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ORIGINAL RESEARCH |
From the *Departments of Obstetrics and Gynecology and Preventive Medicine (Biostatistics), University of Mississippi Medical Center, Jackson, Mississippi.
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ABSTRACT |
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METHODS: Two hundred sixty-four patients with preeclampsia were enrolled. After spontaneous onset of postpartum diuresis and discontinuation of intravenous magnesium sulfate, patients were randomly assigned to receive either no therapy or 20 mg oral furosemide daily for 5 days with oral potassium supplementation. Patient outcomes were compared between treatment groups with regard to classification of hypertensive disease.
RESULTS: Only postpartum patients with severe preeclampsia (n = 70) who received furosemide compared with controls had significantly lower systolic blood pressure by postpartum day 2 (142 ± 13 mm Hg compared with 153 ± 19 mm Hg, P < .004) and required less antihypertensive therapy during hospitalization (14% compared with 26%, P = .371) and at discharge (6% compared with 26%, P = .045). No benefit was shown for patients with mild preeclampsia (n = 169) or superimposed preeclampsia (n = 25). Neither length of hospitalization nor frequency of delayed postpartum complications was positively affected by the intervention.
CONCLUSION: Brief postpartum furosemide therapy for patients with severe preeclampsia seems to enhance recovery by normalizing blood pressure more rapidly and reducing the need for antihypertensive therapy. Shortening of hospitalization and reduction of delayed postpartum complications were not benefitted.
LEVEL OF EVIDENCE: I
Puerperal normalization of patients with the spectrum of preeclampsia proceeds variably over time, possibly exaggerating or impeding the normal extent of blood volume shifts that follow the cessation of gestation in a vascular system that is injured, vasospastic, or inflexible. Although complete recovery from severe preeclampsia can require an extended period of time,1–4 most patients who develop complications do this within the first 2 weeks after delivery.5 These include severe hypertension requiring medication or major fluid shifts that cause cerebral or pulmonary edema. It would be desirable to minimize or eliminate these altogether with use of a low-cost medical intervention such as furosemide to accelerate recovery and shorten hospitalization without adverse maternal or perinatal consequences.
This investigation was undertaken in patients with preeclampsia to assess the efficacy of a short 5-day postpartum course of orally administered furosemide to enhance diuresis and lower blood pressure, thereby reducing the need to initiate antihypertensive agents with their attendant cost, potential side effects, and the need to hold the patient longer in the hospital to assure the attainment of blood pressure control. A secondary goal was to shorten hospitalization and thereby reduce health care cost. Although the size of the study is not adequate to properly assess whether this intervention lessens peripheral edema and prevents subsequent hypertensive and fluid-related complications, we nevertheless assessed our patients for delayed pregnancy-related complications. To prevent excessive contraction of the intravascular space immediately postpartum, diuretic administration was initiated after spontaneous postpartum diuresis was established and patient-individualized magnesium sulfate prophylaxis6 was discontinued.
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MATERIALS AND METHODS |
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After informed consent was obtained, patients were randomly assigned to groups by opening the next previously prepared sequential and numbered opaque study envelope. Treatment was begun at the time that intravenous magnesium sulfate was discontinued and spontaneous diuresis initiated (> 100 mL/h for 2 hours consecutively without stimulus) as soon as 2 hours to as long as 24 hours after delivery. A shortened postpartum course of magnesium sulfate was used as previously described.6 Patients in the treatment group were assigned to receive furosemide (Lasix, Hoechst-Marion Roussel, Inc, Kansas City, MO) 20 mg/d together with an oral potassium supplement (K-Dur, Schering-Plough Co, Kenilworth, NJ) 20 mEq/d for a total of 5 consecutive days during hospitalization and after hospital discharge. Patients in the control group received neither medication.
Patients in both groups received similar postpartum surveillance, including blood pressure and pulse assessment every 4 hours, daily weight measurement, and daily urinary output measurements, while hospitalized. Antihypertensive therapy was administered to patients with intermittent or persistent (
2) elevations of systolic ( 150 mm Hg) or diastolic ( 100 mm Hg) blood pressure(s) after assignment to receive either furosemide or no medication.
Statistical analysis was performed using analysis of variance and, if significant, the Student-Newman-Keuls multiple comparison procedure was used to detect pair-wise difference. If the assumptions for analysis of variance were not tenable, nonparametric Kruskal-Wallis tests based on rank transformations were used. Categorical variables were analyzed using 
2 tests and pair-wise comparisons were adjusted using a Bonferroni correction. A P value of less than .05 was considered significant.
We estimated that 125 patients in each of the 2 treatment arms would be adequate to detect a 5 mm Hg shift in systolic blood pressure (1 standard deviation equals 13 mm Hg) with approximately 80% power at the nominal 5% level of significance. We allowed for a 10% rate of failure to meet the inclusion criteria. Thus 275 sealed envelopes were prepared for random assignment of patients to either treatment or control group. In the initial randomization, no stratification into groups based on diagnostic category was considered. A post hoc analysis based on stratifying by diagnostic group showed that our weakest test, comparing chronic hypertensives with superimposed preeclampsia, would allow us to detect shifts of approximately 15 mm Hg in systolic blood pressure. The sample sizes for severe preeclampsia provide adequate power (80%) for detecting 10 mm Hg shifts in systolic blood pressure. For mild preeclampsia, they are adequate to detect approximately 7-mm Hg shifts.
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RESULTS |
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Blood pressures and pulse rates immediately postpartum and again at the time of discharge from the Labor/Delivery/Recovery Unit to the postpartum ward when therapy was started are depicted in Table 2 for groups of patients with mild, severe, or superimposed preeclampsia. Patients with MPRE immediately postpartum exhibited a pulse rate that was approximately 6 beats per minute faster than patients in the other two groups with a 95% confidence interval of 1.1–10.8. There were no other significant differences at entry among groups. At the time of transfer to the postpartum ward, however, both groups of patients with preeclampsia (MPRE and SPRE) exhibited a lower frequency of hypertension compared with an increase for patients with underlying chronic hypertension. Approximately 20% of those with MPRE and hypertension immediately postpartum became normotensive before transfer to the postpartum ward. Pulse rates were equivalent among groups at the time of transfer to the postpartum ward and initiation of therapy, with a downward trend for patients with MPRE or SPRE and an upward trend for patients with underlying chronic hypertension (CPRE).
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An analysis of blood pressure values revealed that systolic blood pressure was significantly lower on the second postpartum day in furosemide-treated patients with SPRE (142 ± 13 mm Hg) compared with higher values of control patients with SPRE (153 ± 19 mm Hg, P < .004). There were, however, no significant differences in the diastolic blood pressure values or pulse rates observed postpartum between either the MPRE or the chronic hypertension groups that did or did not receive furosemide. The small number of patients in both the treated and control groups with CPRE, however, precludes meaningful evaluation. Data on postpartum maternal weights was inadequate to evaluate.
The frequency of antihypertensive agent use was reduced to some extent in all furosemide-treated patient groups during hospitalization and at the time of hospital discharge (Table 3). The only statistically significant difference observed, however, was an increase in the number of SPRE patients in the control group who required additional antihypertensive medication at the time of hospital discharge (26%) compared with a much lower incidence of 6% in patients with SPRE who were receiving furosemide therapy (P = .045, Table 3).
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Length of hospitalization was related to disease category primarily, not to whether the patient received furosemide (P = .429) and was not different based on mode of delivery. As expected, patients with MPRE required significantly shorter magnesium sulfate infusion (mean 9 hours, range 6.5–13) compared with SPRE (mean 15 hours, range 12–24) and chronic hypertension (mean 13 hours, range 12–22; P < .001). Patients with MPRE also had significantly shorter hospitalizations (mean 2 days, range 2–3) compared with SPRE (mean 3 days, range 2–4) and chronic hypertension (mean 3 days, range 2–5; P < .001).
Delayed postpartum complications requiring intervention of some type occurred in 5.3% of the study population, 8 patients in the control arm (MPRE: wound infection = 2, delayed postpartum hemorrhage = 1, endomyometritis = 1, pulmonary hypertension with congestive heart failure = 1; SPRE: wound infection = 1, vulvar hematoma = 1; and CPRE: pyelonephritis = 1) and 6 patients in the furosemide treatment arm (MPRE: hypertension = 1, urinary tract infection and depression = 1, endometritis = 1, nephrotic syndrome at six weeks postpartum = 1; SPRE: hypertension = 1, wound seroma = 1; CPRE = 0).
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DISCUSSION |
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The potential benefit of diuretic use for patients with severe preeclampsia or eclampsia is an important issue in contemporary obstetrics and maternal-fetal medicine. Patients with severe and superimposed forms of preeclampsia can suffer sustained hypertension, presumably in response to the presence of excess total body water, impaired sodium excretion due to reduced glomerular filtration, mobilization of interstitial and extravascular fluid, and the difficult task of controlling blood pressure while the parturient is volume overloaded. We interpret the findings from our study to suggest that patients with severe preeclampsia who received furosemide more effectively eliminated intravascular fluid that was mobilized from the interstitium during the early puerperium and thereby reduced blood volume and blood pressure, obviating the need to begin antihypertensive medication.
The underlying pathophysiology of preeclampsia is believed to involve diffuse vasospasm with endothelial cell damage.7 Thus transudation of plasma proteins across any damaged membrane surfaces can lead to hypoalbuminemia, a lowered intravascular colloid oncotic pressure, fluid migration into the interstitium, intravascular volume depletion, and systemic edema.8–10 After delivery, fluid that has been sequestered in the extravascular space is mobilized, producing a large autoinfusion of fluid from the extravascular to the intravascular compartment.11 Colloid osmotic pressure decreases while increases in central venous pressure and pulmonary capillary wedge pressure can develop, conditions that favor the development of pulmonary edema, especially in the patient with severe preeclampsia.12,13 Protracted use of intravenous magnesium sulfate can exacerbate this process and itself lead to formation of pulmonary edema.14
Because postpartum pulmonary edema and congestive heart failure can occur to some degree after delivery as a result of this fluid mobilization process, logical management would direct therapy at maintaining a low central venous pressure and pulmonary capillary wedge pressure and attempting to raise the colloid osmotic pressure to preclude the development of pulmonary edema and congestive heart failure.12,15 It follows that fluid restriction in the postpartum period coupled with the administration of a diuretic can be considered appropriate in these circumstances. Risks of low-dose diuretic therapy are minimal and minimized probably by the addition of a modest daily oral potassium supplement. We chose to use furosemide instead of hydrochlorothiazide for this investigation primarily because it has not been associated with neonatal thrombocytopenia in breastfed infants, although it does cross into breast milk and can inhibit milk production.16
This approach to management may also apply to minimizing the risk of central nervous system morbidity in puerperal patients, because cerebral edema and postpartum eclampsia, both hypothetically related to cerebral over perfusion rather than decreased cerebral blood flow,17 might benefit from peripheral fluid offloading and the purported benefit of some diuretics to reduce peripheral venous tone.18
Our study has limitations due to small sample size particularly in the SPRE and CPRE groups. Bias is possible, because the clinicians were not blinded to group assignment. Because each patient in the investigation continued treatment a few days after discharge, we do not know how many patients actually took the medication after leaving the hospital. Significant adverse events are relatively infrequent in most traditionally treated patient populations with preeclampsia, thus requiring a very large patient population studied in multiple sites and circumstances to truly evaluate any impact of postpartum diuretic therapy upon delayed fluid mobilization-related complications. Our study was too small to evaluate this issue, because no patient in either group developed such a complication. The only patient in the entire study to develop congestive heart failure did so as a result of previously undiagnosed pulmonary hypertension in association with mild preeclampsia.
This study does not firmly establish a short course of low dose furosemide begun at the time on spontaneous diuresis as a clearly advantageous adjunct to the routine management of patients with severe or superimposed preeclampsia. Although the need for antihypertensive therapy was reduced whenever furosemide was used, it was only significant in patients with severe preeclampsia, and this may not matter to clinicians, because the benefit was not translated into shorter hospitalizations or fewer complications. A larger investigation in these 2 patient populations, perhaps using a larger systemic dose of furosemide initiated soon after delivery, is needed to determine whether there is benefit and minimal risk to using this approach for the prevention of delayed complications, including pulmonary edema, postpartum eclampsia, preeclampsia-related cerebrovascular accidents, and myocardial infarction.
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Footnotes |
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Reprints are not available. Address correspondence to: James N. Martin Jr, MD, Department of Obstetrics and Gynecology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216; e-mail: jnmartin{at}ob-gyn.umsmed.edu.
Received July 6, 2004. Received in revised form September 15, 2004. Accepted September 23, 2004.
doi:10.1097/01.AOG.0000148270.53433.66
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REFERENCES |
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