivo/metabolismo , Dolor/etiología , Dolor/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
Posttraumatic stress disorder (PTSD) affects approximately 30% of burned Servicemembers returning from Operation Iraqi Freedom/Operation Enduring Freedom. Gabapentin and pregabalin are anticonvulsant drugs that limited evidence suggests may also be effective treatments for some psychological disorders. This study examines the relationship between these anticonvulsants and PTSD development in burned Servicemembers. Drugs received, injury severity score, TBSA burned, length of hospital stay, number of intensive care unit days, number of surgeries, and PTSD Checklist-Military scores and administration dates were collected. Subjects were grouped based on receipt of gabapentin or pregabalin, and the groups were compared. The primary outcome was incidence of a positive screen for PTSD. Because injury severity was significantly different between the two groups, propensity score matching based on injury severity score and TBSA was performed. Two hundred ninety burned Servicemembers received the PTSD Checklist-Military at least 30 days after injury. Of these subjects, 104 received gabapentin, pregabalin, or both and 186 did not. Despite significantly greater injuries, the group that received gabapentin or pregabalin did not develop PTSD at a different rate than those patients who did (P = .727). Propensity score matching resulted in 57 patients in each group; there was no difference between these groups in the incidence of PTSD (P = .663). These data suggest that gabapentin or pregabalin administration may not affect PTSD development in burned Servicemembers. Many factors influence the development and progression of PTSD, but few drugs have been identified that are effective at treating or preventing PTSD.
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Aminas/uso terapéutico , Analgésicos/uso terapéutico , Ansiolíticos/uso terapéutico , Quemaduras/psicología , Ácidos Ciclohexanocarboxílicos/uso terapéutico , Trastornos por Estrés Postraumático/tratamiento farmacológico , Ácido gamma-Aminobutírico/análogos & derivados , Adulto , Quemaduras/complicaciones , Quemaduras/tratamiento farmacológico , Femenino , Gabapentina , Indicadores de Salud , Humanos , Masculino , Personal Militar , Pregabalina , Puntaje de Propensión , Psicología Militar , Psicometría , Estudios Retrospectivos , Estadística como Asunto , Trastornos por Estrés Postraumático/epidemiología , Trastornos por Estrés Postraumático/etiología , Estados Unidos/epidemiología , Ácido gamma-Aminobutírico/uso terapéuticoRESUMEN
BACKGROUND: Acute pain after injury affects the comfort and function of the wounded soldier and the physiology of multiple body systems. In the civilian population, pain alters the function of the autonomic nervous system, causing increased heart rate and blood pressure. However, there are no data regarding the impact of combat-related pain on physiologic responses. This study is a retrospective analysis that examined the relationship of pain and physiologic parameters in injured soldiers. METHODS: After Institutional Review Board approval, the Joint Trauma Theater Registry (JTTR) was queried to identify soldiers who had pain scores recorded in the Emergency Department (ED) in theater. Subject data collected from the JTTR included the following: pain score, Injury Severity Score (ISS), blood pressure, heart rate, and respiratory rate. RESULTS: We identified 2,646 soldiers with pain scores recorded in the ED. The pain score was not related to most physiologic parameters measured in the ED. Pain intensity had no correlation with blood pressure or heart rate. However, there were relationships between the pain score and respiratory rate, with patients reporting a pain score of 10 having a slightly higher respiratory rate. Increasing pain scores were also associated with increased ISS (p < 0.001). CONCLUSIONS: In contrast to data from civilian patients, early pain scores were not related to heart rate or blood pressure. A pain score of 10 corresponded to an increased respiratory rate. Despite little relationship between pain and injury severity in the civilian population, the increasing ISS was proportional to the pain scale in wounded soldiers.
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Sistema Nervioso Autónomo/fisiopatología , Personal Militar , Dolor/etiología , Heridas y Lesiones/fisiopatología , Campaña Afgana 2001- , Presión Sanguínea/fisiología , Frecuencia Cardíaca/fisiología , Humanos , Puntaje de Gravedad del Traumatismo , Guerra de Irak 2003-2011 , Dolor/fisiopatología , Dimensión del Dolor , Frecuencia Respiratoria/fisiología , Estudios Retrospectivos , Heridas y Lesiones/complicacionesRESUMEN
Early acute pain after injury has been linked to long-term patient outcomes, including the development of posttraumatic stress disorder (PTSD). Several studies have identified a negative correlation between early anesthetic/analgesic usage and subsequent development of PTSD. This retrospective study examined the relationship between early acute pain and severity of PTSD symptoms in soldiers with burn injuries. Of the soldiers injured in Overseas Contingency Operations who had pain scores recorded at admission to the Emergency Department, 113 had burn injuries. Of those transferred to the military burn center, 47 were screened for PTSD using the PTSD checklist-military (PCL-M) survey at least 1 month after injury. Soldiers with mild, moderate, and severe pain scores had similar Injury Severity Scores and TBSA burned (P = .339 and .570, respectively). However, there were significant differences in PCL-M scores between the mild and severe pain groups (P = .017). The pain levels positively correlated with the PCL-M score (rho = 0.41, P = .004) but not with injury severity markers (Injury Severity Score and TBSA). These data suggest that early acute pain may be related to increased PCL-M score and PTSD symptoms. The intensity of pain was not related to the injury severity, and these data also show no association between pain intensity and physiological measures, including blood pressure and heart rate. However, this is a small sample size, and many other factors likely influence PTSD development. Further study is necessary to explore the relationship between early acute pain and subsequent development of PTSD symptoms.
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Quemaduras/complicaciones , Quemaduras/psicología , Personal Militar/psicología , Dolor/psicología , Trastornos por Estrés Postraumático/etiología , Trastornos por Estrés Postraumático/psicología , Adulto , Humanos , Puntaje de Gravedad del Traumatismo , Masculino , Dimensión del Dolor , Estudios Retrospectivos , Estadísticas no Paramétricas , Estados UnidosRESUMEN
Enterotoxigenic Escherichia coli (ETEC) produces the ADP-ribosyltransferase toxin known as heat-labile enterotoxin (LT). In addition to the toxic effect of LT resulting in increases of cyclic AMP (cAMP) and disturbance of cellular metabolic processes, this toxin promotes bacterial adherence to intestinal epithelial cells (A. M. Johnson, R. S. Kaushik, D. H. Francis, J. M. Fleckenstein, and P. R. Hardwidge, J. Bacteriol. 191:178-186, 2009). Therefore, we hypothesized that the identification of a compound that inhibits the activity of the toxin would have a suppressive effect on the ETEC colonization capabilities. Using in vivo and in vitro approaches, we present evidence demonstrating that a fluorenone-based compound, DC5, which inhibits the accumulation of cAMP in intoxicated cultured cells, significantly decreases the colonization abilities of adenylyl cyclase toxin-producing bacteria, such as ETEC. These findings established that DC5 is a potent inhibitor both of toxin-induced cAMP accumulation and of ETEC adherence to epithelial cells. Thus, DC5 may be a promising compound for treatment of diarrhea caused by ETEC and other adenylyl cyclase toxin-producing bacteria.
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Inhibidores de Adenilato Ciclasa , Adhesinas Bacterianas/metabolismo , Toxinas Bacterianas/antagonistas & inhibidores , Escherichia coli Enterotoxigénica/patogenicidad , Enterotoxinas/antagonistas & inhibidores , Inhibidores Enzimáticos/administración & dosificación , Infecciones por Escherichia coli/prevención & control , Proteínas de Escherichia coli/antagonistas & inhibidores , Animales , Adhesión Bacteriana/efectos de los fármacos , Línea Celular , Recuento de Colonia Microbiana , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/toxicidad , Células Epiteliales/microbiología , Femenino , Fluorenos/administración & dosificación , Fluorenos/farmacología , Fluorenos/toxicidad , Humanos , Concentración 50 Inhibidora , Intestino Delgado/microbiología , Intestino Delgado/patología , Macrófagos/microbiología , RatonesRESUMEN
Lpf (stands for long polar fimbriae) is one of the few adhesive factors of enterohemorrhagic Escherichia coli O157:H7 associated with colonization of the intestine. E. coli O157:H7 strains possess two lpf loci encoding highly regulated fimbrial structures. Database analysis of the genes encoding the major fimbrial subunits demonstrated that they are present in commensal as well as pathogenic (both intestinal and extraintestinal) E. coli strains and in Salmonella strains and that the lpfA1 and lpfA2 genes are highly prevalent among LEE (locus of enterocyte effacement)-positive E. coli strains associated with severe and/or epidemic disease. Further DNA sequence analysis of the lpfA1 and lpfA2 genes from different attaching-and-effacing E. coli strains has led us to the identification of several polymorphisms and the classification of the major fimbrial subunits into distinct variants. Using collections of pathogenic E. coli isolates from Europe and Latin America, we demonstrated that the different lpfA types are associated with the presence of specific intimin (eae) adhesin variants and, most importantly, that they are found in specific E. coli pathotypes. Our results showed that the use of these fimbrial genes as markers, in combination with the different intimin types, resulted in a specific test for the identification of E. coli O157:H7, distinguishing it from other pathogenic E. coli strains.
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Proteínas de Escherichia coli/genética , Escherichia coli/genética , Escherichia coli/patogenicidad , Fimbrias Bacterianas/genética , Factores de Virulencia/genética , ADN Bacteriano/química , ADN Bacteriano/genética , Escherichia coli/clasificación , Infecciones por Escherichia coli/microbiología , Europa (Continente) , Marcadores Genéticos , Humanos , América Latina , Datos de Secuencia Molecular , Análisis de Secuencia de ADN , Estados Unidos , VirulenciaRESUMEN
The expression of the long polar fimbriae (LPF) of enterohemorrhagic Escherichia coli (EHEC) O157:H7 is controlled by a tightly regulated process, and, therefore, the role of these fimbriae during binding to epithelial cells has been difficult to establish. We recently found that histone-like nucleoid-structuring protein (H-NS) binds to the regulatory sequence of the E. coli O157:H7 lpf1 operon and "silences" its transcription, while Ler inhibits the action of the H-NS protein and allows lpf1 to be expressed. In the present study, we determined how the deregulated expression of LPF affects binding of EHEC O157:H7 to tissue-cultured cells, correlating the adherence phenotype with lpf1 expression. We tested the adherence properties of EHEC hns mutant and found that this strain adhered 2.8-fold better than the wild type. In contrast, the EHEC ler mutant adhered 2.1-fold less than the wild type. The EHEC hns ler mutant constitutively expressed the lpf genes, and, therefore, we observed that the double mutant adhered 5.6-fold times better than the wild type. Disruption of lpfA in the EHEC hns and hns ler mutants or the addition of anti-LpfA serum caused a reduction in adhesion, demonstrating that the increased adherence was due to the expression of LPF. Immunogold-labeling electron microscopy showed that LPF is present on the surface of EHEC lpfA(+) strains. Furthermore, we showed that EHEC expressing LPF agglutinates red blood cells from different species and that the agglutination was blocked by the addition of anti-LpfA serum. Overall, our data confirmed that expression of LPF is a tightly regulated process and, for the first time, demonstrated that these fimbriae are associated with adherence and hemagglutination phenotypes in EHEC O157:H7.
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Adhesión Bacteriana/genética , Proteínas Bacterianas/genética , Proteínas de Unión al ADN/genética , Escherichia coli O157/fisiología , Proteínas de Escherichia coli/genética , Fimbrias Bacterianas/genética , Fimbrias Bacterianas/metabolismo , Transactivadores/genética , Proteínas Bacterianas/metabolismo , Western Blotting , Proteínas de Unión al ADN/metabolismo , Proteínas de Escherichia coli/metabolismo , Regulación Bacteriana de la Expresión Génica , Células HeLa , Humanos , Inmunohistoquímica , Transactivadores/metabolismoRESUMEN
Adherence of pathogenic Escherichia coli strains to intestinal epithelia is essential for infection. For enterohemorrhagic E. coli (EHEC) serotype O157:H7, we have previously demonstrated that multiple factors govern this pathogen's adherence to HeLa cells (A. G. Torres and J. B. Kaper, Infect. Immun. 71:4985-4995, 2003). One of these factors is CadA, a lysine decarboxylase, and this protein has been proposed to negatively regulate virulence in several enteric pathogens. In the case of EHEC strains, CadA modulates expression of the intimin, an outer membrane adhesin involved in pathogenesis. Here, we inactivated cadA in O157:H7 strain 86-24 to investigate the role of this gene in EHEC adhesion to tissue-cultured monolayers, global gene expression patterns, and colonization of the infant rabbit intestine. The cadA mutant did not possess lysine decarboxylation activity and was hyperadherent to tissue-cultured cells. Adherence of the cadA mutant was nearly twofold greater than that of the wild type, and the adherence phenotype was independent of pH, lysine, or cadaverine in the media. Additionally, complementation of the cadA defect reduced adherence back to wild-type levels, and it was found that the mutation affected the expression of the intimin protein. Disruption of the eae gene (intimin-encoding gene) in the cadA mutant significantly reduced its adherence to tissue-cultured cells. However, adherence of the cadA eae double mutant was greater than that of an 86-24 eae mutant, suggesting that the enhanced adherence of the cadA mutant is not entirely attributable to enhanced expression of intimin in this background. Gene array analysis revealed that the cadA mutation significantly altered EHEC gene expression patterns; expression of 1,332 genes was downregulated and that of 132 genes was upregulated in the mutant compared to the wild-type strain. Interestingly, the gene expression variation shows an EHEC-biased gene alteration including intergenic regions. Two putative adhesins, flagella and F9 fimbria, were upregulated in the cadA mutant, suggestive of their association with adherence in the absence of the Cad regulatory mechanism. In the infant rabbit model, the cadA mutant outcompeted the wild-type strain in the ileum but not in the cecum or mid-colon, raising the possibility that CadA negatively regulates EHEC pathogenicity in a tissue-specific fashion.