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    ows-28/790/82 0010 Copygte by viens & wore Vol 8,006.12 Pons aU SA review Induction and Augmentation of Labor: Basis and Methods for Current Practice BETH A. BRINDLEY and ROBERT J. SOKOL Department of Obstetrics and Gynecology, Wayne State Universty/Hutze! Hospital, Detrt, Michigan Medical control ot labor is often necessary in modern obstetrics. The status of the cervix may dictate the method of induction and influence its success. Four milligrams of prostaglandin (PGE;) gel applied intravaginally has been shown to be a safe, efficacious, and extremely well-tolerated agent to promote cervical ripening. The patient should be monitored before and at least 4 hours atter PGE. gel application, since the incidence of uterine activity is high after this treatment and many of these pregnancies are at risk. The rare case of hyperstimulation may be treated with a tocolytic agent. The start of oxytocin may be individually tailored, but we do not recommend its use in less than 4 hours after gel insertion. Oxytocin should be used with great caution if the patient continues to have uterine activity from the PGE. gel. Because, in part, the use of the PGE» {gel for cervical ripening is not approved by the Food and Drug Administration in the United States, itis prudent to discuss its use with the patient, document carefully, and use this medication only if there is cl ication. Protocols for the use of oxytocin currently used in many hospitals seem to be based on outdated pharmacologic data. Relatively new information on the pharmacology and clinical effects. of oxytocin are reviewed to provide a rational approach to its clinical use in accordance with recently published guidelines from the American College of Obstetricians and Gynecologists (ACOG). The current data overwhelmingly indicate that oxytocin should be started at a low dose (0.5-1 mU/min) with @ slow, arithmetical increase every 30 to 60 minutes. Previous reports of a high incidence of fetal distress, uterine dysfunction, and hyperstimulation in induced labor may be related to use of oxytocin at doses higher than currently appear appropriate. The risks of induction and augmentation can be reduced by careful patient selection and preparation. Oxytocin is jective with expert medical management which provides careful monitoring, controlled infusion, persistence, and the knowledge of when to stop. Medical control of the onset or augmentation of labor is an important component of modern perinatal care. Oxytocin, first synthesized in the 1950s, has been widely used for the induction and augmentation of labor. It is a potent uterotonic agent which can be safe and efficacious when used appropriately. Rela- tively new on the scene, but also widely used, is prostaglandin (PG) E, gel for cervical ripening. New guidelines have recently been published by the ‘American College of Obstetricians and Gynecolo- gists (ACOG) (2) which recognize the importance of fa “Tipe” cervix prior to induction and also advocate Reprint requests to: Robert J. Sokol, MO., Department of ‘Obstetrics and Gynecology, Wayne State University Schoo! of Medicine, Hutzel Hospital, 4707 St. Antonie, Detroit, Mi 48201 730 a low starting dose of oxytocin with slow, arithmeti- cal increase. The following review, while not a com- prehensive overview, focuses on detailing practical methods and providing a scientific basis, from the best evidence available, for the induction and aug- mentation of labor. Relatively new information con- cerning the pharmacology and clinical effects of both oxytocin and PGE-2 is emphasized, which should aid in understanding the rationale behind the current recommendations. Although today there is very little role for “elective” induction of labor, induction is indicated when the benefits to either the mother or fetus outweigh the benefits of continuing the pregnancy (2, 72). Ooca- sionally the benefits of delivery would “tip the scale” Induction and Augmentation of Labor 731 only if the fetal lungs were mature and the chance of cesarean due to failed induction low. Therefore, a risk-benefit analysis is necessary prior to induction of labor. The timing of oxytocin augmentation of labor is controversial and based on amazingly limited hard data. Friedman (32) advocates the use of oxytocin only with a secondary arrest of labor or failure of descent when there is no suspicion of cephalopelvic disproportion. Other physicians will also use oxytocin for prolonged latent phase or protracted active- phase disorders (8, 13, 72, 75-77, 79, 94). There is some evidence that preventing prolonged labor by the use of oxytocin will result in a better fetal and maternal outcome (13, 46). This seems to apply even if cephalopelvic disproportion is clinically suspected, since the diagnosis may be arrived at sooner (46, 76). In general, when dysfunctional labor is present and vaginal delivery is deemed possible by the en- hancement of uterine contractions, augmentation of labor may be indicated (2). The interested reader is referred to reviews by Kruse (58), Barber and asso- Ciates (8), and Niswander (72) for a summary of risks, indications and contraindications for the use of oxytocin, Cervical Ripening with PGE. Patients with an indication for induction often have an unripe cervix. Induction of labor with a poor cervical score has been associated with failure of induction, prolonged labor, and a high cesarean birth rate (2, 5, 7, 31, 108). In addition to an increase in maternal-etal morbidity and mortality (14, 46), pro- longed labor is an unpleasant and exhausting expe- tence for the patient. A close relationship between the cervical score and onset of spontaneous labor has been demon- strated (4, 10). The cervix may be an indicator of myometrial sensitivity to oxytocin which increases near the time of spontaneous labor (5). It is possible that the two agents have a similar stimulus and the promotion of cervical ripening may alter inducibility by increasing myometrial sensitivity as well as soft- ening the cervix (62, 73). It would appear reasonable that medically enhanced cervical ripening precede contractions in induction of labor, since it usually does in spontaneous labor. Yonekura and associates (118) describe the ideal ripening agent as one which is “noninvasive, rapidly effective, safe for both the mother and fetus, and would preferably ripen without provoking uterine activity.” Many agents have been investigated and found to induce cervical ripening with varying suc- cess. Estradiol (47) and relaxin (30, 65) gels promote ‘some ripening with a minimum of uterine activity. Laminaria tents effectively ripen, but have been re- Ported to be associated with an increased risk for maternal and fetal infection (56). Lamnicel (Cabot Medical, Philadelphia) has recently been used with some success (55). Oxytocin has been shown to be a poor ripening agent (102, 112, 117). Prostaglandin (PG) E, and F-2-alpha have been administered orally (21, 109), intravenously (9), and extraamnictically (17) to ripen the cervix or induce labor, but these Toutes all have significant drawbacks. The applica- tion of a local hormone (PGE2) near its target organ would be expected to increase efficacy and decrease systemic side effects (113). Indeed, the most suc- cessful and widely used agent to ripen the cervix is PGE: gel applied locally. Mechanism Inthe past the cervix was thought to play a passive role in parturition, with dilatation and effacement ‘occurring only in response to uterine contractions. Cervical ripening is now known to be an active process which is associated with biochemical and histologic, as well as physical changes (62, 117). Danforth and co-workers (23) have described the cervical changes of pregnancy and labor. The basic structure of the nonpregnant cervix is dense fibrous connective tissue with a thin layer of smooth muscle in the periphery. The pregnant cervix shows a scat- tering and dissociation of the collagen fibers with an increase in and altered composition of the glycosa- minoglycans (GAG, ground substance) (23, 103) The distensibility of the cervix increases clinically and, has been quantitated in vitro (20). These changes are likely secondary to altered fibroblast activity (62). A variety of hormones, including prostaglandins, ‘seem to reguiate these events (117). Similar to those cervical changes seen in physio- logical ripening, exogenous PGE-2 has been asso- ciated with the dissociation of collagen (110, 116), an increase in glycosaminoglycans (110, 113, 116), an increase in fibroblast activity (110, 111, 116), and reduction of the stretch modulus (20). Although clin- ically these ripening effects may occur without uter- ine contractions (45), PGEz may also be involved in enhancement of myometrial sensitivity to oxytocin , 62). Myometrial strips taken from the fundus ‘during spontaneous labor have been reported to be stimulated with PGE2, while the smooth muscle of 732 Obstetrical and Gynecological Survey the lower segment and cervix were inhibited (115). Prostaglandins have been reported to accelerate {gap-junction formation (39), leading to more coordi- nated uterine contractions. Gillespie (44) has re- Ported an enhanced uterine response to oxytocin after exposure to PGE.. He has also described po- tentiation of the uterine response when PGE. and ‘oxytocin were administered simultaneously. There- fore, it is possible that PGE, gel applied locally enhances inducibility by combined actions on the cervix and myometrium. Although the biochemical details of this process are not completely under- ‘stood, PGE2 gel applied locally clearly alters consist- ency, effacement and dilatation of the cervix (71) Dose, Route, and Vehicle There are a variety of vehicles for local PGE2 application. It is unlikely that there will be a commer- cially available PGEz gel for cervical ripening in the United States in the near, or possibly distant, future. Food and Drug Administration (FDA) approval has not been obtained. Problems with the extempora- neous preparation of PGE2 gel include instability, especially if heated, lack of a long shelf life, inho- mogeneity, lack of sterility, varied absorption and leakage from the site of application (71, 116, 118). Many of the initial studies used a stable, thick gel vehicle which was manufactured by pharmaceutical ‘companies and tended to stay in the endocervical canal. With extemporaneous preparation in various cellulose gels, the above mentioned problems were recognized. Umsten and associates (113) describe the preparation of a starch polymer vehicle which is thick and solves part of the problem of leakage from the endocervical canal. All intracervical doses of PGE, gel, which range from 0.25 to 1.0 mg (45, 59, 71, 116), have been reported to be efficacious. By far the most commonly reported dose is 0.5 mg (26, 107, 113, 117, 118). This route offers some advan- tages in that if strictly applied to the endocervical canal, there is little uterine activity and greater eff- cacy in the very unripe cervix (28). Because of lack of a proper vehiole for intracervical application in the United States, most olinicians use the vaginal route, which is easy and less invasive (49, 55, 78, 80), although there may be a slight increase in side effects due to systemic absorption (28, 74, 114). The reported doses of PGE2 gel, which have been applied to the posterior vaginal fornix, range from 1.0 to 5.0 mg (29, 49, 78, 81). Graves and co-workers (49) found increasing success in cervical ripening with increasing dose when 1-, 2-, and 3mg doses were compared. Dyson and asso- ciates (26) found no significant difference in efficacy when he compared a 0.5-mg intracervical dose with a 3-mg vaginal dose. Ekman and associates (28) performed dose-titrating studies with 2 to 5 mg of PGE, in 3 to 5 ml of gel and found that the 4-mg dose in 3 mi of gel for vaginal application compared favorably with the 0.5-mg intracervical dose. Rec- ognizing the need for extemporaneous preparation of vaginal PGE. gels in the United States, Gauger (40, 41) has published helpful protocols. It is possible that a lipid-based suppository would have greater stability, easier handing and applica- tion, and a more controlled release of PGE» (42, 96). Buchanan and co-workers (16) found 3-mg (3 mm) slices from a 20-mg suppository of PGE2 to effec- tively ripen the cervix, but expressed concem over an increased incidence of hyperstimulation. Mac- Kenzie and associates (64) found 2.5- and 5-mg lipid-based vaginal suppositories to be associated with rapid labors. It is possible that with the lipid vehicle a lower dose is desirable. Ciinical trials using a 2-mg lipid-based suppository are currently in prog- ‘ess (42). Although comparison of the various doses, routes, and vehicles is difficult, based on review of the literature and practical clinical experience, the 4- ‘mq intravaginal dose in a cellulose-type ge! currently ‘seems a rational choice. Efficacy Local PGE, significantly improves the score of the unripe cervix when compared with placebo (49, 59, 78, 80, 107, 113, 114, 117, 118) and with oxytocin (29, 112, 114). Local PGE: prior to induction of labor has also been shown to decrease duration of labor (29, 59, 78, 81, 107), decrease induction-to-delivery interval (107), decrease oxytocin dose (80, 81, 107, 118), and decrease failure of induction rates (70, 80, 81, 117). Other reported benefits are decreased incidence of amnionitis along with decreased moni- toring time and number of vaginal examinations (107). Labor has been reported to be induced by local PGE, gel alone in 25 to 76 per cent of patients (26, 113, 114). This wide variation may be explained by differences in individual responsiveness, parity, dosage, route, absorption, initial cervical score, and state of the membranes. Montan and co-workers (70), in 92 preeclamptic Patients, were able to show that 0.5 mg of PGEz gel applied intracervically successfully ripened the cervix in 84 per cent of nulliparas and 97.5 per cent of multiparas within 24 hours. in nuliparas with pre- Induction and Augmentation of Labor 733 ‘mature rupture of the membranes, Ekman-Ordeberg and associates (29) found that within 5 hours, 4 mg of PGE2 gel applied intravaginally promoted an in- crease in mean cervical score of 3.6 compared with 1.0 increase in those who received oxytocin. Sixty per cent of these patients delivered within 24 hours and 20 per cent underwent instrumental deliveries in the PGE, group, compared with 10 and 90 per cent, respectively, in the oxytocin group. Umsten and associates (112) found that when 0.5 mg of PGEz gel alone was appiied intracervically to 100 nuli- Paras, 53 per cent delivered and the remaining had an improvement in mean cervical score of 3.4 within 24 hours. The results in the comparison oxytocin ‘group, studied during the same period, were 31 per cent and 0.5, respectively. Laube et al. (59) demonstrated that intracervical application of 0.5 mg of PGE. gel increased the mean ‘cervical score by 4.73 within a 12-hour period, com- pared with 1.53 for placebo gel. When oxytocin was started after a 12-hour preparation phase, the total mean time to onset of labor and mean time to vaginal delivery in the PGE: group were 14.3 and 19.3 hours, respectively, compared with 25.4 and 30.1 hours, respectively, for the placebo group. Trofatter et al (107) also compared 0.5 mg of PGE2 gel applied intracervicaly with placebo and began oxytocin in- duction after a 12-hour ripening period. The mean increase in cervical score after 12 hours of prepara- tion was 5.5 in the PGE. group and 0.7 in the placebo group. The mean interval from time of gel application to delivery was 25.1 hours with PGE. and 41.6 hours in the placebo group. The mean induction-to-delivery interval was 13.3 hours versus 28.8 hours; mean ‘maximum oxytocin dose, 20.8 mU/min versus 36.2 mUjmin; and total time of oxytocin induction, 9.6 hours versus 17.8 hours in the PGE2 and placebo groups, respectively O'Herlihy and MacDonald (78) applied either 2 mg of PGE: or placebo gel intravaginally to 95 nulliparas. Within 16 hours, 48 per cent of the patients in the PGE: group had entered “spontaneous” labor com- pared with none in the placebo group. Oxytocin was started 14 to 16 hours after gel application if the Patient was not in labor. The total mean duration of labor was 8.5 hours in the PGE, group and 13.9 hours in the placebo group. The cesarean rates were 1.5 and 23.9 per cent, respectively. Two of 65 pa- tients in the PGE, group required a repeat dose of gel after 14 to 16 hours to achieve cervical ripening. When induction with 3 mg of PGE, suppositories became routine at Queen Charlotte's Matemity Hos pital in London, the overall cesarean rate for failed induction due to an unripe cervix decreased from 42 to 2.5 per cent (96). However, other authors (49, 59, 107, 117, 118) have found no significant difference in the cesarean birth rate with PGE, cervical priming. Although there is broad variation in the methodology, it appears, nonetheless, that cervical ripening with PGE, gel increases the chances of successful induc- tion and decreases the incidence of prolonged labor. Repeat Doses ‘The effectiveness of repeat doses of PGE2 gel is controversial. Prins and associates (80) have re- Ported a higher incidence of successful induction and lower cesarean birth rate in those patients who had a relatively high post-gel cervical score. Based on these findings, the same group applied 5 mg of PGE: gel intravaginally every 6 hours until the post- gel cervical score was deemed adequate. Forty-eight Per cent of the 200 patients were induced by the gel alone—41.5 per cent after the first dose, 29 per cent (of those remaining) after the second dose, and 5.9 er cent (of those remaining) after the third dose. ‘The increases in cervical score were 1.9, 1.3, and 1.0 for the first, second, and third doses, respec- tively. They concluded that sequential gel was no more effective than a single application followed by ‘an equal period of observation. Wigvist and co-workers (117) applied 0.5 mg of PGE, gel intracervically and, if the patient was not in labor, repeated the same dose in 12 hours. The second dose did not further improve the cervical score, but many of these patients entered active labor after a latency period of several hours. They ‘concluded that the second dose may have triggered endogenous prostaglandin synthesis and/or altered the responsiveness of the myometrium to oxytocin. Ekman and associates (29) found little improvement in cervical score between 5 and 24 hours after application of 4 mg of PGE: gel intravaginally and suggested that repeat doses would be better applied after an 8- to 10-hour interval. Several other authors (26, 45, 70, 78) have applied repeat doses of PGEz ‘ge! within 8 to 24 hours ifthe cervical score remained oor, but provided litle comment on the effective ness of this technique. In clinical practice, we have found that sequential application of 4 mg of PGE, {gel to the posterior vaginal fornix every 4 hours does ‘seem to provide some benefit in ripening the very unfavorable cervix without adverse consequences, given, of course, close observation. 734 Obstetrical and Gynecological Survey Precautions Even though contractions are not necessary for the ripening effects of PGE2 ge! (45), based both on the literature (26, 28, 45, 55, 71, 107, 118), and our experience, a majority of treated patients do, in fact, experience some contractions. The onset of contrac- tions, which are usually irregular and of iow intensity, is similar to that seen in spontaneous labor (45). They usually start within the first 2 hours after gel application and typically stop within 6 hours unless the patient develops a regular labor pattern (26, 45, 59, 74). Ten milligrams of ritodrine administered or- ally 30 minutes prior to gel insertion has been shown to effectively prevent the contractions (45), but one must consider the attendant risks of both medica- tions. The interval between gel application and the start of oxytocin varies in the literature from 4 to 24 hours (26, 28, 55, 59, 70, 78). In general, this can be tailored to individual needs. The important point in that PGE2 seems to potentiate and enhance the myometrial response to oxytocin (44, 73). If the patient appears to be developing a labor pattern from PGEz gel alone, it would be prudent to defer the use of oxytocin unless it becomes indicated for ‘augmentation of dysfunctional labor. Since many inductions, particularly those indicated in the face of ‘an unripe cervix, are performed in high risk pregnan- cies, continuous monitoring for 30 minutes before and at least 4 hours after gel application seems warranted, Although many investigators report no adverse side effects (70, 78, 80, 112, 113. 118), there is a very small incidence of nausea, vomiting, diarthea, pyrexia, and shivering from the systemic absorption of PGE, (26, 28, 29, 49, 59, 96, 107). The occurrence of severe vulvar edema after PGE2 gel application has also been reported (49). Hyperstimulation, typi- cally within the first 30 minutes of gel application, is also infrequent, occurring in about 1 per cent of Patients; this compares favorably with oxytocin (26, 59, 80, 96, 107, 113, 114, 118). The successful treatment of hyperstimulation from local PGE2 has been accomplished by removal with saline and swabs (49), 0.25 to 0.5 mg of terbutaline adminis- tered intravenously (117), or intravenous ritodrine infusion via premature labor protocol (48). Contraindications to the use of the 20-mg sup- pository of dinoprostone—PGE; (Prostin, E-2, Up- John Company, Kalamazoo, Ml)—include hypersen- sitivity, acute pelvic inflammatory disease, and known active cardiac, pulmonary, renal, or hepatic disease. Although the dose used for cervical ripening is much lower, care must be exercised. Thus far, we have used PGE2 gel in patients with hypertension, asthma, and cardiac disease without adverse con- sequences. We have been unable to find any reports in the literature which documented bronchoconstric- tion or significant changes in maternal blood pres- sure within this low dose range of PGE. Finally, neonatal outcome compares favorably with that of induction with oxytocin alone (29, 78, 107). Infant follow-up at 2 to 6 months of age has shown no unusual sequelae due to the use of PGE, gel (29). Guidelines —One Practical Method There have been a number of suggestions as to the method of cervical ripening with PGE. Taking all problems into account we have found the following Quidelines to be relatively safe and efficacious. Gel preparation (40-42). 1) Thinly slice a frozen 20-mg dinoprostone suppository. 2) Stain the slices with 1% methylene blue to serve as a marker for homogeneity. 3) Melt the slices at 30°C in a water bath. 4) Add 25 mi of sterile Surgilube (E. Fougera, Melville, NY), or K-Y Jelly (Johnson & Johnson, New Brunswick, NJ) geometrically until the dye is evenly distributed. 5) Draw 5 mi (4 mg) of PGE2 gel into a plastic syringe, cap, label, and store at 20°C for up to 30 days. Clinical application of gel. Since the use of PGE gel for cervical ripening is not approved by the FDA in the United States, itis prudent to discuss its use with the patient (obtain informed consent), document carefully, and use this medication only if there is clear indication. After a satisfactory monitoring period (at least 30 minutes) in the labor and delivery room we apply the 4-mg dose of thawed gel by attaching a 2- inch, 18-gauge, plastic I.V. cannula to the syringe and sliding it into the posterior vaginal fornix over our fingers. The patient remains recumbant for at least 30 minutes. Monitoring continues for at least 4 hours after application of the gel and may continue longer if contractions are present. If no further treat- ment is planned at that time, the patient may then move to the antepartum ward. We apply repeat doses of PGE: gel as frequently as every 4 hours if the cervix has not adequately ripened and the patient has not continued to con- tract. The initiation of oxytocin may be individually tailored. We do not recommend its use in less than 4 hours after gel insertion. Oxytocin should be used Induction and Augmentation of Labor 735 with great caution if the patient continues to show uterine activity from the PGE2 gel. Although the ideal method of cervical ripening does not exist, we have found the above guidelines to be useful. Perhaps, future extensive study will provide ‘a more definitive methodology for the optimal man- ‘agement of cervical ripening, Oxytocin in Induction and Augmentation In the recent past, typical protocols for the induc- tion and augmentation of labor allowed for relatively high doses and short intervals of increase of oxytocin (1, 8, 57, 99, 100). Such protocols continue to be used on many obstetric services and are only very recently being proposed for modification in a new ‘American College of Obstetrics and Gynecology Technical Bulletin (2). The human nature of resist- lance to change became evident on our obstetric service when attempts were made to change the ‘oxytocin protocol. It was only after the recent phar- macologic data and physiologic basis for these changes were presented to the responsible obste- trician/gynecologists and nursing personnel that a new protocol was accepted. Based on this experi- ence, a brief review of oxytocin in spontaneous, as well as induced or augmented labor may well aid in the implementation of updated protocols, consistent with the new American College of Obstetrics and Gynecology guidelines (2) Much of the information from which the new guide- lines are drawn comes from observations of spon- taneous and augmented labor. It is not certain that the same findings are directly applicable to induced labor, but keeping this in mind and realizing that it is the best evidence available, it seems reasonable that some information may be extrapolated for use in uidelines for the management of induction as well ‘as augmentation of labor. Oxytocin Receptors Oxytocin is an octapeptide which is synthesized in the hypothalamus and transported to axonal termi- nals in the posterior pituitary gland (11). There is wide variablity in the literature regarding plasma concentrations of oxytocin during pregnancy and spontaneous labor (19, 24, 25, 43, 50, 60, 61, 95). These differences may be explained in part by vari- ations between individuals and methodology. Also, in addition to a tonic baseline release of oxytocin, there is now a suggestion of spurt release which may increase in amplitude and frequency during labor (19, 24, 25, 34, 36, 43, 50, 58, 95). Most investigators indicate a slight gradual rise in plasma oxytocin levels throughout gestation with a peak ‘during the second stage of labor (24, 36, 43, 61, 95). Significant secretion of fetal oxytocin during labor has also been reported (24, 25, 50, 58, 95). Although there is no uniform theory for the initiation ‘of human labor, it probably involves, amongst other factors, a complex interaction between oxytocin and prostaglandins (25, 34-37, 53, 54, 58). Oxytocin may have a dual action, since two types of oxytocin receptors (myometrial and decidual) have been iden- tied and quantitated in the human uterus (35). ‘These protein receptors which increase in number progressively with gestational age, are highly spe- Citic, have a fixed affinity and bind oxytocin ina single step (35, 97, 98). ‘A marked increase in the concentration of myome- trial oxytocin receptors in the pregnant rat, with maximal levels at delivery, has been reported (38, 97). Fuchs and co-workers (38) demonstrated a linear correlation between the concentration of my- ‘ometrial oxytocin receptors in the rat and uterine activity induced by oxytocin infusion. Human. my- ‘ometrial oxytocin receptors have been reported to peak in early spontaneous labor and seem to con- tribute to the initiation of uterine contractions (35, 37). Itis probable that the receptor concentration is the major determinant controling uterine response to either endogenous or exogenous oxytocin ‘The decidual oxytocin receptors, which have been reported to increase throughout labor and peak at delivery, seem to play a role in the stimulation of Prostaglandin F-2-alpha production (37, §3). This coupling of receptor activity to PGF:-alpha produc- tion may be a crucial step in producing effective labor (35. 36, 53). PGF,-alpha has been reported to poten- tiate oxytocin-induced contractions and is consid- ered a requirement for their maintenance (34-36, 4, 53, 54, 73), perhaps, by regulating gap junction formation (39). Successful induction has been found to correlate with a rise in 15-keto-13,14 dihydro PGF alpha, a PGF alpha metaboite (53). The stim- tulus for receptor formation is unknown but most probably relates to an increasing estrogen/proges- terone ratio (35). ‘The increase in oxytocin receptors appears to be related to increased sensitivity to oxytocin with in- creasing gestational age (18, 35, 38, 68, 73, 97, 101, 103, 104). Thus, even though plasma levels of oxy- tocin have not been demonstrated to increase sig- nificantly prior to labor, fetal and/or maternal oxyto- 736 Obstetrical and Gynecological Survey ‘cin may very well be a stimulus for initiation of labor due to the decreased threshold of response to oxy- tocin (34, 36). Pharmacokinetics Early protocols for induction and augmentation of labor which called for a starting dose of 2 to 6 mU/ min of oxytocin and an increase every 15 to 20 minutes were based on in vitro pharmacologic stud- ies of oxytocin and indirect methods of determining its haltiife (8, 68, 76, 85, 89, 91, 99, 109, 114). Seitchik and associates (87) have commented on the methods that promoted the prevailing miscon- ception of an oxytocin half-life in the range of 3 to 4 minutes (34, 85): 1) The addition of oxytocin to the plasma of pregnant women led to its rapid metabo- lism by placental oxytocinase. This problem has not been corrected by cooling of the plasma and/or the addition of oxytocinase inhibitors (3, 36, 60, 61, 87, 88). 2) Very large doses of oxytocin (500-16,000 mU) were required to give plasma levels detectable by bioassay. With indirect methods, if the clearance mechanism was saturated at these high doses, the plasma concentration would increase very quickly, giving a response time, which was used to estimate the half life, as low as 1.2 minutes (85). 3) Tritium- labeled oxytocin was given as a 5,000 unit intrave- nous bolus to pregnant women. Clearance mecha- nisms were again likely saturated. The drug concentration at steady state and the concentration at maximal end-organ response are directly proportional to the infusion rate and inversely proportional to systemic clearance. The time to reach steady state is generally accepted as approximately four half-lives of the drug. The misconception of a short oxytocin half-life, and therefore, shorter time to reach steady state, then led to the recommenda- tion to increase the infusion rate every 15 to 20 minutes. The recommendation of a geometric in- crease of oxytocin incorporated in some past pro- tocols was an attempt to save time in reaching the effective dose. It was likely based on reports by Steer (101) of a stable phase of labor which has a relative failure of response to oxytocin at its outset. However, geometric increases in oxytocin reduce the safety margin, with a high potential of over- dosing, and have no pharmacologic basis. In recent in vivo studies, which employed sensitive radioimmunoassays and computer simulations, it has been determined that the interval to reach a steady state concentration of oxytocin in plasma (and maximal response) is 40 to 60 minutes after initiating or altering the infusion (68, 87-90). Thus, the in vivo haltlife of oxytocin is longer than previ- ously thought—approximately 10 to 15 minutes, ‘These studies of plasma oxytocin levels during con- tinuous intravenous infusion have also shown first order saturation kinetics, with a progressive, linear, stepwise increase with each increase in the infusion rate (3, 36). Seitchik and associates (3, 87, 88) measured plasma ‘oxytocin concentrations in women with dysfunctional labor before and then every 20 minutes during con- tinuous intravenous oxytocin infusion at 1 mU/min, with an increase of 1 mL/min every 40 minutes, until an effective cervical dilatation rate occurred. They found that the mean plasma oxytocin concentration before the infusion was 1.01 uU/ml with a range of 0.2 to 2.97 wUjml. These baseline levels are similar to those reported in men, nonpregnant women, and Pregnant women before labor and during the first stage of normal spontaneous labor (60, 61). Fuchs and co-workers (36) measured plasma ox- ytocin levels before and during normal spontaneous labor and induction of labor at term. They found that ‘oxytocin infusion of 1 to 3 mUjmin gave plasma levels similar to baseline values, whereas 4 to 6 mU/ min gave levels similar to those in spontaneous labor. Infusion of 10 to 16 mU/min gave levels not seen in the first stage of spontaneous labor. Seitchik and associates (3, 88) also reported that the increment in plasma oxytocin levels required to produce effec- tive contractions varied widely between individuals, most likely reflecting unpredictable individual uterine sensitivity Amico and co-workers (3) measured oxytocin met- abolic clearance rates (the rate at which the body removes oxytocin from plasma) in men and in women with hypocontractile labor who were receiving oxy- tocin infusion at 1 mU/min with an increase by 1 mU/ min every 40 minutes. The values ‘groups showed individual variation, but overall were similar to each other and to those found by Leake ‘and associates (60) in men, nonpregnant women, and pregnant women at term during infusion of 4 mU/min of oxytocin. The presence of oxytocinase in the plasma of pregnant women did not seem to affect the oxytocin metabolic clearance rate (60). Unpredictably wide individual variabilty in clearance rates would be expected to influence the proper dose of oxytocin required to elicit uterine response. Seitchik and associates (3, 88) reported that the plasma concentration of oxytocin during intravenous infusion of doses between 1 and 9 mU/min increased Induction and Augmentation of Labor 737 linearly with each dose for the first 40 minutes with 1 significant change thereafter. This indicates that the time to reach steady state is 40 minutes. Others (@6, 60, 68) have confirmed the linear correlation of plasma levels with rate of infusion and the 40 to 60 minute time to reach steady state. A mean maximal response time of 40 minutes has also been con- firmed clinically (87, 89, 90, 91). If the oxytocin dose is increased at intervals significantly less than 40 minutes, the myometrium may be exposed to the larger dose before the effects of the lesser dose are appreciated. This, in turn, may result in hyperstimu- lation and/or fetal distress. Based on the preceding information, it can be ‘concluded that the pharmacologic data suggest that the infusion rate of oxytocin should be increased arithmetically every 40 to 60 minutes. However, because of varied response ranges in individuals secondary to differences in clearance rates, as well as sensitivities, this rate of increase is inefficient in a significant portion of patients (69, 90). Steady-state plasma oxytocin levels have been reported to range from 1.09 to 5.76 U/ml (3, 88). Clinically, this vari- ation resulted in an unacceptable delay in reaching an effective maintenance dose of oxytocin in 31 per ‘cent of patients who required =4 mU/min (89). Seit- chik and associates (87) designed an oxytocin deliv- ery regimen to quickly identify the proper mainte- nanos dose for each individual patient. Oxytocin was, delivered at 5 mU/min and the time to elicit myome- trial response was used to calculate the appropriate maintenance dose. The regimen was reasonably effective in identifying the appropriate dose of oxy- tocin, but clinically, this was not a significant factor in the time necessary to achieve complete dilatation. ‘AS a solution to the problem of varied response times, a compromise, proposed by Seitchik and Cas- tilo (89), would be an increase in the infusion rate every 30 minutes with cautious observation for hy- ‘perstimulation (89). This proposal was tested in term nuliparas and muttiparas with dysfunctional labor (89). One group of patients received oxytocin at 1 mUjmin with an increase by 1 mUjmin every 30 minutes or greater based on computer assessment of their contractile patter. The other two groups, same room and other room controls, had their oxy- tocin regulated by house-officer preference. When the oxytocin infusion rate was increased at less than 30 minute intervals, there was a 2-fold increase in the frequency of discontinuing of decreasing the oxytocin infusion because of hyperstimulation or fe- tal distress. A short (less than 30 minutes) interval of rate increase was also shown to be the most important factor resulting in a higher maximum dose of oxytocin and an actual delay in delivery by an average of 3 hours (89). In other words, “haste makes waste.” Oxytocic Effects and Dose Titration ‘The goal and criterion for titration of oxytocin in ‘medical control of labor is to effect cervical dilatation rates which mimic those of normal spontaneous labor (91), without compromising the health of either the mother or fetus. Although the dose-response curve of oxytocin shows it to be a “forgiving” drug, the minimum effective dose is preferable (91, 100, 101), Many of the risks associated with the use of oxytocin are dose related (8, 57, 100), giving further incentive to develop protocols based on the best currently available evidence, which lowers the dose ‘of oxytocin to improve efficacy and safety. ‘The response to oxytocin seems to depend more ‘on preexisting uterine activity and sensitivity than dose (99). The uterine response to oxytocin seems to increase slowly from 20 to 30 weeks’ gestation, with a relatively stable period from 34 weeks’ ges- tation unti a rapid increase just prior to spontaneous labor at term (18, 58, 104). interestingly, uterine sensitivity reportedly decreases if a patient fails to enter spontaneous labor by 40 weeks’ gestation (103, 104). itis important to realize that the change in sensitivity to oxytocin may be gradual or abrupt and may even occur during labor, requiring an ad- justment in the dose of oxytocin (57, 58, 73, 100, 101, 104, 106). There also is wide individual variation in sensitivity to oxytocin, irrespective of gestational age, which is difficult to predict (3, 6). This provides a rational basis for beginning oxytocin infusions at a low dose. Cibiis, in Kruse (58), found that an average of 20 to 40 mUymin of oxytocin was required for effective contractions in the 32-week pregnancy. Studies to evaluate oxytocin requirements for preterm induction are few and difficult to interpret, inasmuch as the reason for induction may involve several variables which, themselves, could alter uterine sensitivity. In general, the preterm uterus is less sensitive to oxy- tocin and may require larger doses to give results comparable to those at term. Theobald and co- workers (104) found that a 2-mU/min infusion of oxytocin at 32 weeks’ gestation induced small con- tractions, but just before, during, or after sponta- 738 neous labor regardless of gestational age, the uterus responded to 0.5 mUj/min. Usually, the nearer a patient is to term, the greater the chances of a successful induction. At term, an oxytocin infusion rate of 2 to 8 mU/ min is usually sufficient to effect cervical dilatation of at least 1-cmjhr (18, 34, 58, 87, 89-91, 99, 100). Doses of 5 mUjmin or less have been found to improve vaginal delivery rates, improve 1-minute Ap- gar scores and cause no hyperstimulation (101). A dose of more than 20 mUjmin at term is rarely necessary (58). The higher the dose required to produce effective contractions, the less likely is suc- cess (94). Seitchik and Castilo (69, 91) found in ‘oxytocin augmentation of labor that, when an initial dose of 1 mU/min and an increase in 1 mU/min every 30 minutes until a dilatation rate of 1 cm/hr was reached, over 90 per cent of multiparas and 85 per cent of nulliparas required =4 mU/min. ‘Although information from the literature may serve ‘as a foundation for the use of oxytocin, the real challenge is to manage each individual patient as expertly as possible. This “art” can only be gained by experience and careful attention to detail. Building upon a pharmacologic foundation, to achieve the goal of appropriate individual management requires a delicate balance among three main criteria: 1) uterine activity, 2) cervical dilatation rate, and 3) the response of the fetus. Uterine activity. Oxytocic effects of the myomet- rium reported by Cibils in Kruse (58) include it creased excitability, increased strength, velocity, and frequency of contractions, and increased intrauterine resting pressure. Posiero and Noriega-Guerra in Kruse (58) reported that the increase in uterine tone was most important when the uterus was already at maximum efficiency or the infusion was started at a high rate. Excessive uterine stimulation may cause inefficiency of uterine contractions. Each uterus has its own level of optimal activity (99, 100). After maximum efficiency is reached, an increase in oxy- tocin rate may result in increased frequency of con- tractions along with increased baseline tone (58). Blood flow through the myometrium slows or stops, ‘metabolites accumulate and the effective magnitude of pressure decreases (58, 101). A 4-old increase in uterine dysfunction during labor induction has been associated with oxytocin misuse (27, 57). If the contraction pattern seems adequate (one every 3-4 minutes), but cervical dilatation is inadequate, a de- ‘crease in the oxytocin dose may improve efficacy. It has been recommended that oxytocin induced Obstetrical and Gynecological Survey uterine activity mimic that of spontaneous labor (8, 101, 106). Vaginal delivery can be conceptualized as requiring a certain amount of uterine work for each individual to overcome the forces of resistance (6, 32, 84). The uterine contractile pattern may provide an initial evaluation of response, but the quantitation of uterine activity is not perfect in identifying hypo- contractile labor or excessive stimulation or in guid- ing oxytocin therapy (51, 91). Because normal labor has wide variabilty in uterine activity within and between individuals (51, 67, 86, 106), other criteria for titrating oxytocin are also recommended. Cervical dilatation rate. Melmed and Evans (66) have shown in the primipara that if the initial cervical dilatation rate in spontaneous labor was at least 1 cmyhour, 93 per cent of patients underwent spon- taneous vaginal delivery, whereas if less than 1 cm/ hour, the operative delivery rate was 67 per cent. Proponents of “active management” of labor (76, 79) also use the cervical dilatation rate of 1 cm/hour to ‘guide their use of oxytocin. Though others (99) claim that this would resuit in too many patients receiving ‘oxytocin, it seems an easy and reasonable rate of dilatation to serve as a guide to both diagnose ‘dysfunctional labor as well as to determine the most effective dose of oxytocin in induction or augmen- tation. Nevertheless, care must be taken not to resort to cesarean section too quickly in prolonged latent phase disorders, since an unripe cervix may require more contractions prior to dilatation (7, 8, 32). Response of the fetus. Fetal response to uterine activity at a particular dose of oxytocin provides a further, and perhaps more appropriate, basis for titration than do uterine activity or cervical dilatation rates alone. Placental venous outflow has been shown to stop during contractions, but adequate exchange follows with good relaxation (12, 72, 82, 106). Arterial inflow continues until pressures of 30 to 70 mm Hg and then may stop completely (15, 82, 105). The fetus continues to extract oxygen from the intervillous blood, but may eventually resort to anaerobic metabolism until oxygen is restored after the contraction (52, 101). Uterine blood flow varies indirectly with resting pressure, frequency, intensity, and duration of contractions (106). There are wide variations in fetal reserve, but excessive uterine tone and frequency of contractions may lead to acidosis, distress, and fetal death, even in the normal fetus (63, 72, 101, 106). if the intensity and frequency of contractions must be kept low to keep the fetus “happy,” so the speak, more contractions will be Induction and Augmentation of Labor 739 needed, but it is possible that this patient may still

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