RESUMEN
OBJECTIVE: In medicine, especially in a preoperative setting, training of effective communication skills is challenging, since communication is often implicatively copied from professional environment. This phenomenological study describes the development and experience of two patient-embodied virtual reality experiences designed to be used as an educational tool. METHOD: Two patient-embodied VR experiences from a first person patient perspective deployed negative or positive communication styles. The authors investigated the lived learning experiences of these VR tools through semi-structured interviews with ten anaesthesiologists adapting a thematic analysis framework. RESULTS: Interviews revealed acknowledgement of the importance of good communication skills. Overall, participants learned and adapted their style of communication 'on the job'. Patient-embodied VR was effective for a full immersive experience as participants expressed to have felt as if they had been a patient. They were able to distinguish differences in communication styles and analysis of the reflection showed a shift in perception, implying effective immersive experimental learning. CONCLUSIONS: This study elaborated the potency of experimental learning with VR in communication in a preoperative setting. Patient-embodied VR can influence beliefs and values and demonstrated effective as an educative tool. PRACTICAL IMPLICATIONS: The findings of this study can contribute to further research and healthcare education programs avid to use immersive learning with VR.
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Realidad Virtual , Humanos , Aprendizaje , Escolaridad , Competencia Clínica , ComunicaciónRESUMEN
Patient-controlled analgesia (PCA) is a popular and efficacious form of postoperative pain relief that, however, is not without complications. Here we describe a 73-year-old Somalian male patient that underwent abdominal surgery and received intravenous morphine PCA for postoperative pain relief. Due to his inability to speak the native language, his son served as interpreter. On the day after surgery, the patient was found unresponsive by the nursing staff with an oxygen saturation of 91%. He was treated with naloxone and transferred to a medium care facility. The son indicated that he had operated the PCA system at regular intervals over the last 12 hours. The dangers of PCA and PCA by proxy in particular are discussed. In this case, the language barrier, and possibly cultural differences and health illiteracy may have contributed to the PCA by proxy.
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Analgesia Controlada por el Paciente/efectos adversos , Barreras de Comunicación , Familia , Morfina/efectos adversos , Sobredosis de Opiáceos/etiología , Dolor Postoperatorio/tratamiento farmacológico , Anciano , Analgésicos Opioides/uso terapéutico , Cultura , Alfabetización en Salud , Humanos , Masculino , Morfina/uso terapéuticoRESUMEN
BACKGROUND: Severely increased right ventricular (RV) afterload is considered a contra-indication for orthotopic liver transplantation (OLT). This study assesses the effects of mildly increased RV afterload on long-term outcome after OLT in relation to RV function. METHODS: 139 OLT recipients (53±12years, 76% male) were included. Preoperative RV afterload was assessed invasively or, if not available, echocardiographically and categorised as normal, high-normal (mean pulmonary artery pressure [PAP] 20-25mmHg or echocardiographic systolic PAP 35-40mmHg) or mildly elevated (mean PAP 25-35mmHg or systolic PAP 40-50mmHg). The association between level of RV afterload, echocardiographic RV function and postoperative outcome was assessed. RESULTS: Right ventricular afterload was high-normal in 17% and mildly elevated in 12% of patients. Patients with elevated RV afterload had higher echocardiographic RV dimensions and left ventricular filling pressures. RV functional parameters were within normal range and not associated with RV afterload. Increased RV afterload was associated with a higher incidence of postoperative haemodynamic complications (8%, 17%, and 29% for normal, high-normal and mildly elevated RV afterload, respectively, p=0.03) and worse survival (8-year survival 74%, 41% and 37% respectively, p=0.01). Preoperative RV function was not associated with outcome after OLT. CONCLUSIONS: Increased RV afterload was associated with increased haemodynamic complications and worse long-term survival in OLT recipients. Right ventricular function in patients with increased RV afterload was within normal range and not associated with postoperative outcome.
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Ecocardiografía , Cirrosis Hepática , Trasplante de Hígado , Disfunción Ventricular Derecha , Función Ventricular Derecha , Adulto , Anciano , Supervivencia sin Enfermedad , Femenino , Humanos , Cirrosis Hepática/mortalidad , Cirrosis Hepática/fisiopatología , Cirrosis Hepática/cirugía , Masculino , Persona de Mediana Edad , Tasa de Supervivencia , Disfunción Ventricular Derecha/etiología , Disfunción Ventricular Derecha/mortalidad , Disfunción Ventricular Derecha/fisiopatologíaRESUMEN
BACKGROUND: Animal studies suggest that N-methyl-d-aspartate receptor (NMDAR) hypofunction and subsequent decline in intracellular nitric oxide (NO) are responsible for development of ketamine-induced psychedelic symptoms. To examine this mechanism in humans, we administered the NO donor sodium nitroprusside during infusion of racemic ketamine (RS-ketamine), containing equal amounts of S(+)- and R(-)-ketamine isomers, or esketamine, containing just the S(+)-isomer. METHODS: In this randomised, double blind, placebo-controlled crossover study, healthy volunteers were treated with sodium nitroprusside 0.5 µg kg-1 min-1 or placebo during administration of escalating doses of RS-ketamine (total dose 140 mg) or esketamine (70 mg). Drug high, internal and external perception, obtained using the Bowdle questionnaire, were scored over time on a visual analogue scale. The area-under-the-time-effect-curve (AUC) was calculated for each end-point. RESULTS: Sodium nitroprusside significantly reduced drug high AUC [mean (standard deviation); placebo 9070 (4630) vs sodium nitroprusside 7100 (3320), P=0.02], internal perception AUC [placebo 1310 (1250) vs nitroprusside 748 (786), P<0.01] and external perception AUC [placebo 4110 (2840) vs nitroprusside 2890 (2120), P=0.02] during RS-ketamine infusion, but was without effect on any of these measures during esketamine infusion. CONCLUSIONS: These data suggest that NO depletion plays a role in RS-ketamine-induced psychedelic symptoms in humans. The sodium nitroprusside effect was observed for R(-)- but not S(+)-isomer-induced psychedelic symptoms. Further studies are needed to corroborate our findings and assess whether higher sodium nitroprusside doses will reduce esketamine-induced psychedelic symptoms. CLINICAL TRIAL REGISTRATION: NTR 5359.
Asunto(s)
Analgésicos/farmacología , Alucinaciones/inducido químicamente , Ketamina/farmacología , Neurotransmisores/farmacología , Óxido Nítrico/farmacología , Nitroprusiato/farmacología , Adolescente , Adulto , Estudios Cruzados , Método Doble Ciego , Humanos , Masculino , Donantes de Óxido Nítrico/farmacología , Valores de Referencia , Adulto JovenRESUMEN
BACKGROUND: Opioids can produce life-threatening respiratory depression. This study tested whether subanaesthetic doses of esketamine stimulate breathing in an established human model of opioid-induced respiratory depression. METHODS: In a study with a randomised, double blind, placebo controlled, crossover design, 12 healthy, young volunteers of either sex received a dose escalating infusion of esketamine (cumulative dose 40 mg infused in 1 h) on top of remifentanil-induced respiratory depression. A population pharmacokinetic-pharmacodynamic analysis was performed with sites of drug action at baseline ventilation, ventilatory CO2-chemosensitivity, or both. RESULTS: Remifentanil reduced isohypercapnic ventilation (end-tidal PCO2 6.5 kPa) by approximately 40% (from 20 to 12 litre min-1) in esketamine and placebo arms of the study, through an effect on baseline ventilation and ventilatory CO2 sensitivity. The reduction in ventilation was related to a remifentanil effect on ventilatory CO2 sensitivity (~39%) and on baseline ventilation (~61%). Esketamine increased breathing through an exclusive stimulatory effect on ventilatory CO2 sensitivity. The remifentanil concentration that reduced ventilatory CO2 sensitivity by 50% (C50) was doubled at an esketamine concentration of 127 (84-191) ng ml-1 [median (interquartile range)]; the esketamine effect was rapid and driven by plasma pharmacokinetics. Placebo had no systematic effect on opioid-induced respiratory depression. CONCLUSIONS: Esketamine effectively countered remifentanil-induced respiratory depression, an effect that was attributed to an increase in remifentanil-reduced ventilatory CO2 chemosensitivity.
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Analgésicos Opioides/efectos adversos , Analgésicos/farmacología , Ketamina/farmacocinética , Insuficiencia Respiratoria/inducido químicamente , Insuficiencia Respiratoria/tratamiento farmacológico , Adolescente , Adulto , Estudios Cruzados , Método Doble Ciego , Femenino , Humanos , Masculino , Valores de Referencia , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Tapentadol is an analgesic agent for treatment of acute and chronic pain that activates the µ-opioid receptor combined with inhibition of neuronal norepinephrine reuptake. Both mechanisms are implicated in activation of descending inhibitory pain pathways. In this study, we investigated the influence of tapentadol on conditioned pain modulation (CPM, an experimental measure of endogenous pain inhibition that gates incoming pain signals as a consequence of a preceding tonic painful stimulus) and offset analgesia (OA, a test in which a disproportionally large amount of analgesia becomes apparent upon a slight decrease in noxious heat stimulation). METHODS: Twenty-four patients with diabetic polyneuropathy (DPN) were randomized to receive daily treatment with tapentadol sustained-release (SR) [average daily dose 433 (31) mg] or placebo for 4 weeks. CPM and OA were measured before and on the last day of treatment. RESULTS: Before treatment, none of the patients had significant CPM or OA responses. At week 4 of treatment, CPM was significantly activated by tapentadol SR and coincided with significant analgesic responses. CPM increased from 9.1 (5.4)% (baseline) to 14.3 (7.2)% (placebo) and 24.2 (7.7)% (tapentadol SR, P<0.001 vs placebo); relief of DPN pain was also greater in patients treated with tapentadol than placebo (P=0.028). Neither placebo nor tapentadol SR treatment had an effect on the magnitude of the OA responses (P=0.78). CONCLUSIONS: Tapentadol's analgesic effect in chronic pain patients with DPN is dependent on activation of descending inhibitory pain pathways as observed by CPM responses. CLINICAL TRIAL REGISTRATION: The study was registered at trialregister.nl under number NTR2716.
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Analgésicos Opioides/uso terapéutico , Dolor Crónico/tratamiento farmacológico , Neuropatías Diabéticas/tratamiento farmacológico , Fenoles/uso terapéutico , Anciano , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/farmacología , Dolor Crónico/fisiopatología , Preparaciones de Acción Retardada , Neuropatías Diabéticas/fisiopatología , Método Doble Ciego , Esquema de Medicación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/fisiopatología , Nocicepción/efectos de los fármacos , Nocicepción/fisiología , Dimensión del Dolor/métodos , Fenoles/administración & dosificación , Fenoles/farmacología , Receptores Opioides mu/agonistas , Tapentadol , Resultado del TratamientoRESUMEN
BACKGROUND: Descending inhibition of pain, part of the endogenous pain modulation system, is important for normal pain processing. Dysfunction is associated with various chronic pain states. Here, the effect of ketamine and morphine on descending inhibition is examined using the conditioned pain modulation (CPM) paradigm in chronic neuropathic pain patients. METHODS: CPM responses were obtained in 10 adult neuropathic pain subjects (two men/eight women). All subjects had peripheral neuropathy as defined by abnormal quantitative sensory testing. The effects of S(+)-ketamine (0.57 mg kg(-1) h(-1) for 1 h) and morphine (0.065 mg kg(-1) h(-1) for 1 h) were tested in a randomized, placebo-controlled double-blind study. CPM was measured at baseline and 100 min after the start of treatment and was induced by immersion of the leg into a cold-water bath. The test stimulus was a 30 s static thermal stimulus to the skin of the forearm. RESULTS: Without treatment, no CPM was detectable. Treatment with ketamine, morphine, and placebo produced CPM responses of 40.2 (10.9)%, 28.5 (7.0)%, and 22.1 (12.0)%, respectively (for all treatments, CPM effect P<0.05), with no statistical difference in the magnitude of CPM among treatments. The magnitude of CPM correlated positively with the magnitude and duration of spontaneous pain relief. CONCLUSIONS: The observed treatment effects in chronic pain patients suggest a role for CPM engagement in analgesic efficacy of ketamine, morphine, and placebo treatment.
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Analgésicos/uso terapéutico , Dolor Crónico/tratamiento farmacológico , Ketamina/uso terapéutico , Morfina/uso terapéutico , Estudios Cruzados , Método Doble Ciego , Femenino , Humanos , Ketamina/efectos adversos , Masculino , Persona de Mediana Edad , Morfina/efectos adversosRESUMEN
We describe the first cases of reuse of auxiliary liver grafts for orthotopic transplantation in chronic liver disease. A reduced liver graft (segments 2, 3, half of 4) was first transplanted auxiliary for acute liver failure using a new technique. After regeneration of both native liver and graft, the auxiliary graft was removed and immunosuppression discontinued in the first recipients. After informed consent of donors and recipients, both auxiliary grafts were then orthotopically transplanted into second recipients. Both grafts function normally. Reuse of auxiliary grafts may help to reduce the shortage or liver grafts available for transplantation.
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Hepatopatías/cirugía , Trasplante de Hígado/métodos , Reoperación/métodos , Adolescente , Adulto , Enfermedad Crónica , Femenino , Humanos , Trasplante de Hígado/mortalidad , Donadores Vivos , Análisis de SupervivenciaRESUMEN
The objective of this study was to characterize the pharmacokinetic/pharmacodynamic (PK/PD) relationship of buprenorphine and fentanyl for the respiratory depressant effect in healthy volunteers. Data on the time course of the ventilatory response at a fixed P(ET)CO(2) of 50 mm Hg and P(ET)O(2) of 110 mm Hg following intravenous administration of buprenorphine and fentanyl were obtained from two phase I studies (50 volunteers received buprenorphine: 0.05-0.6 mg/70 kg and 24 volunteers received fentanyl: 0.075-0.5 mg/70 kg). The PK/PD correlations were analyzed using nonlinear mixed effects modeling. A two- and three-compartment pharmacokinetic model characterized the time course of fentanyl and buprenorphine concentration, respectively. Three structurally different PK/PD models were evaluated for their appropriateness to describe the time course of respiratory depression: (1) a biophase distribution model with a fractional sigmoid E(max) pharmacodynamic model, (2) a receptor association/dissociation model with a linear transduction function, and (3) a combined biophase distribution-receptor association/dissociation model with a linear transduction function. The results show that for fentanyl hysteresis is entirely determined by the biophase distribution kinetics, whereas for buprenorphine hysteresis is caused by a combination of biophase distribution kinetics and receptor association/dissociation kinetics. The half-time values of biophase equilibration (t(1/2, k(eo))) were 16.4 and 75.3 min for fentanyl and buprenorphine, respectively. In addition, for buprenorphine, the value of k(on) was 0.246 ml/ng/min and the value of k(off) was 0.0102 min(-1). The concentration-effect relationship of buprenorphine was characterized by a ceiling effect at higher concentrations (intrinsic activity alpha=0.56, 95% confidence interval (CI): 0.50-0.62), whereas fentanyl displayed full respiratory depressant effect (alpha=0.91, 95% CI: 0.19-1.62).
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Analgésicos Opioides/efectos adversos , Analgésicos Opioides/farmacocinética , Buprenorfina/efectos adversos , Buprenorfina/farmacocinética , Fentanilo/efectos adversos , Fentanilo/farmacocinética , Modelos Biológicos , Insuficiencia Respiratoria/inducido químicamente , Adulto , Método Doble Ciego , Femenino , Semivida , Humanos , Masculino , Tasa de Depuración MetabólicaRESUMEN
Auxiliary liver transplantation (ALT) is a treatment for acute liver failure when regeneration of the native liver is possible or for metabolic disorders. In selected cases ALT and orthotopic liver transplantation (OLT) have similar survival when ALT is performed in the orthotopic position (auxiliary partial orthotopic liver transplantation, APOLT). Drawback of ALT with portal vein to portal vein anastomosis is the frequent occurrence of thrombosis, compromising both graft and native liver, and the necessity of a significant resection. To avoid division of portal flow we performed ALT with an end-to-end anastomosis between the graft portal vein and the left renal vein of the recipient (reno-portal ALT, REPALT). The hepatic artery was anastomosed to the aorta using an iliac arterial graft conduit. The bile duct was anastomosed to the stomach. In the two cases presented here excellent immediate graft function occurred with rapid regeneration of the graft and without early vascular complications.
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Hepatectomía/métodos , Trasplante de Hígado/métodos , Donadores Vivos , Enfermedad Aguda , Adulto , Anastomosis Quirúrgica , Duodeno/anatomía & histología , Hígado Graso/cirugía , Femenino , Arteria Hepática/cirugía , Humanos , Ligamentos , Hígado/anatomía & histología , Vena Porta/cirugía , Circulación Renal , Recolección de Tejidos y Órganos/métodos , Resultado del TratamientoRESUMEN
BACKGROUND: We measured the effect of two weight adjusted i.v. doses (0.2 mg per 70 kg and 0.4 mg per 70 kg) of the potent opioid buprenorphine on analgesia and respiratory depression in healthy volunteers. The aim of the study was to compare buprenorphine's behaviour with respect to the occurrence of ceiling (or apparent maximum) in these typical micro-opioid protein-(MOP) receptor effects. METHODS: Ten subjects (5 males) received 0.2 mg per 70 kg, 10 others (5 males) 0.4 mg per 70 kg i.v. buprenorphine. Steady-state inspired minute ventilation at a fixed end-tidal Pco(2) of 7 kPa was measured before drug infusion and at regular intervals after drug infusion. Experimental pain was induced using transcutaneous electrical stimulation and a gradually increasing current. Pain tolerance was measured at regular intervals before and after drug infusion. The studies lasted 8 h. RESULTS: After infusion of the drug ventilation showed a rapid decline and reached peak depression between 150 and 180 min after drug administration. This effect was dose-independent with respect to timing and magnitude. At peak respiratory depression minute ventilation was 13.1 (sd 1.8) litre min(-1) in the 0.2 mg group vs 12.0 (sd 1.3) litre min(-1) in the 0.4 mg group (n.s.). At buprenorphine 0.2 mg a small short-lived analgesic effect was observed with a maximum increase in pain tolerance current of 6.7 (sd 2.8) mA occurring at 75 min after drug administration. Peak analgesic effect was 29% above baseline current. In contrast, buprenorphine 0.4 mg caused a large and long-lived analgesic effect with a maximum increase in pain tolerance current of 23.8 (sd 7.4) mA occurring at 130 min after drug administration. Peak analgesic effect was 160% above baseline current (0.4 vs 0.2 mg, P<0.01). CONCLUSIONS: While buprenorphine's analgesic effect increased significantly, respiratory depression was similar in magnitude and timing for the two doses tested. We conclude that over the dose range tested buprenorphine displays ceiling in respiratory effect but none in analgesic effect.
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Analgésicos Opioides/efectos adversos , Buprenorfina/efectos adversos , Umbral del Dolor/efectos de los fármacos , Insuficiencia Respiratoria/inducido químicamente , Adulto , Analgésicos Opioides/administración & dosificación , Buprenorfina/administración & dosificación , Relación Dosis-Respuesta a Droga , Estimulación Eléctrica/métodos , Femenino , Humanos , MasculinoRESUMEN
BACKGROUND: A recent genetic study in mice and humans revealed the modulatory effect of MC1R (melanocortin-1 receptor) gene variants on kappa-opioid receptor mediated analgesia. It is unclear whether this gene affects basal pain sensitivity or the efficacy of analgesics acting at the more clinically relevant mu-opioid receptor. OBJECTIVE: To characterise sensitivity to pain and mu-opioid analgesia in mice and humans with non-functional melanocortin-1 receptors. METHODS: Comparisons of spontaneous mutant C57BL/6-Mc1r(e/e) mice to C57BL/6 wildtype mice, followed by a gene dosage study of pain and morphine-6-glucuronide (M6G) analgesia in humans with MC1R variants. RESULTS: C57BL/6-Mc1r(e/e) mutant mice and human redheads--both with non-functional MC1Rs--display reduced sensitivity to noxious stimuli and increased analgesic responsiveness to the mu-opioid selective morphine metabolite, M6G. In both species the differential analgesia is likely due to pharmacodynamic factors, as plasma levels of M6G are similar across genotype. CONCLUSIONS: Genotype at MC1R similarly affects pain sensitivity and M6G analgesia in mice and humans. These findings confirm the utility of cross species translational strategies in pharmacogenetics.
Asunto(s)
Analgesia , Variación Genética , Dolor/genética , Receptor de Melanocortina Tipo 1/genética , Receptores Opioides mu/efectos de los fármacos , Adolescente , Adulto , Analgésicos Opioides/farmacocinética , Analgésicos Opioides/uso terapéutico , Animales , Relación Dosis-Respuesta a Droga , Femenino , Genotipo , Color del Cabello/genética , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Morfina/farmacocinética , Morfina/uso terapéutico , Derivados de la Morfina/farmacocinética , Derivados de la Morfina/uso terapéutico , Dolor/tratamiento farmacológico , Dimensión del Dolor/efectos de los fármacos , Umbral del Dolor/efectos de los fármacos , Valores de ReferenciaRESUMEN
BACKGROUND: There is evidence from animal studies suggesting the existence of a ceiling effect for buprenorphine-induced respiratory depression. To study whether an apparent ceiling effect exists for respiratory depression induced by buprenorphine, we compared the respiratory effects of buprenorphine and fentanyl in humans and rats. METHODS: In healthy volunteers, the opioids were infused i.v. over 90 s and measurements of minute ventilation at a fixed end-tidal PCO2 of 7 kPa were obtained for 7 h. Buprenorphine doses were 0.7, 1.4, 4.3 and 8.6 microg kg(-1) (n=20 subjects) and fentanyl doses 1.1, 2.1, 2.9, 4.3 and 7.1 microg kg(-1) (n=21). Seven subjects received placebo. In rats, both opioids were infused i.v. over 20 min, and arterial PCO2 was measured 5, 10, 15 and 20 min after the start of fentanyl infusion and 30, 150, 270 and 390 min after the start of buprenorphine infusion. Doses tested were buprenorphine 0, 100, 300, 1000 and 3000 microg kg(-1) and fentanyl 0, 50, 68 and 90 microg kg(-1). RESULTS: In humans, fentanyl produced a dose-dependent depression of minute ventilation with apnoea at doses > or = 2.9 microg kg(-1); buprenorphine caused depression of minute ventilation which levelled off at doses > or = 3.0 microg kg(-1) to about 50% of baseline. In rats, the relationship of arterial PCO2 and fentanyl dose was linear, with maximum respiratory depression at 20 min (maximum PaCO2 8.0 kPa). Irrespective of the time at which measurements were obtained, buprenorphine showed a non-linear effect on PaCO2, with a ceiling effect at doses > 1.4 microg kg(-1). The effect on PaCO2 was modest (maximum value measured, 5.5 kPa). CONCLUSIONS: Our data confirm a ceiling effect of buprenorphine but not fentanyl with respect to respiratory depression.
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Analgésicos Opioides/efectos adversos , Buprenorfina/efectos adversos , Fentanilo/efectos adversos , Insuficiencia Respiratoria/inducido químicamente , Adulto , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/toxicidad , Animales , Buprenorfina/administración & dosificación , Buprenorfina/toxicidad , Dióxido de Carbono/sangre , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Fentanilo/administración & dosificación , Fentanilo/toxicidad , Humanos , Masculino , Presión Parcial , Ratas , Ratas WistarRESUMEN
BACKGROUND: Morphine-6-glucuronide (M6G) is a metabolite of morphine with potent analgesic properties. The influence of M6G on respiratory and antinociceptive responses was investigated in mice lacking the micro -opioid receptor (MOR) and compared with morphine. METHODS: Experiments were performed in mice lacking exon 2 of the MOR (n=18) and their wild type (WT) littermates (n=20). The influence of M6G and morphine on respiration was measured using whole body plethysmography during three elevations of inspired carbon dioxide. Antinociception was assessed using tail flick and hotplate tests. RESULTS: In WT but not null mutant mice, a dose-dependent depression of the slope of the ventilatory carbon dioxide response was observed after M6G and morphine. Similarly, both opioids were devoid of antinociceptive effects in null mutant mice, but showed potent dose-dependent analgesia in WT animals. Potency differences between M6G and morphine in WT mice were of the same order of magnitude for analgesia and respiration. CONCLUSIONS: The data indicate that the desired (antinociceptive) and undesired (respiratory depression) effects of M6G and morphine are linked to the same gene product; that is the MOR. Other opioid- and non-opioid-receptor systems may play a minor role in the actions of M6Gs and morphine. The clinical implications of our findings are that any agent acting at the MOR will invariably cause (potent) analgesia in combination with (variable) respiratory depression.
Asunto(s)
Analgésicos Opioides/farmacología , Derivados de la Morfina/farmacología , Umbral del Dolor/efectos de los fármacos , Receptores Opioides mu/fisiología , Insuficiencia Respiratoria/inducido químicamente , Animales , Dióxido de Carbono , Relación Dosis-Respuesta a Droga , Femenino , Masculino , Ratones , Ratones Noqueados , Morfina/farmacología , Pletismografía Total , Tiempo de Reacción/efectos de los fármacos , Receptores Opioides mu/deficiencia , Receptores Opioides mu/genética , Insuficiencia Respiratoria/fisiopatología , Sensación/efectos de los fármacosRESUMEN
Ventilatory control in humans depends on complex mechanisms which aim to maintain a cellular CO2-, O2- and H(+)-homeostasis under physiological conditions. This regulation is based on chemical control which predominantly acts via peripheral chemoreceptors in the carotid bodies and central chemoreceptors in the ventral medulla of the brainstem on the one hand, and behavioural control on the other, by which it is possible to adapt respiration to conditions of daily living. The influence of anaesthesia and related conditions may depress respiration and have a sustained effect on ventilatory control. Perioperative respiratory depression remains a serious clinical problem in perioperative medicine. This review will give an overview of ventilatory control and discuss the most relevant responses, describe the effects of pain, anaesthetics and opioids on ventilatory control and their interaction. The current body of knowledge is put into perspective to identify patients at risk for perioperative respiratory depression.
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Anestésicos/efectos adversos , Mecánica Respiratoria/efectos de los fármacos , Analgésicos Opioides/efectos adversos , Dióxido de Carbono/sangre , Interacciones Farmacológicas , Humanos , Oxígeno/sangre , Dolor/fisiopatología , Mecánica Respiratoria/fisiologíaAsunto(s)
Alfentanilo/farmacocinética , Analgésicos Opioides/farmacocinética , Anestésicos por Inhalación/farmacocinética , Anestésicos Intravenosos/farmacocinética , Sistema Cardiovascular/efectos de los fármacos , Éteres Metílicos/farmacocinética , Ventilación Pulmonar/efectos de los fármacos , Adulto , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Masculino , Modelos Cardiovasculares , SevofluranoAsunto(s)
Exones , Ventilación Pulmonar/fisiología , Receptores Opioides mu/fisiología , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/farmacología , Animales , Temperatura Corporal , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Morfina/administración & dosificación , Morfina/farmacología , Derivados de la Morfina/administración & dosificación , Derivados de la Morfina/farmacología , Narcóticos , Pletismografía Total , Ventilación Pulmonar/efectos de los fármacos , Receptores Opioides mu/genética , Respiración/efectos de los fármacosRESUMEN
UNLABELLED: N-methyl-D-aspartate receptor antagonism probably accounts for most of ketamine's anesthetic effects; its analgesic properties are mediated partly via N-methyl-D-aspartate and partly via opioid receptors. We assessed the involvement of the mu-opioid receptor in S(+) ketamine-induced respiratory depression and antinociception by performing dose-response curves in exon 2 mu-opioid receptor knockout mice (MOR(-/-)) and their wild-type littermates (WT). The ventilatory response to increases in inspired CO(2) was measured with whole body plethysmography. Two antinociceptive assays were used: the tail-immersion test and the hotplate test. S(+) ketamine (0, 10, 100, and 200 mg/kg intraperitoneally) caused a dose-dependent respiratory depression in both genotypes, with greater depression observed in WT relative to MOR(-/-) mice. At 200 mg/kg, S(+) ketamine reduced the slope of the hypercapnic ventilatory response by 93% +/- 15% and 49% +/- 6% in WT and MOR(-/-) mice, respectively (P < 0.001). In both genotypes, S(+) ketamine produced a dose-dependent increase in latencies in the hotplate test, with latencies in MOR(-/-) mice smaller compared with those in WT animals (P < 0.05). In contrast to WT mice, MOR(-/-) mice displayed no ketamine-induced antinociception in the tail-immersion test. These results indicate that at supraspinal sites S(+) ketamine interacts with the mu-opioid system. This interaction contributes significantly to S(+) ketamine-induced respiratory depression and supraspinal antinociception. IMPLICATIONS: The involvement of the mu-opioid receptor system in S(+) ketamine-induced respiratory depression and spinal and supraspinal analgesia was demonstrated by performing experiments in mice lacking the mu-opioid receptor and in mice with intact mu-opioid receptors.
Asunto(s)
Analgesia , Analgésicos/farmacología , Ketamina/farmacología , Receptores Opioides mu/fisiología , Respiración/efectos de los fármacos , Animales , Dióxido de Carbono/fisiología , Depresión Química , Relación Dosis-Respuesta a Droga , Ratones , Ratones Noqueados , Umbral del Dolor/efectos de los fármacos , Receptores Opioides mu/genéticaRESUMEN
BACKGROUND: Propofol has a depressant effect on metabolic ventilatory control, causing depression of the ventilatory response to acute isocapnic hypoxia, a response mediated via the peripheral chemoreflex loop. In this study, the authors examined the effect of sedative concentrations of propofol on the dynamic ventilatory response to carbon dioxide to obtain information about the respiratory sites of action of propofol. METHODS: In 10 healthy volunteers, the end-tidal carbon dioxide concentration was varied according to a multifrequency binary sequence that involved 13 steps into and 13 steps out of hypercapnia (total duration, 1,408 s). In each subject, two control studies, two studies at a plasma target propofol concentration of 0.75 microg/ml (P(low)), and two studies at a target propofol concentration of 1.5 microg/ml (P(high)) were performed. The ventilatory responses were separated into a fast peripheral component and a slow central component, characterized by a time constant, carbon dioxide sensitivity, and apneic threshold. Values are mean +/- SD. RESULTS: Plasma propofol concentrations were approximately 0.5 microg/ml for P(low) and approximately 1.3 mg/ml for P(high), Propofol reduced the central carbon dioxide sensitivity from 1.5 +/- 0.4 to 1.2 +/- 0.3 (P(low); P < 0.01 vs. control) and 0.9 +/- 0.1 l x min(-1) x mmHg(-1) (P(high); P < 0.001 vs. control). The peripheral carbon dioxide sensitivity remained unaffected by propofol (control, 0.5 +/- 0.3; P(low), 0.5 +/- 0.2; P(high), 0.5 +/- 0.2 l x min(-1) x mmHg(-1)). The apneic threshold was reduced from 36.3 +/- 2.7 (control) to 35.0 +/- 2.1 (P(low); P < 0.01 vs. control) and to 34.6 +/- 1.9 mmHg (P(high); P < 0.01 vs. control). CONCLUSIONS: Sedative concentrations of propofol have an important effect on the control of breathing, showing depression of the ventilatory response to hypercapnia. The depression is attributed to an exclusive effect within the central chemoreflex loop at the central chemoreceptors. In contrast to low-dose inhalational anesthetics, the peripheral chemoreflex loop, when stimulated with carbon dioxide, remains unaffected by propofol.
Asunto(s)
Anestésicos Intravenosos/farmacología , Propofol/farmacología , Reflejo/efectos de los fármacos , Sistema Respiratorio/efectos de los fármacos , Adolescente , Adulto , Algoritmos , Anestésicos Intravenosos/administración & dosificación , Apnea/sangre , Dióxido de Carbono/sangre , Células Quimiorreceptoras/efectos de los fármacos , Electroencefalografía/efectos de los fármacos , Femenino , Humanos , Masculino , Modelos Biológicos , Oxígeno/sangre , Sistema Nervioso Periférico/efectos de los fármacos , Propofol/administración & dosificaciónRESUMEN
BACKGROUND: Respiratory depression is a serious side effect of anesthetics and opioids. The authors examined the influence of the combined administration of sevoflurane and alfentanil on ventilatory control, heart rate (HR), and Bispectral Index (BIS) in healthy volunteers. METHODS: Step decreases in end-tidal partial pressure of oxygen from normoxia into hypoxia (approximately 50 mmHg) at constant end-tidal partial pressure of carbon dioxide (approximately 48 mmHg) were performed in nine male volunteers at various concentrations of alfentanil and sevoflurane, ranging from 0 to 50 ng/ml for alfentanil and from 0 to 0.4 end-tidal concentration (ET%) for sevoflurane, and with various combinations of alfentanil and sevoflurane. The alfentanil-sevoflurane interactions on normoxic resting (hypercapnic) ventilation (Vi), HR, hypoxic Vi, and HR responses and BIS were assessed by construction of response surfaces that related alfentanil and sevoflurane to effect using a population analysis. RESULTS: Concentration-effect relations were linear for alfentanil and sevoflurane. Synergistic interactions were observed for resting Vi and resting HR. Depression of Vi by 25% occurred at 38 +/- 11 ng/ml alfentanil (population mean +/- SE) and at 0.7 +/- 0.4 ET% sevoflurane. One possibility for 25% reduction when alfentanil and sevoflurane are combined is 13.4 ng/ml alfentanil plus 0.12 ET% sevoflurane. Additive interactions were observed for hypoxic Vi and HR responses and BIS. Depression of the hypoxic Vi response by 25% occurred at 16 +/- 1 ng/ml alfentanil and 0.14 +/- 0.05 ET% sevoflurane. The effect of sevoflurane on the BIS (25% reduction of BIS occurred at 0.45 +/- 0.08 ET%) was independent of the alfentanil concentration. CONCLUSIONS: Response surface modeling was used successfully to analyze the effect of interactions between two drugs on respiration. The combination of alfentanil and sevoflurane causes more depression of Vi and HR than does the summed effect of each drug administered separately. The effects of combining alfentanil and sevoflurane on hypoxic Vi and HR responses and BIS could be predicted from the separate dose-response curves. Over the dose range tested, the hypoxic response is more sensitive to the effects of anesthetics and opioids relative to resting ventilation.