University Department of Anaesthesia, Queens Medical Centre, Nottingham NG7 2UH, UK
Corresponding author. E-mail: iain.moppett@nottingham.ac.uk
Accepted for publication: April 17, 2003
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Abstract |
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Methods. Ten healthy male volunteers were studied. Forearm skin blood flow was measured using laser Doppler flowmetry. Two non-invasive probes were placed on the volar surface of the forearm. The magnitude of hyperaemic response to brief (20 s) and prolonged (5 min) occlusion of the axillary artery was measured before and 23 h after administration of ibuprofen 800 mg or rofecoxib 25 mg. The transient hyperaemic response ratio (THRR), defined as the net peak hyperaemic flow-flux divided by the net baseline flow-flux, was calculated. Each volunteer received both drugs in random order at least 1 week apart.
Results. Ibuprofen and rofecoxib increased net baseline blood flow (median (range): ibuprofen, from 23.3 (12.140.8) to 31.5 (17.477.3); rofecoxib, from 22.0 (14.641.0) to 29.9 (19.5112.0); P<0.01). The net hyperaemic peak flow-flux after brief and prolonged occlusion was unchanged after both drugs. THRR was reduced by both drugs (ibuprofen, from 2.92 (2.383.86) to 2.09 (1.453.54); rofecoxib, from 3.36 (2.065.16) to 2.67 (1.15 3.84); P<0.01).
Conclusions. Both COX-2 and non-selective non-steroidal anti-inflammatory drugs, when given to healthy volunteers as single therapeutic doses, decrease skin microvascular tone but do not impair maximal vasodilatory ability.
Br J Anaesth 2003; 91: 3536
Keywords: analgesics, non-steroidal anti-inflammatory drugs; blood, flow; blood, vessels, vasodilation; complications, ischaemia; hormones, prostaglandins
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Introduction |
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Methods |
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Ten subjects underwent hyperaemic response measurements using laser Doppler flowmetry measurements of blood flow-flux. Measurements were made before and 23 h after a single oral dose of ibuprofen 800 mg or rofecoxib 25 mg. The order of drug administration was random and the drugs were studied on two separate occasions at least 7 days apart. Subjects were unaware which drug they were given. Non-invasive blood pressure was recorded on the contralateral arm after a period of rest during each experiment. All subjects were fasted for 23 h for food and caffeinated or alcoholic drinks before the start of each experiment.
The details of the hyperaemic response tests have been described recently elsewhere.3 4 Blood flow-flux was measured using two laser Doppler probes (DRT4; Moor Instruments, Axminster, UK) applied to the volar aspect of the right forearm, avoiding obvious superficial veins. Flow-flux is calculated from the scatter of the frequency shift of the reflected laser light. The sampling volume is approximately 1 mm3. Flow-flux is measured in arbitrary units after calibration of the probes against a known standard. To measure the hyperaemic response to brief arterial occlusion, the axillary artery was compressed manually for 20 s and then released. The changes in flow flux were displayed in real time to ensure complete occlusion. This procedure was repeated four times at intervals of 90120 s. The transient hyperaemic response ratio (THRR)3 4 was calculated as the increase in flow-flux after occlusion release divided by the fall in flow-flux on occlusion.
The mean of 10 s of flow-flux preceding compression was taken as the baseline and the minimal flow-flux during occlusion was taken as biological zero.5 All values were calculated automatically using custom software (DRT4WIN; Moor Instruments).
The peak hyperaemic flow-flux in response to 5 min of ischaemia with a pneumatic tourniquet inflated to 250 mm Hg around the upper arm was also recorded.
After the control measurements, the subjects were given the study drug and left the study area. They returned 23 h later and underwent an identical protocol.
Previous studies have shown that the mean value of THRR is 3.2, with a standard deviation of 1.29. We estimated that 10 subjects acting as their own control would be needed to find a 25% reduction in THRR with a power of 0.8 and P<0.05 taken as significant. AndersenDarling tests were used to test for normality of data distribution. Statistical analyses were performed with paired t-tests or Wilcoxon tests as appropriate, using Minitab v13 software (Manitab Inc., State College, PA, USA).
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Results |
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Control values of net baseline blood flow, net peak hyperaemic flow-flux after brief and prolonged ischaemia and THRR were similar between the two experimental days. Ibuprofen and rofecoxib both increased significantly the net baseline flow-flux. THRR (20 s compression) was reduced significantly. The magnitude of the net peak hyperaemic flow-flux after brief and prolonged occlusion was unchanged (Table 1).
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Discussion |
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Cyclo-oxygenase, the enzyme responsible for prostaglandin (PG) production, exists in two isoforms, COX-1 and COX-2. Traditionally, COX-1 has been thought to be the constitutive, physiological enzyme and COX-2 the inducible, proinflammatory enzyme. However, more recent studies have suggested that the distinction is not so clear-cut and that up to 80% of basal PGI2 production may be as a result of COX-2.2
In humans, studies have shown conflicting results on the effects of NSAIDs on vascular function. Carlsson and colleagues6 7 found a reduction in postischaemic reactive hyperaemia (120 min of tourniquet) of up to 75% after single doses of non-selective NSAIDs using forearm strain-gauge plethysmography. They found no change in baseline flow. Verma and colleagues,8 again using forearm strain-gauge plethysmography, assessed the vasodilatory responses to intra-arterial infusions of endothelium-dependent (acetylcholine) and -independent (sodium nitroprusside) vasodilators. They found no effect of 7 days of naproxen or rofecoxib on baseline flow or degree of drug-induced vasodilation.
There are various possible explanations for a rise in baseline flow-flux, both methodological and physiological. Although each study acted as his own control, there was no placebo arm. Lack of a placebo arm can be perceived as a limitation of the study as the changes in flow-flux and THRR could be ascribed to the effects of time. However, the measurements made were objective evaluations of skin blood flow-flux and were unlikely to have been influenced by the subjects knowledge of whether they had received a drug. Previous studies in our department have shown no difference between repeated measurements of blood flow-flux or THRR taken 23 h apart.9
Small changes in the position of the probe can affect recorded values without any change in overall microvascular function or skin blood flow. However, the probe site was kept as constant as possible and two probes were used to allow average values to be taken. Of note, as previously shown, there was no significant difference in baseline flow-flux or THRR between controls on the different days.4 In theory, increasing skin temperature to greater than 33 °C increases baseline flow-flux and reduces THRR.9 In this study, skin temperature remained constant and below 33 °C throughout the experiment. If NSAIDs were to lower the thermoregulatory set point, the peripheral effect would be skin vasodilation. However, this effect is antipyretic and does not occur in afebrile individuals.10
We hypothesize that the increase in baseline flow-flux was a result of reduction in microvascular tone. A high baseline flow-flux because of increased overall blood flow should result in a greater stimulus to vasodilation on occlusion and a larger transient hyperaemic response. The THRR should therefore remain the same. If the increased baseline flow-flux is a result of diminished vascular tone, the ability to further vasodilate is also reduced. THRR will therefore fall, as observed in this study. The ability to vasodilate per se is preserved, however, as evidenced by the unchanged net hyperaemic response to both brief and prolonged occlusion.
The lack of effect of NSAIDs on overall vasodilatory ability is in agreement with some8 but not all studies.6 7 In any drug study, the possibility of an insufficient dose must be considered. However, we do not believe this to be the case for several reasons. First, the dose and timing of ibuprofen used in this study were the same as those used with positive effect in previous studies.6 7 Secondly, the pharmacokinetic data for both ibuprofen and rofecoxib suggest that PGI2 production would be blocked using our experimental protocol.2 Finally, a positive effect (i.e. rise in baseline flow-flux) was observed.
Previous studies68 assessing the role of PGs and NSAIDs in reactive hyperaemia have used forearm strain-gauge plethysmography. This technique assesses the blood flow response of the whole forearm. Laser Doppler flowmetry, as used in this study, assesses only superficial skin microvasculature. It is conceivable that the control mechanisms for reactive hyperaemia are different in different vascular beds. Repeating this study with parallel measurement of muscle microvascular flow in the presence of NSAIDs may answer this question.
Translating this into effects on endothelial health is complex. Numerous studies using laser Doppler flowmetry and forearm strain gauge plethysmography have demonstrated associations between impaired endothelial microvascular function and known risk factors and outcomes for cardiovascular disease1113 and sepsis.14 15
This study was performed using healthy, male volunteers in order to avoid confounding effects of the menstrual cycle and cardiovascular disease, both of which alter vascular reactivity. It is not possible to be sure what the results would be in a patient population with cardiovascular disease or sepsis.
In summary, this study investigated the effects of non-selective COX inhibition (ibuprofen 800 mg) and COX-2-selective inhibition (rofecoxib 25 mg) on the hyperaemic responses to brief (20 s) and prolonged (5 min) ischaemia, provoking myogenic and metabolic responses respectively in the forearm skin in healthy volunteers. Both drugs cause an increase in baseline flow-flux, which, with the reduction in THRR, is interpreted as a result of a reduction in microvascular tone. The hyperaemic response to prolonged ischaemia is unchanged. The effect of non-selective and COX-2-specific NSAIDs on the macro- and microvasculature in patients with cardiovascular disease or at risk of sepsis warrants further investigation.
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Acknowledgements |
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References |
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