Administration of carperitide in cases of pulmonary edema with preeclampsia: a pilot case series

Abstract

Carperitide, a recombinant form of alpha-human atrial natriuretic peptide, has been widely used in patients with acute heart failure and pulmonary congestion. Here we report five cases of severe pulmonary edema due to preeclampsia treated with carperitide. Five postpartum patients underwent emergency cesarean section because of maternal organ failure at 30⁺² (25⁺²–34⁺²) weeks of gestation and were diagnosed with pulmonary edema prior to or immediately after delivery. Carperitide 0.025 (0.023–0.029) μg/kg/min was administrated postpartum for 3 (2–5) days. After treatment, air space opacification improved, and the cardiothoracic ratio significantly decreased from 54.4% (52.0–61.1) to 49.5% (44.7–51.5) (P=0.038), with a decrease in blood pressure and rapid increase in urine output after initiation of carperitide. Dyspnea improved in all patients, with favorable maternal outcomes and no adverse effects attributable to carperitide. Carperitide may effectively alleviate severe pulmonary edema attributed to preeclampsia, thereby potentially enhancing the overall postpartum health status of affected individuals.

Introduction

Pulmonary edema, defined as an excessive accumulation of extravascular fluid in the lung parenchyma, is the most common and challenging cardiopulmonary complication affecting approximately 3% of patients with severe preeclampsia.^1,2) Since pulmonary edema is evidence of severe maternal organ dysfunction in patients with preeclampsia, the presence of pulmonary edema alone is an indication for expeditious termination of pregnancy irrespective of gestational age.³⁾ Moreover, pulmonary edema can be lethal if not treated promptly and appropriately, as it often coexists with other cardiopulmonary complications such as congestive heart failure and acute respiratory distress syndrome. Indeed, roughly half of preeclampsia-related deaths are due to pulmonary edema.^4,5) Furthermore, pulmonary edema often develops and/or is exacerbated after delivery due to a reduction in postpartum colloid osmotic pressure.¹⁾ Thus, while termination of pregnancy is certainly the only fundamental resolution for preeclampsia, conservative treatments including diuretic administration, fluid restriction, and respiratory support are mainly performed, even though immediate effects are not expected since it is difficult to cure pulmonary edema quickly.

Alpha-human atrial natriuretic peptide (ANP), a peptide hormone comprising 28 cyclic amino acid residues, was isolated from the human atrium by Kangawa et al. in 1984.⁶⁾ Carperitide is a recombinant form of ANP introduced in Japan in 1995 as an intravenous treatment for acute decompensated heart failure. Carperitide reduces both cardiac preload and afterload through vasodilation, natriuretic effects, and inhibition of the renin-angiotensin-aldosterone system, and has been widely used in patients with acute heart failure and pulmonary congestion.^7,8,9) In a multicenter prospective observational study, 83.2% of patients with acute heart failure with pulmonary congestion recovered after carperitide monotherapy with an improvement in the degree of dyspnea.¹⁰⁾ Moreover, carperitide has been reported to significantly reduce congestion, as assessed by chest radiography and a composite of all-cause death or rehospitalization in patients with acute heart failure with moderate-to-severe pulmonary congestion, indicating favorable short- and long-term effects.⁸⁾

Given the pharmacological effects of carperitide, it is reasonable to speculate that it may also be effective in treating pulmonary edema caused by preeclampsia. However, to date, no studies have examined the efficacy of carperitide in cardiopulmonary complications associated with preeclampsia. Accordingly, here we report five cases of severe pulmonary edema due to preeclampsia treated with carperitide in postpartum patients.

This study was approved by the ethics committee of Kyoto University (R2262-3). Informed consent was obtained in the form of opt-out. Data other than blood pressure are presented as median (range). Blood pressure data are presented as mean±standard deviation. A paired t-test was used to compare the cardiothoracic ratio (CTR) before and after carperitide administration using GraphPad Prism 10 (GraphPad Software, San Diego, CA, USA). A P-value less than 0.05 was considered statistically significant.

Cases

Between January 2016 and December 2023, five patients with pulmonary edema due to preeclampsia were administered carperitide postpartum at Kyoto University Hospital. Table 1 shows the clinical characteristics of the five patients. The terminology, definition, and classification of hypertensive disorders of pregnancy conformed to the committee report published by the Japan Society for the Study of Hypertension in Pregnancy.¹¹⁾ Among the five patients, median age was 41 (33–42) years, and four were primiparas. All patients were diagnosed with severe preeclampsia and underwent emergency cesarean section because of maternal organ failure, including deteriorated dyspnea (patients 1 and 3), elevated liver enzyme levels (patients 2, 4, and 5), and worsening renal function (patients 2 and 5), at a median gestational age at delivery of 30⁺² (25⁺²–34⁺²) weeks. Patients 1, 2, 3, and 4 were diagnosed with pulmonary edema prior to delivery and required oxygenation; patient 1 was managed with noninvasive positive-pressure ventilation during pregnancy. Patient 5 was diagnosed with pulmonary edema after cesarean section. Carperitide was started on the day of cesarean section or postpartum day 1, and administered for 3 (2–5) days at 0.025 (0.023–0.029) μg/kg/min. The oxygen requirement period after carperitide treatment was 7 (5–8) days. All patients were administered nifedipine, a calcium channel blocker, prenatally and throughout the postpartum period (80 mg/day in patients 1 and 2; 60 mg/day in patient 3; 40 mg/day in patients 4 and 5). None of the patients received albumin replacement therapy.

Table 1. Clinical characteristics of the five patients

Patient	Age	Parity	Diagnosis	Gestational age at cesarean section	Carperitide administration duration (days)	Dose of carperitide (μg/kg/min)	O2 requirement period after carperitide administration (days)
1	42	P	PE	25w2d	5 (ppt day 0–4)	0.025	6
2	41	P	PE/HELLP syndrome	25w4d	5 (ppt day 0–4)	0.025	7
3	41	M	PE/AF	30w2d	2 (ppt day 0–1)	0.025	7
4	40	P	PE/MD twin	34w2d	3 (ppt day 0–2)	0.029	5
5	33	P	PE/GDM	32w6d	3 (ppt day 1–3)	0.023	8

P, primipara; M, multipara; PE, preeclampsia; HELLP syndrome, hemolysis, elevated liver enzymes, and low platelet syndrome; AF, atrial fibrillation; MD twin, monochorionic diamniotic twin; GDM, gestational diabetes mellitus; ppt, postpartum.

Figure 1 shows chest radiographs of all patients at the start and end of carperitide treatment. In each patient, air space opacification was observed in the bilateral lung fields, especially around the heart, with the so-called butterfly sign at the start of carperitide administration. At the end of administration, the opacity improved, although it did not completely disappear. The CTR after carperitide treatment was 49.5% (44.7–51.5), showing a significant decrease from 54.4% (52.0–61.1) before treatment (P=0.038) (Figure 2). Systolic and diastolic blood pressures decreased from 153.0±17.5 mmHg to 138.2±12.4 mmHg (9.7%) and from 95.1±8.6 mmHg to 86.6±7.3 mmHg (8.9%), respectively, within 24 hours of carperitide administration, with no notable changes thereafter (Figure 3). Urine output increased rapidly over the first few days after the initiation of carperitide treatment (Figure 4). In all patients, carperitide treatment led to an improvement in dyspnea and favorable maternal clinical outcomes. No adverse effects attributable to carperitide treatment were observed.

Figure 1. Chest radiographs of five patients. At the beginning of carperitide administration (left panels), and at the end of administration (right panels).

Figure 2. Changes in cardiothoracic ratio. The cardiothoracic ratio was significantly decreased after carperitide treatment: 54.4% (52.0–61.1) before treatment vs. 49.5% (44.7–51.5) after treatment. P=0.038.

Figure 3. Trends in systolic and diastolic blood pressure. Systolic blood pressure (left panel) and diastolic blood pressure (right panel) decreased from 153.0±17.5 mmHg to 138.2±12.4 mmHg (9.7%) and from 95.1±8.6 mmHg to 86.6±7.3 mmHg (8.9%), respectively, within 24 hours of carperitide administration, with no notable changes thereafter. BP: blood pressure.

Figure 4. Urine output. Urine output increased rapidly over the first few days after the initiation of carperitide. Circles indicate the time of first peak urine volume after carperitide administration.

Discussion

This is the first pilot case series of patients with cardiopulmonary complications of severe preeclampsia treated with carperitide. In postpartum patients with pulmonary edema due to severe preeclampsia, low-dose carperitide treatment improved cardiac enlargement on chest radiographs, gently decreased blood pressure, and increased urine output. Collectively, these observations suggest that carperitide may be beneficial in ameliorating pulmonary edema and general postpartum conditions in patients with severe preeclampsia.

The precise mechanisms and pathophysiology underlying pulmonary edema in patients with preeclampsia are complex and poorly understood. Generally, it is thought to be caused by a reduction in plasma oncotic pressure due to protein loss, increased vascular permeability due to endothelial dysfunction, and elevated capillary hydrostatic pressure.^1,12) It remains controversial whether cardiac diastolic dysfunction plays a role in the development of pulmonary edema in preeclampsia.⁵⁾ However, the median plasma level of brain natriuretic peptide just before the termination of pregnancy was 98.0 (16.2–528.6) pg/ml (normal range: <18.4 pg/ml) in the present cases, suggesting possible heart failure. In this setting, carperitide, which exhibits vasodilatory and diuretic effects to reduce cardiac load, appeared to be an effective treatment option to address pulmonary edema. Another major advantage of carperitide is that it suppresses the renin-angiotensin-aldosterone system and sympathetic nervous system, both of which are overactive in preeclampsia.

In patients with acute heart failure undergoing carperitide treatment, common indicators of short-term treatment efficacy include improvements in subjective symptoms such as dyspnea and palpitation, heart failure severity, urine volume, blood pressure, chest radiography findings, and echocardiography findings.^8,10,13,14) In the present case series, we used the CTR on chest radiography and urine output because both can be assessed retrospectively and objectively in patients with pulmonary edema associated with preeclampsia. Carperitide treatment led to a marked increase in urine output within 48 hours of administration and a significant decrease in the CTR at the end of treatment. These changes occurred simultaneously with improved subjective symptoms of dyspnea, suggesting that carperitide ameliorated pulmonary edema. Systolic blood pressure >120 mmHg, young age, and no prior use of loop diuretics are significant predictors of a good carperitide response.^14,15) Since patients with pulmonary edema due to preeclampsia fulfill all these criteria, they might be considered suitable candidates for carperitide treatment.

In the present case series, carperitide administered at a low dose of 0.025 (0.023–0.029) μg/kg/min provided sufficient clinical efficacy. According to the package insert, the recommended dose of carperitide is 0.1–0.2 μg/kg/min; however, a low dose of 0.025–0.05 μg/kg/min is often adopted for real-world use in cardiovascular medicine.¹⁰⁾ A placebo-controlled randomized trial reported that carperitide treatment at 0.025 μg/kg/min in patients with acute myocardial infarction reduced infarct size, decreased reperfusion injuries, and improved outcomes.¹⁶⁾ Another randomized control trial demonstrated that perioperative carperitide treatment at 0.02 μg/kg/min has a cardiorenal protective effect in patients undergoing on-pump coronary artery bypass grafting.¹⁷⁾ Our observations are in line with these reports that have provided robust evidence, and we propose that carperitide for obstetric use be started at an initial dose of 0.025 μg/kg/min as well.

Hypotension is the most prevalent adverse event associated with carperitide. In a prospective registry analysis involving 3,777 patients with acute heart failure, treatment requiring blood pressure reduction by carperitide occurred in 9.5% of patients, and was predominantly observed within the initial 3 hours post-administration.¹³⁾ Patients with systolic blood pressure <90 mmHg and those with a large blood pressure fall are at an increased risk of acute kidney injury.¹⁸⁾ In our patients, systolic blood pressure decreased from 153.0±17.5 mmHg to 138.2±12.4 mmHg (9.7%), and diastolic blood pressure decreased from 95.1±8.6 mmHg to 86.6±7.3 mmHg (8.9%), within 24 hours of carperitide administration. This reduction is not solely attributable to carperitide; it is also the result of pregnancy termination and antihypertensive agent administration for the treatment of preeclampsia. Nevertheless, since intravascular volume depletion is often comorbid with preeclampsia, blood pressure trends should be carefully monitored during carperitide infusion. It should also be noted that carperitide doses below the limit of 0.025 μg/kg/min have been suggested to be effective in preventing severe hypotension and worsening of renal function.¹⁹⁾

In the present case series, carperitide was initiated postpartum in all patients. However, the administration of carperitide during pregnancy is not necessarily contraindicated.²⁰⁾ Although excluded from this study, carperitide was administered to a pregnant patient at 23 weeks of gestation to manage severe pulmonary edema induced by a high dose of a tocolytic agent. This intervention rapidly ameliorated pulmonary edema. Carperitide for severe pulmonary edema in the periviable period (23–26 weeks of gestation) may be an effective treatment option for prolonging the gestational period. Nevertheless, the patient’s condition should be closely monitored, and appropriate pregnancy termination should not be missed.

Our study has some limitations. The sample size of the present retrospective pilot case series was small, and the lack of appropriate controls with matched conditions made it difficult to evaluate the true effects of carperitide. Further studies with larger sample sizes and propensity score-matched controls will be necessary to assess the efficacy and safety of carperitide for pulmonary edema in patients with preeclampsia. However, we demonstrated that carperitide is an effective therapeutic option for managing severe pulmonary edema due to preeclampsia, which is significant given that few effective interventions are available.

In conclusion, carperitide treatment was effective in alleviating severe pulmonary edema due to preeclampsia, and may potentially enhance the overall postpartum health status of affected individuals.

Acknowledgments

This study was supported by a grant from the Smoking Research Foundation in Japan (2023G021). We also thank Editage (www.editage.jp) for English language editing.

Conflict of interest

The authors declare that they have no conflicts of interest.

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