Activation of spinal N-methyl-D-aspartate (NMDA) receptors stimulates cyclooxygenase and nitric oxide pathways. Compounds that block the activity of these NMDA receptor systems reduce pain hypersensitivity. However, their usefulness is limited by the side effects they produce. One way of reducing side effects is by combining drugs that produce the same overt effect by different mechanisms, which hopefully increase the net effect. In these series of studies, drugs that interact with NMDA receptor systems and their combinations were screened in vitro to identify spinal antinociceptive synergistic combinations that could be assessed in vivo. Based on developmental changes in thresholds, conduction velocities and blocking actions of the local anaesthetic lignocaine in neonatal rat L4/L5 dorsal root potentials, it was decided to use spinal cord in vitro preparation from 5- to 7-day-old rat pups. In single drug studies, the NMDA receptor channel blocker ketamine (1-50 µM) and the non-steroidal anti-inflammatory drug (NSAID) ketoprofen (200-600 µM), but not the NSAID salicylate (1000 µM) and the nitric oxide synthase inhibitor Nω-nitro-L-arginine methyl ester (L-NAME; 1-100 µM), reduced spinal NMDA receptor-mediated transmission. Ketamine also depressed non-NMDA receptor-mediated transmission. Using isobolographic and composite additive line analyses, fixed-ratio combinations of ketamine and ketoprofen, ketamine and L-NAME, and ketopofen and L-NAME synergistically depressed NMDA receptor-mediated transmission. The two former combinations had a subadditive effect on non-NMDA receptor-mediated transmission, and the latter had no significant effect. These studies identified that all combinations synergistically reduced both nociceptive transmission and potential side effects. In free-moving sheep implanted with indwelling cervical intrathecal catheters, 100 µ1 subdural administration of ketamine (25-400 µM) and ketoprofen (200-3200 µM) alone and in a fixed-ratio combination (873.95-3350.78 µM, 0.045:0.955) did not raise nociceptive thresholds as assessed by mechanical stimulation of one foreleg. Subdural administration of NMDA (2 mM) decreased mechanical nociceptive thresholds, and this was prevented by the highest concentrations of ketamine and ketoprofen alone and in combination. These findings demonstrated that NMDA receptor channel blockers and NSAIDs alone or in combination had no direct hypoalgesic effects when given onto the spinal cord of sheep, but they prevented NMDA-induced pain hypersensitivity. Simultaneous blockade of NMDA receptor systems could have important clinical implications.

<p>Systemic infection, major surgery, trauma and many other causes can lead to impaired organ function. Compensated shock is not detected by global hemodynamic and oxygen measurements, as they take no account for regional variations. Focus has therefore gradually turned from looking at systemic changes to selective investigations of regional blood flow and ischemia. This thesis presents a series of experiments evaluating new application and validation of various monitoring techniques.</p><p>An experimental porcine model with anesthetized and invasively monitored animals was used. The circulatory interventions included endotoxin infusion (septic shock), aortic constriction and selective clamping of splanchnic arteries. The aim was to compare air with saline tonometry, to validate the intraperitoneal use of tonometry and to reexamine the use of endoluminal reflectance pulse oxymetry. To investigate the relative contributions of regional blood flow and detection of ischemia, measurements of hepatic venous oxygen saturation (ShvO₂), lactate concentrations and PCO₂ gap were used.</p><p>Our findings support the use of air instead of saline as the preferred technique for tonometric measurements. With the intraperitoneal application of tonometry we gain more information on regional aspects of the splanchnic circulation, and it appears to be a reliable monitoring option for early detection of ischemia in the small intestine. Measurements of ShvO₂will give an overall reflection of the intestinal circulation. The sigmoid colonic pulse oximetry showed a non-linear response in relation to regional blood flow, and will therefore not be able to detect gradual changes in oxygen saturation. Determination of the regional to endtidal PCO₂ gap might prove valuable for monitoring of the intestinal circulation.</p><p>Because of sophisticated interactions between portal and hepatic arterial blood flow and hepatic compensation for regional ischemia, a combination of monitoring techniques might be needed. The results of this study will hopefully encourage clinical evaluation of intraperitoneal tonometry and endtidal PCO₂ gap recordings for non-invasive, semi-continuous, trend monitoring of the splanchnic circulation.</p>

Systemic infection, major surgery, trauma and many other causes can lead to impaired organ function. Compensated shock is not detected by global hemodynamic and oxygen measurements, as they take no account for regional variations. Focus has therefore gradually turned from looking at systemic changes to selective investigations of regional blood flow and ischemia. This thesis presents a series of experiments evaluating new application and validation of various monitoring techniques. An experimental porcine model with anesthetized and invasively monitored animals was used. The circulatory interventions included endotoxin infusion (septic shock), aortic constriction and selective clamping of splanchnic arteries. The aim was to compare air with saline tonometry, to validate the intraperitoneal use of tonometry and to reexamine the use of endoluminal reflectance pulse oxymetry. To investigate the relative contributions of regional blood flow and detection of ischemia, measurements of hepatic venous oxygen saturation (ShvO2), lactate concentrations and PCO2 gap were used. Our findings support the use of air instead of saline as the preferred technique for tonometric measurements. With the intraperitoneal application of tonometry we gain more information on regional aspects of the splanchnic circulation, and it appears to be a reliable monitoring option for early detection of ischemia in the small intestine. Measurements of ShvO2 will give an overall reflection of the intestinal circulation. The sigmoid colonic pulse oximetry showed a non-linear response in relation to regional blood flow, and will therefore not be able to detect gradual changes in oxygen saturation. Determination of the regional to endtidal PCO2 gap might prove valuable for monitoring of the intestinal circulation. Because of sophisticated interactions between portal and hepatic arterial blood flow and hepatic compensation for regional ischemia, a combination of monitoring techniques might be needed. The results of this study will hopefully encourage clinical evaluation of intraperitoneal tonometry and endtidal PCO2 gap recordings for non-invasive, semi-continuous, trend monitoring of the splanchnic circulation.