- Email: [email protected]
Influence of COX-inhibiting Analgesics on the Platelet Function of Patients with Subarachnoid Hemorrhage
Influence of COX-inhibiting Analgesics on the Platelet Function of Patients with Subarachnoid Hemorrhage Vera Parkhutik, MD,* Aida Lago, MD, PhD,* Jose Ignacio Tembl, MD,* Concepcion Rubio, MD,† Maria Paz Fuset, MD,† Juana Valles, PhD,‡ Maria Teresa Santos, PhD,‡ and Antonio Moscardo, PhD‡
Background: Platelet function of patients with subarachnoid hemorrhage (SAH) may play an important part in both rebleeding and delayed cerebral ischemia, but little is known about aggregation pathways during the acute phase of stroke. Analgesics are used regularly in the first days after bleeding, and some can potentially inhibit the cyclooxygenase (COX) enzyme. We examined the platelet function of patients with SAH in order to describe their basal situation and determine whether the administration of intravenous nonsteroidal antiinflammatory drugs (NSAIDs) affected platelet aggregation. Methods: Arachidonic acid (AA)–induced aggregation and the platelet function analyzer (PFA)-100 test with collagen/epinephrine cartridges were used to study a group of SAH patients that was treated with dexketoprofen and dipyrone and to compare them to patients that had received no analgesia. Results: Ninety-six consecutive SAH patients prospectively enrolled in platelet studies. Twenty-seven patients were taking NSAIDs (10 on dexketoprofen and 17 on dipyrone), and there were 15 cases in the control group. AA-induced aggregation was 10% 6 3.2% for NSAIDs (mean 6 standard error), specifically 17.2% 6 7% for dexketoprofen and 5.7% 6 1% for dipyrone. Aggregation in the control group was 72.4% 6 6% (P 5 .001). Both analgesics slowed the platelet plug formation during the PFA-100 test, with closure times of 237.2 6 25 seconds for dexketoprofen and 198.4 6 22 seconds for dipyrone and 138.1 6 21 seconds in controls (P 5 .02). Conclusions: The administration of COX-inhibiting analgesics leads to an hypoaggregability state in the first days of SAH. Further insight into their impact on complications such as rebleeding and delayed cerebral ischemia is needed in order to optimize the headache treatment of SAH. Key Words: Analgesia—antiaggregation—delayed ischemic deficit—NSAID—platelet— rebleeding—subarachnoid hemorrhage—vasospasm. Ó 2012 by National Stroke Association
From the *Department of Neurology; †Intensive Care Unit; and ‡Research Center, La Fe University Hospital, Valencia, Spain. Received February 9, 2011; revision received April 3, 2011; accepted April 3, 2011. Supported in part by the Bancaja Fundacion La Fe research grants and the RETICS-RENEVAS grant (RD06/0026/0006) of the Carlos III Health Institute. Address correspondence to Vera Parkhutik, MD, Servicio de Neurologia, Hospital Universitario La Fe, Avda. Campanar 21, 46009 Valencia, Spain. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2012 by National Stroke Association doi:10.1016/j.jstrokecerebrovasdis.2011.04.002
Acute management of subarachnoid hemorrhage (SAH) includes the administration of a variety of drugs. The use of analgesics is essential because of frequent and severe headaches, but management guidelines do not address the question of optimal pain treatment.1 Opiates and paracetamol are the drugs of choice in most intensive care units, but in the absence of well-established universal protocols, other pain medications are used either as stand-alone options or as a means to decrease opiate consumption. Some of those analgesics, especially nonsteroidal antiinflammatory drugs (NSAIDs), can inhibit the cyclooxygenase (COX) enzyme and therefore
Journal of Stroke and Cerebrovascular Diseases, Vol. 21, No. 8 (November), 2012: pp 755-759
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affect platelet function. This fact has been scarcely studied in hemorrhagic stroke patients.2 Because SAH patients are especially vulnerable to both rebleeding and delayed cerebral ischemia (DCI), modifications of their platelet function may directly affect their outcomes.3 In order to increase the data available on this subject, we analyzed the platelet function of SAH patients who had received intravenous NSAIDs (dexketoprofen or dipyrone) and compared it to that of patients who had received no analgesia.
Methods Patients Patients receiving intravenous NSAIDs (dexketoprofen or dipyrone) during the 24 hours before blood extraction were identified from a series of consecutive patients with spontaneous SAH who were prospectively enrolled in platelet studies at our hospital. The typical dose was dexketoprofen 50 mg every 12 hours intravenously and dipyrone 1000 mg to 2000 mg every 6 hours intravenously. The control group consisted of patients who were not taking any kind of analgesic medication during the same time window. The inclusion criteria were SAH confirmed with a computed tomographic (CT) scan of the brain, no history of previous head trauma or bleeding diathesis, no intake of antiaggregants before or during the hospital stay, and normal platelet count and coagulation parameters at hospital admission. Series records included patients’ demographic data, full clinical history, severity of SAH (Hunt–Hess and Fisher scales), and day-by-day medication charts. All patients were admitted to our intensive care unit. Prevention of vasospasm was performed according to the established guidelines, including the administration of nimodipine and in some cases magnesium.1,4,5 All patients underwent early angiography, except those whose short-term outcome was judged to be devastating. Surgical or endovascular treatment was performed if a brain aneurysm was discovered. During endovascular procedures, intravenous heparin was routinely administered if coiling of the aneurysm took place. Heparin use was recorded but was not taken into account during the data processing, because it is generally accepted that it does not affect platelet aggregation. The use of analgesia was left to the discretion of the treating physician and depended on individual demand. The no-analgesia group consisted mostly of patients who had their blood extracted before the start of pain treatment.
Sample Collection Whole venous blood was collected in tubes containing 0.129 M citrate after a fast of a minimum of 8 hours, and the blood was kept at room temperature and analyzed
during the next 1 to 2 hours. Platelet function parameters analyzed during this study were as follows: (1) arachidonic acid (AA)–induced aggregation, in which platelet-rich plasma was prepared by centrifugation at 200 g for 15 minutes; aggregation was induced in the sample by adding AA (1 mmol/L) and measured turbidimetrically using a platelet aggregometer (Chronolog 540, Havertown, PA) as previously described6; and (2) the platelet function analyzer (PFA)-100 closure time, which is a test that measures the time required for platelets to plug an opening in a membrane coated in collagen and epinephrine (the manufacturer’s normal values are under 170 seconds). The study was approved by the Hospital La Fe Ethics Committee and was conducted in accordance with the Helsinki Declaration. All patients or their family members gave their written informed consent.
Statistical Treatment Continuous variables are expressed as mean 6 standard error of mean. Categorical variables are reported as frequencies. Comparisons between groups are made using the analysis of variance test with the Bonferroni correction or the Chi-square test. P # .05 was considered statistically significant.
Results Patient Characteristics Out of 96 patients enrolled in platelet studies at our hospital between February 2008 and March 2010, 42 fulfilled the criteria of the present study. Forty percent were men, with a mean age of 59 6 2 years. The NSAID group consisted of 27 patients (10 on dexketoprofen and 17 on dipyrone), and the control group consisted of 15 patients. Their relevant medical history and clinical characteristics are summarized in Table 1. There were no statistical differences in variables such as sex, age, presence of vascular risk factors, or SAH severity between groups. In 29 patients, an aneurysm was discovered and treated (8 by surgical clipping and 21 by endovascular coiling). Six could not undergo the arteriographic procedure because of their poor clinical conditions. In the remaining 7 patients, no aneurysm was detected despite repeat angiography. There were 5 rebleedings, 3 in the NSAID group and 2 in the control group. The overall mortality rate was 20%.
Aggregation Studies The mean sample extraction time was 2.3 6 0.4 days postbleeding. Platelet activity measured by the AA-induced aggregation method was found to be noticeably low in the NSAID group: 10% 6 3.2% (17.2% 6 7% for dexketoprofen and 5.7% 6 1% for dipyrone). The aggregation intensity in the no-analgesia control group was
ANALGESICS AND PLATELET FUNCTION IN SAH
757
Table 1. Previous medical history and subarachnoid hemorrhage severity
Sex, male Age, y (6SD) Hypertension Dislipemia Active smoker Diabetes mellitus Hunt–Hess grade 1 2 3 4 5 Fisher scale grade 1 2 3 4
No analgesia
Dexketoprofen
Dipyrone
Significance
35% 56 6 2 45% 25% 30% 10%
29% 52 6 7 29% 10% 10% 0%
40% 57 6 2 43% 17% 47% 7%
NS NS NS NS NS NS
20% 20% 13% 27% 20%
22% 44% 0% 11% 33%
6% 53% 12% 29% 00%
NS NS NS NS NS
0 40% 13% 47%
0 50% 10% 40%
0 29% 24% 47%
NS NS NS NS
Abbreviations: NS, not significant; SD, standard deviation.
significantly higher, but still far from normal: 72.4% 6 6% (P 5 .001; Fig 1). Similar results were seen using the PFA-100 test. This point of care test measures the time it takes for the whole blood to form a platelet plug and close an opening in a collagen/epinephrine coated membrane under shear stress conditions. Patients who had received no analgesia were the only ones with closure times within the manufacturer’s limits of normality (138.1 6 21 seconds). The closure times were abnormally prolonged the NSAID group, with patients taking dexketoprofen having the most altered results (237.2 6 25 seconds) compared to the patients taking dipyrone (198.4 6 22 seconds; P 5 .02; Fig 2).
Figure 1.
Arachidonic acid–induced aggregation (%; P 5 .001).
Discussion Dexketoprofen is a water-soluble salt of the dextrorotatory enantiomer of the NSAID ketoprofen.7 Its parenteral formulation has shown an opioid-sparing effect, and it is one of the first-choice intravenous analgesics in general clinical practice.8-10 The use of dexketoprofen and other NSAIDs in SAH is not infrequent. A recent survey of French intensive care units confirmed that paracetamol and morphine are the most frequently used analgesics, but while 75% of centers were reluctant to use NSAIDs, only 7 out of 24 units declared to never prescribe the drug, compared to 17 units that would use it at least
Figure 2. Platelet function analyzer-100 collagen/epinephrine cartridges closure times (seconds; P 5 .02).
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occasionally. Although platelet inhibition is one of the potential side effects of all drugs that affect the COX enzyme,12 the impact of NSAID administration on neurosurgical patients has not been systematically examined. In one of the few reports on the subject, dexketoprofen’s mother drug, ketoprofen, has been compared to paracetamol in a small randomized study that enrolled 9 SAH patients in each arm. A lower aggregation was noted in the ketoprofen group, and one of the patients developed postoperative intracraneal hematoma, leading the authors to conclude that the drug may have increased the bleeding risk.2 Dipyrone is an analgesic drug with potent analgesic and antipyretic properties that is useful in multimodal analgesia in the intensive care setting13 and is especially effective in treating headaches.14 It had been initially theorized that its nociceptive effect may be mediated by central mechanisms,15 but more recent data have pointed to peripheral reversible inhibition of both COX-1 and COX-2.16 Dipyrone is not used in some countries because of an association with agranulocytosis,17-19 but it is prescribed widely across Europe, Japan, Russia, and Central and South America20-22 and in countries with marketing approval is a very popular choice of analgesia for SAH patients.23 There are few studies in which the effect of dipyrone on platelet aggregation is analyzed and that involved patients with no relevant neurologic history.24-26 It should be noted that all analgesia was administered intravenously in our study; in fact, both dexketoprofen and dipyrone were chosen in part because they have available intravenous preparations. In our opinion, the fact that SAH headaches are usually severe and frequently accompanied by nausea, and that many patients present an impaired level of conscience, makes the intravenous route the one of choice. However, we are aware that this study may not be directly applicable to patients taking oral analgesics. In contrast to ischemic stroke patients, the platelet function of patients with SAH is poorly understood. Previous data from ex vivo laboratory studies have suggested that a hypoaggregability state may exist in the first days after the bleeding,27 implying that aggregation pathways could be spontaneously disrupted in an unclear way. Considering that one of the most dangerous complications of SAH is rebleeding, hypoactive platelets can definitely be elevating this risk. On the contrary, SAH patients with enhanced aggregation have been shown to carry a higher risk of DCI, possibly mediated through platelet-derived vasoconstrictive substances such as thromboxane B2.3 Antiplatelet drugs taken in the days that precede SAH protect against ischemia,28 and several clinical trials have shown that aspirin administration after aneurysm treatment can offer a modest protection against DCI.28-31 In short, both too high and too low platelet activity may lead to complications in SAH, and the optimal middle ground has yet to be found.
Our study has confirmed the initial hypoaggregability state in SAH. Even in the absence of any potential antiplatelet medications, our patients’ platelets responded poorly to stimulation with AA (AA-induced aggregation in the no-analgesia group of only 72%). Those values were further lowered through the administration of COXinhibiting analgesics dexketoprofen and dipyrone (17.2% and 5.7%, respectively). Regarding the PFA-100 closure times, to our best knowledge our study represents the first time an aggregation point of care test has been used for assessment of SAH patients. The closure times for untreated patients were within the normal range, but a prolongation of closure time was noted in both treatment groups. The clinical impact of our findings is difficult to assess without additional data. Prolonged PFA-100 closure times (collagen/epinephrine cartridges) have been associated with a tendency for surgical, posttraumatic, and spontaneous bleeding,32 although there are no data in the literature to confirm that NSAIDs specifically increase the risk of spontaneous or postsurgical bleeding in SAH. We detected 5 rebleedings among our subjects, and these cases were found in both the treatment and control groups. Nevertheless, the small sample size of the study makes it difficult to directly tie the lowering of the platelet function to clinical outcome. Day to day SAH management varies between countries and even between individual intensive care units.33 Proper pain management is not discussed in SAH management guidelines,1 and it is safe to assume that a wide selection of analgesic protocols is used. Taking into account the existing data, it is our opinion that maximal precautions should be taken regarding NSAIDs and any other pain medication potentially able to interact with aggregation pathways. Platelet function is spontaneously reduced in the first days after SAH. It is further decreased by the administration of intravenous COX-inhibiting analgesics. More evidence on their possible influence on clinical outcome of SAH patients is needed in order to establish comprehensive guidelines on optimal treatment of SAH headaches.
References 1. Bederson JB, Connolly ES Jr, Batjer HH, et al. American Heart Association Guidelines for the management of aneurysmal subarachnoid hemorrhage: A statement for healthcare professionals from a special Writing Group of the Stroke Council, American Heart Association. Stroke 2009;40:994-1025. 2. Niemi T, Tanskanen P, Taxell C, et al. Effects of nonsteroidal anti-inflammatory drugs on hemostasis in patients with aneurismal subarachnoid hemorrhage. J Neurosurg Anesthesiol 1999;11:188-194. 3. Juvela S, Hillbom M, Kaste M. Platelet thromboxane release and delayed cerebral ischemia in patients with subarachnoid hemorrhage. J Neurosurg 1991;74:386-392.
ANALGESICS AND PLATELET FUNCTION IN SAH 4. Keyrouz SG, Diringer MN. Clinical review: Prevention and therapy of vasospasm in subarachnoid hemorrhage. Crit Care 2007;11:220-230. 5. Parkhutik V, Lago A, Tembl JI, et al. Spontaneous subarachnoid haemorrhage: a study of 462 patients [in Spanish]. Rev Neurol 2008;46:705-708. 6. Santos MT, Valles J, Lago A, et al. Residual platelet thromboxane A2 and prothrombotic effects of erythrocytes are important determinants of aspirin resistance in patients with vascular disease. J Thromb Haemost 2008;6:615-621. 7. Barbanoj MJ, Antonijoan RM, Gich I. Clinical pharmacokinetics of dexketoprofen. Clin Pharmacokinet 2001; 40:245-262. 8. Barden J, Derry S, McQuay HJ, et al. Single dose oral ketoprofen and dexketoprofen for acute postoperative pain in adults. Cochrane Database Syst Rev 2009;CD007355. 9. Moore RA, Barden J. Systematic review of dexketoprofen in acute and chronic pain. BMC Clin Pharmacol 2008; 31(8):11. 10. Rodriguez MJ, Arbos RM, Amaro SR. Dexketoprofen trometamol: Clinical evidence supporting its role as a painkiller. Exp Rev Neurother 2008;8:1625-1640. 11. Binhas M, Walleck P, El Bitar N, et al. Pain management in subarachnoid haemorrhage: A survey of French analgesic practices. Ann Fr Anesth Reanim 2006;25:935-939. 12. Herrero JF, Romero-Sandoval EA, Gaitan G, et al. Antinociception and the new COX inhibitors: Research approaches and clinical perspectives. CNS Drug Rev 2003; 9:227-252. 13. Tempel G, von Hundelshausen B, Reeker W. The opiatesparing effect of dipyrone in post-operative pain therapy with morphine using a patient-controlled analgesic system. Intensive Care Med 1996;22:1043-1047. 14. Ramacciotti AS, Soares BG, Atallah AN. Dipyrone for acute primary headaches. Cochrane Database Syst Rev 2007;CD004842. 15. Neugebauer V, Schaible HG, He X, et al. Electrophisiological evidence for a spinal antinociceptive action of dipyrone. Agents Actions 1994;41:62-70. 16. Hinz B, Cheremina O, Bachmakov J, et al. Diprone elicits substancial inhibition of peripheral cyclooxygenases in humans: New insights into the pharmacology of an old analgesic. FASEB J 2007;21:2343-2351. 17. Edwards JE, McQuay HJ. Dipyrone and agranulocitosis: What is the risk? Lancet 2002;360:1438. 18. Iba~ nez L, Vidal X, Ballarin E, et al. Agranulocytosis assotiated with dipyrone (metamizol). Eur Journal Clin Pharmacol 2005;60:821-829. 19. Kaufman DW, Kelly JP, Levy M, et al. The drug etiology of agranulocytosis and aplastic anemia. Vol. 18 of
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Monographs in epidemiology and biostatistics. New York: Oxford University Press, 1991. Fendrich Z. Metamizol—A new effective analgesic with a long history. Overview of its pharmacology and clinical use. Cas Lek Cesk 2000;139:440-444. Hohlfeld T, Zimmermann N, Weber AA, et al. Pyrazolinone analgesics prevent the antiplatelet effect of aspirin and preserve human platelet thromboxane synthesis. J Thromb Haemost 2007;6:166-173. Torres LM, Rodriguez MJ, Montero A, et al. Efficacy and safety of dipyrone versus tramadol in the management of pain after hysterectomy: A randomized, double-blind, multicenter study. Reg Anesth Pain Med 2001;26:118-124. Guerrero Lopez F, de la Linde Valverde CM, Pino Sanchez FI. General management in intensive care of patients with spontaneous subarachnoid hemorrhage. Med Intensiva 2008;32:342-353. Bozzo J, Escolar G, Hernandez MR, et al. Prohemorrhagic potential of dipyrone, ibuprofen, ketorolac and aspirin: Mechanisms associated with blood flow and erythrocyte deformability. J Cardiovasc Pharmacol 2001;38:183-190. Geisslinger G, Peskar BA, Pallapies D, et al. The effects on platelet aggregation and prostanoid biosynthesis of two parenteral analgesics: Ketorolac tromethamine and dipyrone. Thromb Haemost 1996;76:592-597. Graff J, Arabmotlagh M, Cheung R, et al. Effects of parecoxib and dipyrone on platelet aggregation in patients undergoing meniscectomy: A double blind, randomised, parallel-group study. Clin Ther 2007;29:438-447. Tsementzis SA, Gill JS, Hitchcock ER, et al. Reduced platelet function in subarachnoid hemorrhage. J Neurosurg 1986;64:907-910. Juvela S. Aspirin and delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage. J Neurosurg 1995; 82:945-952. Dorhout Mees S, Rinkel GJE, Hop JW, et al. Antiplatelet therapy in aneurysmal subarachnoid haemorrhage: A systematic review. Stroke 2003;34:2285-2289. Dorhout Mees S, van den Bergh WM, Algra A, et al. Antiplatelet therapy for aneurysmal subarachnoid haemorrhage. Cochrane Database Syst Revs 2007;CD006184. Toussaint LG 3rd, Friedman JA, Wijdicks EF, et al. Influence of aspirin on outcome following aneurysmal subarachnoid hemorrhage. J Neurosurg 2004;101:921-925. Podda GM, Bucciarelli P, Lussana F, et al. Usefulness of PFA-100 testing in the diagnostic screening of patients with suspected abnormalities of hemostasis: Comparison with the bleeding time. J Thromb Haemost 2007; 5:2393-2398. Stevens RD, Naval NS, Mirski MA, et al. Intensive care of aneurismal subarachnoid hemorrhage: An international survey. Intensive Care Med 2009;35:1556-1566.
Background: Platelet function of patients with subarachnoid hemorrhage (SAH) may play an important part in both rebleeding and delayed cerebral ischemia, but little is known about aggregation pathways during the acute phase of stroke. Analgesics are used regularly in the first days after bleeding, and some can potentially inhibit the cyclooxygenase (COX) enzyme. We examined the platelet function of patients with SAH in order to describe their basal situation and determine whether the administration of intravenous nonsteroidal antiinflammatory drugs (NSAIDs) affected platelet aggregation. Methods: Arachidonic acid (AA)–induced aggregation and the platelet function analyzer (PFA)-100 test with collagen/epinephrine cartridges were used to study a group of SAH patients that was treated with dexketoprofen and dipyrone and to compare them to patients that had received no analgesia. Results: Ninety-six consecutive SAH patients prospectively enrolled in platelet studies. Twenty-seven patients were taking NSAIDs (10 on dexketoprofen and 17 on dipyrone), and there were 15 cases in the control group. AA-induced aggregation was 10% 6 3.2% for NSAIDs (mean 6 standard error), specifically 17.2% 6 7% for dexketoprofen and 5.7% 6 1% for dipyrone. Aggregation in the control group was 72.4% 6 6% (P 5 .001). Both analgesics slowed the platelet plug formation during the PFA-100 test, with closure times of 237.2 6 25 seconds for dexketoprofen and 198.4 6 22 seconds for dipyrone and 138.1 6 21 seconds in controls (P 5 .02). Conclusions: The administration of COX-inhibiting analgesics leads to an hypoaggregability state in the first days of SAH. Further insight into their impact on complications such as rebleeding and delayed cerebral ischemia is needed in order to optimize the headache treatment of SAH. Key Words: Analgesia—antiaggregation—delayed ischemic deficit—NSAID—platelet— rebleeding—subarachnoid hemorrhage—vasospasm. Ó 2012 by National Stroke Association
From the *Department of Neurology; †Intensive Care Unit; and ‡Research Center, La Fe University Hospital, Valencia, Spain. Received February 9, 2011; revision received April 3, 2011; accepted April 3, 2011. Supported in part by the Bancaja Fundacion La Fe research grants and the RETICS-RENEVAS grant (RD06/0026/0006) of the Carlos III Health Institute. Address correspondence to Vera Parkhutik, MD, Servicio de Neurologia, Hospital Universitario La Fe, Avda. Campanar 21, 46009 Valencia, Spain. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2012 by National Stroke Association doi:10.1016/j.jstrokecerebrovasdis.2011.04.002
Acute management of subarachnoid hemorrhage (SAH) includes the administration of a variety of drugs. The use of analgesics is essential because of frequent and severe headaches, but management guidelines do not address the question of optimal pain treatment.1 Opiates and paracetamol are the drugs of choice in most intensive care units, but in the absence of well-established universal protocols, other pain medications are used either as stand-alone options or as a means to decrease opiate consumption. Some of those analgesics, especially nonsteroidal antiinflammatory drugs (NSAIDs), can inhibit the cyclooxygenase (COX) enzyme and therefore
Journal of Stroke and Cerebrovascular Diseases, Vol. 21, No. 8 (November), 2012: pp 755-759
755
V. PARKHUTIK ET AL.
756
affect platelet function. This fact has been scarcely studied in hemorrhagic stroke patients.2 Because SAH patients are especially vulnerable to both rebleeding and delayed cerebral ischemia (DCI), modifications of their platelet function may directly affect their outcomes.3 In order to increase the data available on this subject, we analyzed the platelet function of SAH patients who had received intravenous NSAIDs (dexketoprofen or dipyrone) and compared it to that of patients who had received no analgesia.
Methods Patients Patients receiving intravenous NSAIDs (dexketoprofen or dipyrone) during the 24 hours before blood extraction were identified from a series of consecutive patients with spontaneous SAH who were prospectively enrolled in platelet studies at our hospital. The typical dose was dexketoprofen 50 mg every 12 hours intravenously and dipyrone 1000 mg to 2000 mg every 6 hours intravenously. The control group consisted of patients who were not taking any kind of analgesic medication during the same time window. The inclusion criteria were SAH confirmed with a computed tomographic (CT) scan of the brain, no history of previous head trauma or bleeding diathesis, no intake of antiaggregants before or during the hospital stay, and normal platelet count and coagulation parameters at hospital admission. Series records included patients’ demographic data, full clinical history, severity of SAH (Hunt–Hess and Fisher scales), and day-by-day medication charts. All patients were admitted to our intensive care unit. Prevention of vasospasm was performed according to the established guidelines, including the administration of nimodipine and in some cases magnesium.1,4,5 All patients underwent early angiography, except those whose short-term outcome was judged to be devastating. Surgical or endovascular treatment was performed if a brain aneurysm was discovered. During endovascular procedures, intravenous heparin was routinely administered if coiling of the aneurysm took place. Heparin use was recorded but was not taken into account during the data processing, because it is generally accepted that it does not affect platelet aggregation. The use of analgesia was left to the discretion of the treating physician and depended on individual demand. The no-analgesia group consisted mostly of patients who had their blood extracted before the start of pain treatment.
Sample Collection Whole venous blood was collected in tubes containing 0.129 M citrate after a fast of a minimum of 8 hours, and the blood was kept at room temperature and analyzed
during the next 1 to 2 hours. Platelet function parameters analyzed during this study were as follows: (1) arachidonic acid (AA)–induced aggregation, in which platelet-rich plasma was prepared by centrifugation at 200 g for 15 minutes; aggregation was induced in the sample by adding AA (1 mmol/L) and measured turbidimetrically using a platelet aggregometer (Chronolog 540, Havertown, PA) as previously described6; and (2) the platelet function analyzer (PFA)-100 closure time, which is a test that measures the time required for platelets to plug an opening in a membrane coated in collagen and epinephrine (the manufacturer’s normal values are under 170 seconds). The study was approved by the Hospital La Fe Ethics Committee and was conducted in accordance with the Helsinki Declaration. All patients or their family members gave their written informed consent.
Statistical Treatment Continuous variables are expressed as mean 6 standard error of mean. Categorical variables are reported as frequencies. Comparisons between groups are made using the analysis of variance test with the Bonferroni correction or the Chi-square test. P # .05 was considered statistically significant.
Results Patient Characteristics Out of 96 patients enrolled in platelet studies at our hospital between February 2008 and March 2010, 42 fulfilled the criteria of the present study. Forty percent were men, with a mean age of 59 6 2 years. The NSAID group consisted of 27 patients (10 on dexketoprofen and 17 on dipyrone), and the control group consisted of 15 patients. Their relevant medical history and clinical characteristics are summarized in Table 1. There were no statistical differences in variables such as sex, age, presence of vascular risk factors, or SAH severity between groups. In 29 patients, an aneurysm was discovered and treated (8 by surgical clipping and 21 by endovascular coiling). Six could not undergo the arteriographic procedure because of their poor clinical conditions. In the remaining 7 patients, no aneurysm was detected despite repeat angiography. There were 5 rebleedings, 3 in the NSAID group and 2 in the control group. The overall mortality rate was 20%.
Aggregation Studies The mean sample extraction time was 2.3 6 0.4 days postbleeding. Platelet activity measured by the AA-induced aggregation method was found to be noticeably low in the NSAID group: 10% 6 3.2% (17.2% 6 7% for dexketoprofen and 5.7% 6 1% for dipyrone). The aggregation intensity in the no-analgesia control group was
ANALGESICS AND PLATELET FUNCTION IN SAH
757
Table 1. Previous medical history and subarachnoid hemorrhage severity
Sex, male Age, y (6SD) Hypertension Dislipemia Active smoker Diabetes mellitus Hunt–Hess grade 1 2 3 4 5 Fisher scale grade 1 2 3 4
No analgesia
Dexketoprofen
Dipyrone
Significance
35% 56 6 2 45% 25% 30% 10%
29% 52 6 7 29% 10% 10% 0%
40% 57 6 2 43% 17% 47% 7%
NS NS NS NS NS NS
20% 20% 13% 27% 20%
22% 44% 0% 11% 33%
6% 53% 12% 29% 00%
NS NS NS NS NS
0 40% 13% 47%
0 50% 10% 40%
0 29% 24% 47%
NS NS NS NS
Abbreviations: NS, not significant; SD, standard deviation.
significantly higher, but still far from normal: 72.4% 6 6% (P 5 .001; Fig 1). Similar results were seen using the PFA-100 test. This point of care test measures the time it takes for the whole blood to form a platelet plug and close an opening in a collagen/epinephrine coated membrane under shear stress conditions. Patients who had received no analgesia were the only ones with closure times within the manufacturer’s limits of normality (138.1 6 21 seconds). The closure times were abnormally prolonged the NSAID group, with patients taking dexketoprofen having the most altered results (237.2 6 25 seconds) compared to the patients taking dipyrone (198.4 6 22 seconds; P 5 .02; Fig 2).
Figure 1.
Arachidonic acid–induced aggregation (%; P 5 .001).
Discussion Dexketoprofen is a water-soluble salt of the dextrorotatory enantiomer of the NSAID ketoprofen.7 Its parenteral formulation has shown an opioid-sparing effect, and it is one of the first-choice intravenous analgesics in general clinical practice.8-10 The use of dexketoprofen and other NSAIDs in SAH is not infrequent. A recent survey of French intensive care units confirmed that paracetamol and morphine are the most frequently used analgesics, but while 75% of centers were reluctant to use NSAIDs, only 7 out of 24 units declared to never prescribe the drug, compared to 17 units that would use it at least
Figure 2. Platelet function analyzer-100 collagen/epinephrine cartridges closure times (seconds; P 5 .02).
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occasionally. Although platelet inhibition is one of the potential side effects of all drugs that affect the COX enzyme,12 the impact of NSAID administration on neurosurgical patients has not been systematically examined. In one of the few reports on the subject, dexketoprofen’s mother drug, ketoprofen, has been compared to paracetamol in a small randomized study that enrolled 9 SAH patients in each arm. A lower aggregation was noted in the ketoprofen group, and one of the patients developed postoperative intracraneal hematoma, leading the authors to conclude that the drug may have increased the bleeding risk.2 Dipyrone is an analgesic drug with potent analgesic and antipyretic properties that is useful in multimodal analgesia in the intensive care setting13 and is especially effective in treating headaches.14 It had been initially theorized that its nociceptive effect may be mediated by central mechanisms,15 but more recent data have pointed to peripheral reversible inhibition of both COX-1 and COX-2.16 Dipyrone is not used in some countries because of an association with agranulocytosis,17-19 but it is prescribed widely across Europe, Japan, Russia, and Central and South America20-22 and in countries with marketing approval is a very popular choice of analgesia for SAH patients.23 There are few studies in which the effect of dipyrone on platelet aggregation is analyzed and that involved patients with no relevant neurologic history.24-26 It should be noted that all analgesia was administered intravenously in our study; in fact, both dexketoprofen and dipyrone were chosen in part because they have available intravenous preparations. In our opinion, the fact that SAH headaches are usually severe and frequently accompanied by nausea, and that many patients present an impaired level of conscience, makes the intravenous route the one of choice. However, we are aware that this study may not be directly applicable to patients taking oral analgesics. In contrast to ischemic stroke patients, the platelet function of patients with SAH is poorly understood. Previous data from ex vivo laboratory studies have suggested that a hypoaggregability state may exist in the first days after the bleeding,27 implying that aggregation pathways could be spontaneously disrupted in an unclear way. Considering that one of the most dangerous complications of SAH is rebleeding, hypoactive platelets can definitely be elevating this risk. On the contrary, SAH patients with enhanced aggregation have been shown to carry a higher risk of DCI, possibly mediated through platelet-derived vasoconstrictive substances such as thromboxane B2.3 Antiplatelet drugs taken in the days that precede SAH protect against ischemia,28 and several clinical trials have shown that aspirin administration after aneurysm treatment can offer a modest protection against DCI.28-31 In short, both too high and too low platelet activity may lead to complications in SAH, and the optimal middle ground has yet to be found.
Our study has confirmed the initial hypoaggregability state in SAH. Even in the absence of any potential antiplatelet medications, our patients’ platelets responded poorly to stimulation with AA (AA-induced aggregation in the no-analgesia group of only 72%). Those values were further lowered through the administration of COXinhibiting analgesics dexketoprofen and dipyrone (17.2% and 5.7%, respectively). Regarding the PFA-100 closure times, to our best knowledge our study represents the first time an aggregation point of care test has been used for assessment of SAH patients. The closure times for untreated patients were within the normal range, but a prolongation of closure time was noted in both treatment groups. The clinical impact of our findings is difficult to assess without additional data. Prolonged PFA-100 closure times (collagen/epinephrine cartridges) have been associated with a tendency for surgical, posttraumatic, and spontaneous bleeding,32 although there are no data in the literature to confirm that NSAIDs specifically increase the risk of spontaneous or postsurgical bleeding in SAH. We detected 5 rebleedings among our subjects, and these cases were found in both the treatment and control groups. Nevertheless, the small sample size of the study makes it difficult to directly tie the lowering of the platelet function to clinical outcome. Day to day SAH management varies between countries and even between individual intensive care units.33 Proper pain management is not discussed in SAH management guidelines,1 and it is safe to assume that a wide selection of analgesic protocols is used. Taking into account the existing data, it is our opinion that maximal precautions should be taken regarding NSAIDs and any other pain medication potentially able to interact with aggregation pathways. Platelet function is spontaneously reduced in the first days after SAH. It is further decreased by the administration of intravenous COX-inhibiting analgesics. More evidence on their possible influence on clinical outcome of SAH patients is needed in order to establish comprehensive guidelines on optimal treatment of SAH headaches.
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