Letters

Volume 163 Number 2

precipitate myocardial ischemia and, if not treated properly, may proceed to myocyte damage. 2. Pharmacologic effects of ritodrine are different from changes considered as physiologic adaptations of exercise. These changes consist of metabolic effects, including those of glucose, sodium, potassium, renin, angiotensin, and arginine vasopressin, water homeostasis, and renal and cardiopulmonary effects. These changes individually or cumulatively predispose the patient to cardiopulmonary complications that are quite different from tachycardia seen during exercise. 3. Additional increases in blood volume and cardiac output in pregnant women, especially in twin gestations will be added risk factors to cardiopulmonary complications. The authors' most recent study, which already included two life-threatening cases of angina with normal ECGs and in one of which pulmonary edema developed, supports the notion that an ECG alone cannot be used as the sole marker of therapy in these cases. In view of the life-threatening cardiovascular and pulmonary nature of ritodrine complications and the lack of adequate data in this regard, we believe, in the presence of ECG changes and / or chest pain, that ritodrine tocolysis should be discontinued. Furthermore, patients should be given oxygen and additional cardiac assessment and cardiology consultation should be carried out. Finally, we agree with Drs. Henricks and Katz that further insight regarding this complex issue requires development of an animal model and more detailed cardiac studies before we suggest that ECG changes are not an indication for discontinuation of ritodrine therapy. Hamid A. Hadi, MD Department of Obstetrics and Gynecology, East Carolina University, School of Medicine, Greenville, NC 27858-4354

SabahJ. Albazzaz, MD Department of Internal Medicine, Section of Cardiology, Medical College of Georgia, Augusta, GA 30912

I. 2. 3.

4. 5.

REFERENCES Roberts R. Diagnostic assessment of myocardial infarction based on lactate dehydrogenase and creatine kinase isoenzymes. Lung Heart 1981; I 0:486-505. Fuller T, Movahed A. Current review of exercise testing: application and interpretation. Clin Cardiol 1987; 10: 189200. Spellacy WN, Cruz AC, Buhi WC, et al. The acute effects of ritodrine infusion on maternal metabolism: measurements of levels of glucose, insulin, glucagon, triglycerides, cholesterol, placental lactogen, and chorionic gonadotropin. AM] OBSTET GYNECOL 1978;131:637-42. Bieniarz], Ivankovich A, Scommegna A. Cardiac output during ritodrine treament in premature labor. AM] OBSTET GYNECOL 1974;118:910-20. Katz M, Robertson PA, Creasy RK. Cardiovascular complications associated with terbutaline treatment for preterm labor. AM] OBSTET GYNECOL 1981; 139:605-8.

Inhibitory cofactor of anti phospholipid antibody in normal pregnancy sera To the Editors: Lockwood et al. recently reported a study to establish the causative nature of anti phospholipid

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antibody on adverse pregnancy outcomes (Lockwood Cj, Romero R, Feiberg RF, Clyne LP, Coster B, Hobbins JC. The prevalence and biologic significance of lupus anticoagulant and anticardiolipin antibodies in a general obstetric population. AM J OBSTET GYNECOL 1989; 161:369-73). We would like to complement their observations with our recent finding of high levels of antiphospholipid antibody, commonly present in sera from normal healthy individuals. 1 These antiphospholipid antibodies in sera from normal healthy individuals are normally undetectable by a sensitive enzyme-linked immunosorbent assay (ELISA), but their presence is revealed when sera are first preheated at 56° C for 30 minutes before ELISA testing! The anti phospholipid antibodies in normal healthy individuals were mostly IgG and exhibited the classical selective binding, as reported for anti phospholipid antibody in clinical sera, to negatively charged phospholipids including cardiolipin, phosphatidylserine, and phosphatidic acid. I. 3 This strongly indicates the existence of heat-labile serum inhibitory cofactor(s) of anti phospholipid antibody, with such complexes in normal healthy individuals being undetectable by ELISA. The ELISA detection of such autoantibodies may thus reflect a reduction of anti phospholipid antibody-masking factor(s). In other words, any pathogenicity of antiphospholipid antibody may not necessarily result from a hyperimmune response to cell membrane phospholipids but rather a consequence of a pathophysiologic decrease in the antiphospholipid antibody inhibitor. In this regard, we have similarly found anti phospholipid antibody in 29 of 31 normal pregnancy sera after heat inactivation of the sera. We are progressing with investigations to characterize the anti phospholipid antibody regulatory cofactor and to better understand the immunogenesis of antiphospholipid antibody in nonclinical sera. Hwee-Ming Cheng, PhD Department of Physiology, Faculty of Medicine, Universiti Malaya, 59100 Kuala Lumpur, Malaysia

REFERENCES I. Cheng HM, Phuah EB. Heat-labile serum inhibitor of antiphospholipid antibody binding in ELISA. Immunol Lett 1989;22:263-6. 2. Cheng HM, Ngeow YF, Sam CK. Heat-inactivation of serum potentiates anti-cardiolipin antibody binding in ELISA.] Immunol Methods 1989;124:235-8. 3. Cheng HM. Anticardiolipid antibodies and habitual abortion. AM] OBSTET GYNECOL 1988;158:441-2.

Response declined

The local anesthetic dose is an important Issue in evaluation of effects of epidural analgesia in nulliparous women To the Editors: My colleagues and I appreciated the article by Thorp et al. (Thorp JA, Parisi VA, Boylan PC, Johnston DA. The effect of continuous epidural analgesia on cesarean section for dystocia in nulliparous women. AM J OBSTET GYNECOL 1989;161:670-5). We thought the authors did an excellent job in describing the relationship between epidural analgesia during la-

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Letters

August 1990 Am J Obstet Gynecol

bor and incidence of cesarean section for dystocia, which may stem from such a technique. The results were analyzed, taking into account objective sources of error, and suggested a need for further investigation. However, there was a point in the study that may need clarification. Thorp and colleagues did not specify the dose of bupivacaine administered. Indeed, the first injection was described as an "initial bolus injection of bupivacaine 0.25%," whereas the following dose was indicated as a "continuous infusion of 6 to 12 ml/hr of 0.125% solution." The mean infusion time was not given. It has been widely discussed that pregnancy increases the effectiveness of local anesthetics. I Therefore it has been suggested that the administered dose should be as small as possible to avoid untoward effects such as instrumental delivery and distressing motor blockade! In the aforementioned work it was quite difficult to quantitate either the first or the total dose of bupivacaine. We believe this is a very important issue to address because dystocia could be related to the total amount of local anesthetic received by the patient. In addition, we would like to reflect on the continuous infusion method used to maintain analgesia. Different epidural analgesia techniques may produce different drug levels and relative effects on the body. In a previous study Griffiths and colleagues' demonstrated that epidural analgesia, given by a constant infusion of bupivacaine 0.25% to 0.125%, yields a cumulative dose twice as large as that produced by repeated 0.5% bupivacaine injections. Also, in the first condition bupivacaine plasma levels were close to the toxic threshold, whereas no bupivacaine was found in plasma in the second one. In Thorp et al.'s study there was no comparison of incidence of cesarean section for dystocia between a nulliparous group of women in which a continuous infusion of 0.125% bupivacaine was given, and one receiving small 0.25% bipuvacaine topup injections under patient request. What if the infusion time were such to allow bupivacaine accumulation? If that were the case, the results may represent an uncontrolled bupivacaine dose-effect. Finally, the epidural use of other drugs should be explored. Opioids such as fentanyl citrate have been successfully used to relieve pain in the first stage of labor.4 Although opioids may not be sufficient to provide adequate analgesia in all stages of labor, the synergism between local anesthetics and opioids is suitable for further investigation. s It may be possible that such a pharmacologic association reduces both local anesthetic dose and unwanted effects on delivery. Andrea Della Puppa, MD, and Luciano Dalla Torre, MD Department of Anesthesia, USL 12, Presidio Ospedaliero di Valdobbiadene, Valdobbiadene, Italy 31049

Laura Favretti, MD Department of Obstetrics and Gynecology, USL 12, Presidio Ospedaliero di Valdobbiadene, Valdobbiadene, Italy 31049

REFERENCES 1. Bromage PR. Epidural analgesia. Philadelphia: WB Saunders, 1978:522-5. 2. Thorburn J, Moir D. Extradural analgesia: the influence of volume and concentration of bupivacaine on the mode

of delivery, analgesic efficacy and motor block. Br J Anaesth 1981 ;53:933-9. 3. Griffiths DPG, Diamond AW, Cameron JD. Postoperative extradural analgesia following thoracic surgery: a feasibility study. Br J Anaesth 1975;47:48-54. 4. Carrie LES, O'Sullivan GM, Seegobin R. Epidural fentanyl labor. Anaesthesia 1981 ;36:965-9. 5. Writer DR, James FM, Wheeler S. Double-blind comparison of morphine and bupivacaine for continuous epidural analgesia in labor. Anesthesiology 1981 ;54(3):215-9.

Reply To the Editors: We appreciate the interest in our research. Puppa and colleagues make several valid criticisms about any retrospective study design (i.e., there are numerous variables that were not controlled). The mean epidural infusion time was not analyzed. We agree that the total dose of bupivacaine may well be an important determinant of labor outcome. Despite the data of Griffiths et al., I there are legitimate concerns about repeated boluses of 0.5% bupivacaine during labor. Continuous infusion technique is generally considered safer than repeated boluses because of the potential for toxic reactions from inadvertent intravascular bolus injection. In addition, the 0.5% bupivacaine solution would have a greater potential to affect the course of labor because it causes a more dense motor blockade than that of the 0.125% or 0.25% solution. In institutions in which the staff are acutely aware of the potential of epidural analgesia to interfere with labor, the adverse effects may be limited. However, in institutions in which there is a lack of experience or concern, epidural analgesia may have a profound effect on the incidence of instrumental delivery and cesarean section. There is a large variation in epidural technique between institutions. Many factors involved with the epidural technique may influence the course of labor (e.g., fluid bolus, cervical dilatation at which the epidural infusion is placed, concentration of anesthetic agent, volume of anesthetic agent, and management of the epidural infusion in the second stage of labor). Perhaps as important as the epidural technique itself is the variation in the obstetrician's response to dystocia. A recent stud y2 showed that with the same anesthetic service, epidural analgesia was associated with a 16-fold greater incidence of cesarean section for dystocia in the private service as compared with the clinic service. In this study,2 epidural analgesia was associated with an increase in cesarean section for dystocia on the private service but not on the clinic service. The authors2 speculate that the difference may be attributed to a more aggressive use of oxytocin in the clinic patients compared with the private patients. As Neuhoff et aU point out, if uterine activity is not restored in a timely fashion, "the psychology of prolonged and non-progressive labor dominates management strategies, as the physicians, patients, and families become exhausted and frustrated .... " The question of whether epidural analgesia increases the incidence of instrumental vaginal delivery or ce-