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Idiopathic systemic capillary leak syndrome

Idiopathic systemic capillary leak syndrome
Rajesh Aneja, MD, FAAP
Section Editor:
Scott Manaker, MD, PhD
Deputy Editor:
Geraldine Finlay, MD
Literature review current through: Feb 2023. | This topic last updated: Sep 17, 2021.

INTRODUCTION — Idiopathic systemic capillary leak syndrome (ISCLS) is a rare disorder characterized by episodes of severe hypotension, hypoalbuminemia, and hemoconcentration [1,2]. During "attacks" of ISCLS, profound derangements of the vascular endothelium develop, resulting in leakage of plasma and proteins into the interstitial compartment [1,2]. Episodes vary in severity and frequency and may be fatal. ISCLS was first described by Clarkson in 1960 and is variably referred to as Clarkson's disease or syndrome [1].

EPIDEMIOLOGY — Approximately 260 cases of idiopathic systemic capillary leak syndrome (ISCLS) have been reported worldwide [3,4]. These have been diagnosed primarily in middle-aged adults, although cases in children as young as five months old have been reported [5-10]. There is no apparent gender predilection.

PATHOGENESIS — The cause(s) of idiopathic systemic capillary leak syndrome (ISCLS) is not known, although there is an associated monoclonal gammopathy in many patients. Several theories of pathogenesis have been proposed and are discussed in this section. It is helpful first to review mechanisms of capillary leakage in other diseases.

Mechanisms of capillary leakage — The vascular endothelium is a semi-permeable barrier that controls the passage of fluid and macromolecules between the intravascular and interstitial spaces. Dysfunction of this barrier leads to leakage, with loss of intravascular fluid and protein into the interstitial compartment. Cells and platelets are generally retained within the vasculature, resulting in elevations in white blood cell, red blood cell, and platelet counts. The resulting intravascular fluid depletion can cause hypotension and impair the delivery of oxygen to the tissues. Severe capillary leakage can result in hypotension and shock.

There are many known causes of capillary leak, which can be categorized as follows:

Increased hydrostatic pressure within the capillaries can force fluid and protein through the endothelial barrier and into the interstitium. This is the mechanism of capillary leak in heart failure, renal failure, hepatic venous obstruction (eg, cirrhosis), and lower extremity deep vein thrombosis.

Decreased capillary oncotic pressure may fail to retain fluid within the vascular space. This is the mechanism of capillary leak in conditions characterized by albumin loss (eg, nephrotic syndrome, protein losing enteropathy) or decreased albumin synthesis (eg, liver disease).

Increased capillary permeability allows fluid and protein to readily pass through the endothelial barrier and into the interstitium. This is the mechanism of capillary leak in many medical conditions, including sepsis, the systemic inflammatory response syndrome, acute pancreatitis, anaphylaxis, snake bites [11,12], and certain infectious syndromes (eg, Dengue hemorrhagic fever, brucellosis [13], hantavirus cardiopulmonary syndrome [14], and Coronavirus-2019 (COVID-19) or COVID-19 vaccination [15,16]). (See "Pathophysiology of sepsis" and "Pathophysiology of anaphylaxis" and "Snakebites worldwide: Clinical manifestations and diagnosis" and "Dengue virus infection: Clinical manifestations and diagnosis".)

The mechanisms of capillary leak are discussed in greater detail elsewhere. (See "Pathophysiology and etiology of edema in adults", section on 'Pathophysiology of edema formation'.)

Hypotheses in ISCLS — Several hypotheses have been proposed to explain ISCLS, although the evidence for any one theory is incomplete.

Monoclonal proteins – Several studies have found that the majority of patients in series and case reports had a monoclonal gammopathy [1,17-20]. One study noted that plasma levels of paraproteins increased during the acute phase of capillary leak and decreased during remission [21]. (See "Laboratory methods for analyzing monoclonal proteins".)

The role of these paraproteins in the pathogenesis of ISCLS has not been determined. Paraproteins are probably not directly responsible for disrupting the vascular endothelial barrier, since studies in which healthy endothelial cells were exposed in vitro to paraproteins from three patients found no detectable cytotoxic effects [18,22]. It is possible that the paraproteins are an epiphenomenon rather than a pathogenic factor.

In the largest report in children, ISCLS does not appear to be associated with a monoclonal gammopathy [10].

Abnormalities in VEGF and angiopoietin 2 – Elevated levels of vascular endothelial growth factor (VEGF) and angiopoietin 2 at baseline, with further elevations during attacks, were noted in a series of 23 patients and in several smaller reports [22-24], although not in others [25,26]. The source of these factors in ISCLS is unknown. They have been proposed to disrupt endothelial cell junctions and cause cell retraction, in the absence of apoptosis [22]. VEGF has been implicated in other disorders, such as sepsis. (See 'Acute pharmacologic treatments and novel therapies' below.)

Endothelial cell apoptosis – Contraction of endothelial cells due to apoptosis (ie, programmed cell death) during attacks of ISCLS has been proposed as a possible mechanism. This hypothesis is supported by histologic changes consistent with endothelial cell apoptosis in muscle biopsies obtained during attacks of ISCLS [27]. In addition, serum taken from patients with ISCLS mediated extensive apoptosis and contraction of endothelial cells in vitro [28].

Involvement of IL-2 – The proposal that endogenous interleukin-2 (IL-2) may contribute to the pathogenesis of ISCLS is based upon the observation that patients who receive high-dose recombinant IL-2 therapy can develop a capillary leakage syndrome [6,29,30]. In addition, increased IL-2 expression was demonstrated on the perivascular blood mononuclear cells of symptomatic patients with ISCLS [31].

Inflammatory mediators – Several inflammatory mediators have been studied in the pathogenesis of ISCLS, including leukotrienes and tumor necrosis factor-alpha (TNF-alpha). In contrast, defects in other factors and pathways capable of altering capillary permeability (eg, complement, kinins, prostaglandin, coagulation, histamine, serotonin) have not been identified [17,27].

Leukotrienes, chemical mediators produced from arachidonic acid metabolism within leukocytes, may increase capillary permeability in patients with ISCLS. One study found that leukocyte platelet suspensions from patients with ISCLS contained abnormalities of in vitro leukotriene production, compared with normal controls [32].

A small series of three patients reported elevations of TNF-alpha during episodes [20]. TNF-alpha is an inflammatory mediator that can increase vascular permeability [33,34]. One patient was treated acutely with a TNF-alpha antagonist, with apparent benefit. (See 'Acute pharmacologic treatments and novel therapies' below.)

CLINICAL MANIFESTATIONS — Attacks of idiopathic systemic capillary leak syndrome (ISCLS) usually demonstrate three phases: a prodromal phase, an extravasation phase, and a recovery phase. The frequency and severity of attacks varies significantly among patients. Some individuals have a single attack in a lifetime, while others have several per year. In one series of 25 patients, patients experienced a median of three acute attacks per year [8].

Prodromal symptoms and triggers — Nearly 50 percent report other prodromal symptoms that precede more serious signs by one to two days [35,36]. Common prodromal symptoms include oligo-anuria, fatigue, edema, syncopal episodes, abdominal pain, nausea, myalgias of the extremities, polydipsia, and a sudden increase in body weight.

Approximately 30 percent of patients report an antecedent upper respiratory tract infection (URI) or a flu-like illness with fever including coronavirus disease 2019 (COVID-19) [15]. Small case series suggested that COVID-19 vaccination may be a trigger for a flare [16,37]. (See "COVID-19: Clinical features" and "COVID-19: Vaccines".)

Sustained physical exertion may also trigger attacks [3,38].

Women may be more prone to attacks during menses [3].

Fluid extravasation phase — Capillary leakage develops over one to four days after the prodromal period. As this occurs, the triad of hypotension, hemoconcentration, and hypoalbuminemia develops. Prior to diagnosis, most patients present at this extravasation stage because any prodromal symptoms do not prompt the patient to seek care [19]:

Hypotension – Intravascular hypovolemia causes hypotension, which is generally defined as a systolic blood pressure <90 mmHg, a mean blood pressure <65 mmHg, or a decrease in systolic blood pressure of more than 40 mmHg from baseline. The hypotension can be severe upon presentation. Hypotension develops in nearly all patients and its major consequence is shock, defined as reduced oxygen delivery to the tissues due to systemic hypoperfusion [19,36]. Although previously underappreciated, myocardial dysfunction is frequent in patients with SCLS and is present in 28 percent of patients who present with severe attacks of ISCLS [39,40].

Hemoconcentration – Severe hemoconcentration is an important diagnostic clue in ISCLS because it distinguishes this disorder from many other causes of shock. In the series of 25 patients, the median hematocrit during attacks was 60.5 percent [8]. Another review reported a mean hematocrit of 64 ± 9 percent and a mean white blood cell count of 30 cells/mm3 [19].

Hypoalbuminemia – Patients with ISCLS had a mean serum albumin of 1.7 ± 0.7 gm/dL in the same review [19].

Other findings that are caused by capillary leakage include generalized edema, ascites, bilateral pleural effusions, pericardial effusions, and cerebral edema and encephalopathy [19,28,36,41-47]. There may also be symptoms and signs related to the hypotension and systemic hypoperfusion. These include cool and vasoconstricted skin, restlessness or obtundation, oliguria or anuria, lactic acidosis, and diminished pulses. Acute right axis deviation may be present on electrocardiogram. The median duration of SCLS episodes is 3.8 days (range, 1 to 27 days) [4].

Recovery (fluid recruitment) phase — The extravasation phase resolves after several days and the recovery phase begins. The transition can occur quickly and is characterized by a decrease in the amount of intravenous fluids that are necessary to maintain an adequate intravascular volume.

During the recovery phase, extravasated fluids are recruited back into the intravascular space. The patient is at high risk for intravascular volume overload and pulmonary edema during this period (even those patients with normal renal function). (See 'Pulmonary edema' below.)

Chronic forms — A small number of reports describe chronic forms of systemic capillary leak syndrome, in which patients present with subacute edema and monoclonal gammopathies [48-50]. In the series of 25 patients mentioned previously, two patients developed what appeared to be a chronic form of the disease, with progressive generalized edema and pleural and pericardial effusions [8].

EVALUATION AND DIAGNOSIS — Hypotension requires immediate intervention to prevent the complications of prolonged hypoperfusion, and the diagnostic evaluation should take place concurrently with initial management. Resuscitative efforts should not be delayed by the diagnostic evaluation. (See 'Stabilization' below.)

Initial assessment — The initial assessment is the same as that for hypotension or shock of uncertain etiology. The first step is to try and determine the type of shock, thereby narrowing the differential diagnosis. There are three types of shock: hypovolemic shock, cardiogenic shock, and distributive shock. (See "Definition, classification, etiology, and pathophysiology of shock in adults", section on 'Classification and etiology'.)

Idiopathic systemic capillary leak syndrome (ISCLS) is a form of distributive and hypovolemic shock. Distributive shock is initially characterized by warm, flushed skin. The jugular venous pressure and central venous pressure (CVP) may be low due to hypovolemia. As capillary leak persists, patients become hemodynamically unstable. Initial considerations in a patient with possible ISCLS include more common causes of shock complicated by a systemic capillary leak (eg, severe sepsis, septic shock, toxic shock syndrome [TSS], anaphylaxis, and certain drug reactions). ISCLS should be considered in the setting of hemoconcentration and the absence of an identifiable cause of shock. In addition, patients with ISCLS are more likely to present with generalized edema, while patients with distributive shock are more likely to develop generalized edema during fluid resuscitation. However, patients with ISCLS can also develop dramatically worsening edema with fluid resuscitation, since a large portion of the intravenous fluids will leak into the interstitial space. The skin frequently becomes cool and clammy during this period as blood is redirected to the core organs. The shock phase lasts 24 to 36 hours [51]. (See 'Differential diagnosis' below.)

Laboratory studies — Initial laboratory studies are the same as those required to evaluate a patient with distributive shock of any cause.

Once ISCLS is suspected and the patient has been stabilized, serum immunoglobulin levels, a serum protein electrophoresis, and serum free light chains should be obtained to evaluate for a monoclonal gammopathy. A monoclonal gammopathy was reported in the majority of patients in at least two series [3,8]. The paraproteins are most often of the immunoglobulin G1 (IgG1) subclass with kappa light chains and are typically identified in the serum, rather than the urine [8,18,52]. (See 'Hypotheses in ISCLS' above and "Laboratory methods for analyzing monoclonal proteins".)

Diagnosis — ISCLS is ultimately a diagnosis of exclusion that is made when a patient presents with one or more episodes of intravascular hypovolemia, generalized edema, and the diagnostic triad (hypotension, hemoconcentration, hypoalbuminemia) in the absence of an identifiable alternative cause. The presence of a monoclonal gammopathy supports the diagnosis, but it is not required.

DIFFERENTIAL DIAGNOSIS — Several disorders may mimic idiopathic systemic capillary leak syndrome (ISCLS), including severe sepsis or septic shock, toxic shock syndrome (TSS), anaphylaxis (as part of systemic mastocytosis or in response to a specific allergen), and certain drug reactions. Hereditary angioedema should also be considered since ISCLS occasionally presents with acute cutaneous edema without hypotension.

Severe sepsis or septic shock – Sepsis is a clinical syndrome characterized by systemic inflammation due to infection. There is a continuum of severity, ranging from sepsis to severe sepsis and septic shock. Normal levels of serum albumin can help distinguish sepsis from ISCLS. Sepsis is described separately. (See "Sepsis syndromes in adults: Epidemiology, definitions, clinical presentation, diagnosis, and prognosis" and "Evaluation and management of suspected sepsis and septic shock in adults".)

Recurrent toxic shock syndrome in women – TSS is a rapidly developing toxin-induced illness that usually affects otherwise healthy individuals (typically young women, but children and men are also susceptible). Patients usually have fever, hypotension, and cutaneous findings. The skin changes are variable, ranging from a sunburn-like rash to erythroderma or a maculopapular eruption. Other manifestations include chills, malaise, headache, sore throat, myalgias, fatigue, vomiting, watery diarrhea, abdominal pain, and orthostatic dizziness or syncope. In menstrual cases, symptoms begin within two to three days of the onset of menstruation, and in postsurgical cases, approximately two days after the procedure. The presence of skin findings, a history of antecedent menstruation, or a recent medical procedure is helpful in distinguishing TSS from ISCLS. TSS can be recurrent [53]. (See "Staphylococcal toxic shock syndrome".)

Anaphylaxis – Anaphylaxis is an acute syndrome resulting from the sudden release of mast cell- and basophil-derived mediators into the circulation, usually due to immunologic reactions to foods, medications, and insect stings. If anaphylaxis is suspected, the patient should be treated with epinephrine and fluid resuscitation, and a serum tryptase level should be drawn as soon as possible. Tryptase is found almost exclusively in mast cells and basophils, and is released into the serum when these cells become activated. Any degree of elevation in serum tryptase suggests anaphylaxis, although a normal level does not exclude the possibility of anaphylaxis. In contrast, tryptase levels in ISCLS should be normal. Patients with anaphylaxis have normal albumin levels as well. (See "Differential diagnosis of anaphylaxis in adults and children" and "Laboratory tests to support the clinical diagnosis of anaphylaxis".)

Anaphylactic attacks of systemic mastocytosis – Systemic mastocytosis is a rare disorder of excessive mast cell accumulation in one or more tissues, most often afflicting adults. Patients present with sudden episodes of symptoms caused by massive release of mast cell mediators. Symptoms include flushing, syncope, vascular collapse, and anaphylaxis. Mastocytosis "attacks" may be precipitated by triggers that nonspecifically activate mast cells, such as exercise, alcohol, emotional stress, aspirin and nonsteroidal antiinflammatory drugs (NSAIDs), morphine, opiates, infections, exposure to iodinated contrast, and medical/surgical procedures. Serum tryptase is constitutively elevated in most patients and is an important diagnostic clue. (See "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis".)

Drug reactions – Certain medications have been reported to induce systemic capillary leak, although the precise mechanism is uncertain. They include recombinant interleukin-2 (IL-2) [6,29,30], granulocyte colony-stimulating factor (G-CSF) [54], interferon alfa [55], gemcitabine [56], sirolimus [57], and acitretin (a systemic retinoid) [58]. (See "Cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted agents, and fluoropyrimidines" and "Differentiation syndrome associated with treatment of acute leukemia" and "Interleukin 2 and experimental immunotherapy approaches for advanced melanoma", section on 'Interleukin 2'.)

Hereditary angioedema – Hereditary angioedema is a rare disorder of C1 inhibitor (C1-INH) deficiency or dysfunction, which typically presents in adolescence with recurrent attacks of cutaneous or gastrointestinal edema. Edema may also affect the upper respiratory tract, leading to life-threatening airway obstruction. The swelling gradually worsens for 12 to 36 hours and then subsides over a few days. Unlike the generalized edema of ISCLS, the cutaneous swelling of hereditary angioedema is localized, usually asymmetric, and most often affects the face, extremities, genitals, or a limited area of the trunk. Patients with gastrointestinal angioedema can become hypotensive if they have repeated vomiting or diarrhea, but they do not have concomitant generalized edema and do not develop cutaneous and intestinal angioedema simultaneously. However, if there is uncertainty, hereditary angioedema can be distinguished by the presence of a low level of complement component 4 (C4) during attacks in nearly all cases. In contrast, C4 should be normal in patients with ISCLS. Hereditary angioedema is reviewed in detail separately. (See "Hereditary angioedema (due to C1 inhibitor deficiency): Pathogenesis and diagnosis" and "Hereditary angioedema: Epidemiology, clinical manifestations, exacerbating factors, and prognosis".)

TREATMENT — The management of idiopathic systemic capillary leak syndrome (ISCLS) is extrapolated from the treatment of septic shock because the clinical presentations are similar and there is little direct evidence from patients with ISCLS [59].

This section summarizes our approach to the management of ISCLS.

Stabilization — The first priority in any patient with ISCLS or shock of unknown etiology is stabilization of his/her airway and breathing. Supplemental oxygen should be supplied to all patients and oxygenation should be monitored continuously with pulse oximetry. Intubation and mechanical ventilation may be required to support an increased work of breathing (caused by compensation for the lactic acidosis that results from hypotension and systemic tissue hypoperfusion) or for airway protection (since encephalopathy can be caused by cerebral edema or hypoperfusion of the brain).

Intubation and mechanical ventilation are described elsewhere. (See "Induction agents for rapid sequence intubation in adults for emergency medicine and critical care" and "Overview of advanced airway management in adults for emergency medicine and critical care" and "Rapid sequence intubation for adults outside the operating room" and "The decision to intubate" and "Approach to the difficult airway in adults for emergency medicine and critical care" and "Overview of initiating invasive mechanical ventilation in adults in the intensive care unit" and "Ventilator management strategies for adults with acute respiratory distress syndrome".)

Management of volume status — Volume status, tissue perfusion, blood pressure, and the presence or absence of pulmonary edema must be assessed before and after each infusion and throughout the illness. In particular, the clinician should be watching carefully for signs that the patient is transitioning from the extravasation to the recovery phases of the episode. Inadequate fluid resuscitation can lead to stroke and other end-organ ischemia [60], while overly aggressive fluid resuscitation can lead to pulmonary edema and compartment syndrome [42,43,61-68].

Assess perfusion — While the airway and breathing are being stabilized, the adequacy of perfusion should be evaluated. The blood pressure needs to be assessed early and often because it is the most common indicator that perfusion is inadequate. However, hypoperfusion can occur even in the absence of hypotension. Common signs of hypovolemia and hypoperfusion include, tachycardia, cool and vasoconstricted skin, restlessness or obtundation, oliguria or anuria, and lactic acidosis. Patients with chronic hypertension may develop critical hypoperfusion at a higher blood pressure than healthy patients (ie, relative hypotension). (See "Evaluation and management of suspected sepsis and septic shock in adults".)

Although not essential, most patients will require a central venous catheter (CVC). A CVC can be used to infuse intravenous fluids, infuse medications, infuse blood products, and draw blood. It can also be used for hemodynamic monitoring. Mean arterial blood pressure, central venous oxyhemoglobin saturation (ScvO2), central venous pressure (CVP), and urine output are frequently used to monitor the response to fluid therapy. (See "Evaluation and management of suspected sepsis and septic shock in adults", section on 'Establish venous access'.)

Insertion of an arterial catheter may be helpful if the blood pressure is labile or restoration of arterial perfusion pressures is expected to be a protracted process, because a sphygmomanometer may be unreliable in hypotensive patients. (See "Intra-arterial catheterization for invasive monitoring: Indications, insertion techniques, and interpretation".)

Restore perfusion — Measures to restore perfusion include sequential infusions of intravenous fluids (preferentially crystalloids) and if needed, vasopressors, red cell transfusions, and inotropic medications.

Intravenous fluids — During the shock phase, the clinician should use a conservative rather than an aggressive fluid resuscitation strategy [59]. In one study, high volume intravenous fluid volume greater than 10.7 L was associated with a poor prognosis, although it is unknown whether this was due to more severe illness or directly fluid-related [69].

Crystalloids (eg, normal saline) are the fluids of choice, as colloids (eg, intravenous albumin, fresh frozen plasma) have not convincingly been shown to be superior in patients with shock. Colloids are alternative intravenous fluids that normally expand the plasma volume by increasing intravascular oncotic pressure. However, they are costly and their effectiveness is probably greatly reduced in patients with ISCLS because proteins with a molecular weight ≤200 kilodaltons (eg, albumin) leak from the intravascular to the interstitial space during the extravasation phase [17]. For this reason, a trial of colloid is most appropriate as a rescue therapy for patients whose perfusion is not restored by crystalloid alone. Hetastarch solutions have been associated with harm in patients with hypovolemic and septic shock and therefore it is reasonable to also avoid their administration in ISCLS.

Other agents — Intravenous vasopressors may be useful in patients who remain hypotensive despite adequate fluid resuscitation or who develop cardiogenic pulmonary edema. There is no definitive evidence of the superiority of one vasopressor over another for ISCLS. We prefer norepinephrine, although dopamine is also a reasonable first choice among vasopressors [59]. Phenylephrine, a pure alpha-adrenergic agonist, may be particularly useful when tachycardia or arrhythmias preclude the use of agents with beta-adrenergic activity. (See "Use of vasopressors and inotropes" and "Evaluation and management of suspected sepsis and septic shock in adults", section on 'Vasopressors'.)

For patients whose perfusion remains inadequate despite intravenous fluids and vasopressors, occasionally red cell transfusions and inotropic therapy targeted at increasing cardiac output may be helpful. This strategy has been studied in septic shock and is discussed separately. (See "Evaluation and management of suspected sepsis and septic shock in adults", section on 'Additional therapies'.)

Reassess perfusion — Patients should continue to have their clinical and laboratory parameters followed during fluid resuscitation and following resolution of hypoperfusion. Mean arterial blood pressure, ScvO2, CVP, and urine output are frequently used to monitor the response to fluid therapy. However, it is unclear if targeting hemodynamic parameters used to treat shock (ie, ScvO2 ≥70 percent), CVP 8 to 12 mmHg, a mean arterial pressure (MAP) ≥65 mmHg, and a urine output ≥0.5 mL/kg per hour] are helpful in treatment of ISCLS. Additional parameters that are frequently monitored include creatinine, platelet count, lactate, Glasgow coma score, oxygenation (ie, arterial oxygen tension or oxyhemoglobin saturation), and ventilation (ie, arterial carbon dioxide tension and pH).

Although the lactate level often remains elevated despite restoration of perfusion, a rising level is suggestive of recurrent hypoperfusion. Evidence of recurrent hypoperfusion should prompt a renewed effort to restore perfusion as described above.

Detecting the start of recovery — The transition from the extravasation phase to the recovery phase can be recognized by a decrease in the volume of intravenous fluid that is required to maintain adequate perfusion. When this occurs, the clinician's focus must shift from the treatment of intravascular hypovolemia to the prevention of intravascular volume overload and its complications. Nearly all patients require diuretics (we prefer loop diuretics) during the recovery phase to avoid intravascular volume overload. Patients with renal insufficiency may require ultrafiltration. (See 'Complications of acute episodes' below.)

Acute pharmacologic treatments and novel therapies — There are no established acute pharmacologic therapies for ISCLS, although case reports describe several treatment modalities that have been given to small numbers of patients.

A series of three patients described successful acute treatment with high doses of intravenous immune globulin (IVIG) [70]. These patients also received IVIG monthly for prophylaxis. However, in a retrospective study of 59 attacks occurring in 37 patients, the majority of whom had monoclonal immunoglobulin G gammopathy, IVIG was not associated with improved survival [69]. (See 'Other treatments' below.)

A case report found that the combination of terbutaline and intravenous aminophylline (with a serum target theophylline level of 15 to 25 mcg/dL) appeared to be beneficial in one of two patients, and administration of infliximab seemed to help another patient refractory to terbutaline and aminophylline [20]. All three patients had received terbutaline and theophylline prophylactically. However, since tumor necrosis factor-alpha (TNF-alpha) antagonists such as infliximab have been shown to be harmful in some patients with sepsis, this latter experimental approach should only be considered if sepsis is believed to be unlikely. (See 'Prevention of future episodes' below and "Investigational and ineffective therapies for sepsis", section on 'Augmentation of immunomodulation'.)

A case report from Japan described the use of anti-vascular endothelial growth factor (VEGF) antibody (bevacizumab, Chugai, Tokyo) to treat the acute phase of life-threatening ISCLS [26]. Despite low plasma VEGF levels, the authors administered intravenous bevacizumab (5 mg per kg of body weight) over a 90-minute period. They reported that urine output improved and blood pressure and CVP returned to the normal range within 48 hours. Adverse effects of this agent are reviewed separately. (See "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects", section on 'Bevacizumab and aflibercept' and "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects", section on 'Bevacizumab'.)

A case report form Argentina describes the use of extracorporeal membrane oxygenation (ECMO) for eight days to achieve hemodynamic stability during the acute phase of capillary leak [71].

COMPLICATIONS OF ACUTE EPISODES — The most common complications of acute idiopathic systemic capillary leak syndrome (ISCLS) are, compartment syndrome, pulmonary edema, and end-organ damage leading to multi-organ failure. Other complications include arrhythmia, pericardial effusion, myocardial edema, pancreatitis, and deep venous thrombosis [3].

Pulmonary edema — One of the most common complications of the aggressive fluid resuscitation required during the extravasation phase is subsequent pulmonary edema, which can develop rapidly once the patient enters the recovery phase. In one series, 10 of 25 patients developed pulmonary edema during treatment [8]. (See "Noncardiogenic pulmonary edema", section on 'Treatment'.)

Compartment syndrome — Compartment syndrome is a serious complication of ISCLS that is frequently reported during both the extravasation and recovery phases [42,43,61-68]. It is caused by the leakage of fluid into the muscular compartment, which increases the pressure inside that compartment. Fluid resuscitation may exacerbate the problem.

The muscle compartments should be carefully monitored throughout intravascular resuscitation for signs of compartment syndrome. Early symptoms of acute compartment syndrome include progressive pain out of proportion to the injury. Signs include tense swollen compartments and pain with passive stretching of muscles within the affected compartment. Symptoms and signs may progress over a few hours.

The tissue pressure needs to be measured if clinical signs of compartment syndrome develop. Immediate surgical consultation should be obtained whenever acute compartment syndrome is suspected, and fasciotomy is indicated when tissue pressures are within 10 to 30 mmHg of the diastolic pressure [72]. Compartment syndrome can lead to rhabdomyolysis, with moderate to severe elevations of creatine phosphokinase (CPK) [63,64]. Renal insufficiency or failure sometimes follows.

Alkalinization of the urine and diuretics may be required if the patient develops rhabdomyolysis. In the series of 25 patients, the development of rhabdomyolysis correlated to the degree to which albumin declined during an attack [8]. Compartment syndrome and rhabdomyolysis are discussed in detail elsewhere. (See "Acute compartment syndrome of the extremities" and "Rhabdomyolysis: Clinical manifestations and diagnosis".)

End-organ ischemia — Another complication of ISCLS is ischemic end-organ damage due to prolonged hypoperfusion. The most common injuries related to prolonged hypoperfusion include acute kidney injury (ie, acute tubular necrosis), ischemic brain injury, and/or ischemic hepatitis. Each of these entities is discussed in more detail separately. (See "Etiology and diagnosis of prerenal disease and acute tubular necrosis in acute kidney injury in adults" and "Hypoxic-ischemic brain injury in adults: Evaluation and prognosis" and "Ischemic hepatitis, hepatic infarction, and ischemic cholangiopathy".)

A single case report describes splenic and gastrointestinal ulcerations, and dysarthria as acute complications of ISCLS [73].

PREVENTION OF FUTURE EPISODES — Patients who have survived idiopathic systemic capillary leak syndrome (ISCLS) should be counseled to seek medical care quickly if they recognize prodromal symptoms in the future. Prophylactic therapy to prevent future attacks appears to be beneficial based upon case series. Agents used in practice include intravenous immune globulin (IVIG), terbutaline, and theophylline. Early administration of monthly IVIG is highly successful in preventing acute systemic capillary leak syndrome flares [74]. Anecdotally, the combination of terbutaline and theophylline may also be effective. There are no data to support the combined use of IVIG and terbutaline/theophylline.

Intravenous immune globulin — In the last decade, multiple case reports have described apparently successful use of monthly infusions of IVIG to reduce the frequency of attacks in some patients [3,70,75-78].

In a series of 28 patients followed for a median of 55 months (range 1 to 161 months), all five of the patients who did not receive prophylactic IVIG therapy died, compared with only 3 out of the 23 patients who received prophylactic IVIG therapy [3]. Eight of the patients receiving IVIG had no new attacks over multiple years of follow-up. Doses ranged from 0.4 grams to 2 grams per kg per month.

In a case-series of 69 patients with monoclonal gammopathy-associated systemic capillary leak syndrome (Clarkson disease) in whom several preventative agents were used, prophylactic treatment with IVIG (48 patients) was an independent predictor of survival (hazard ratio 0.27, 95% CI 0.1 to 0.7 and 0.35 95% CI 0.13 to 0.96, respectively) [78]. Five- and 10-year survival rates in patients treated with IVIG were 91 and 77 percent, respectively, compared with 47 and 37 in patients not treated with IVIG. In addition, compared with no IVIG treatment, IVIG reduced the rate of recurrence and severity of attacks and severity of attacks.

However, a few case reports have described treatment failures [20,79].

The dose used in most case reports has been 2 grams per kg intravenously per month and we would suggest using this dose, although 1 gram per kg per month was noted to be effective in another report [3,76].

Terbutaline and theophylline — A second approach to prevention is administration of the combination of terbutaline plus theophylline. A variety of doses have been reported. A reasonable regimen is sustained release theophylline (dosed to achieve a serum concentration of 10 to 20 mcg/mL) and terbutaline (5 mg four times daily).

The theory that terbutaline plus theophylline may prevent ISCLS is based on the observations that both agents increase intracellular cyclic adenosine monophosphate (cAMP) content [28] and that elevated cAMP inhibits capillary leak [80-84]. Terbutaline increases cAMP by facilitating its production of cAMP, while theophylline blocks its degradation.

Much of the data supporting the use of terbutaline and theophylline was published prior to the widespread availability of IVIG. The most compelling evidence for treatment with these agents was a retrospective series that evaluated the clinical course of eight patients with ISCLS who were followed for 18 years [43]. All of the patients were treated with oral terbutaline (dose not specified) and theophylline (serum target level 10 to 20 micrograms/L). The patients had a median of six severe attacks per year prior to being diagnosed with ISCLS. In contrast, the median attack rate was reduced to 0.2 attacks per year after receiving the combination of terbutaline and theophylline. Many of the episodes that occurred while receiving therapy were mild enough that hospitalization was not required [43]. The one patient who continued to have severe attacks, and eventually died of shock, never achieved a therapeutic level of theophylline. Breakthrough attacks seemed to correlate to subtherapeutic levels of theophylline in two other patients. Sustained release theophylline appeared to be the most effective formulation. Adverse effects from sympathomimetic stimulation were frequent with therapy, but improved with minor dose adjustments and time. A few patients received glucocorticoids intermittently.

There are additional reports that support the use of terbutaline and theophylline to prevent ISCLS [19,20,23,65,68,85,86]. According to one review, theophylline and terbutaline alone or in combination seemed to be effective in 17 out of 50 cases [19]. Another study of 69 patients reported that terbutaline was associated with a reduced risk of death (hazard ratio 0.35 95% CI 0.13 to 0.96) [78]; however, compared with patients not on terbutaline, those receiving terbutaline had more frequent recurrence and more severe attacks.

Dosing of terbutaline varied among the available reports, but a dose of 5 mg four times daily is at the lower end of the reported range [35]. Some patients require higher serum levels of theophylline to avoid attacks [20].

Reports that terbutaline and theophylline prevent ISCLS have not been universal. In a series of 13 patients with ISCLS who were followed for a mean period of 6.4 years, aminophylline and terbutaline did not appear to be beneficial [35]. However, serum theophylline levels were not used to guide therapy and treatment was usually discontinued if patients had recurrent attacks, potentially accounting for some of the differences in outcome.

Other treatments — Other therapies that have been administered to patients with ISCLS with variable success include glucocorticoids, spironolactone, indomethacin, leukotriene-modifying agents, verapamil, cyclosporine, thalidomide, and Ginkgo biloba [8,19].

PROGNOSIS — The fatality rate during acute attacks of idiopathic systemic capillary leak syndrome (ISCLS) is not well defined. Early case reports often described fatalities, although better supportive care and more widespread recognition of the disorder have probably reduced mortality. Patients who die during attacks tend to die either of flash pulmonary edema during the recovery phase, or of ischemic organ failure due to hypoperfusion during the extravasation phase [23].

In a review of 50 cases of ISCLS, 70 percent of the patients who survived initial attacks were alive a mean of five years after diagnosis [19]. The estimated five-year survival in the series of 25 patients mentioned previously was 76 percent [8]. In the series of 28 patients described above, five-year survival was 73 percent [3]. However, survival may be improved when immune globulin is used. For example, in a large series of 133 cases, the 1-, 5-, and 10-year survival rate when patients were treated with immune globulin was 100 percent, 94 percent, and 94 percent [36]. Some patients with monoclonal gammopathies will eventually develop multiple myeloma [8,35,44,50]. However, in one group of 25 patients followed for variable numbers of years, none progressed [23]. One group has suggested that the prognosis in children is better than that in adults [8].

SUMMARY AND RECOMMENDATIONS — Idiopathic systemic capillary leak syndrome (ISCLS) is a rare disorder that typically begins in midlife. It is characterized by episodes of severe hypotension, hypoalbuminemia, and hemoconcentration. (See 'Introduction' above and 'Epidemiology' above.)

Episodes of ISCLS usually begin with prodromal symptoms, followed by hypotension and edema. The hypotension and edema are due to fluid extravasation, which typically worsens over one to four days and may be complicated by a compartment syndrome. The capillary leakage then abruptly reverses and the fluid moves back into the vasculature. During the recovery phase, the patient is at risk for volume overload and pulmonary edema. (See 'Clinical manifestations' above.)

The diagnostic evaluation is the same as that for hypotension or shock of uncertain etiology. ISCLS is a diagnosis of exclusion that is made when a patient manifests intravascular hypovolemia, generalized edema, and the triad of hypotension, hemoconcentration, and hypoalbuminemia in the absence of an identifiable alternative cause. The diagnostic evaluation generally occurs concurrently with initial management. (See 'Evaluation and diagnosis' above.)

Initial management of ISCLS is aimed at securing the airway and correcting hypoxemia. This may require intubation and mechanical ventilation. While the patient's respiratory status is being stabilized, the adequacy of perfusion should be assessed. Patients with hypoperfusion should have their tissue perfusion restored using a strategy of conservative fluid administration and intravenous vasopressors, if indicated.

After initial resuscitation and stabilization, treatment should then shift toward the prevention of intravascular volume overload and its complications (eg, compartment syndrome or pulmonary edema). Meticulous monitoring of the patient's fluid status is critical. Once the recovery phase has begun, nearly all patients require diuretics. Patients with renal insufficiency may require ultrafiltration. (See 'Detecting the start of recovery' above.)

Therapy to prevent future episodes of ISCLS should be administered to all patients who have been diagnosed with ISCLS. We suggest monthly infusions of intravenous immune globulin (IVIG) (Grade 2C). Most reports have used a dose of 2 grams per month. (See 'Intravenous immune globulin' above.)

For patients who do not tolerate or do not appear to improve with IVIG, we suggest the combination of theophylline and terbutaline (Grade 2C). A reasonable regimen is sustained release theophylline (dosed to achieve a serum concentration of 10 to 20 mcg/mL) and terbutaline (5 mg four times daily). (See 'Terbutaline and theophylline' above.)

Among patients who survive an initial attack, at least 70 percent are alive five years after diagnosis. Some patients with monoclonal gammopathies develop multiple myeloma over time. (See 'Prognosis' above.)

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