Ovarian Hyperstimulation Syndrome

Classification

To understand OHSS and its management, one must first be aware of its various grades of severity, (1) mild OHSS, (2) moderate OHSS, and (3) severe OHSS. (See Presentation and Workup)[2]

Mild OHSS is classified as follows:

• Grade 1 - Abdominal distention and discomfort

• Grade 2 - Grade 1 disease plus nausea, vomiting, and/or diarrhea, as well as ovarian enlargement of 5-12 cm

Moderate OHSS is classified as follows:

• Grade 3 - Features of mild OHSS plus ultrasonographic evidence of ascites

Severe OHSS is classified as follows:

• Grade 4 - Features of moderate OHSS plus clinical evidence of ascites and/or hydrothorax and breathing difficulties

• Grade 5 - All of the above plus a change in the blood volume, increased blood viscosity due to hemoconcentration, coagulation abnormalities, and diminished renal perfusion and function

Abdominal pain, nausea, and vomiting

Enlargement of the ovaries causes abdominal pain, nausea, and vomiting. The enlargement is sometimes as much as 25 cm.

Ascites and tense distention

Another consequence of ovarian hyperstimulation syndrome (OHSS) is discomfort resulting from increased intra-abdominal pressure due to ascites.[3, 4]

Ascites and tense abdominal distention occur because of extravasation and increased leakage of protein-rich fluid from the intravascular space into the abdominal cavity, owing to an osmolar differential.

In addition, leakage of fluid from large follicles, increased capillary permeability (due to the release of vasoactive substances), or frank rupture of follicles can all contribute to ascites.[3]

Localized or generalized peritonitis

Localized or generalized peritonitis is caused by peritoneal irritation secondary to blood from ruptured cysts, protein-rich fluid, and inflammatory mediators.

Acute abdominal pain

Acute abdominal pain may be due to ovarian torsion, intraperitoneal hemorrhage, or rupture of cysts secondary to enlarged ovaries with fragile walls.

Hypotension and/or hypovolemia

Follicular fluid and perifollicular blood containing large amounts of vascular endothelial growth factor (VEGF), which is thought to increase vascular permeability, escape into the peritoneal cavity.

Blood vessels within and outside the ovary become functionally impaired, resulting in the leakage of fluid through those vessels and a massive fluid shift from the intravascular to the extravascular compartment. This process results in intravascular hypovolemia with the concomitant development of edema, ascites, hydrothorax, and/or hydropericardium.[5]

Hypotension and/or hypovolemia are also caused by compression of the inferior vena cava because of enlarged cysts or ascites. As a result, venous return and preload decrease. Eventual outcomes are reduced cardiac output and hypotension.

Dyspnea

Pulmonary function may be compromised as enlarged ovaries and ascites restrict diaphragmatic movement.

Other possible causes of dyspnea are the relatively rare manifestations of OHSS, such as pleural effusion, pulmonary edema, atelectasis, pulmonary embolism, acute respiratory distress syndrome (ARDS), and pericardial effusion.[6]

Hypercoagulable state

A hypercoagulable state is likely due to hemoconcentration and hypovolemia resulting from third spacing and fluid shift. It is also related to increased estrogen levels. Patients have an increased risk of developing deep venous thromboses and pulmonary embolisms.

Electrolyte imbalance

Electrolyte imbalance occurs due to the extravasation of fluid and resultant renal dysfunction resulting from decreased perfusion. Increased reabsorption of sodium and water occurs in the proximal tubule, leading to oliguria and low urinary sodium excretion.

The exchange of hydrogen and potassium for sodium in the distal tubule is reduced. As a result, hydrogen and potassium ions accumulate and cause hyperkalemia and a tendency to develop acidosis. Compensatory and electrolyte-retaining mechanisms fail.[7]

Acute renal failure

Hypovolemia in OHSS leads to hemoconcentration and creates a hypercoagulable state. Microthrombi form in tubules, leading to decreased renal perfusion. Acute renal failure may result.

The pathogenesis of ovarian hyperstimulation syndrome (OHSS) is unknown, but the process is related to increased vascular permeability in the region surrounding the ovaries and their vasculature.[8] Beta human chorionic gonadotropin (hCG) and its analogs, as well as estrogen, estradiol, prolactin, histamine, and prostaglandins, have been implicated in the past.

Vasoactive substances such as interleukins, tumor necrosis factor (TNF)-alpha, endothelin-1, and VEGF secreted by the ovaries have been implicated in increasing vascular permeability.[9, 10]

Human chorionic gonadotropin

Withholding hCG decreases OHSS. Hence, it plays a critical role in enhancing ovarian angiogenesis and triggering the cascade of vascular permeability in ovarian vessels that leads to third spacing and OHSS.[11] Exogenous and endogenous gonadotropins from molar pregnancy, gonadotroph adenomas, and even pregnancy can aggravate OHSS.[12] These changes in the ovarian vasculature are exaggerated responses to normal luteinizing hormone (LH).

Indeed, the function of hCG is similar to that of LH. As a result, the actions of hCG mimic these changes. Moreover, hCG exerts a follicle stimulating hormone–like action in stimulating the ovaries. In addition, it has a prolonged half-life. All of these properties of hCG lead to ovarian stimulation and changes in periovarian vasculature even after ovulation. These effects lead to poor control of the induction process, initiating and/or aggravating OHSS.[9]

Exogenous recombinant hCG precipitates OHSS more than endogenous agents (gonadotropin-releasing hormone [GnRH] analogs) do. Other precipitating factors for OHSS are induction in a hyperestrogenic state and poor timing.

Risk factors

Age younger than 35 years, low body mass index (BMI), gonadotropin treatment, high estradiol concentrations, large number of follicles, history of polycystic ovarian syndrome, administration of exogenous hCG, and endogenous hCG from treatments resulting in pregnancy increase a patient’s risk of developing OHSS.[13]

According to Martin et al, if the pre-hCG estradiol amount is greater than 6000 mcg and/or if more than 30 follicles are present, the rate of severe OHSS approaches 80%.[14]

The incidence of ovarian hyperstimulation syndrome (OHSS) depends on definitions, risk factors, stimulation protocols, and conception. Rates of occurrence have been estimated as follows[4] :

• Mild - 8-23%

• Moderate - 1-7%

• Severe - 0.25-5%

The frequency of OHSS may increase if the ovary is overstimulated, as documented by high levels of estradiol and depicted as an increased number of follicles on ultrasonography. The incidence rises when protocols combine GnRH agonists and gonadotropins, as compared with gonadotropins alone, to induce ovulation.[4]

Only women of childbearing age are affected by ovarian hyperstimulation syndrome.

The prognosis in mild or moderate cases of ovarian hyperstimulation syndrome (OHSS) is excellent. However, morbidity may be clinically significant in cases of severe OHSS, and fatalities do occur. However, the prognosis is optimistic in severe OHSS if proper (or adequate) treatment is given.

Death from OHSS is largely due to hypovolemic shock and electrolyte imbalance, hemorrhage, and thromboemboli (hypercoagulability may endanger the patient). Estimated fatality rates are 1 per 400,000-500,000 stimulated cycles.

A retrospective cohort study that used data from the National Assisted Reproductive Technology Surveillance System found that women who had OHSS were at higher risk for preterm delivery and infants with low birth weight.[15]

Patients are instructed to record their weight on a daily basis, to avoid exercise and intercourse, and to maintain adequate hydration after in vitro fertilization. They should measure their abdominal girth, intake, and output and should report urinary output of less than 1000mL in any 24-hour period.

Patients are also instructed to report progressive bloating, abdominal discomfort, decreases or increases in urination, cramping, dizziness, shortness of breath, and weight gain of more than 5 lb/wk.

History

Women with ovarian hyperstimulation syndrome (OHSS) will have recently had gonadotropin stimulation to induce ovulation or will have been treated with an assisted reproductive technology such as in vitro fertilization.

Early OHSS is usually mild to moderate and manifests 3-7 days after the administration of hCG. Late OHSS is usually severe and occurs 12-17 days after hCG treatment.[16] The early type is due to exogenously administered hormone, and the late type often occurs during an implanting or an implanted pregnancy, because pregnancy hCG exacerbates the disease.[11]

Signs of OHSS

Signs of OHSS include those listed below (percentages refer to all classes of OHSS)[6, 17] :

• Ascites

• Hypercoagulability - 6.2%

• Thrombosis

• Pleural effusion and pericardial effusion

• Hemoconcentration

• Leukocytosis - White blood cell (WBC) count over 20,000/mm3

• Electrolyte abnormalities - Eg, hyponatremia, hyperkalemia

• Elevated transaminase values - 26%

• Acute respiratory distress syndrome - 2%

• Pulmonary embolism - 2%

• Acute renal failure - 1%

Symptoms of OHSS

Symptoms of OHSS include those listed below (percentages refer to cases of severe OHSS)[6, 17] :

• Shortness of breath - 92%

• Abdominal discomfort - 99%

• GI disturbances - Nausea, vomiting, diarrhea; 54%

• Oliguria - 30%

• Peripheral edema - 13%

• Lethargy

• Rapid weight gain

Although OHSS usually manifests with a constellation of symptoms, atypical presentations can occur. Rare presentations such as thromboembolism (venous and arterial) have been observed. Atypical locations of venous thromboembolism include the internal jugular vein, the subclavian vein, the inferior vena cava, the ileofemoral veins, and the intracerebral veins.[18]

Other abnormal forms of presentation include isolated hydrothorax and isolated thromboembolism. Additional situations leading to elevated hCG concentrations, such as molar pregnancy and the presence of gonadotroph adenomas, may in rare cases lead to mild forms of OHSS.[19]

Physical examination

Physical findings of OHSS include right or left lower quadrant pain below the umbilicus, as well as edema.

Of note, abdominal palpation must be performed gently to avoid the possibility of rupturing a large cyst. Pelvic examination should be deferred in favor of ultrasonography of the pelvis.

In ovarian hyperstimulation syndrome (OHSS), the hematocrit is the most important measure in deciding if a patient should be hospitalized. If the patient's hematocrit level is greater than 60% and if she has ascites, hospitalize her immediately.

Laboratory monitoring may involve the following parameters:

• Complete blood count (CBC) with differential - This is helpful because decreased intravascular volume leads to hemoconcentration and an increased hematocrit

• Coagulation profile, including the prothrombin time (PT), activated partial thromboplastin time (aPTT), and international normalized ratio (INR) - These findings aid in detecting a hypercoagulable state and in monitoring anticoagulation

• Leukocyte count - A count higher than 22,000 cells/µL is related to the seriousness of OHSS and predictive of thromboembolism[20, 21]

Beta-hCG concentration

A beta-hCG measurement is especially useful at more than 12 days after an injection of hCG. A positive result at this stage indicates pregnancy, an endogenous source of hCG for OHSS. Vascular endothelial growth factor (VEGF) receptors are upregulated by hCG; this upregulation increases third spacing.[22] Mild OHSS may deteriorate to severe OHSS because of the increased availability of hCG.

Complete metabolic panel

Liver function is decreased, as indicated by increased concentrations of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase.

Renal function is reduced, blood urea nitrogen (BUN) and creatinine values are increased, and albumin and protein levels are decreased. Electrolyte imbalances, hyperkalemia, and acidosis may be present.

Estradiol levels

Estradiol levels are increased. Laboratory findings of a serum estradiol concentration of greater than 2000 pg/mL and a progesterone concentration of greater than 30 ng/mL in the early part of the luteal phase are warning signs of developing OHSS.[23]

Signs of worsening OHSS

Signs that may indicate a progression in the severity of OHSS are increases in the hCG level, increases in hematocrit level, hypoproteinemia, and hypoalbuminemia (third spacing). Additional signs are decreasing renal and liver function.

OHSS is critical when the signs and symptoms of severe OHSS are present with any of the following findings: renal failure, ARDS, thromboembolism, or a hematocrit level greater than 60%.

Imaging studies

Ultrasonography may be needed to measure the size of the ovaries, to assess the follicles, and to evaluate ascites (see image below). Chest radiography may be indicated if dyspnea is present.

In the ideal situation, the ovaries should be stimulated to the desired level when ovulation is induced. However, the unpredictable response of the ovaries to induction makes the prediction and prevention of OHSS difficult.[4] Hence, heightened clinical suspicion and early intervention are paramount to the reduction of morbidity and mortality.

Treatment should include the following:

• Maintenance of a high degree of clinical suspicion and a low threshold for admission

• Early surgical intervention in cases of ovarian torsion or hemorrhage

• Paracentesis to address ascites - This decreases pressure on the inferior vena cava and diaphragm

• Placement of a transthoracic tube to manage pleural effusions

Treatment should not include the following:

• Aggressive palpation of the abdomen - This can precipitate follicular rupture

• Early surgical intervention - Early surgery may cause extensive bleeding from ovarian cysts; as stated above, however, surgery is mandated if torsion or rupture causing hemorrhage has occurred

• Neglect of organ and system deterioration - Remember that OHSS is a syndrome of multiorgan dysfunction

Surgery

Ovarian hyperstimulation syndrome is a self-limiting disease. Therefore, treatment should be conservative and directed at symptoms, with medical therapy being sufficient for most patients. Women with severe symptoms often require intensive medical care.

Surgical management further aggravates electrolyte imbalances and increases morbidity. Indeed, surgery is necessary only in extreme cases, such as in the case of ovarian torsion, a ruptured cyst, or an internal hemorrhage. Ascites can be tapped by means of paracentesis. Laparotomy during torsion and intraperitoneal hemorrhage is lifesaving and recommended.

Consultations

In severe cases of OHSS, consultation with a physician specializing in fluid and electrolyte imbalances is warranted. For some cases, aggressive treatment in the surgical intensive care unit may be required.

Diet

Ensure that the patient receives plenty of hydration.

Activity

Patient activity should be minimal.

Conservative management in the outpatient setting is appropriate for mild-to-moderate ovarian hyperstimulation syndrome (OHSS) until spontaneous resolution occurs. However, management in the inpatient setting should be considered if any of the following criteria are present:

• Inability to tolerate oral food or hydration

• Severe abdominal pain

• Unclear diagnosis

• Hypotension

• Shortness of breath

• Tense ascites

• Peritoneal signs

• Hematocrit greater than 48%

• Sodium less than 135 mEq/L

• Potassium greater than 5 mEq/L

• Creatinine greater than 1.2 mg/dL

Mild hyperstimulation

Treatment for OHSS is supportive. Mild ovarian hyperstimulation can develop into moderate or severe disease, especially if conception ensues. Therefore, women with mild disease should be observed for enlarging abdominal girth, acute weight gain, and abdominal discomfort on an ambulatory basis for at least 2 weeks or until menstrual bleeding occurs.

Moderate hyperstimulation

The treatment of moderate OHSS consists of observation, bed rest, the provision of adequate fluids, and ultrasonographic monitoring of the size of cysts. Serum electrolyte concentrations, hematocrits, and creatinine levels should also be evaluated.

Some physicians have their outpatients keep track of their fluid intake and output. Intake or output of less than 1000 mL daily or a discrepancy in fluid balance of greater than 1000 mL daily is a cause for concern.[20]

The beginning of the resolution of OHSS is apparent when the cysts shrink, as seen on 2 consecutive ultrasonographic examinations, and when clinical symptoms recede. In contrast, early detection of progression to the severe form of the syndrome is marked by continuous weight gain (≥2 lb daily), increased severity of existing symptoms, or the appearance of new symptoms (eg, vomiting, diarrhea, or dyspnea).[19]

Severe hyperstimulation

Clinician experience with severe OHSS is mandatory for appropriate treatment. One should transfer the patient to a different center if no one who is experienced in managing severe OHSS is available at the present location.

Severe OHSS is not common, but it is dangerous. Severe and critical forms of OHSS are potentially fatal disorders, and history taking and physical examination are paramount at the time of admission. In most clinical situations, patients require bed rest. Daily physical examination should consist of measuring the patient's weight and abdominal girth. Fluid balance must be assessed every 4 hours.

Medical treatment of severe hyperstimulation is directed at maintaining intravascular blood volume. Simultaneous goals are correcting the disturbed fluid and electrolyte balance, relieving secondary complications of ascites and hydrothorax, and preventing thromboembolic phenomena.

The main interventions are fluid management and correction of hypovolemia. These measures consist of initial intravenous (IV) administration of 1 L normal saline over 1 hour. Dextrose 5% in normal saline or normal saline is then infused at a rate of 125-150mL/h, with 4-hour tabulations of urine production. If urine production is restored or improved, IV hydration at a maintenance rate of 125-150 mL/h is continued.

If urine output is unsatisfactory, hyperosmolar IV therapy is indicated, with an infusion of 50-200 mL of 25% human albumin every 6 hours. The use of diuretics in patients with low urine production and intravascular volume depletion is counterproductive and dangerous.[19] Adequate intravascular volume as evidenced by normalizing hematocrit levels should be present before diuretics are used.

Close surveillance of fluid management is necessary. IV fluid administration is stopped when urine production, appetite, or interest in drinking increases and when overall clinical improvement is observed. In the resolution phase of severe OHSS, the patient's fluid intake should be restricted to avoid renewed hemodilution.

To prevent thrombosis, subcutaneous heparin 5000-7500 U daily is begun on the first day of admission. It is stopped after adequate ambulation is achieved.

To manage ascites, ultrasonographically guided abdominal or vaginal paracentesis is indicated if the patient has severe discomfort or pain or if she has pulmonary or renal compromise.[24] The vaginal procedure entails the same setup as that used for transvaginal follicular puncture. Whelan and Vlahos advise that an anesthesiologist be present. Paracentesis may be repeated if necessary.[20] Use of an indwelling pig-tail catheter may be considered for extended drainage.

Critical hyperstimulation

Grade 5 OHSS may include renal failure, hepatic damage, thromboembolic phenomena, ARDS, and multiorgan failure.[25] Its management and treatment require intensive care in a critical care unit. Such care should include invasive monitoring of circulatory indicators, including venous pressure and wedge pressure. The patient may need extra oxygenation (assisted ventilation).

If renal failure is present, an IV dopamine regimen should be started. To treat thromboembolism, therapeutic doses of anticoagulants should be administered. Thoracocentesis should be performed in cases of severe hydrothorax. Finally, if a pregnancy is maintaining a life-threatening OHSS, therapeutic abortion must be considered.

After several days, third-space fluid begins to reenter the intravascular space, hemoconcentration reverses, and natural diuresis ensues. IV fluids may be tapered as the patient's oral intake increases. Complete resolution typically takes 10-14 days from the onset of initial symptoms.

Careful maintenance of blood volume, correction of electrolyte imbalances, and relief of secondary complications of ascites and hydrothorax are generally sufficient to support the patient during the severe phase of ovarian hyperstimulation. If these treatments are promptly administered, anticoagulant therapy is usually unnecessary. Blood coagulation may be monitored because of the danger of disseminated intravascular clotting.

Ovarian hyperstimulation syndrome (OHSS) is a self-limiting disease of the luteal phase. Without luteinizing hormone (LH) or its imitator, hCG, ovulation or the luteal phase does not occur. Avoidance of hCG during ovarian stimulation offers an opportunity to prevent OHSS in high-risk patients. However, those patients do not conceive. Other options are delaying hCG (coasting) for 1-3 days until estradiol levels plateau or decline (< 2500 pg/mL), using a GnRH agonist to induce ovulation, or lowering doses of hCG.[19]

The best preventive method is to adapt the treatment and closely monitor patients at risk. Remember that women at risk are those with high levels of estrogen and many follicles at the assumed time of ovulation. Patients with polycystic ovarian syndrome should be closely monitored as well.

Two trials, involving 230 women with moderate risk of bias, found evidence that a daily oral dose of 0.5 mg of the dopamine agonist cabergoline may reduce the risk of ovarian hyperstimulation in high-risk women, with no influence on pregnancy outcome.[26]

Laboratory findings of a serum estradiol concentration of greater than 2000 pg/mL and a progesterone concentration of greater than 30 ng/mL in the early part of the luteal phase are warning signs of developing OHSS.[23]

Vaginal intercourse is restricted in women with any grade of OHSS because of the risk of rupturing a cyst. Patients should also avoid impact-type activities or strenuous exertion.

Prevention guidelines

A 2014 clinical practice guideline from the Society of Obstetricians and Gynaecologists of Canada (SOGC), The Prevention of Ovarian Hyperstimulation Syndrome, includes the following recommendations[27] :

• The addition of metformin should be considered in patients with polycystic ovarian syndrome who are undergoing in vitro fertilization, because it may reduce the incidence of OHSS

• Gonadotropin dosing should be carefully individualized, taking into account the patient’s age, body mass, antral follicle count, and previous response to gonadotropins

• Cycle cancellation before administration of hCG is an effective strategy for the prevention of OHSS, but the emotional and financial burden it imposes on patients should be considered before the cycle is cancelled

• GnRH antagonist stimulation protocols are recommended in patients at high risk for OHSS; the risk of severe OHSS in patients on GnRH antagonist protocols who have a very robust ovarian stimulation response can be reduced by using a GnRH agonist as a substitute for hCG to trigger final oocyte maturation

• A GnRH antagonist protocol with a GnRH agonist trigger for final oocyte maturation is recommended for donor oocyte and fertility preservation cycles

• Albumin or other plasma expanders at the time of egg retrieval are not recommended for the prevention of OHSS

• Elective single-embryo transfer is recommended in patients at high risk for OHSS

• Progesterone, rather than hCG, should be used for luteal-phase support

• Outpatient culdocentesis should be considered for the prevention of disease progression in severe OHSS

Medical therapy is aimed at the correction of fluid and electrolyte balance. Normal saline is used to restore the patient’s intravascular and extravascular volume. In addition, albumin can be used to expand plasma volume, and dopamine can be employed to increase blood pressure.

Thrombosis can occur in the arteries (25%) and veins (75%). Therefore, the use of heparin, low molecular weight heparin (enoxaparin sodium [Lovenox] and others), antiembolism stockings, and sequential compression devices (boots) are all recommended as prophylaxis against thrombosis. Heparin prophylaxis is usually started in patients with a history of thrombosis, factor V Leiden deficiency, or other thrombophilic states before the induction of ovulation.

Class Summary

These agents inhibit key factors involved in thrombogenesis.

Heparin

Heparin augments the activity of antithrombin III and prevents the conversion of fibrinogen to fibrin. It does not actively lyse, but heparin can inhibit further thrombogenesis, and it prevents reaccumulation of a clot after spontaneous fibrinolysis. To prevent thrombosis, subcutaneous heparin 5000-7500 U daily is begun on the first day of admission. It is stopped after adequate ambulation is achieved.

Enoxaparin (Lovenox)

Enoxaparin is a low-molecular-weight heparin (LMWH) produced by partial chemical or enzymatic depolymerization of unfractionated heparin (UFH). It binds to antithrombin III, enhancing its therapeutic effect. The heparin-antithrombin III complex binds to and inactivates activated factor X (Xa) and factor II (thrombin). LMWH differs from UFH by having a higher ratio of anti–factor Xa to anti–factor IIa.

Enoxaparin does not actively lyse thrombi but is able to inhibit further thrombogenesis. It prevents reaccumulation of clot after spontaneous fibrinolysis. Its advantages include intermittent dosing and a decreased requirement for monitoring. Heparin anti–factor Xa levels may be obtained if needed to establish adequate dosing. There is no point in checking the aPTT; the drug has a wide therapeutic window, and aPTT does not correlate with anticoagulant effect.

Desirudin (Iprivask)

Desirudin is a highly selective thrombin inhibitor. It inhibits fibrin formation, activation of coagulation factors, and thrombin-induced platelet aggregation. This results in prolongation of activated partial thromboplastin time.

Lepirudin (Refludan)

Lepirudin, a recombinant hirudin derived from yeast cells, is a highly specific direct thrombin inhibitor. It is indicated for anticoagulation in HIT and associated thromboembolic disease. Its action is independent of antithrombin III. Lepirudin blocks the thrombogenic activity of thrombin. It affects all thrombin-dependent coagulation assays (eg, aPTT values increase in a dose-dependent manner). Adjust the dose on the basis of aPTT ratios (target, 1.5-2.5 times normal) determined every 4 hours and then daily.

Class Summary

These are used to replenish intravascular and extravascular volume.

Normal saline

Normal saline is used to restore interstitial and intravascular volume.

Class Summary

These agents are used to expand plasma volume.

Albumin (Albuminar, Albutein, Buminate, Plasbumin-25)

Albumin is a major plasma protein that is responsible for the colloid oncotic pressure of blood. It is pooled from blood, serum, plasma, or placenta from healthy donors. Albumin is administered in certain types of shock or impending shock. Use a 5% solution to expand plasma volume and maintain cardiac output. Use a 25% solution to raise oncotic pressure.

Class Summary

These agents increase blood pressure.

Dopamine

Dopamine is a naturally occurring, endogenous catecholamine that stimulates beta1-adrenergic, alpha1-adrenergic, and dopaminergic receptors in dose-dependent fashion; it stimulates the release of norepinephrine.

At low dosages (2-5 mcg/kg/min), dopamine acts on dopaminergic receptors in renal and splanchnic vascular beds, causing vasodilation-selective dilation of the renal vasculature, enhancing renal perfusion. It also reduces sodium absorption, decreasing the energy requirements of damaged tubules. This enhances urine flow, which, in turn, helps to prevent tubular cast obstruction. Most clinical studies have failed to establish this beneficial role for renal-dose dopamine infusion.

At midrange dosages (5-15 mcg/kg/min), dopamine acts on beta-adrenergic receptors to increase heart rate and contractility.

At high dosages (15-20 mcg/kg/min), the drug acts on alpha-adrenergic receptors to increase systemic vascular resistance and raise blood pressure.