Rapid resolution of symptomatic acute pericarditis with ketorolac tromethamine: A parenteral nonsteroidal antiinflammatory agent

Volume 125, Number 5, Part 1 American Heart Journal

has been debated because of the discrepant results obtained from the few published studies of bacteremia during TEE. In this report we present the results of a prospective study designed to assess the prevalence of transient bacteremia during the practice of TEE in our patient population. Methods. Three blood samplesof 15 ml eachfor aerobic and anaerobicblood cultures were obtained under particularly strict asepticconditions from 45 unselectedpatients submitted for TEE, all of them without clinical or analytic evidence of infection. The first blood sample was drawn immediately before the study, the secondwasobtained 10 minutes after the introduction of the probe during the examination, and the third was drawn 10 minutes after the removal of the probe. The venous blood obtained in each samplewasproportionally inoculated into two aerobicmedia, liquid (Liquoid, Hoffmann-LaRoche and Co., Basel, Switzerland) and biphasic (Biomeriux, Charbonnieres,Les Bans,France), that werevented transiently on their receipt at the laboratory, and into one anaerobicmedium (Hemoline-DUO, Merieux, Lyon, France), incubated at 35O C for 7 days. After that period, if the results were negative, the contents of the bottles were partially subcultured into chocolateagar and blood agar plates at 35” C for 48 hours, under aerobicand anaerobicconditions, respectively. Blood culture flaskswere reincubated for another 15 days. At the end of that period, in the caseof negative results, blinded subculturing was performed following the sameprotocol. Results. From a total of 135blood samplesobtained, only three blood cultures from three different patients were positive. In one case a Bacillus speciesorganism was isolated from a blood culture, corresponding to a sample obtained before TEE. In the secondcasePropionibacterium acnes wasisolated from a subculture performed after 21 days of incubation of a blood sampleobtained during TEE. In the third casea Corynebacterium speciesorganism and coagulase-negativestaphylococcuswere cultured from a sampleobtained after the end of TEE. All these isolateswere consideredas contaminants according to accepted criteria.lv 2 Comments. Gorge et a1.3were the first to call attention to transient bacteremiaduring TEE, their results showing a relatively high number of patients (17%) with positive blood samplesduring the procedure. Although the number of patients included in their study was limited to 24, they concludedthat bacteremiaasa result of TEE wascommon and that antibiotic prophylaxis should be routinely performed. Subsequently, Steckelberg et a1.4published a prospective study in 49 patients, detecting positive cultures in only two preprocedure blood samplesand in two of the 141 peri- and postprocedure cultures; all the isolated agents were considered as contaminants. Their conclusion was that TEE is a low-risk procedure and thus antibiotic prophylaxis shouldnot be generally recommended.Our results agreewith this last experience, as well as with reports by others5,6in which the few positive blood cultures obtained were all consideredto be due to contaminant bacteria. In fact, not a singlecaseof infective endocarditishas beendescribed during the clinical follow-up of these patients. Cardiologistsare now faced with the sameproblem that

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gastroenterologistshad a few years ago,when gastrointestinal procedures such as diagnostic fiberoptic endoscopy were considereda potential risk for endocarditis. In their discipline, after the low prevalenceof transient bacteremia during these procedures had been demonstrated, it was concludedthat no prophylaxis wasrequired, asneither the risk of endocarditisnor the effectivenessof prophylaxis had been established.7In a similar fashion in the caseof TEE, current

evidence, including

the results of the present study,

suggeststhat the procedure is not a causeof transient bacteremia, or at least not of bacteremia detectable by the current microbiologic procedures. As a consequence and in

keepingwith the conclusionsof other groups,4-6, 8 wedo not recommendprophylaxis against infective endocarditis before the practice of TEE, even in the caseof high-risk patients. REFERENCES 1.

BryanCS.Clinicalimplicationsof positivebloodcultures.Clin

Microbial Rev 1989;2:329-53. 2. Weinstein MP, Reller LB, Murphy JR, Lichtenstein KA. The clinical significance of positive blood cultures: a comprehensive analysis of 500 episodes of bacteremia and fungemia in adults. Laboratory and epidemiologic observations. Rev Infect Dis 1983;5:35-53. 3. Gorge G, Erbel R, Henrichs KJ, Wenchel HM, Werner HP, Meyer J. Positive blood cultures during transesophageal echocardiography. Am J Cardiol 1990;65:1404-5. 4 Steckelberg JM, Khanderia BK, Anhalt JP, Ballard DJ, Seward JB, Click RL, Wilson WR. Prospective evaluation of the risk of bacteremia associated with transesophageal echocardiography. Circulation 1991;84:177-80. 5. Melendez LJ, Chan KL, Cheung PK, Sochowski RA, Wong S, Austin TW. Incidence of bacteremia in transesophageal echocardiography: a prospective study of 140 consecutive patients. J Am Co11 Cardiol 1991;18:1650-4. 6. Nikutta P, Mantey-Stiers F, Becht I, Hausmann D, Miigge A, Bohm T, Pletschette M, Daniel WG. Risk of bacteremia induced by transesophageal echocardiography: analysis of 100 consecutive procedures. J Am Sot Echocardiogr 1992;5:16812. 7. Shorvon PJ, Eykyn SJ, Cotton PB. Gastrointestinal instrumentation, bacteremia, and endocarditis. Gut 1983;24:107893. 8. Khandheria BK. Prophylaxis or no prophylaxis before transesophageal echocardiography? J Am Sot Echocardiogr 1992; 5:285-7.

Rapid resolution of symptomatic acute pericarditis with ketorolac tromethamine: A parenteral nonsteroidal antiinflammatory agent Siva Arunasalam, MD, and Robert J. Siegel, MD Los Angeles,

Calif.

From the Department of Medicine and the Sinai icine.

Medical

Center,

University

Division of California-Los

of Cardiology, Angeles School

Cedarsof Med-

Reprint requests: Robert J. Siegel, MD, Division of Cardiology, Room 5314, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048. AM HEART J 1993;125:1455-1458, Copyright (3 1993 by Mosby-Year Book, 0002-8703/93/$1.00 + .lO 4/4/44896

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Arunasalam

Table

I. Patient

69 74 68 46 69 83 77 76 68 08 78 56 52 40 56 7: 73 64 69 72 49 79 I, Idiopathic:

and Siegel

American

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Journal

profile

M F F M M M F

M M M F M M F M F M M M F M M D, Dressier’s syndrome;

100.6 101.2 100.” 99.6 100.6 101.0 99.4 100.2 100.2 99.2 100.4 101.1) 101.2 99.8 99.0 99.8 99.6 101.0 99.4 100.6 100.2 99.6 P, Postcardiotomy

98.8 99.x 98.1) 98.0 99.” 99.2 98.8 lOO.(J 98.4 97.6 99.6 98.X 99.8 98.0 97.‘2 98.6 99.4 99.(1 100.0 98.X 98.4 99.0 syndrome:

P P D I P P P P P I P D I I P P D I P P I P

and dose of ketorolac

Acute pericarditis is characterized by the abrupt onset of retrosternal and precordial chest pain aggravated by lying supine, coughing, and inspiration; acute pericarditis is lessened by sitting and leaning forward.’ Irrespective of cause, other clinical features often include pericardial friction rub, low-grade fever, and dyspnea.” ECG in acute pericarditis reveals diffuse ST-segment elevation in all leads except aVR and VI in 907 of cases.” Laboratory tests for acute pericarditis are nonspecific but include findings associated with inflammation such as leukocytosis and an elevated erythrocyte sedimentation rate. Cardiac enzymes are usually normal, but modest elevation of the MB fraction of creatine phosphokinase may occasionally occur because of epicardial inflammation accompanying acute pericarditis.” The pathophysiologic findings of acute pericarditis are acute inflammation with infiltration of the pericardium with polymorphonuclear leukocytes, fibrin deposition, and pericardial vascularization.” Rapid relief from acute pericarditis chest pain can be problematic. Nonsteroidal, antiinflammatory drugs are usually considered the agents of first choice for pericarditis, and corticosteroids are frequently used t.o treat repeated or severe recurrences. Another treatment modality used is colchitine, which has been shown to have antiinflammatory properties and which is especially useful in refractory and recurrent pericarditis.6 Some difficulties in managing acute pericarditis with conventional treatment modalities are delayed onset of response, recurrence of symptoms, and

used in study.

often complications from treatment such as gastrointestinal distress caused by repeated doses of nonsteroidal antiinflammatory agents. Ketorolac tromethamine, a potent, parenterally administered, nonsteroidal, antiinflammatory drug, became available for clinical use in 1990. Our pilot study was performed to evaluate the potential effectiveness of ketorolac for rapid symptomatic relief of acute pericarditis. Methods. Our study included 22 consecutive patients (Table I) in whom acute pericarditis developed. Thirteen of the patients were postcardiotomy patients whose pericarditis developed 3 days after open-heart surgery. Dressler’s syndrome developed in three patients; six patients in the study group had idiopathic pericarditis. None had received prior conventional treatment for pericarditis. Diagnosis of pericarditis was based on pericardial friction rub on clinical examination, elevated erythrocyte sedimentation rate, pericarditic chest pain, low-grade fever, and ECG findings consistent with pericarditis. Patients who were eligible and had no contraindications for ketorolac or other nonsteroidal antiinflammatory drugs were given a single 30,60, or 90 mg injection of ketorolac. One hour after initiation of therapy the patients were interviewed about relief of chest pain. Patients with continued chest discomfort 1 hour after ketorolac administration were given an additional 30 mg parenteral injection. Clinical examination for pericardial rub, erythrocyte sedimentation rate, temperature profile, and ECG were performed ini-

Volume 125, Number 5, Part 1 American Heart Journal

tially and for up to 36 hours after beginning ketorolac. Patients were monitored for adverse reactions, especially gastrointestinal symptoms or bleeding complications. Results. All 22 patients treated with ketorolac responded to therapy (Table I). All had significant reduction of chest pain within 60 minutes of initiation of therapy. One patient in the postcardiotomy group and one with Dressler’s syndrome required an additional 30 mg of ketorolac for complete relief of chest pain. All 22 patients were symptom-free within 2 hours of initiation of therapy. No one required additional therapy in the 36-hour follow-up period. No changes were noted in the ECG or erythrocyte sedimentation rate 20 hours after ketorolac administration. On clinical examination 11 of 13 postcardiotomy patients treated no longer had an audible friction rub 20 hours after treatment. All six patients with idiopathic pericarditis and the three patients with Dressier’s syndrome continued to have an audible friction rub 36 hours post treatment. During follow-up, no side effects or adverse reactions were reported associated with ketorolac administration. Comments. In this study ketorolac given parenterally was effective in alleviating pericarditic chest pain associated with pericarditis. Moreover, 20 of 22 patients had relief in
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who may not tolerate respiratory depression with narcotics.14, l5 It has also been shown to be beneficial in the management of renal colic, biliary colic, sickle cell crisis, and migraine headaches. I6 Ketorolac is rapidly absorbed when given intramuscularly and reaches maximal plasma concentration in 45 minutes. The plasma half-life is 4 to 6 hours in normal adults.17 In conclusion, ketorolac administration resulted in prompt relief of pain associated with acute pericarditis. Doses of 30,60, or 90 mg injected parenterally alleviated chest discomfort within 120 minutes of initiation of therapy, and no adverse reactions directly attributable to ketorolac were observed. In the cohort of patients studied, the parenteral administration of ketorolac was effective in the management of symptomatic patients with acute pericarditis whether it was idiopathic, caused by postcardiotomy, or Dressier’s syndrome. REFERENCES

1. Spodick DH. Acute pericarditis. New York: Grune and Stratton, 1959:133, 153, 180-3. 2. Sodeman WA, Smith RH. A re-evaluation of the diagnostic criteria for acute Dericarditis. Am J Med Sci 1958:235: 672-6.

Surawicz B, Lasseter KC. Electrocardiogram in pericarditis. Am J Cardiol 1970;26:471-6. 4. Tiefenbrunn AJ. Roberts R. Elevation of olasma MB creatine kinase and the development of new Q waves in association with pericarditis. Chest 1980;77:438-43. 5. Permanyer-Miralda G, Sagrista-Sauleda J, Soler-Soler J. Primary acute pericardial disease. A prospective series of 231 consecutive patients. Am J Cardiol 1985;56:623-9. 6. Guindo J, Rodriguez de la Serna A, Ramio J, de Miguel Diaz MA, Subriana MI, Perez Aguso MI, Cosin J, Bayes de Luna A. Recurrent pericarditis. Relief with colchicine. Circulation 1990;82:117-20. 7. Rooks II WH, Maloney PJ, Shott LD, Schuler ME, Sevelius H. The analgesic and anti-inflammatory profile of ketorolac and its tromeihamine salt. Drugs Exp Clin kes 1985;11:479-92. 8. Rooks WH II, Tomolonis AJ, Maloney PJ, Wallech MB, Schuler ME. The analgesic and anti-inflammatory profile of (c)-5-benzoyl-1,2-dihydro-3H-pyrolo [1,2al pyrrole-l-car_. boxylic acid -(RS-37615). Age&Actions 1982;12:684-90. 9. Roszkowski AP. Rooks II WH. Tomolonis AJ. Miller LM. Antiinflammatory and analgesic properties of U:2-(6’-methoxy2-naphthyl)-propionic acid (naproxen). J Pharmacol Exp Ther 1971;179:114-23. 10. Bruno JJ, Yang D, Taylor LA. Differing effects of ticlopidine and two prostaglandin synthetase inhibitors on maximum rate of ADP-induced aggregation [Abstract]. Thromb Haemost 1981;46:412. 11. Roe RL, Bruno JJ, Ellis DJ. Effects of a new nonsteroidal antiinflammatory agent on platelet function in male and female subiects [AbstractI. Clin Pharmacol Ther 1981:29:277. 12. Spiwart ‘K, Green IA, McLauren M, Lloyd j, Bullingham RES, Forbes CD. Haemostatic effects of ketorolac with and without concomitant heparin in normal volunteers. Thomb Haemost 1988;60:382-6. 13. Conrad KA, Fegan TC, Mackie MJ; Mayshary V. Effects of ketorolac tromethamine on hemostasis in volunteers. Clin Pharmacol Ther 1988;43:542-6. 14. Yee JP, Koshiver JE, Allboy C, Brown CR. Comparison of intramuscular ketorolac tromethamine and morphine sulfate for analgesia of pain after major surgery. Pharmacotherapy 1986;6:253-61. 15. O’Hara DA, Fragen RJ, Kinzer M, Pemberton D. Ketorolac 3.

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tromethamine as compared with morphine sulfate for treat ment of postoperative pain. Clin Pharmacol Ther 1987:41:5X 61. 16. Oosterlinck W, Philip WH, Charig C, Gillies G, Hetherington .JW, Lloyd J. A double-blind single-dose comparison of intramuscular ketorolac tromethamine and pethidine in t.rea!ment of renal colic. J Clin Pharmacol 1990;30:336-41. 17. Buckley MM, Bropden RN. Ketorolac. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential. Drugs 1990;39:86-109.

Impaired ventricular repolarization associated with disturbed left ventricular sympathetic function and diastolic filling in diabetes Matti Mgntysaari, MD,a, d Jyrki Kuikka, PhD, Juha Mustonen, MD,b Kari Tahvanainen, MSC,~ Esko Vanninen, MD,” Esko Liinsimies, MD,a and Matti Uusitupa, MD” Kuopio and Helsinki, Finland

Abnormal cardiac systolic and diastolic mechanical function has been observed in patients with diabetic autonomic neuropathy. 1,2 Cardiac enlargement, mechanical stiffness of the ventricular wall, and alterations in myocardial energy metabolism have been proposed as possible linking mechanisms between autonomic neuropathy and abnormalities in left ventricular mechanical function in diabetes. Because a lengthened QT interval also has been found to be associated with diabetic autonomic neuropathy,2 we hypothesized that disturbed left ventricular repolarization could be the link between autonomic neuropathy and abnormal diastolic filling in diabetes. 1231-metaiodobenzylguanidine (MIBG) is a guanethidine analogue that is accumulated in noradrenalin storage granules in postgangiionic sympathetic neurons. Radioactive labeling of MIBG allows visualization and quantification of the functioning sympathetic nervous tissue in richly innervated organs such as the heart.” We recently observed that myocardial lp31-MIBG accumulation is reduced in diabetic patients with autonomic neuropathy.4 Methods. Eleven male patients with diabetes were selected for study-six with decreased heart rate variation during deep breathing (clinical autonomic neuropathy) and five with normal heart rate variation (no clinically evident autonomic neuropathy). In the entire group with diabetes, the mean age (+ SEM) was 55 * 3 years and the duration of diabetes was 13 ? 2 years. Four of the patients From the Departments of Tlinical Physiology, “Medicine, Nutrition, Kuopio University Hospital: and the dResearch itary Medicine. Reprint Medicine, AVI Htww

requests: Matti Mtintysaari, MD, P.O. Box 50, SF-00301 Helsinki,

Research Finland.

Institute

‘Clinical of MiL

of Militw

had insulin-dependent diabetes and seven had non-insrilin-dependent diabetes. None of the patients was taking medication known to affect neuronal ‘““I-MIBG accumulation, and none had findings suggestive of myocardial ischemia on exercise testing. A single photon emission computed tomographic study was performed 6 hours after injection of ““I-MIBG (160 MBq/ 4 mCi, Cygne hv, Eindhoven, The Netherlands). The myocardial “‘II-MIBG uptake was determined from tomographic images of the left ventricle.i The QT interval was measured as a mean of 10 consecutive cardiac cycles in a precordial bipolar iead (electrodes in positions VI and Vs). The QT measurements were made after 5 minutes rest with patients in the supine position and after 7 minutes in the upright position. Alterations in the QT interval were calculated as percentage changes from resting values to make the change independent of the value at rest. Left ventricular size, fractional shortening, and ratio of peak early to peak atria1 (late) flow velocities of left. ventricular filling (E/A ratio) were determined from two-dimensional and pulsed Doppler ultrasound recordings (Aloka SSD-650, Aloka Co., Ltd., Tokyo. Japan). Resub. In the supine position the heart rate (mean + SEM) was 69 2 5 beats/min, systolic blood pressure was 126 ? 6 mm Hg, diastolic blood pressure was 80 +_ 3 mm Hg, and the QT interval was 380 + 15 msec. After 7 minutes in the upright position the heart rate increased 15 + 3 beats/min, systolic blood pressure decreased 5 ir 4 mm Hg. diastolic blood pressure increased 7 f 1 mm Hg, and the QT interval shortened 33 -t 4 msec. Comments. The relative (percentage) shortening of the QT interval resulting from a change to the upright position correlated significantly with the myocardial accumulation of lZ31-MIBG and with the E/A ratio (Figs. 1 and 2). Recently we reported that the E/A ratio and the myocardial lz31-MIBG accumulation show a significant positive correlation in patients with diabetes.” However, the heart rate did not correlate significantly with the E/A ratio or the myocardial accumulation of ‘““I-MIBG. Neither did the change in heart rate resulting from the upright position correlate significantly with the respective change in the QT interval. Therefore the known dependence of the Q? interval and the E/A ratio on heart rate can hardly explain the observed correlations. In conclusion, we found in our patients with diabetes that reductions in myocardial ““IMIBG accumulation and in the echocardiographic E/A ratio were associated with decreased shortening of the QT interval in the upright position. Sympathetic activation has been shown to shorten the QT interval independent of the change in heart rate,h and therefore cardiac sympathetic neuropathy can be expected to reduce the shortening of the QT interval during stress. Thus our observations suggest that ventricular repolarization abnormality can be a linking mechanism between sympathetic neuropathy and impaired left ventricular diastolic filling in diabetes. REFERENCES

J 1993;125:1458-1460.

Copyright 1993 by Moshy-Year Book, OOW8iO:1/9:3/$1 .OO + .lCl 414144900

and Institute

Heart Journal

Inc.

1. Kahn JK, Zola B, Juni .JE, Vinik of left ventricular diastolic filling

AI. Radionuclide assessmen in diabetes mellitus with and