Platelet dysfunction after intravenous ketorolac or propacetamol

BACKGROUND: Paracetamol is a weak cyclo-oxygenase inhibitor in vitro. A recent study in children has shown that high doses of paracetamol are effective and safe. We studied the effect of propacetamol on haemostasis in adult volunteers. METHODS: Ten volunteers were investigated in a double-blind, randomized, crossover study. They received propacetamol 60 mg kg(-1) or ketorolac 0.4 mg kg(-1) in saline i.v. (30 min) in two different sessions. Platelet function was evaluated before the test infusion (S-0), two (S-2) and 24 h (S-24) after the start of the infusion. Coagulation parameters (PT, APTT, factor V and VII activities) were measured at S-0, S-24 and 48 h (S-48). RESULTS: One of the volunteers had no secondary platelet aggregation in S-0 and was excluded from the final analysis. Two hours (S-2) after propacetamol and ketorolac administration the adrenaline (0.9 microg ml(-1) and 9.0 microg ml(-1)) induced maximal platelet aggregation was decreased compared with S-0. At S-2 platelet aggregation was inhibited more after ketorolac than after propacetamol. At 24 h after ketorolac, but not after propacetamol, there was still a decrease in the adrenaline-induced maximal platelet aggregation. Propacetamol did not affect adenosine diphosphate (ADP)-induced maximal platelet aggregation, whereas ketorolac decreased 3 and 6 microM ADP-induced maximal platelet aggregation at S-2 and S-24. However, 2 h after both ketorolac and propacetamol, thromboxane B2 (TxB2) concentration decreased in platelet rich plasma after 5 min aggregation induced by 8 microM ADP. Coagulation was unaffected. CONCLUSION: Propacetamol 60 mg kg(-1) i.v. causes reversible platelet dysfunction demonstrated by a decrease in maximal platelet aggregation and TxB2 concentration. After 0.4 mg kg(-1) ketorolac i.v. platelet aggregation and TxB2 formation are inhibited more in comparison with propacetamol, and platelet dysfunction is still seen after 24 h.     

Platelet aggregation in humans and nonhuman primates: relevance to xenotransplantation

Iwase H, Ekser B, Zhou H, Dons EM, Cooper DKC, Ezzelarab MB. Platelet aggregation in humans and nonhuman primates: relevance to xenotransplantation. Xenotransplantation 2012; 19: 233–243.. © 2012 John Wiley & Sons A/S. Abstract: Introduction: Platelet activation/aggregation plays a key role in the dysregulation of coagulation and the development of thrombotic microangiopathy in nonhuman primate recipients of pig xenografts. As a preliminary to the study of anti‐platelet therapy in vitro and in vivo, the present study aimed to compare platelet aggregation in whole blood from humans, baboons, and cynomolgus monkeys. Methods: Using “Chrono‐log” technology (two‐sample four‐channel Chrono‐log Whole Blood Aggregometer), we studied aggregation of platelets in healthy humans (n = 8), baboons (n = 5), and monkeys (n = 8). Whole blood (WB) samples were collected, and platelet aggregation was assessed using three different volumes of blood (1, 0.5, and 0.25 ml). Platelet activation was induced using collagen (at 3 and 5 μg/ml), ristocetin (at 0.5 and 1.0 mg/ml), adenosine diphosphate (ADP; at 10, 20, and 40 μm ), or thrombin (at 1 and 5 IU/ml). Inhibition of agonist‐induced platelet aggregation by heparin and low molecular weight heparin (LMWH) (at 1, 10, and 100 IU/ml) was evaluated. Results: Mean platelet counts were 222.1, 263.2, and 276.1 (×10³/μl) in humans, baboons, and monkeys, respectively. In all three species, platelet aggregation was induced by collagen, ristocetin, ADP, or thrombin in a dose‐dependent manner. A blood volume of 0.5 ml provided the most consistent results with all agonists in all three species. Dilution studies indicated that there was a significant positive correlation between platelet count and percent aggregation of platelets (P < 0.05). Collagen (3 and 5 μg/ml), ADP (10, 20, and 40 μm ), and thrombin (1 and 5 IU/ml) induced significantly greater platelet aggregation in humans than in baboons. ADP (20 and 40 μm ) and thrombin (1 and 5 IU/ml) induced significantly greater platelet aggregation in monkeys than in baboons. There was no species difference with ristocetin (0.5 or 1.0 mg/ml). In all species, thrombin (1 or 5 IU) induced greater platelet aggregation than any of the other reagents. Heparin at 1 IU/ml and LMWH at 10 IU/ml in all species almost completely abrogated thrombin‐induced platelet aggregation. Heparin at 100 IU/ml effectively inhibited platelet aggregation induced by collagen, but only partially inhibited aggregation induced by ADP or ristocetin. LMWH only partially inhibited aggregation induced by collagen, ristocetin, and ADP. Conclusions: The “Chrono‐log” technology proved to be a reliable method of evaluating platelet activation and aggregation in vitro in primates. Species differences may play a role in platelet aggregation, with the monkey being more comparable to the human than the baboon, although overall trends were similar. In all species, thrombin induced greater platelet aggregation than other agonists. Even a concentration of heparin of 1 IU/ml, which is probably the maximal concentration that is clinically‐applicable, prevented platelet aggregation induced by thrombin, but was less effective in preventing aggregation induced by collagen, ADP, or, particularly, ristocetin.     

Platelet function following administration of a novel formulation of intravenous diclofenac sodium versus active comparators: a randomized, single dose, crossover study in healthy male volunteers

Study ObjectiveTo assess platelet function and safety following single-dose administration of a novel formulation of intravenous (IV) diclofenac sodium (Dyloject) 37.5 mg versus oral diclofenac 50 mg, IV ketorolac 30 mg, and oral acetylsalicylic acid (ASA) 325 mg.DesignOpen-label, randomized, single-dose, 4-treatment crossover study.SettingClinical research unit.Patients30 healthy, ASA physical status I adult men.InterventionsSubjects were randomized to one of 6 treatment sequences that included 4 single-dose treatments. Study drug administration occurred on Days 1, 3, 5, and 7.MeasurementsPlatelet count, closure time as measured by platelet function analyzer (PFA-100), prothrombin time (PT), activated partial thromboplastin time (aPTT), and plasma concentrations of the study drugs were obtained over 24 hours after each treatment. The primary endpoint was the area under the curve for PFA collagen-epinephrine (CEPI) closure time difference from 0-6 hours post-drug administration (AUC_0-6h). Secondary endpoints included the maximum change from baseline in PFA CEPI closure time.Main ResultsAUC_0-6h (mean ± SD) for CEPI closure time difference was significantly smaller after IV diclofenac 37.5 mg (249 ± 216 sec.hrs) than after ketorolac [and ASA (950 ± 287 sec.hrs and 834 ± 237 sec.hrs, respectively); P ≤ 0.0001 for both] but not after the oral diclofenac control (286 ± 265 sec.hrs; P = 0.40). Similarly, the maximum change from baseline in PFA CEPI closure time was lower after IV diclofenac than after ketorolac or ASA across all time intervals examined. There were no significant changes in PT or aPTT at any time point with any treatment. There was a low frequency of adverse events.ConclusionsAcetylsalicylic acid and ketorolac both substantially disrupted platelet function in contrast to IV diclofenac 37.5 mg or oral diclofenac 50 mg control. Diclofenac, with its balanced COX-1 and COX-2 inhibitory profile, may pose less risk of postoperative bleeding than nonsteroidal antiinflammatory drugs (NSAIDs) such as ketorolac and ASA, which predominantly inhibit COX-1.     

Propacetamol augments inhibition of platelet function by diclofenac in volunteers

Background. Acetaminophen (paracetamol) enhances the analgesiceffect of non-steroidal anti-inflammatory drugs (NSAIDs). Acetaminophenis a weak inhibitor of cyclooxygenase (COX), and its combinationwith an NSAID may augment COX inhibition-related side effects. Methods. Ten healthy male volunteers (21–30 yr) were givendiclofenac 1.1 mg kg^–1 alone, a combination of propacetamol30 mg kg^–1 (which is hydrolysed to 50% acetaminophen)and diclofenac 1.1 mg kg^–1 or placebo intravenously ina double blind, crossover study. Platelet function was assessedat 5 min, 90 min and 22–24 h by photometric aggregometry,platelet function analyser (PFA-100^TM) and by measuring therelease of thromboxane B₂ (TxB₂). Analgesia was assessed withthe cold pressor test. Results. Platelet aggregation induced with arachidonic acidwas fully inhibited by both diclofenac alone and the combinationat the end of the 30-min drug infusion. Propacetamol augmentedthe inhibition by diclofenac at 90 min (P=0.014). At 22–24h, platelet function had fully recovered. TxB₂ release was inhibitedby the combination of propacetamol and diclofenac at 90 minin comparison with diclofenac alone (P=0.027). PFA-100^TM detectedno difference in platelet function between these two groups.No analgesic effect was detected with the cold pressor test. Conclusions. The combination of propacetamol and diclofenacinhibits platelet function more than diclofenac alone. Thisshould be considered when assessing the risk of surgical bleeding. Br J Anaesth 2003; 91: 357–62     

Effects of nonsteroidal anti-inflammatory drugs on hemostasis in patients with aneurysmal subarachnoid hemorrhage.

Platelet function is impaired by nonsteroidal anti-inflammatory drugs (NSAIDs) with prominent anti-inflammatory properties. Their safety in patients undergoing intracranial surgery is under debate. Patients with aneurysmal subarachnoid hemorrhage (SAH) were randomized to receive either ketoprofen, 100 mg, three times a day (ketoprofen group, n = 9) or a weak NSAID, acetaminophen, 1 g, three times a day (acetaminophen group, n = 9) starting immediately after the diagnosis of aneurysmal SAH. Treatment was continued for 3 days postoperatively. Test blood samples were taken before treatment and surgery as well as on the first, third, and fifth postoperative mornings. Maximal platelet aggregation induced by 6 microM of adenosine diphosphate decreased after administration of ketoprofen. Aggregation was lower (P < .05) in the ketoprofen group than in the acetaminophen group just before surgery and on the third postoperative day. In contrast, maximal platelet aggregation increased in the acetaminophen group on the third postoperative day as compared with the pretreatment platelet aggregation results (P < .05). One patient in the ketoprofen group developed a postoperative intracranial hematoma. Coagulation (prothrombin time [PT], activated partial thromboplastin time [APPT], fibrinogen concentration, and antithrombin III [AT III]) was comparable between the two groups. Ketoprofen but not acetaminophen impaired platelet function in patients with SAH. If ketoprofen is used before surgery on cerebral artery aneurysms, it may pose an additional risk factor for hemorrhage.     

Effect of local hemostatics on platelet aggregation

The platelets play an important role in the normal hemostasis, and it is known that both natural and synthetic macromolecules may induce platelet activation and aggregation. Thus, the purpose of the present study was to investigate the platelet aggregating effect of five different local hemostatics. Platelet aggregation was assessed by aggregometry. Unwoven fleece of bovine collagen polymer in fibrillar form induced aggregation in combination with small amounts of platelet agonists; ADP and adrenaline. Ordinary, nonabsorbable bone wax also induced aggregation in combination with the agonists, but larger concentrations of agonists were needed. Bioerodible polyorthoester with physical properties such as bone wax, oxidized cellulose and gelatin sponge did not promote platelet aggregation.     

Activation of platelets in patients with chronic proliferative glomerulonephritis and the nephrotic syndrome

Platelet count, volume and aggregation and plasma levels of beta-thromboglobulin (beta-TG) and platelet factor 4 (PF-4) were measured in 54 patients with chronic glomerulonephritis (CGN). Platelet count and platelet aggregation induced by ADP, adrenaline and collagen were significantly higher in the patients than in normal subjects, and platelet aggregation was markedly increased in the cases with progressive glomerular lesions. Plasma levels of beta-TG and PF-4 were significantly higher in the patients than in the normal subjects. There was a significant inverse correlation between plasma beta-TG and creatinine clearance. Nephrotic patients showed significantly smaller platelet volume and markedly elevated plasma beta-TG levels when compared to the controls. Plasma beta-TG decreased remarkably in 3 out of 4 patients with markedly increased beta-TG levels when they were given antiplatelet drugs. The results suggest that platelet aggregation and the release reaction were increased in patients with CGN. Activated platelets may be an important factor in the genesis of the thrombotic tendency in the nephrotic syndrome.     

Influence of different anticoagulation regimens on platelet function during cardiac surgery

Qualitative platelet defects are of great importance as a causeof bleeding in cardiac surgery. We have studied the effectsof different anticoagulation regimens on platelet function in60 patients undergoing elective aorto-coronary bypass graftingwith cardiopulmonary bypass (CPB). Patients were allocated randomlyto four groups (each group n=15) to receive either: bovine heparin300 u. kg^–1 (standard); heparin 300 u. kg^–1 followedby a continuous infusion of 10000 u. kg^–1 until the endof CPB; heparin 600 u. kg^–1; or heparin 600 u. kg^–1in addition to high-dose aprotinin 2 million iu before CPB,500000 iu h^–1 until the end of operation and 2 millioniu added to the prime. Platelet function was evaluated by aggregometry(turbidometric technique) using adenosine triphosphate (ADP)2.0 (imol litre^–1, collagen 4 µl ml^–1, adrenaline25 urnol litre^–1 and saline solution (control) as inducers.Both maximum aggregation and maximum gradient of aggregationwere measured in arterial blood samples before, during and afterCPB until the first day after operation. Mean total dose ofheparin given in groups 2, 3 and 4 was more than 50000 u. anddiffered significantly from that of group 1 (28150 (SD 4700)u.). Platelet aggregation variables were most depressed duringCPB and until the end of surgery in groups 2 and 3 (maximumaggregation –54% to –75% of baseline values). Inthe postoperative period, platelet function recovered but didnot completely reach baseline values in these patients. Bloodloss and the use of homologous blood and blood products werealso highest in these high-dose heparin groups. The additionof aprotinin (group 4) prevented the effects of high-dose heparinon platelet aggregation. Bleeding was also significantly lessthan in the other high-dose heparin groups but did not differfrom the standard heparin regimen. We conclude that high-doseheparin, whether given as a single dose or administered continuously,adversely affected platelet function and aprotinin preventedthese adverse effects on platelet aggregation.     

Intravenous ketorolac vs diclofenac for analgesia after maxillofacial surgery

Purpose

To compare the efficacy of the nonsteroidal antiinflammatory drugs (NSAID), ketorolac and diclofenac in prevention of pain after maxillofacial surgery.

Methods

Sixty ASA I– II patients (30 in each group) received randomly, and double blindly either ketorolac 0.4 mg · kg^{? 1} or diclofenac 1.0 mg · kg^{? 1} iv after general anaesthesia induction, before surgical incision. In the ketorolac group, the same dose was repeated iv three times at six hour intervals. The diclofenac group patients received diclofenac 1.0 mg μ kg^{? 1} after 12 hr iv. Rescue analgesic medication consisting of oxycodone 0.03 mg · kg^{? 1} iv, was administered by a patient controlled analgesia apparatus.

Results

Two patients in the ketorolac and three patients in the diclofenac group did not need oxycodone during the study period. On average, 12 and 11 doses of oxycodone were needed in the ketorolac and the diclofenac groups, respectively (NS). Sideeffects were similar in both groups. All patients except one were satisfied with the pain therapy.

Conclusion

Parenteral ketorolac (0.4 mg · kg^{? 1} four times in 24 hr) and diclofenac (1 mg · kg^{? 1} twice in 24 hr) were similar, but insufficient alone, for analgesia after maxillofacial surgery.     

Comparison of the opioid-sparing efficacy of diclofenac and ketoprofen for 3 days after knee arthroplasty

BACKGROUND: Comparative postoperative non-steroidal anti-inflammatory drug (NSAID) studies in orthopedic patients have usually been restricted in time to the first postoperative day. The opioid-sparing effect of NSAIDs may be beneficial postoperatively as long as pain otherwise restricts ambulation and rehabilitation. We therefore compared the analgesic efficacy of the maximum recommended doses of diclofenac and ketoprofen for 3 days after knee arthroplasty. METHODS: We studied 64 knee arthroplasty patients, operated on under spinal anesthesia. In a randomized, double-blind and placebo-controlled fashion, the patients received either i.v. diclofenac 75 mg (n = 24), ketoprofen 100 mg (n = 24) or saline (n = 16) in the recovery room, followed by oral diclofenac 150 mg/day, ketoprofen 300 mg/day or placebo, respectively, for 3 days, supplemented by patient-controlled analgesia (PCA) with i.v. oxycodone. RESULTS: The mean consumption of oxycodone during the first, second and third study days was 45.3, 22.3 and 15.2 mg in the diclofenac group, 43.5, 37.5 and 21.8 mg in the ketoprofen group, and 61.2, 45.9 and 36.1 mg, respectively, in the placebo group. Oxycodone consumption was significantly lower (P < 0.05) in the ketoprofen group than in the placebo group in the postoperative period 13-24 h and 61-72 h. Diclofenac was superior to placebo in the postoperative period 25-48 h (P < 0.01), 49-60 h (P < 0.05) and to ketoprofen at 49-60 h (P < 0.05). During administration of diclofenac on days 1-3 and ketoprofen on day 2, the mean pain scores (VAS) were lower than in the placebo group (P < 0.05). Six patients had difficulties in operating the PCA device. There were no differences in blood loss. CONCLUSION: We conclude that in the first day after knee arthroplasty (13-24 h), ketoprofen exerted an opioid-sparing effect. After day 1 (25-60 h), with the doses used, diclofenac proved to be better than placebo, whereas ketoprofen was not.     

Ketoprofen, diclofenac or ketorolac for pain after tonsillectomy in adults?

We have compared the analgesic and opioid sparing effect of three i.v. non-steroidal anti-inflammatory drugs with placebo in a randomized, double-blind, placebo-controlled study in 80 adult patients after elective tonsillectomy. A standard anaesthetic was used. After induction of anaesthesia, patients received ketoprofen 100 mg, diclofenac 75 mg or ketorolac 30 mg by i.v. infusion over 30 min. Patients in the placebo group received saline. Ketoprofen and diclofenac infusions were repeated after 12 h and ketorolac infusion at 6 h and 12 h. Oxycodone was used as rescue analgesic. Patients in the ketoprofen group requested 32% less opioid and patients in the diclofenac and ketorolac groups 42% less opioid than those in the placebo group (P < 0.05). There were one, two and six patients in the placebo, diclofenac and ketorolac groups, respectively, but none in the ketoprofen group, who did not request opioid analgesia during the study (P < 0.05, ketorolac vs placebo and ketoprofen). Visual analogue pain scores were similar in all groups. Visual analogue satisfaction scores were significantly higher in the diclofenac group compared with the placebo group. The incidence of nausea was 44-54%. There were no differences in the incidence of other adverse reactions. We conclude that all three non-steroidal anti-inflammatory drugs were superior to placebo after tonsillectomy.      

A randomised controlled trial of dexmedetomidine for suspension laryngoscopy

We randomly allocated 80 patients to intravenous dexmedetomidine (0.25, 0.5, or 1 μg.kg^?1) or placebo 15 min before anaesthetic induction. Dexmedetomidine 0.5 and 1.0 μg.kg^?1 significantly reduced the mean (95% CI) propofol effect‐site concentrations by 0.83 (0.63–1.03) μg.ml^?1, p = 0.001 and 1.29 (1.12–1.46) μg.ml^?1, p = 0.0003 at intubation, by 1.05 (0.85–1.25 μg.ml^?1, p = 0.0006 and 1.33 (1.15–1.51) μg.ml^?1, p = 0.0002 when surgery started, and by 0.59 (0.39–0.79) μg.ml^?1, p = 0.030 and 0.72 (0.57–0.87) μg.ml^?1, p = 0.004 on completion of surgery, respectively. Patients’ tracheas were extubated sooner after 0.5 and 1.0 μg.kg^?1 dexmedetomidine, by 5.36 (2.39–8.32) min, p = 0.009 and 7.37 (3.24–11.51) min p = 0.003, respectively. Tachycardic responses to intubation were present in five placebo patients and no dexmedetomidine patients. Bradycardia was treated after dexmedetomidine in six patients: five after 1.0 μg.kg^?1; and one after 0.25 μg.kg^?1. Single‐dose dexmedetomidine can reduce anaesthetic requirements, with both desirable and undesirable haemodynamic effects.     

Platelet Aggregation and Haemostatic Response in Dogs Naturally Co‐infected by Leishmania infantum and Ehrlichia canis

Haemostatic alterations in dogs naturally infected by ehrlichiosis and/or leishmaniasis were studied. Platelet count, ADP and collagen‐induced platelet aggregation, prothrombin time, activated partial thromboplastin time (APTT) and plasma fibrinogen concentration were measured. An evident reduction of platelet aggregation response was shown for Leishmania–Ehrlichia co‐infected dogs where platelet aggregation was lower in comparison with control and leishmaniotic dogs (ADP and collagen, P ≤ 0.01) and ehrlichiotic dogs (ADP 10 and 7.5 μm , P ≤ 0.05). Moreover, a significant increase in APTT as well as a reduction of the albumin/globulin rate (A/G) for leishmaniotic and co‐infected dogs versus control and ehrlichiotic dogs was detected. The hypothesis of a synergism between leishmaniosis and ehrlichiosis in altering platelet function by different pathways is discussed.     

Inhibition of baboon platelet aggregation in vitro and in vivo by the garlic derivative,ajoene

Abstract: Background: The infusion of pig growth factor‐mobilized peripheral blood leukocytes (containing 1 to 2% progenitor cells) (pPBPC) into baboons is associated with a thrombotic microangiopathy, which results from a direct effect of these pig cells on platelet aggregation. Ajoene is a synthetic derivative of garlic that inhibits aggregation of human platelets induced by all known agents. To assess its potential use in models of xenotransplantation, this agent was tested for its effect on baboon platelet aggregation in vitro and in vivo. Methods: In vitro studies: Baboon platelet aggregation assays, using adenosine diphosphate (ADP) (20 or 40 μm ) or collagen (12.5 μg/ml), were performed after incubation with ajoene (0 to 150 μg/ml) or dipyridamole (0 to 200 μg/ml). Platelets were also incubated with pPBPC (5 × 10⁶ cells) without or with ajoene in the absence of a known agonist. In vivo studies: Baboons received either a single intravenous dose of ajoene (10 to 25 mg/kg) or dipyridamole (0.8 mg/kg), or repeated doses of both agents at 2 to 3 h intervals. Platelet‐rich plasma was obtained for platelet aggregation assays at time points up to 4 h post‐drug administration. Results: In vitro, platelet aggregation was inhibited by 95% (ADP assay) and 89% (collagen assay) by ajoene at concentrations of ≥75 μg/ml. Dipyridamole had no effect at concentrations of <100 μg/ml, but inhibited aggregation almost completely at higher concentrations. Ajoene inhibited the aggregation caused by pPBPC by 33 to 50%. In vivo, platelet aggregation was completely inhibited for 2 h by ajoene at 25 mg/kg. Dipyridamole at 0.8 mg/kg reduced aggregation by 20% for 15 min, but the effect was lost by 60 min. In combination, the two agents prolonged inhibition marginally. Repeated doses of both agents at 2 h intervals maintained complete inhibition of aggregation, but did not do so when the interval between doses was extended to 2.5 or 3 h. Combined therapy was not associated with any bleeding complications. Conclusions: Although ajoene is a powerful inhibitor of platelet aggregation, the need for repeated administration and its partial effect on pPBPC‐induced platelet aggregation would suggest that it may be of only limited value in preventing the thrombotic microangiopathy that develops when pPBPC are infused into baboons. However, it would seem worthy of further investigation when used in combination with other agents.     

Effects of the sulphonylurea drugs gliclazide and glibenclamide on blood glucose control and platelet function.

Platelet aggregation and adhesion are commonly increased in diabetes mellitus. These abnormalities may in part be responsible for the increased incidence of vascular disease in diabetics. We have investigated the effects of diet, diet plus glibenclamide, and diet plus gliclazide on plasma glucose control and platelet function in 10 newly diagnosed maturity-onset diabetics who had not previously been treated. Before treatment, the mean postprandial plasma glucose value was 13,4 +/- 0,8 mmol/l, which fell insignificantly on dietary treatment, to 12,2 +/- 1,0 mmol/l (P greater than 0,05). Both glibenclamide and gliclazide, when added to the diet, significantly lowered mean plasma glucose values to 9,3 +/- 0,8 mmol/l and 7,8 +/- 0,8 mmol/l respectively (P less than 0,05). Platelet aggregation in response to 1 mumol adenosine diphosphate (ADP) was increased in the diet period, whereas aggregation in response to 10 mumol and 100 mumol was normal. This suggests an increased sensitivity of the platelets to ADP in diabetic patients. The addition of both glibenclamide and gliclazide reduced the magnitude of the response to within the normal range. Platelet aggregation in response to 10 mumol adrenaline and 750 micrograms/ml collagen was significantly reduced by glibenclamide (P less than 0,05). We conclude that sulphonylurea therapy appears to reduce the increased platelet aggregation which occurs in diabetics. This may play a role in the prevention of vascular disease.     

Comparison of parenteral diclofenac and ketoprofen for postoperative pain relief after maxillofacial surgery

Non-steroidal anti-inflammatory drugs (NSAID) effectively reduce the need for opioid analgesia after various types of surgery. The efficacy of diclofenac and ketoprofen to relieve pain after maxillofacial surgery was compared in the present study. In a randomized and double-blind fashion, 90 ASA I–II patients (16–60 yrs) were studied, divided into three groups: Thirty patients received 1.0 mg · kg^?1 diclofenac i.v. after general anaesthesia induction, before surgical incision, and four hours later the same dose was given i.m. Thirty patients received ketoprofen 1.35 mg · kg^?1 i.v. and i.m., as above, and a third group of 30 patients received a comparable volume of saline i.v. and i.m. The patients received supplemental analgesia using a patient controlled analgesia apparatus; the rescue medication consisted of 0.03 mg · kg^?1 oxycodone i.v. (four-hour maximum dose was 0.4 mg · kg^?1) during the 24-hour follow-up. The three groups were comparable regarding the type of maxillofacial surgery (osteotomies vs. soft tissue surgery). Overall, there was a lower need for i.v. oxycodone during the 24-hour period in the diclofenac group (269 doses) than in the ketoprofen group and in the saline group (388 doses, each) (P<0.01). The significantly lower number of oxycodone administrations in the diclofenac group was a result of a distinguishable difference, particularly during the first four hours after surgery. There was no statistically significant difference in the incidence of side effects of the analgesic therapy between the three groups.     

Effect of non-selective, non-steroidal anti-inflammatory drugs and cyclo-oxygenase-2 selective inhibitors on the PFA-100 closure time

The place of cyclo-oxygenase (COX)-2 selective non-steroidal anti-inflammatory drugs (NSAIDs) in the peri-operative period remains under discussion. Due to the absence of COX-2 in platelets, the risk of bleeding in patients who use selective NSAIDs is thought to be decreased. We studied the influence of aspirin, diclofenac, lornoxicam and rofecoxib on the in vitro bleeding time using the platelet function analyser (PFA-100). The PFA-100 simulates the process of platelet adhesion and aggregation after vascular injury in vitro. Measurements in 43 volunteers were performed at three time points: before, 3 h, and 12 h after oral ingestion of one of the randomly assigned study medications. Aspirin, diclofenac and lornoxicam had a significant effect on the in vitro closure time, while rofecoxib did not show this effect. This supports the use of COX-2 selective drugs in the peri-operative period to minimise the risk of bleeding.     

吸入麻醉药对人血浆和血小板血栓素B2生成与血小板聚集的影响

目的：探讨吸入麻醉剂氟烷、安氟醚和异氟醚对人血浆血栓素Ｂ２（ＴＸＢ２），血小板ＴＸＢ２生成与血小板聚集的影响。方法：血浆ＴＸＢ２和血小板ＴＸＢ２的生成量用放免分析法测量，血小板聚集率用比浊法测量。结果：吸入１ＭＡＣ氟烷３０分钟后，血浆ＴＸＢ２浓度、二磷酸腺苷（ＡＤＰ）和肾上腺素（Ｅ）诱导的血小板ＴＸＢ２生成量与血小板聚集率显著下降，吸入１ＭＡＣ安氟醚３０分钟后，血浆ＴＸＢ２浓度和血小板ＴＸＢ２生成量与血小板聚集率亦显著下降，其降低的程度比氟烷轻。吸入１ＭＡＣ异氟醚对上述指标无明显影响。血小板ＴＸＢ２生成的减少与血小板聚集率的下降呈显著正相关。结论：氟烷显著抑制血小板聚集，安氟醚次之，异氟醚对血小板聚集无明显影响。其机制可能与氟烷和安氟醚通过抑制血小板上血栓素Ａ２受体的亲和力，降低ＡＤＰ和Ｅ诱导的血小板ＴＸＢ２的生成有关。     

Differential effects of low-dose tissue plasminogen activator and streptokinase on platelet aggregation

Despite increasing success with low-dose intra-arterial thrombolysis, early rethrombosis still occurs. Platelet aggregation is thought to play a major part in this process. We have therefore investigated the effects of recombinant tissue plasminogen activator (rt-PA) and streptokinase on platelet function at doses currently used for peripheral arterial thrombolysis. Platelet-rich plasma was stirred at 37 degrees C, with either streptokinase (100, 300 or 1000 units ml-1) or rt-PA (10 (T10), 30 (T30) and 100 (T100) mg l-1), with immediate addition of an agonist for platelet aggregation (thrombin, collagen, adenosine diphosphate (ADP) or adrenaline) at a predetermined threshold dose. Significant inhibition of collagen-induced and adrenaline-induced platelet aggregation was produced with rt-PA at all doses used (P less than 0.05). With adrenaline as the agonist, T100 produced disaggregation to a mean (s.d.) level of 26 per cent. Thrombin-stimulated platelet aggregation was significantly reduced by T100 (P less than 0.001) and T30 (P less than 0.01) only, disaggregation being dose-dependent and complete with T100. Using ADP as the agonist, T100 produced a significant reduction in maximum platelet aggregation (P less than 0.01), and disaggregation was achieved to a mean (s.d.) level of 48(13) per cent. Streptokinase did not produce any significant changes in any parameter of aggregation.     

Plasma concentrations of bupivacaine in young infants after continuous epidural infusion

This study reports plasma bupivacaine concentration in seven infants who during major abdominal surgery received lumbar epidural or caudal block anaesthesia. Plasma concentrations (CP) were measured postoperatively after six and twelve h of continuous infusion. Postnatal age ranged from one day to seven months. The local anaesthetic block was performed after induction of anaesthesia. Postoperatively bupivacaine 1.25-2.5 mg·ml^?1 without adrenaline was infused at a rate of 0.5 to 0.83 mg·kg^?1·h^?1. After six h of infusion the mean value measured was 1.59 μg·ml^?1 (range 1.2-1.94 μg·ml^?1). After 12 h the mean value measured was 2.06 μg·ml^?1 (range 1.53-2.98 μg·ml^?1). A marked increase in bupivacaine plasma concentration was seen between six and 12 hours of infusion. Bupivacaine plasma concentration never exceeded 4 μg·ml^?1. Adverse effects that possibly were due to a toxic reaction to bupivacaine were seen in three patients. In conclusion, the dose administered in this study appears to be high and cannot be recommended as safe dosage in this age group.;