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Complications of Epidural Analgesia During Labor

JAMES A. THORP, M.D.
St. Luke's Hospital of Kansas City,
Kansas City, Missouri

In this issue of American Family Physician, Vincent and Chestnut¹ provide an excellent review of epidural analgesia for labor from the anesthesia perspective. Epidural analgesia is the most effective method for pain relief during labor, and it is relatively safe. As with all other medical procedures, epidural analgesia does have drawbacks. It is much more invasive and expensive than other alternatives for labor analgesia. Hypotension, transient changes in the fetal heart rate tracing and severe headache caused by inadvertent dural puncture are the most common side effects. Other more serious and rare complications may occur, including permanent neurologic injury and death.

See Article in this issue.

From a perinatologist's perspective, the suggestion of Vincent and Chestnut¹ that epidural analgesia may be used in the presence of non-reassuring fetal heart rate patterns is concerning. Regional anesthesia in pregnant women with normal uteroplacental function may result in deterioration of fetal acid-base status (severe hypoxic-induced acidemia) caused by reduced uteroplacental blood flow.^2,3 In the presence of non-reassuring fetal heart rate tracings caused by uteroplacental insufficiency, epidural analgesia could further impair uteroplacental function and inflict hypoxic brain damage or exacerbate existing damage in already compromised fetuses. Further study is required before epidural analgesia is considered safe for use in parturients presenting with non-reassuring fetal heart rate tracings.

Another issue that deserves more attention is the well-established association between epidural analgesia and the occurrence of maternal fever during labor.^4-7 The clinical dilemma is that fever during labor is one of the cardinal signs of chorioamnionitis. Chorioamnionitis is a clinical diagnosis that may present with fever alone. Unusual but devastating consequences (newborn sepsis, severe morbidity or death) may occur if one assumes that fever during labor is caused by epidural analgesia instead of chorioamnionitis. Thus, it is not surprising that at least two studies suggest that epidural-induced fever during labor results in more antibiotic use and invasive work-ups for sepsis in newborns.^5,8

The effect of epidural analgesia on labor and delivery is indeed controversial.⁹ Vincent and Chestnut¹ espouse the viewpoint that epidural analgesia is associated with, but does not cause, labor abnormalities or an increase in operative delivery. It is my perspective that epidural analgesia is one of many variables that has caused labor abnormalities, increased operative delivery rates and has contributed to the current high rates of cesarean delivery. However, I do agree that physicians and institutions experienced with epidural analgesia and committed to limiting rates of intervention may use epidural analgesia without increasing rates of cesarean delivery.

Both St. Luke's Hospital of Kansas City, Mo., and Dallas Parkland Memorial Hospital published prospective trials demonstrating an increase in cesarean delivery in patients randomized to receive epidural analgesia and, afterward, both institutions have used epidural analgesia liberally without increasing cesarean delivery rates.^4,6,10 Vincent and Chestnut¹ would contend that these studies and others suggesting that epidural analgesia increases cesarean delivery are flawed. In contrast, I would maintain that Dallas Parkland Memorial Hospital and St. Luke's Hospital of Kansas City are committed to minimizing rates of intervention and have become more experienced with epidural analgesia. During the years after our trial, there has been a progressive decline in cesarean delivery in cases of dystocia in nulliparous patients using epidural analgesia.

The vast majority of parturients receive their care from physicians and institutions that do not publish formal studies regarding epidural analgesia and labor outcome. The possibility of reporting bias must be considered. Physicians and institutions conducting formal studies are distinctly different from those that do not. Those conducting formal studies are more apt to focus on labor outcome surveillance and on limiting rates of intervention. It is important to recognize that conclusions drawn from research centers may not necessarily apply to other institutions.

This is especially true of a trial that was conducted by Sharma and colleagues⁶; their institution used a unique combination of management practices that resulted in a 5 percent rate of cesarean delivery in their spontaneously laboring nulliparous population. They concluded that although epidural analgesia did not affect cesarean delivery rates, it did have significant effects on labor. Epidural analgesia resulted in a prolongation in the first stage of labor, more frequent requirement of oxytocin augmentation and more frequent occurrence of maternal fever in labor. Nonetheless, their practice patterns and outcomes should be emulated.

Each individual hospital and its care providers should monitor their own statistics regarding epidural analgesia and intervention rates. It is well known that observation alone will result in outcome improvement (Hawthorne effect). Implementing this surveillance by both obstetric and anesthesia care providers or, better yet, initiating a formal study will have important benefits to patients, clinicians and hospitals. Comparison of nulliparous epidural analgesia and nonepidural analgesia groups is valuable. Epidural analgesia cannot be implicated in having an adverse effect on rates of cesarean delivery if the rates do not differ between nulliparous women using epidural analgesia and those not using epidural analgesia.

Benchmarking: An Institutional Report Card for Cesarean Birth in Nulliparas Using Epidural Analgesia Institution or practitioner grade Cesarean rate for dystocia in nulliparas with epidural analgesia (%) Cesarean rate for non-reassuring fetal status in nulliparas with epidural analgesia (%) A 5 (3 to 7) 2 (0.0 to 2.9) B 10 (8 to 12) 4 (3.0 to 4.9) C 15 (13 to 17) 6 (5.0 to 6.9) D 20 (18 to 22) 8 (7.0 to 9.9) F 25 (23 or higher) 10 (10 or higher) Used with permission from Thorp JA. Labor epidurals: effect on the cesarean delivery rate. Clin Obstet Gynecol 1998;41:449-60.

Clinicians or hospitals could also use a benchmark to assess their ability to limit or eliminate the potential adverse effects of epidural analgesia. Based on previously published literature, institutional or practitioner "report cards" may be considered (see table). It is unlikely that epidural analgesia has a clinically significant effect on cesarean delivery rates if an institution or a clinician receives a grade of "A." However, if a less than desirable grade is achieved, then obstetric and anesthesia care providers may consider epidural analgesia and other factors as potential contributors to the excessive cesarean delivery rates.

Dr. Thorp is associate professor at the University of Missouri­Kansas City School of Medicine. He is also associate director at St. Luke's Hospital Perinatal Center.

REFERENCES

1. Vincent RD, Chestnut DH. Epidural analgesia during labor. Am Fam Physician 1998;58:1785-92.
2. Roberts SW, Leveno KJ, Sidawi JE, Lucas MJ, Kelly MA. Fetal acidemia associated with regional anesthesia for elective cesarean delivery. Obstet Gynecol 1995;85:79-83.
3. Mueller MD, Bruhwiler H, Schupfer GK, Luscher KP. Higher rate of fetal acidemia after regional anesthesia for elective cesarean delivery. Obstet Gynecol 1997;90:131-4.
4. Ramin SM, Gambling DR, Lucas MJ, Sharma SK, Sidawi JE, Leveno KJ. Randomized trial of epidural versus intravenous analgesia during labor. Obstet Gynecol 1995;86:783-9.
5. Lieberman E, Lang JM, Frigoletto F, Richardson DK, Ringer SA, Cohen A. Epidural analgesia, intrapartum fever, and neonatal sepsis evaluation. Pediatrics 1997;99:415-9.
6. Sharma SK, Sidawi JE, Ramin SM, Lucas MJ, Leveno KJ, Cunningham FG. Cesarean delivery. A randomized trial of epidural versus patient-controlled meperidine analgesia during labor. Anesthesiology 1997;87:487-94.
7. Mayer DC, Chescheir NC, Spielman FJ. Increased intrapartum antibiotic administration associated with epidural analgesia in labor. Am J Perinatol 1997;14:83-6.
8. Kennell J, Klaus M, McGrath S, Robertson S, Hinkley C. Continuous emotional support during labor in a US hospital. A randomized controlled trial. JAMA 1991;265:2197-201.
9. Thorp JA, Breedlove G. Epidural analgesia in labor: an evaluation of risks and benefits. Birth 1996;23: 63-83.
10. Thorp JA, Hu DH, Albin RM, McNitt J, Meyer BA, Cohen GR, Yeast JD. The effect of intrapartum epidural analgesia on nulliparous labor: A randomized, controlled, prospective trial. Am J Obstet Gynecol 1993;169:851-8.

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Single Daily Dosing of Aminoglycosides

ROBERT L. DEAMER, PHARM.D., B.C.P.S.
University of Southern California, Los Angeles,
and University of California, San Francisco

In this issue of American Family Physician, Gonzalez and Spencer¹ update us on the current status of aminoglycosides, presenting new insight into their mechanism of action, and revisiting their clinical roles and the pharmacologic and therapeutic basis for single daily dosing vis-à-vis multiple daily dosing. As the authors explain,¹ 50 years after the introduction of aminoglycosides and despite the long-held association of these agents with nephrotoxicity and ototoxicity, they remain important in the treatment of serious infections with gram-negative and selected gram-positive microorganisms.

See Article in this issue.

Strategies to minimize these toxicities are a topic that Gonzalez and Spencer¹ briefly explore and have been the subject of numerous studies and published papers. As described, two basic strategies currently exist to safely and effectively administer aminoglycosides to patients. Optimal multiple daily dosing of aminoglycosides uses pharmacokinetic principles to guide patient-specific dosing, with the goal of achieving appropriate "peak" serum drug levels to ensure antimicrobial response and sufficiently low "trough" levels to minimize the risks for toxicity. Because this has been the standard approach for aminoglycoside dosing for decades, it is ironic that there continues to be conflicting data on the effectiveness of pharmacokinetic-based multiple daily dosing for reducing the risks for toxicity.^2,3

The literature regarding single daily dosing is no less frustrating. The scores of papers found in the literature evaluating the safety and efficacy of single large doses of several different aminoglycosides given at extended intervals have generally lacked sufficient statistical power to reach clinically definitive conclusions. Consequently, studies on single daily dosing have been the subject of meta-analysis; nine meta-analyses have been published to date.^4-12 Given the variability that exists in how a meta-analysis may be conducted, the lack of uniform conclusions from meta-analyses on single daily dosing of aminoglycosides is perhaps not surprising (see Table 4 in the Gonzalez and Spencer article¹).

But what do these studies tell us? In many of these meta-analyses, an association was found between the use of single daily dosing regimens of aminoglycosides and a reduced risk of clinical or microbiologic failure and a relative decrease in the risk of mortality, compared with multiple daily dosing of the same aminoglycoside using the same total daily dosages. A reduction in the relative risk of aminoglycoside toxicity was observed in several meta-analyses as well. Also, several of the remaining meta-analyses describe so-called trends that suggest benefit from single daily doses but lack sufficient power to achieve statistical significance. Importantly, in no meta-analysis was there a finding or a trend indicating a greater risk for therapeutic failure or toxicity associated with single daily dosing.

By design, these meta-analyses do not incorporate relevant data from nonrandomized trials. Perhaps the largest study evaluating any method of aminoglycoside dosing is the experience of Nicolau and colleagues¹³ at Hartford Hospital. These investigators first pharmacokinetically validated a single daily dosing gentamicin protocol using a dose of 7 mg per kg (with the dosage interval extended to 36 or 48 hours based on diminishing creatinine clearance) in study patients and subsequently followed the protocol to treat 2,184 patients for an average of 4.5 days. They documented a 1.2 percent incidence of nephrotoxicity that compared favorably with their historical rate of 3 to 5 percent. Since their original report, more than 2,000 additional patients have been treated according to this protocol, with no significant deviation from the original findings (personal communication, Nicolau). While this was not a controlled clinical trial, the magnitude of the Hartford experience gives additional support to the safety of single daily dosing. Further, the decrease in the cost of antimicrobial therapy associated with the reduction in the number of intravenous administrations of aminoglycosides, the reduced need for serum drug level monitoring and lower rates of toxicity provide evidence for the cost-effectiveness of single daily dosing with aminoglycosides.¹⁴

So what may be considered the current standard of practice with regard to aminoglycoside dosing? Recent information indicates that approximately 28 percent of all intravenous gentamicin administered in the United States is given using regimens of single daily dosing.¹⁵ In Europe, an aminoglycoside (isepamicin) undergoing clinical trials will have a formally approved once-daily dosing regimen. The U.S. Food and Drug Administration has indicated support for approving labeling of aminoglycosides for once-daily dosage, but no pharmaceutical manufacturer has responded, presumably in part because of the lack of an economic incentive given the number of generic aminoglycoside products available.¹⁶

Patient Groups in whom Single Large Doses / Extended-Interval Dosing (Single Daily Dosing) of Aminoglycosides Should Be Avoided Creatinine clearance of < 20 mL per minute Endocarditis Extensive burns Hemodialysis Hypovolemia Meningitis Neuromuscular disease Pregnant Severe liver disease with ascites

Despite the lack of regulatory and industry guidance in the United States, the clinical use of single-daily-dose regimens of aminoglycosides has steadily grown, and now may be routinely recommended for many patient populations (see table) based on numerous published clinical studies and the meta-analyses that have shown them to be clinically safe and effective.

Dr. Deamer is assistant professor of clinical pharmacy at the University of Southern California, Los Angeles, and the University of California, San Francisco. He is clinical services director in the Department of Pharmacy Services, Cedars-Sinai Medical Center, Los Angeles.

REFERENCES

1. Gonzalez LS, Spencer JP. Aminoglycosides: a practical review. Am Fam Physician 1998;58:1811-20.
2. Kemme DJ, Daniel CI. Aminoglycoside dosing: a randomized prospective study. South Med J 1993; 86:46-51.
3. Leehey DJ, Braun BI, Tholl DA, Chung LS, Gross CA, Roback JA, et al. Can pharmacokinetic dosing decrease nephrotoxicity associated with aminoglycoside therapy. J Am Soc Nephrol 1993;4:81-90.
4. Galloe AM, Graudal N, Christensen HR, Kampmann JP. Aminoglycosides: single or multiple daily dosing? A meta-analysis on efficacy and safety. Eur J Clin Pharmacol 1995;48:39-43.
5. Hatala R, Dinh T, Cook DJ. Once-daily aminoglycoside dosing in immunocompetent adults: a meta-analysis. Ann Intern Med 1996;124:717-25.
6. Ali MZ, Goetz MB. A meta-analysis of the relative efficacy and toxicity of single daily dosing versus multiple daily dosing of aminoglycosides. Clin Infect Dis 1997;24:796-809.
7. Bailey TC, Little JR, Littenberg B, Reichley RM, Dunagan WC. A meta-analysis of extended-interval dosing versus multiple daily dosing of aminoglycosides. Clin Infect Dis 1997;24:786-95.
8. Hatala R, Dinh TT, Cook DJ. Single daily dosing of aminoglycosides in immunocompromised adults: a systematic review. Clin Infect Dis 1997;24:810-5.
9. Freeman CD, Strayer AH. Mega-analysis of meta-analysis: an examination of meta-analysis with an emphasis on once-daily aminoglycoside comparative trials. Pharmacotherapy 1996;16:1093-102.
10. Ferriols-Lisart R, Alos-Alminana M. Effectiveness and safety of once-daily aminoglycosides: a meta-analysis. Am J Health Syst Pharm 1996;53:1141-50.
11. Barza M, Ioannidis JPA, Cappelleri JC, Lau J. Single or multiple daily doses of aminoglycosides: a meta-analysis. BMJ 1996;312:338-45.
12. Munckhoff WJ, Grayson JL, Turnidge JD. A meta-analysis of studies on the safety and efficacy of aminoglycosides given either once daily or in divided doses. J Antimicrob Chemother 1996;37:645-63.
13. Nicolau DP, Freeman CD, Belliveau PP, Nightingale CH, Ross JW, Quintiliani R. Experience with a once-daily aminoglycoside program administered to 2,184 adult patients. Antimicrob Agents Chemother 1995;39:650-5.
14. Lacy MK, Hitt CM, Nightingale CH, Quintiliani MD, Nicolau DP. The pharmacoeconomic benefits of once-daily aminoglycoside dosing. Drug Benefit Trends 1996;8(8):36-9.
15. Centers for Disease Control and Prevention. Multistate endotoxin-like reactions associated with IV gentamicin. MMWR Morb Mortal Wkly Rep 1998; (in press).
16. Deamer RL, Dial LK. The evolution of aminoglycoside dosing: a single daily dose. Am Fam Physician 1996;53;1782-6.

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