Postoperative pain, although frequently encountered, is often underestimated and badly treated. A new method of treating postoperative pain is preemptive/preventive analgesia, which seeks to prevent or diminish pain when it is caused by the surgical procedure [1,2].
Lornoxicam (Xefo®; Nycomed Pharma AS, Roskilde, Denmark) is a highly potent, short-acting non-steroidal anti-inflammatory drug (NSAID) of the oxicam class . It has been shown to possess equivalent analgesic effect to morphine and tramadol for perioperative pain, reduced the reduction of opioid consumption postoperatively and be of value for patients suffering from chronic back pain [4-14]. Lornoxicam exerts its analgesic effect not only via inhibition of cyclooxygenase (COX) I and II, but also by leading to a release of endogenous dynorphin and beta-endorphin . Furthermore, Lornoxicam features a more favourable tolerability profile and longer duration of effect than other NSAIDs [13,14,16]. Due to these properties and for its availability for both enteral and parenteral administration routes, lornoxicam might be beneficial for perioperative pain therapy [17,18]. Lornoxicam, like other NSAIDs, is said to impair platelet function in healthy volunteers to a lower extent than diclofenac, but more than COX-II inhibitors . However, as with other NSAIDs the principal mechanism of action relates to the inhibition of COX, the key enzyme of the arachidonic acid pathway, resulting in the inhibition of prostaglandin synthesis. Related adverse effects mainly concern reduced platelet aggregation, renal and gastrointestinal mucosal injury . Though gastrointestinal bleeding and impairment of renal function were reported after perioperative use of the NSAID ketolorac, the multifactorial nature of these complications makes it difficult to ascribe them to the NSAID alone [21,22]. Regarding bleeding complications in particular, the administration of indometacin resulted in increased perioperative blood loss after abdominal hysterectomy, whereas diclofenac had no significant effect on blood loss after transurethral prostatectomy . Ketolorac has been shown to inhibit platelet aggregation and to prolong bleeding time in healthy awake volunteers, although it failed to have the same effects during knee arthroscopy under general anaesthesia . This finding might be related to trauma-induced activation of haemostasis during surgery and does not contribute to a perioperative bleeding tendency .
The goal of this study was to investigate platelet aggregation and invitro bleeding time before and within 8 h after administration of a single preoperative dose of lornoxicam in thoracic surgery in a prospective, randomized, placebo-controlled trial.
After institutional Ethics Committee approval and patients' written, informed consent, 20 patients scheduled for lobectomy at the Department of Thoracic Surgery, Medical University Vienna, were enrolled for this study. Exclusion criteria for this study were history of asthma or hypersensitivity to NSAID, haematological abnormalities and also any kind of known clotting diseases, gastrointestinal problems contraindicating the application of NSAID, concomitant medication with furosemide, digoxin, warfarin, oral hypoglycaemic drugs or any medication that could affect platelet function, any complication during surgery and 25% increased duration of surgery than normal. Pregnant women were not included.
Patients were randomly allocated to receive either a single dose of 16 mg lornoxicam (n = 10) or placebo (n = 10) intravenously (i.v.), 20 min before the induction of anaesthesia. The randomization criteria were age, weight and sex.
Premedication consisted of 7.5 mg midazolam (Dormicum®) given orally 45 min before the patients arrived in the operating room. Anaesthesia was induced by target-controlled infusion (TCI) of 5 μg mL−1 plasma propofol (Diprifusor), 0.5-1 μg kg−1 min−1 remifentanil (Ultiva®) and 0.01 mg kg−1 vecuronium (Norcuron®) to facilitate intubation. General anaesthesia was maintained by total i.v. anaesthesia with target plasma propofol 2-4 μg mL−1 and 0.2-0.5 μg kg−1 min−1 remifentanil. Ventilation was controlled to maintain end-tidal CO2 tension at 35-45 mmHg (Cicero®; Dräger, Austria). A 20-G radial artery catheter was inserted for continuous monitoring of arterial blood pressure and to obtain blood samples. Heart rate, oxygen saturation and body core temperature were monitored during anaesthesia. All patients received human albumin 20% to maintain colloid osmotic pressure above 14 mmHg. Fluid substitution was achieved by crystalloid Ringer's solution; no colloid solution was used. 50 mg ranitidine (Zantac®) and 8 mg ondansetron (Zofran®) were administered intraoperatively for prophylaxis of gastrointestinal mucosal injury and postoperative nausea. At the time of skin closure the remifentanil infusion was stopped and patients received 0.1 mg kg−1 piritramide (Dipidolor®) i.v. as an analgesic loading dose. On arrival in the post anaesthesia care unit (PACU) pain was evaluated using a visual analogue scale (VAS 1-10) and treated if necessary by piritramide, 3 mg boluses with 10 min lock out time, using a patient-controlled analgesia system (PCA, Pharmacia®).
Blood sampling was performed via the arterial line directly into silicone-coated Vacutainer tubes containing 0.5 mL of 0.129 M buffered sodium citrate 3.8% (VacutainerTM; Becton Dickinson Europe, Meylan Cedex, France) before, 15 min, 4 h and 8 h after the study medication was administered.
Platelet adhesiveness was assessed within 1 h after blood collection using corrected whole blood impedance aggregometry, (Chrono-Log®; four-channel whole blood aggregometer, Chrono-Log Corporation, Havertown, PA, USA) [26-29]. Aggregation was induced using collagen type I (COL, final concentration 5 μg mL−1), adenosine diphosphate (ADP, final concentration 10 μM) and arachidonic acid (AA, final concentration 500 μM as trigger substances (Chrono-Par®, Chrono-Log Corporation). One mL whole blood was transferred into each aggregometer cuvette and was allowed to incubate for 2 min at a stirring speed of 700 rpm and 37°C until drifting of the baseline-impedance had stopped. After calibration of each aggregometer chamber by a 20 Ω signal, platelet aggregation was started by adding the trigger substance to each cuvette and data were recorded for 10 min. The integral of the aggregation curve (Ω s) was used in order to quantify corrected whole blood platelet aggregability. Routine plasma coagulation tests, including platelet count (PLC) prothrombin time (PT), thrombin time (TT), activated partial thromboplastin time (aPTT), fibrinogen (FIB) and antithrombin III (ATIII) were investigated before and 60 min after surgery. pH, PO2, PCO2, base excess, serum electrolytes, colloid osmotic pressure, haematocrit and haemoglobin values were monitored by arterial blood gas analysis every 60 min.
Ten patients per group were calculated to detect with a power of 80% (and an α error of 0.05) a difference >30% between the placebo and lornoxicam groups for collagen-activated aggregometry measurements. Mean ± SD for power analysis calculation were derived from a previous pilot study (not published).
Data were tested for normal distribution with QQ-Plot and Kolmogorov-Smirnov test. Statistical analysis included Kruskall-Wallis test, Wilcoxon signed rank-sum test and Wilcoxon matched-pairs test; area under the curve (AUC) was calculated for aggregometry data over time. Unless otherwise noted, values are expressed as mean ± SD. All calculations were performed with SPSS software (SPSS®, Chicago, IL, USA). P < 0.05 was considered significant.
There was no significant difference with regard to patient characteristics and duration of anaesthesia between the study groups (see Table 1). There was also no significant difference in mean arterial pressure, heart rate, temperature, oxygen saturation and blood pH during the observation period. Haematocrit was significantly reduced postoperatively compared to preoperative values, but without significant difference between the study groups (P > 0.05). There was no difference for routine plasma coagulation measurements between the groups, including platelet count (PLC) (P = 0.3), prothrombin time (PT) (P = 0.8), thrombin time (TT) (P = 0.1), activated partial thromboplastin time (aPTT) (p = 0.4), fibrinogen (FIB) (P = 0.8) and antithrombin III (ATIII) (P = 0.3), similarly there was no difference for standard coagulation measurements in comparison to baseline values (P > 0.05). Table 2 shows haemostatic parameters for both study groups before and after surgery. None of the patients required blood substitution.
Platelet aggregation induced by collagen, ADP and arachidonic acid was significantly reduced after lornoxicam administration compared to baseline values (P < 0.05) and in comparison with the placebo group (AUC, P < 0.05; Figs 1-3). Significant differences between the groups for collagen activation were observed after 15 min, 4 h and 8 h; for ADP activation after 15 min. Arachidonic acid activation in the lornoxicam group was markedly reduced 15 min, 4 h and 8 h after lornoxicam administration. Platelet function was already significantly impaired 15 min after lornoxicam administration: −75.3 ± 15% for ADP activation, −46.0 ± 10% for collagen activation and −85.5 ± 18% for arachidonic acid activation (P < 0.05, vs. baseline, Figs 1-3). Postoperative pain at admission in the recovery room was significantly reduced after lornoxicam administration with pain score 5.8 ± 1.9 for the lornoxicam group vs. 8.1 ± 1.7 for the placebo group (P < 0.01). No patient complained about any side-effects.
Adjuvant NSAIDs for perioperative analgesia have been shown to decrease postoperative pain and time to discharge after moderate to major surgical procedures [8,9,23]. However, concerns have been raised regarding their side-effects on haemostasis, since several studies have documented platelet function defects following NSAIDs. So far the effect of lornoxicam on platelets has been described only in healthy volunteers [19,30]. In contrast to that, we took into considerations that there are perioperative alterations in haemostasis including platelet dysfunction due to physiological and even pharmacological reasons in our study protocol [25,31-33]. Propofol, ketamine, local anaesthetics, sevoflurane, halothane and nitrous oxide are reported to interact with platelet function whereas opioids and muscle relaxants show neglible effect . Aoki and colleagues describe a propofol-induced reduced response of platelets on ADP stimulation, which could also be observed in our patients in both groups . ADP-induced aggregometry causes platelet activation through the release of dense granule stored ADP [32,33]. In contrast, collagen and arachidonic acid stimulated platelet function remained nearly unchanged in our placebo group. Arachidonic acid-induced aggregometry in general is used to assess the viability of the thromboxane pathway and therefore detects the cyclooxygenase 1 inhibiting effect. Collagen-induced aggregometry depends on intact membrane receptors, membrane phospholipase pathway integrity and normal cyclooxygenase and thromboxane pathway function. It is decreased for example in von-Willebrand disease. Our placebo group shows the same alterations in aggregometry as described by Kokores and colleagues .
Niemi and colleagues showed reversible antiplatelet effects for ketoprofen, ketolorac and diclofenac when administered to volunteers . Diclofenac had the mildest effect, while platelet dysfunction was still seen 24 h after ketolorac. Similar results were described by Blaicher and colleagues [17,30]. Blaicher and colleagues observed a prolonged significant effect on PFA (Platelet Function Analyzer)-closure time, an invitro bleeding parameter, as well as measured by CD 62 P expression on healthy volunteers after oral intake of acetylsalicylic acid, diclofenac, lornoxicam and rofecoxib. In contrast, Sommers and colleagues, in accordance with other investigators, reported exvivo induced platelet aggregation in volunteers to be unaffected by a single dose of diclofenac [35,36]. The differences previously observed, may be in part due to differences in pharmacokinetics, or to a certain extent, be related to different actions of NSAIDs on COX. Accordingly, lornoxicam and diclofenac might be expected to be comparable with regard to analgesic efficacy, COX I/II inhibiting characteristics and half-life time. Regarding inhibition profiles of COX I and COX II, lornoxicam and diclofenac are equipotent supposing a similar effect on platelet function . However, in contrast to previous reports of minimal antiplatelet effects of diclofenac, lornoxicam markedly inhibited collagen-induced platelet aggregation. Half-life of lornoxicam is determined to be in the range of 4 h compared with 2 h for diclofenac . Since we found platelet function activated by arachidonic acid to be reduced to 75% 8 h after lornoxicam administration, our findings support the theory, that NSAIDs inhibit platelet function approximately as long as they remain in sufficient concentrations in the blood .
Although lornoxicam reduces the platelets aggregability in the perioperative setting, there was no difference in the fibrinogen levels and blood loss in both groups indicating a higher bleeding tendency. Surgery-induced neurohumoral responses might counteract the effects of NSAIDs on platelet aggregation, thus account for controversial findings in several trials [24,25]. However, we found significantly inhibited platelet aggregation within 8 h after a single parenteral dose of lornoxicam in patients with moderate surgical trauma.
In accordance with previous, well-documented trials on NSAIDs and platelet function, we have shown that lornoxicam is an effective antiaggregant. We investigated perioperative platelet aggregation in ASA II-III patients with malignant lung disease and therefore susceptible for haemostatic disorders during surgery.
In summary, we propose that perioperative analgesia using NSAIDs like lornoxicam should be administered carefully with regard to bleeding complications due to pronounced platelet dysfunction.
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