Anaesth Intens Care (1991),19,495-520

Reviews The Effect of Anaesthetic Agents on Platelet Function N. M. GIBBS*

Department of Anaesthesia, Sir Charles Gairdner Hospital, Perth, Western Australia SUMMARY

This paper reviews studies which have investigated the effect ofanaesthetic agents on platelet function. The results ofthese studies suggest that halothane is the only agent in current use which inhibits platelet function in concentrations used clinically. Nitrous oxide appears to cause only a modest inhibition, while enflurane and isoflurane appear to have minimal or negligible effects. There is no current evidence that intravenous induction agents, opiates, or muscle relaxants affect platelet function. Reports indicate that local anaesthetic agents inhibit platelet aggregation, but only at concentrations far greater than peak plasma concentrations found during clinical use. Epidural anaesthesia may be associated with a reduction in platelet aggregation through a mechanism unrelated to direct local anaesthetic inhibition. The clinical significance of the effect ofhalothane on platelet function is not known. However, it is possible that halothane may affect bleeding or thrombotic complications in a similar manner to other 'anti-platelet' drugs.

Key Words: ANAESTHETICS: local, intravenous, inhalational; BLOOD: platelets, function

Over the last decade there have been considerable advances in the understanding of platelet function. 1.3 This has led to an increased awareness of the effect of platelet dysfunction on normal haemostasis, and of the pivotal role of platelet activation in arterial thrombosis.4-8 There has also been an increase in the knowledge of the mechanism of action and the clinical effects of 'anti-platelet drugs' such as aspirin and dipyridamole. 7.11 It has also been recognised that many other drugs, not previously considered 'anti-platelet', inhibit platelet function. These include among others, non-steroidal antiinflammatory drugs,7,9,12 anti-histamines,9 calcium antagonists,7,13,14 (1- and j3-adrenergic blocking agents,15,16 nitroglycerin,17 sodium nitroprusside 18,19 and possibly certain anaesthetic agents. Anaesthetists are often involved in the pe rioperative management of patients who have abnormal platelet function or who have recently ingested 'anti-platelet' drugs. Anaesthetists also participate in measures to reduce the incidence of arterial or venous thrombosis. However, rarely does an anaesthetist consider whether the choice of *F.F.A.R.A.C.S., Consultant Anaesthetist. Address for Reprints: Dr. N. M. Gibbs, Department of Anaesthesia, Sir Charles Gairdner Hospital, Nedlands, W.A. 6009, Australia. Accepted for publication July

15,1991

Anaesthesia and Intensive Care, Vol. 19. No. 4, November. 1991

anaesthetic agent per se affects intra-operative platelet function. Nevertheless, there have been numerous studies which have demonstrated an effect of anaesthetic agents on platelet function. Unfortunately, the results of many such studies have been conflicting, and the results of others have been inconclusive. The aim of this paper is to review previous studies which have examined the effects of anaesthetic agents on platelet function. Due to the complex nature of platelet activation, and the multitude of platelet function tests used in previous studies, a brief summary of platelet physiology and the more common platelet function tests will be included. PLATELET PHYSIOLOGY There are several recent reviews of platelet function 1-3,8 and only a brief overview will be presented here. Platelets are smooth anucleate discoid cells which circulate in the blood for seven to ten days. Platelets are required for primary haemostasis which involves the formation of a haemostatic plug at sites of vascular injury. Platelets can be stimulated by collagen, or by a number of other agonists such as adenosine diphosphate (ADP), thrombin, or platelet activating factor (PAF). At high shear rates, such as those found in the arterial circulation, factor VIII related antigen/v on Willebrand factor (VIII Rag/ vWF) is required for binding of platelets to

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N. M. GIBBS

subend othelia l collagen. Stimula ted platelet s Platelet count The normal platelet count is 150,000-45,000 per underg o an immed iate shape change , and undergo tion, Abnormal bleeding rarely occurs if the platelet Ill. stimula depending on the strength of is above 50,000 per Ill, and spontan eous the of count release the in results which a release reaction g is uncomm on if the platelet count is above three bleedin contents of platelet granules. Platelets contain per Ill. However, if platelet function is which 20,000 bodies) (dense les O-granu s: granule types of prolonged or spontan eous bleeding can al, (ATP), abnorm phate contain ADP, adenos ine triphos counts. 21 ,22 platelet higher at which les a-granu ions; calcium and in, seroton lin boglobu contain thromb ospond in, ~-throm Bleeding time (B-TG), platelet factor 4 (PF4), platelet derived The bleeding time is depend ent on many growth factor, VIIIRaglvWF, and fibrinogen; and variables such as length, depth, direction, and lysosomes which contain lysosomal enzymes. Very position of the incision, the venous pressure, and low concentrations of collagen or other agonists do the degree of vasodilatation. 22-24 Several of these not initiate the release reaction and result in a factors are standar dised using the templa te localised, reversible platelet aggregate. Higher modification of the Ivy technique. 22 ,25 However, concentrations of agonists activate the release due to slight variations in methodology, each reaction, which results in the stimula tion of laboratory must establish a normal range for the surrounding platelets and the formation of a larger exact method used. 22 Abnormal clinical bleeding is irreversible platelet plug. There are at least three uncomm on if the bleeding time is less than 10 pathways to the release reaction in human platelets. minutes. The bleeding time can be performed at the The first involves the freeing of arachid onic acid bedside and is a sensitive measure of platelet plug from memb rane phosp holipi ds by low formation. However, it is nonspecific and can be concentrations of collagen, ADP, or other agonists. altered by defective vessel walls (such as in The arachidonic acid is converted by cyclo- uraemia), by low levels of fibrinogen or VIIIRagl oxygenase to cyclic endoperoxides, most of which vWF, or by severe anaemia. 22 are unstabl e and are rapidly conver ted by aggregation tests thromb oxane synthet ase to thromb oxane A2 Platelet aggregation tests are performed using a Platelet and ore ionoph calcium (TXA2). TXA2 acts as a spectro photom eter to measur e the increases cytosolic free calcium ion concentrations. modifie d of 'platelet-rich' plasma. As platelet This results in the release of granule contents. turbidit y tion proceeds, more light is transm itted TXA2 has a short half-life and is rapidly converted aggrega the 'aggregometer' and this can be by TXB 2 synthetase to TXB 2. This pathwa y can be through ed and quantified. The most commo n blocked by inhibito rs of cyclo-oxygenase. Cyclo- calibrat of the aggregation response is the oxygenase is inactiv ated irreversibly by aspirin, measure height of the aggregation trace after a and reversibly by other non-ste roidal anti- maxim um 7 ,8 The second pathwa y standar d time (usually 3 minutes). Other measures inflamm atory drugs. the threshold concentrations of agents include and s agonist requires higher concen trations of induce a set amount of platelet d involves the release of diacyl-glycerol and inositol- require to the slope of the aggregation trace. or tion, aggrega . olipids phosph triphos phate from membr ane ting agents include ADP, aggrega on These compou nds initiate a sufficiently brisk Comm arachid onic acid, and ine, adrenal n, collage the e promot to increase in cytosolic free calcium ionoph ore 23187 are calcium and PAF in. thromb release reaction indepen dently of the activation of used for research are which s agonist potent y pathwa third A y. the arachidonic acid pathwa 22 s. purpose involves platelet activati ng factor which promot es the release reaction directly. Following the release Tests of the release reaction The specific a-granule contents platelet factor 4 (a reaction there are conform ational changes in the nt coagula e promot which hepari n neutra lising factor 2,22), and 2 ~­ platelet membr ane of n thromboglobulin (an inhibito r of prostacyclin ,26) activity on the platelet surface. This functio the to utes contrib 3) factor can be measured in plasma and are indices of in platelets (platelet format ion of an interdi gitatin g fibrino us vivo platele t activat ion and release . The measurement of adenine nucleotides and 14C_ haemostatic plug or secondary haemostasis. serotonin (O-granule contents) can be performed PLATEL ET FUNCTI ON TESTS in vitro.22 only The diagnosis of platelet dysfunction is based 2o ,21 Viscoelastic measures of platelet function primarily on history and physical findings. are tests Thromboelastography and Sonoclot® analysis ory laborat ng However, the followi measure the comm only used to confir m platel et (Sienco Inc., Morrison, CO., U.S.A.) recalcified or blood whole of ies propert stic viscoela 8,20-22 abnormalities. Anaesthesia and Intensive Care, Vol. 19, No. 4, November, 1991

ANAES THETIC S AND PLATEL ETS

plasma during clot formation. 27 ,28 The maximu m amplitu de of the thromboelastogram is a measure of the absolute strength of the blood clot and is in part depend ent on platelet number and function. The 'peak' impedance of the Sonoclot"'" trace is also an index of platelet function. These viscoelastic measures often correlate poorly with routine coagulation tests. However, they have proved useful in the intra-operative management of patients with abnorm al bleeding. 29 ,3o INHALATIONAL AGENTS

Laboratory studies: In 1971 Ueda examin ed the effects of several volatile anaesth etic agents on platelet aggregation in vitro. 3l He found that clinica lly used concen trations of methoxyflurane, halotha ne, diethylether, and nitrous oxide all inhibite d ADP(O.l-1.0~M)-induced aggregation of canine platelets. In 1979 Bjoraker examin ed the effect of halotha ne on ADP(50JlM)-induced aggregation of human platele tsY He found that halotha ne induced a dose-related and reversible suppression, but that this effect was only significant at halotha ne concen trations above 5%. However, he used a very high ADP concen tration (5 to 50 times greater than the concen tration used by most investigators 22). In 1980 Dalsgaard-Nielsen and Gormse n examin ed the effect of halotha ne on platelet aggregation, and seroton in uptake and release, in human platelets. 33 They found that halotha ne inhibite d ADP(0.255.0JlM)-induced platelet aggregation in a doserelated manner . Halotha ne 2% produce d complete inhibiti on. The inhibiti on lasted less than ten minute s post-e xposur e at low haloth ane concen trations « 1%), but was only partially reversed at ten minute s at higher halotha ne concentrations. They found that halotha ne reduced the rate, but not the total amount of serotonin taken up and released following exposure of platelets to ADP(5.0~M). This suggested that halotha ne did not reduce the storage potential of platelet dense bodies. Also in 1980, Walter et al. demons trated that halotha ne (0.5-10%) increas ed platele t adenylcyclase activity in a dose-related manner (93% increase in activity by halotha ne 5%), and reduced platelet aggregation in vitro.34 In the same study, phoshodiesterase activity was not affected by halotha ne. Waiter et al. postula ted that halotha ne inhibit ed platele t aggrega tion by stimula ting adenylcyclase activity, thus increasing platelet c-AMP levels. In 1983 Cambri a et al. used a technique of yimaging to examin e the effect of halotha ne anaest hesia on platele t depos ition on polytetrafluoroethylene arterial grafts in dogs. 35 They found that halotha ne significantly decreased Anaesthesia and Intensive Care, Vol. 19, No. 4. November, 1991

497

platelet uptake on the grafts, but that this effect was reversible within 24 hours. In 1986 Fauss et al. investigated the effects of isoflurane and nitrous oxide on aggregation of human platelets in vitro and in vivo. 36 Nitrous oxide (80%) reduce d ADP(5~M)-induced platele t aggregation from 70.2% (control) to 58.3% in vitro (P < 0.05). The additio n of isoflurane 1.6% did not result in a further reducti on in platelet aggregation. However, isoflurane 1.6% alone reduced platelet aggregation from 73.4% (contro l) to 69.2% (P< 0.05). The combin ation of nitrous oxide 60% and isoflurane 1-2% produc ed a minima l ( < 10%), but statistically significant reducti on of ADP(5~M and 10IlM)-induced platelet aggregation in vivo. A recent study by Bertha et al. reporte d an interesting and potentially importa nt effect of halotha ne on acute thromb us format ion in artificially stenosed coronary arteries in dogs. 37 Cyclical flow reductions occur in stenosed dog and pig coronary arteries due to cycles of acute thromb us formati on and breakdown. 37 ,38 These flow reductions are exacerbated by adrenal ine. Bertha et al. found that halotha ne abolished both sponta neous and adrena line-in duced cyclic coronary flow reductions. However, enflura ne and isoflurane had no effect. The cyclic flow reducti ons recurred within minute s of stopping halothane. The author s indicat ed that althoug h the significance of their findings was as yet unknow n, it was possible that halotha ne has a protective effect against acute thromb us formati on in stenosed coronary arteries. Clinical studies: In 1971 O'Brien et al. studied platelet functio n in ten patien ts underg oing major thorac ic procedures. 39 They found that during surgery there was a gross reducti on in the aggregation response to both ADP(0.2-2IlM) and collagen which persisted one to three hours postoperatively. They did not identify the inhalational anaesthetic agents used, although they indicate d that some patients received halothane. This study was one of the first to demons trate that platelet aggregation did not increase during surgery, but rather decreased. In 1977 Kokores et al. perform ed several platelet function tests on patients before and during abdom inal surger y for gastro -intest inal carcinoma. 4o Patient s were anaesthetised with thiopen tone followed by halotha ne 0.3-1.5% and nitrous oxide 60-66% in oxygen (all anaesth etic concen trations stated in clinical studies are inspired). They found that 30 minutes into the operati on the templa te bleedin g time was significantly increased (4.6 mins vs 3.9 min preinduction, P < 0.05). Platelet aggregation induced by ADP( 1.0-2IlM) was reduced by about 25%.

498

N. M. GIBBS

These changes were similar at three hours into the operation. Minor changes in collagen- and adrenaline-induced platelet aggregation were also noted. In 1979 Lichtenfeld et al. examined platelet function in twelve patients undergoing minor surgery.41 Anaesthesia was induced with thiopentone and maintained with halothane or enflurane 0.5-1.0%, and nitrous oxide in oxygen. During surgery there were slight reductions in ADP( 1.0-5.0J.LM)-induced platelet aggregation but the changes were not significant. The study did not differentiate between patients receiving halothane or enflurane. Dalsgaard-Nielsen and Gormsen suggested that the reason Lichtenfeld et al. did not observe an effect of halothane was because the halothane in their blood samples had evaporated during preparation for aggregometry. 33 In 1980 Gotta et al. investigated the effect of enflurane and fentanyl anaesthesia on platelet function in thirty surgical patients. 42 Patients received nitrous oxide 60% in oxygen and either enflurane 0.5-2.0%, or intermittent boluses of fentanyl IV. They found that there were no significant changes in ADP(20J.LM)- or collagen (0.26 mg.ml-I)-induced platelet aggregation in either group, although there was considerable variability in response in both groups. The thromboelastographic pattern was also unchanged. In 1981 Dalsgaard-Nielsen et al. examined platelet aggregation and bleeding times in ten patients anaesthetised with halothane 1% and nitrous oxide 66% in oxygen for minor surgery.43 They found that bleeding time increased significantly during surgery (9.9 min vs 6.4 min preoperatively, P< 0.005). There was also a reduction in the sensitivity of platelets to aggregation by ADP in vitro, and this change correlated closely with the increase in bleeding times. The authors attributed the observed changes to a direct effect of halothane on platelet function. However, they also remarked on a wide variation in both bleeding times and platelet responses in their study. In 1984 Fyman et at. examined the effect of volatile anaesthetic agents on bleeding times in elective surgical patients. 44 They randomised 51 patients to receive either halothane 0.5-2.0% in oxygen, enflurane 1.0-3.5% in oxygen, isoflurane 1.2-3.0% in oxygen, or nitrous oxide 66% in oxygen plus fentanyl boluses IV. Bleeding times were measured using a template device. Blood pressure and heart rate were maintained at ±20% of preoperative values. They found that there was considerable variability in the responses within each group. However, in the halothane group there was an average 33% increase in bleeding time

(P < 0.01). There was a 19% increase in bleeding

time in the N 20-fentanyl group but this change was not statistically significant. There was no change in mean bleeding time in either the enflurane or the isoflurane groups. The authors interpreted their findings as indicating an in vivo effect of halothane on platelet function, and cautioned against the use of halothane in situations where optimal haemostasis was critical. They argued that the increase in bleeding times in the halothane group were not due to anaesthetic-induced vasodilation alone, because no change in bleeding times was observed in either the enflurane or isoflurane group. In 1987 Sweeney and Williams examined the effect of halothane on platelet function in children undergoing major craniofacial surgery or conservative dental surgery.45 They found that ADP-, collagen- and adrenaline-induced platelet aggregation were reduced intra-operatively in both groups. In 1988 Rosen et at. compared the effects of halothane, enflurane, and isoflurane on platelet function in 108 elective surgical patients. All patients also received thiopentone and nitrous oxide. 46 A Sonoclof8 analyser28 was used to determine the viscoelastic properties of blood during clot formation. It was found that all three agents induced platelet dysfunction, but that halothane produced the greatest changes. There has been no published report on the effect of the newer volatile anaesthetic agents, sevoflurane and desflurane, on platelet function. INTRAVENOUS AGENTS

Laboratory studies: In 1978 Vairo et al. found that pentobarbitone 25 mg.kg- I, thiopentone 15 mg.kg-I, and ketamine 10 mg.kg- I, all reduced ADP(20J.LM)- and thrombin (0.1 u.ml- I)-induced platelet aggregation in rabbits.47 In 1985, Glen et at. found that neither thiopentone 30 mg.kg- I nor propofol 15 mg.kg- I altered ADP(2.0J.LM)-induced platelet aggregation in rats.48 However, Glen et al. found that the emulsion vehicle ofpropofol1.5 ml.kg-I produced a significant reduction in platelet reactivity.48 In 1988 Oleson and Jorgensen examined the effect of the imidazole derivatives etomidate and mid~zolam on platelet function. 49 However, despite the fact that imidazole is a potent inhibitor of TXB 2 synthetase (the enzyme that inactivates TXA 250), they found that clinical concentrations of the drugs did not alter arachidonic acid (0.8 mmol.l-I)-induced aggregation of human platelets in vitro. Clinical studies: In 1971 O'Brien et at. found that after the induction of anaesthesia with methohexitone or Anaesthesia and Intensive Care, Vol. 19, No. 4, November, 1991

ANAESTHETICS AND PLATELETS

thiopentone, there was no change in ADP- or collagen-induced platelet aggregation. 39 In 1977 Kokores et al. found that following the induction of anaesthesia with thiopentone 300 mg-400 mg IV there was no significant change in bleeding time, ADP( 1.0-20~M)-, collagen- or adrenaline-induced platelet aggregation, or in ADP release in fifteen patients. 4o In 1979, Lichtenfeld et al. found that platelet aggregation induced by ADP(1.0-20~M), adrenaline(50~M), and collagen(O.26J.1M) was unchanged following the induction of anaesthesia with thiopentone 200 mg-400 mg IV in twelve patients. 41 In 1980 Gotta et al. found that thiopentone 3-4 mg.kg- I produced no change in ADP(20J.1M)-induced platelet aggregation in ten patients. 42 In 1985 Naesh et al. found that there was no change in platelet ADP sensitivity following the induction of anaesthesia with thiopentone and droperido1. 51 In 1988 Mayne et al. reported that PF4 and f3-TG levels did not change during maintenance anaesthesia with propofol and alfentanil:52 OPIOIDS There have been few studies which have specifically examined the effect of opioid analgesics on platelet function. However, O'Brien et al. in 1971 noted that neither IV pethidine nor papaveretum altered ADP- or collagen-induced platelet aggregation prior to the induction of anaesthesia. 39 Similarly, Dalsgaard-Nielsen et al. 43, and Naesh et al. 51 found that patients premedicated with morphine and hyoscine showed no alteration in ADP-induced platelet aggregation prior to the induction of anaesthesia. Gotta et al. found that patients anaesthetised with nitrous oxide 66% in oxygen and fentanyl boluses IV had no reduction in ADP- or collagen-induced platelet aggregation. 42 Fyman et al. found that patients anaesthetised with nitrous oxide 70% in oxygen and fentanyl 0.15-0.75 mg IV had a moderate but statistically insignificant increase in bleeding time. 44 In 1989 Hines and Barash found that a control group receiving enflurane and fentanyl (> 30 J.1g.kg- l ) did not demonstrate abnormal platelet aggregation or an increase in bleeding time. 19 MUSCLE RELAXANTS No study has specifically examined the effect of muscle relaxant drugs on platelet function .. However, O'Brien et al. found that ADP- or collagen-induced platelet aggregation was not altered by succinylcholine or tubocurarine. 39 Similarly, in the study by Gotta et al., succinylcholine was used to facilitate tracheal intubation and there was no change in ADP- or collagen-induced platelet aggregation postintubation. 42 Also in the study by Gotta et al., all Anaesthesia and Intensive Care. Vol. 19. No. 4. November. 1991

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patients received pancuronium bromide intraoperatively without a significant change in platelet aggregation. 42 In the study by Hines and Barash, the control group received pancuronium to maintain muscle relaxation but no changes in bleeding time or platelet aggregation were observed. 19 LoCAL ANAESTHETICS Laboratory studies: In 1962 O'Brien, while investigating the processes of adhesion and aggregation of platelets, noted that cocaine (2.5 X 1O-3M), procaine (5.0 X 1O-2M), lignocaine (8.0 X 1O-2M), and dibucaine (5 X 1O-3M), prevented thrombin (0.4 u.ml- I)- and ADP( 4mM)-induced platelet aggregation in vitro. 53 The mechanism of local anaesthetic inhibition of platelet function was investigated by Feinstein et al. in 1976. 54 They found that dibucaine (0.1-1.0 mM) and tetracaine (0.1-1.0 mM) reduced thrombin(O.25u.ml- I)-, collagen(30 J.1g.ml- I)-, and calcium ionophore A23187(5J.1M)-induced platelet aggregation in vitro. Both agents reduced extracellular calcium uptake and prevented the release of ADP, calcium, and serotonin from activated platelets. The authors postulated that local anaesthetics affect platelets by blocking either calcium influx, or the mobilisation of intracellular calcium stores. In 1979, Cazenave et al. found that lignocaine (1.0 mM) was one of several lipid soluble drugs that prevented PAFinduced platelet aggregation and release. 55 In 1981, Luostarinen et al. examined the antithrombotic effects of lignocaine (2%), its metabolite monoethylglycine xylidide (2%), tocainide (2%), and bupivacaine (0.5%) on laserinduced microvascular injury in hampsters. 56 They found that the topical application of these compounds inhibited thrombus formation, and promoted the restoration of blood flow following microvascular injury. In 1985, Borg and Modig examined the effect of lignocaine, bupivacaine, and tocainide on ADP(1.0J.1M)- and collagen(1.0J.1g.ml- I)-induced platelet aggregation in vitro. 57 They incubated the local anaesthetics with platelets for either 5 or 45 minutes prior to aggregometry. They found that after five minutes lignocaine and bupivacaine (lOJ.1g.ml- l ) inhibited platelet aggregation slightly, whereas a concentration of25 J.1g.ml- 1was required to inhibit platelet aggregation more distinctly. Increasing the incubation time to 45 minutes increased the percentage inhibition. Tocainide 100 ~g.ml-I also inhibited platelet aggregation. Increasing the ADP concentration to 10 J.1M overcame the inhibitory effect of all three agents. The authors noted that the concentrations of the

500

N. M. GIBBS

local anaesthetics required to inhibit platelet aggregation in vitro were much higher than the peak plasma concentrations that occur in vivo. 58·60 In 1989 O'Doom et al. found that bupivacaine 10-25 Ilg.ml-1 inhibited ADP(1.0-2.0IlM)- and collagen(0.4llg.ml-1)-induced platelet aggregation in vitro. 6I Bupivacaine 25 Ilg.ml-1 also reduced f3-TG release. However, bupivacaine 2Ilg.ml-1 (the usual upper limit in plasma during clinical use 59) had no effect on platelet aggregation or 13-TG release. Pipecoloxylidide, the principal metabolite of bupivacaine, also had no effect on platelet aggregation or f3-TG release. Also in 1989, Grant et al. examined the effect of bupivacaine, lignocaine, and 2-chloroprocaine on maternal and neonatal platelet function in vitro. 62 Neonatal platelets were more susceptible to the effect of local anaesthetics than maternal platelets. However, neither was affected by local anaesthetic concentrations likely to occur in plasma during clinical use. The authors concluded that epidural anaesthesia with these three agents was unlikely to affect either maternal or neonatal platelet function in vivo. Clinical studies: In 1986 Henny et al. examined the effect of epidural bupivacaine on the haemostatic system in patients undergoing transurethral resection of the prostate gland. 63 They found that ADP(I.OIlM)and collagen(O.4llg. ml- 1)-induced platelet aggregation was inhibited in patients receiving epidural anaesthesia with 0.5% bupivacaine. In 1988 O'Doom et al. also reported that platelet aggregation was inhibited in patients receiving epidural anaesthesia with bupivacaine. 64 In their study, a peak plasma bupivacaine concentration of 470±270r]g.ml- 1 occurred thirty minutes following bupivacaine administration. This concentration was much lower than the concentration of bupivacaine required to inhibit platelet aggregation in vitro. O'Doom et al. speculated that the intracellular concentration of bupivacaine in platelets might be higher than in the plasma, and that this might explain the observed inhibition of

platelet aggregation at low plasma bupivacaine concentrations. In 1989 Nielsen et al. examined collagen-induced platelet aggregation and TXB 2 synthesis in plasma from patients undergoing either general or epidural anaesthesia for arthroscopic meniscectomy. 65 They found that epidural anaesthesia with bupivacaine was associated with an increase in the threshold collagen concentration required to induce platelet aggregation, but the change was not significant. TXB 2 synthesis decreased in patients receiving epidural but not general anaesthesia. The addition of epidural morphine augmented the changes in the epidural group. DISCUSSION

Injury to blood vessels initiates a series of reactions which results in the formation of a blood clot. Following initial local vasoconstriction there is a rapid formation of a platelet plug at the site of vascular injury. Fibrin deposition then commences through activation of either the intrinsic or extrinsic pathway. Abnormal bleeding may result from defects in the vessel wall, from abnormalities in platelet numbers or function, or from defective coagulation. 8,20,21 During surgery, bleeding may occur from any of the above factors or from incomplete surgical haemostasis. On the other hand, excessive coagulation or thrombosis may occur peri-operatively if there are abnormalities in vessel walls, in blood components, or in local blood flOW. 21 ,66 At low shear rates such as in the venous circulation, thrombosis may occur with the activation of relatively few platelets, because aggregatory and clotting factors accumulate and are not diluted. 21 However, in the arterial circulation, a much larger number of platelets must be activated for propagation of thrombus. 21 In this way platelet dysfunction has a greater impact on the incidence of arterial thrombosis than it does on venous thrombosis. The central role of platelet activation in arterial thrombosis is underscored by the widespread use of anti-platelet drugs to reduce the morbidity from

TABLE I

The effect of halothane on ADP-induced platelet aggregation in vitro Year

Author(s)

1971 1979 1980 1980

Ueda 31 Bjoraker32 Dalsgaard-Nielsen and Gormsen 33 Waiter et al. 34

1981

Dalsgaard-Nielsen et al. 43

ADP concentration 0.51lM 50llM 51l M 10llM 0.25-16JlM

Effect 50% inhibition by halothane 1% 50% inhibition by halothane > 10% 100% inhibition by halothane 2% 30% inhibition by halothane 1%* 75% inhibition by halothane 5%* Reduced sensitivity at halothane 1%*

*plus nitrous oxide in oxygen Anaesthesia and IntensiYe Care, Vo!. 19, No. 4, Noyember, 1991

501

ANAESTHETICS AND PLATELETS TABLE 2 The effect of halothane on ADP-induced platelet aggregation in vivo

Year

Author(s)

n

Halothane*

ADP (I!M)

1977

Kokores et al. 4o

15

0.3-1.5%

1979

Lichtenfeld et al. 41

12

0.5-\.0%

1981 1987

Dalsgaard-Nielsen et al. 43 Sweeney and Williams 45

6 9

1.0% not stated

1.0-2.0 20 1.0 5.0 20 0.25-16 1.6

Effect 25% inhibition (P < 0.05) 10% inhibition (ns) 30% inhibition (ns) 10% inhibition (ns) No effect No effect§ 30% inhibition (P < 0.025)

*Inspired concentration (plus nitrous oxide in oxygen) ns = not significant §Halothane may have evaporated during preparation of samples 43 cerebrovascular or coronary artery disease.4-8 Of particular importance is the recognition that myocardial infarction is frequently a result of coronary artery thrombosis, and is not always precipitated by an imbalance in myocardial oxygen supply and demand. 67 This has implications for anaesthetists, because in the management of patients with coronary artery or cerebrovascular disease it may be important to continue 'anti-platelet' therapy through the peri-operative period. Moreover, it is possible that anaesthetic agents that have 'anti-platelet' effects protect against intravascular thrombosis during surgery. The results of the numerous studies on the effect of anaesthetic agents on platelet function indicate that the only agent in current use that alters platelet function in concentrations used clinically is halothane. The effect of halothane has been demonstrated using platelet aggregometry in vitro and in vivo (Tables 1, 2). The inhibition of platelet aggregation occurs mostly with low concentrations of ADP, which suggests that halothane inhibits the arachidonic acid pathway to the release reaction. Halothane also increases bleeding times (Table 3), and alters platelet deposition on artificial arterial grafts. 35 More importantly, it has been shown that halothane protects against thrombus formation in stenosed coronary arteries in dogsY Many of these

studies indicate that the magnitude of the effect of halothane on platelets varies between patients. However, an overall inhibitory effect has been demonstrated in almost every study that has examined the effect of halothane on platelet function. In contrast, the other volatile agents in current use, enflurane and isoflurane, do not appear to significantly alter platelet function. Nitrous oxide appears to have only a modest effect (Table 4). Moreover, there is no current evidence that clinically used doses of intravenous induction agents, opioids, or muscle relaxants affect platelet function. It is not known how halothane affects platelet function. However, data from WaIter et at. suggests that it is by stimulating platelet adeny1cyclase. 34 Several in vitro studies indicate that local anaesthetic agents inhibit platelet aggregation, but only at concentrations far greater than those likely to occur in plasma during clinical use (Table 5). However, recent studies suggest that epidural anaesthesia per se may be associated with an inhibition of platelet aggregation despite subinhibitory plasma concentrations of local anaesthetic. 63 -65 The mechanism by which epidural anaesthesia reduces platelet aggregation in this manner is not known. Nevertheless, it is possible

TABLE

3

The effect of halothane on bleeding time

Year

Author(s)

n

Halothane*

1977

Kokores et al. 4o

15

0.3-1.5%§

1981 1984

Dalsgaard-Nielsen et al. 43 Fyman et al. 44

10 19

1.0% 0.5-2.0%

*Inspired concentration §plus nitrous oxide in oxygen Anaesthesia and Intensive Care. Vol. 19, No. 4, November, 1991

Effect 18% 25% 54% 33%

increase at increase at increase at increase at

30 min. (P < 0.05) 3 hours (P < 0.02) 30 min (P < 0.005) 30 min. (P B Major inhibition* L> B No effect No effect No effect 6% inhibition (ns) 47% inhibition (P< 0.05) No effect 10% inhibition (ns) 30% inhibition (P < 0.02) No effect 20% inhibition (P < 0.05) 33% inhibition (P < 0.05) 20% inhibition (ns) 30% inhibition (P < 0.05) 40% inhibition (P < 0.05)

*Increased at 45 min incubation ns = not significant §similar results with ADP 2.0 I1M Anaesthesia and Intensive Care. Vol. 19. No. 4. November. 1991

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affect platelet function. Local anaesthetics inhibit platelet aggregation, but only at much higher concentrations than occur in vivo. Epidural anaesthesia per se may be associated with an inhibitory effect on platelet aggregation through a mechanism independent of direct local anaesthetic inhibition. The clinical significance of the effect of halothane on platelet function is not known but deserves further study. ACKNOWLEDGEMENTS

I would like to thank Dr. G. P. M. Crawford, Head, Department of Haematology, Sir Charles Gairdner Hospital, Nedlands, W.A. 6009 for his comments on haematological aspects of the manuscript.

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The effect of anaesthetic agents on platelet function.

This paper reviews studies which have investigated the effect of anaesthetic agents on platelet function. The results of these studies suggest that ha...
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