Idiopathic Systemic Capillary Leak Syndrome Research Articles

Hypersensitive blood vessels in Clarkson disease.

Idiopathic systemic capillary leak syndrome (ISCLS) is a rare, recurrent condition with dramatically increased blood vessel permeability and, therefore, induction of systemic edema, which may lead to organ damage and death. In this issue of the JCI, Ablooglu et al. showed that ISCLS vessels were hypersensitive to agents known to increase vascular permeability, using human biopsies, cell culture, and mouse models. Several endothelium-specific proteins that regulate endothelial junctions were dysregulated and thereby compromised the vascular barrier. These findings suggest that endothelium-intrinsic dysregulation underlies hyperpermeability and implicate the cytoplasmic serine/threonine protein phosphatase 2A (PP2A) as a potential drug target for the treatment of ISCLS.

Intrinsic endothelial hyperresponsiveness to inflammatory mediators drives acute episodes in models of Clarkson disease.

Clarkson disease, or monoclonal gammopathy-associated idiopathic systemic capillary leak syndrome (ISCLS), is a rare, relapsing-remitting disorder featuring the abrupt extravasation of fluids and proteins into peripheral tissues, which in turn leads to hypotensive shock, severe hemoconcentration, and hypoalbuminemia. The specific leakage factor(s) and pathways in ISCLS are unknown, and there is no effective treatment for acute flares. Here, we characterize an autonomous vascular endothelial defect in ISCLS that was recapitulated in patient-derived endothelial cells (ECs) in culture and in a mouse model of disease. ISCLS-derived ECs were functionally hyperresponsive to permeability-inducing factors like VEGF and histamine, in part due to increased endothelial nitric oxide synthase (eNOS) activity. eNOS blockade by administration of N(γ)-nitro-l-arginine methyl ester (l-NAME) ameliorated vascular leakage in an SJL/J mouse model of ISCLS induced by histamine or VEGF challenge. eNOS mislocalization and decreased protein phosphatase 2A (PP2A) expression may contribute to eNOS hyperactivation in ISCLS-derived ECs. Our findings provide mechanistic insights into microvascular barrier dysfunction in ISCLS and highlight a potential therapeutic approach.

Unlocking endothelial barrier restoration: FX06 in systemic capillary leak syndrome and beyond

Increased vascular permeability is a prevalent feature in a wide spectrum of clinical conditions, but no effective treatments to restore the endothelial barrier are available. Idiopathic systemic capillary leak syndrome (ISCLS) is a life-threatening Paroxysmal Permeability Disorder characterized by abrupt, massive plasma extravasation. This condition serves as a robust model for investigating therapeutic approaches targeting interendothelial junctions. We conducted a single-center, interventional in vitro study at the Referral Center for ISCLS in Italy, involving four diagnosed ISCLS patients, aiming at investigating the effects of FX06, a Bβ15–42 fibrin-derived peptide binding to VE-Cadherin, on endothelial barrier exposed to intercritical and acute ISCLS sera. The Transwell Permeability Assay was used to assess the permeability of human umbilical vein endothelial cells (HUVECs) exposed to ISCLS sera with or without FX06 (50 µg/ml). Acute ISCLS serum was also tested in a three-dimensional microfluidic device. Nitric oxide (NO), VE-Cadherin localization, and cytoskeletal organization were also assessed. In two and three-dimensional systems, ISCLS sera increased endothelial permeability, with a more pronounced effect for acute sera. Furthermore, acute sera altered VE-Cadherin localization and cytoskeletal organization. NO levels remained unchanged. FX06 restored the endothelial barrier function by influencing cellular localization rather than VE-Cadherin levels. In conclusion, FX06 prevents and reverts the hyperpermeability induced by ISCLS sera. These preliminary yet promising results provide initial evidence of the in vitro efficacy of a drug targeting the underlying pathophysiological mechanisms of ISCLS. Moreover, this approach may hold potential for addressing hyperpermeability in a spectrum of clinical conditions beyond ISCLS.

A ligand-independent Tie2-activating antibody reduces vascular leakage in models of Clarkson disease.

Vascular dysfunction resulting from endothelial hyperpermeability is a common and important feature of critical illness due to sepsis, trauma, and other conditions associated with acute systemic inflammation. Clarkson disease [monoclonal gammopathy-associated idiopathic systemic capillary leak syndrome (ISCLS)] is a rare, orphan disorder marked by spontaneous and recurrent episodes of hypotensive shock and peripheral edema due to widespread vascular leakage in peripheral tissues. Mortality from acute flares approaches 30% due to lack of effective therapies. We evaluated a monoclonal antibody (4E2) specific for the endothelial receptor tyrosine kinase Tie2 in ISCLS models. 4E2 activated Tie2 in ISCLS patient-derived endothelial cells and reduced baseline and proinflammatory mediator-induced barrier dysfunction. 4E2 also reduced mortality and/or vascular leakage associated with systemic histamine challenge or influenza infection in the SJL/J mouse model of ISCLS. These findings support a critical role for Tie2 dysregulation in ISCLS and highlight a viable therapeutic approach to this catastrophic disorder.

Identification of a heterozygous pathogenic variant in IRAK4 in an adult patient with pneumococcal sepsis, monoclonal gammopathy of uncertain significance, and idiopathic systemic capillary leak syndrome.

Identification of a heterozygous pathogenic variant in IRAK4 in an adult patient with pneumococcal sepsis, monoclonal gammopathy of uncertain significance, and idiopathic systemic capillary leak syndrome.

Exacerbations of Idiopathic Systemic Capillary Leak Syndrome following BNT162b2 mRNA COVID-19 Vaccine (Pfizer-BioNTech).

A Japanese man experienced three episodes of hypovolemic shock and was diagnosed with systemic capillary leak syndrome (SCLS). He developed SCLS exacerbation 2 days after receiving a second dose of the Pfizer-BioNTech BNT162b2 mRNA COVID-19 vaccine, 1 year after the third episode. After fluid therapy and albumin administration, we initiated terbutaline and theophylline prophylaxis for SCLS. A literature review revealed that SCLS attacks often occur 1-2 days after the second COVID-19 vaccination. Patients with a history of SCLS should avoid COVID-19 vaccination and be carefully monitored for 1-2 days if they receive the vaccine.

Idiopathic systemic capillary leak syndrome: a case report

BackgroundIdiopathic systemic capillary leak syndrome (ISCLS) is a rare disease characterized by recurrent episodes of acute life-threatening attacks of shock, hemoconcentration, and hypoalbuminemia. Increase in capillary permeability results in reversible plasma movement into the interstitial spaces followed by appearance of related symptoms or complications, including renal failure. This condition can be potentially life-threatening; however, it is easily misdiagnosed.Case presentationA 47-year-old man with no previous medical history presented to the emergency department after experiencing general weakness and abdominal pain. He developed hypovolemic shock within 3 h of presentation and initial laboratory tests showed hemoconcentration, hypoalbuminemia and acute kidney injury. Following vigorous fluid therapy and supportive care, the patient recovered, but a similar episode recurred after 4 months without any specific trigger. Based on the combined clinical manifestations and laboratory findings of both the attacks, he was diagnosed with ISCLS. Symptomatic relief was achieved via oxygen supplementation and massive volume replacement using normal saline and the patient was prescribed bambuterol 10 mg and theophylline 400 mg once-a-day. He was discharged from the hospital on day 5 of hospitalization. Thereafter, the patient has been followed for 5 years without any symptoms or recurrence of ISCLS even in the situation of COVID-19 infection.ConclusionsISCLS is an extremely infrequent and commonly misdiagnosed disease. However, early diagnosis, treatment and prophylaxis through accumulated clinical data can prevent ISCLS recurrence and the development of related fatal complications. Therefore, clinicians need to be well aware of the variety of clinical characteristics and treatment options of this disease.

Cardiac Tamponade in Idiopathic Capillary Leak Syndrome: Philippines’ First

Background: Clarkson’s disease, more known as idiopathic systemic capillary leak syndrome (SCLS) is a rare condition characterized by hypotensive episodes due to capillary hyperpermeability, which may be manifested by fluid accumulation in any organ or potential space, causing range of complications: respiratory failure (from pulmonary edema or pleural effusion), mesenteric hypoperfusion (from hepatic congestion and severe intestinal edema), compartment syndrome and rhabdomyolysis, and even shock from hypovolemia or cardiac tamponade. Very few cases of cardiac tamponade have been reported and certainly a serious and life-threatening complication. Case Summary: A 44-year-old female, reported to have intermittent episodes of angioedema aggravated by menstruation and infection, came in due to persistent hypotension. Patient presented with flu-like symptoms and tested positive for COVID – 19 infection. Initial laboratories revealed hemoconcentration, slightly elevated creatinine and hypoalbuminemia. Electrolytes and urinalysis were normal. 2D echocardiography showed large pericardial effusion with right atrial and ventricular collapse suggestive of cardiac tamponade, hence patient underwent emergency pericardial windowing. Initial chest X-ray was normal but repeat study showed pleural effusion on the 4th day of admission which was drained surgically. Additional diagnostic tests revealed negative for hepatitis, Mycoplasmal and Epstein-Barr virus. Direct and indirect Coomb’s test were also negative and Lupus panel was unremarkable. Serum free light chain panel showed suspicious for low level monotypic serum free lambda light chains (based only on the free light ratio). Immunopathology results showed no overt evidence of monoclonal bands. Protein electrophoresis pattern showed decreased albumin fraction and increased alpha, beta, and gamma fractions. C1 inhibitor was slightly elevated while serum tryptase was within normal values. Patient was managed as a case of idiopathic systemic capillary leak syndrome or Clarkson’s disease. Aside from judicious fluid resuscitation and vasopressors assist Methylprednisolone pulse therapy (MPPT) and intravenous immunoglobulin (IVIg) were administered. Patient was discharged with tapering doses of oral steroids and scheduled monthly IV immunoglobulin infusion. Conclusion: Cardiac tamponade, an uncommon yet severe and life-threatening complication of systemic capillary leak syndrome (SCLS) or Clarkson’s disease, requires immediate intervention. While the exact cause remains unclear, research suggests that during acute SCLS episodes and hyperinflammatory states, fluid accumulation in the pericardial space can impede ventricular filling, leading to hemodynamic compromise.

Abstract 10594: Cardiac Tamponade in a Covid-19 Positive Patient With Idiopathic Capillary Leak Syndrome: A Perilous Combination

Introduction: Clarkson’s disease, more known as idiopathic systemic capillary leak syndrome (SCLS) is a rare condition characterized by hypotensive episodes due to capillary hyperpermeability and can manifest as fluid accumulation in any organ or potential space. This may cause a range of complications: respiratory failure (from pulmonary edema or pleural effusion), mesenteric hypoperfusion (from hepatic congestion and severe intestinal edema), compartment syndrome and rhabdomyolysis, and even shock from hypovolemia or cardiac tamponade. Very few cases of cardiac tamponade in Clarkson's disease and COVID-19 have been reported, and when present, is certainly a serious and life-threatening complication. Case Summary: A 44-year-old female - with prior episodes of angioedema, pleural and pericardial effusions aggravated by menstruation and infection - presented with hypotension and diaphoresis. She was exposed to a COVID patient and eventually tested positive for COVID-19 infection. Persistent hypotension warranted triple inotropic support. Initial laboratories revealed hemoconcentration and hypoalbuminemia. Urinalysis was normal. 2D echocardiography showed normal left ventricular ejection fraction but with large pericardial effusion and signs of cardiac tamponade, hence, she underwent emergency pericardial windowing. She then developed pleural effusion which was drained surgically. Hepatitis, mycoplasmal and Epstein-Barr virus were negative. Direct and indirect Coomb’s test, and Lupus panel were unremarkable. Serum free light chain panel, immunopathology and C1 inhibitor results were non-diagnostic. Patient was managed as a case of idiopathic SCLS or Clarkson's disease. Methylprednisolone pulse therapy (MPPT) and intravenous immunoglobulin (IVIg) were administered. Patient was discharged with tapering doses of oral steroids and scheduled monthly IVIg infusion. Conclusions: Cardiac tamponade is a very rare but life-threatening complication of Clarkson’s disease, and on top of a COVID-19 infection, warrants emergent intervention. The pathogenesis is not yet fully elucidated. Diagnosis of SCLS is challenging thus recurrent pericardial and pleural effusions should raise the clinician’s index of suspicion.

Autologous hematopoietic stem cell transplantation in Clarkson disease

Idiopathic systemic capillary leak syndrome (ISCLS) flares are frequently preceded by infections, particularly respiratory virus infections including coronavirus disease 2019.1,2 Hemodynamic collapse occurs at the onset of episodes, typically followed by massive peripheral edema resulting from intravenous (IV) fluid administration. Flares may be complicated by multiorgan dysfunction syndrome, vascular thrombosis due to hemoconcentration, and compartment syndrome.1 Indefinite monthly prophylaxis with high-dose intravenous immunoglobulins (IVIGs) induces disease remission but is expensive and inconvenient to administer.

Diagnostic and therapeutic considerations in idiopathic systemic capillary leak syndrome: a case report

Diagnostic and therapeutic considerations in idiopathic systemic capillary leak syndrome: a case report

Markers of endothelial glycocalyx dysfunction in Clarkson disease

BackgroundClarkson disease (monoclonal gammopathy-associated idiopathic systemic capillary leak syndrome, ISCLS) is a rare idiopathic condition marked by transient, relapsing-remitting episodes of systemic microvascular hyper-permeability, which liberates plasma fluid and macromolecules into the peripheral tissues. This pathology manifests clinically as the abrupt onset of hypotensive shock, hemoconcentration, and hypoalbuminemia.MethodsWe analysed endothelial glycocalyx (eGCX)-related markers in plasma from patients with ISCLS during acute disease flares and convalescence by ELISA and comprehensive proteomic profiling. We evaluated eGCX-related components and gene expression in cultured endothelial cells using RNA-sequencing, real-time PCR, and fluorescence staining.ResultsSerum levels of eGCX-related core components including hyaluronic acid (HA) and the core proteoglycan soluble syndecan-1 (sCD138) were elevated at baseline and during acute ISCLS flares. Serial measurements demonstrated that sCD138 levels peaked during the recovery (post-leak) phase of the illness. Proteomic analysis of matched acute and convalescent ISCLS plasma revealed increased abundance of eGCX-related proteins, including glypicans, thrombospondin-1 (TSP-1), and eGCX-degrading enzymes in acute compared to remission plasma. Abundance of endothelial cell damage markers did not differ in acute and baseline plasma. Expression of several eGCX-related genes and surface carbohydrate content in endothelial cells from patients with ISCLS did not differ significantly from that observed in healthy control cells.ConclusionseGCX dysfunction, but not endothelial injury, may contribute to clinical symptoms of acute ISCLS.Serum levels of of eGCX components including sCD138 may be measured during acute episodes of ISCLS to monitor clinical status and therapeutic responses.

Idiopathic systemic capillary leak syndrome, a unique complement and interferon mediated endotheliopathy syndrome: The role of the normal skin biopsy in establishing the diagnosis and elucidating pathogenetic mechanisms

Idiopathic Systemic Capillary Leak Syndrome (ISCLS), also known as Clarkson's Syndrome, is due to primary fluid and protein leak across capillaries that leads to an accumulation of interstitial fluids and cardiovascular collapse from intravascular hypovolemia. Viral infections are a putative trigger of these episodes. ISCLS is typically associated with a monoclonal gammopathy. Here we present four patients with idiopathic systemic capillary leak syndrome. The cohort consists of three men and one woman who range in age from 55 to 72 years old. All of the patients had a monoclonal gammopathy. Two patients had viral triggers. Biopsies of normal skin were examined throughout all phases of the disease. During an acute attack, we identified perivascular mixed CD4+ and CD8+ T cell lymphocytic infiltrates in the superficial dermis. We observed significant microvascular deposits of C5b-9 and upregulation of type I interferon signaling in endothelium along with reduced serum levels of complement during very active disease. We also identified deposits of immunoglobulin along the dermal epidermal junction mirroring the monoclonal immunoglobulin isotype implicated in each patient. During a post treatment recovery or mild disease phase there was reduced inflammation and decreased amounts of C5b-9 and type I interferon expression. Sudden onset capillary leak syndrome reflects enhanced endothelial cell permeability as a unique form of endothelial injury mediated by the combined effects of complement pathway activation and upregulation of type I interferon signaling on endothelium.

Management of Acute Episodes of Clarkson Disease (Monoclonal Gammopathy-Associated Systemic Capillary Leak Syndrome) With Intravenous Immunoglobulins.

Monoclonal gammopathy-associated idiopathic systemic capillary leak syndrome (ISCLS, Clarkson disease) is a rare disorder defined by transient but recurrent bouts of hypotensive shock and anasarca resulting from plasma extravasation. Although prophylactic treatment with high-dose intravenous immunoglobulins (IVIG, 1–2 g/kg/mo) prevents most disease flares, its utility for acute episodes of ISCLS is unclear. Here, we report the results of a retrospective study of subjects with acute ISCLS treated at or near the onset of symptoms with IVIG. We found that administration of IVIG with minimal additional intravenous fluids was safe and associated with rapid clinical improvement. IVIG given close to the onset of ISCLS-related symptoms is associated with a favorable outcome.

HP41: Idiopathic systemic capillary leak syndrome with severe peripheral nervous system involvement. Case report

Idiopathic systemic capillary leak syndrome (ISCLS) a rare condition characterised by repeated relapses of leaking of plasma from blood vessels into body cavities and muscles. In one third of cases the disease is associated with variable severity peripheral nervous system damage. 26 years old male was admitted to hospital after repeated fainting with complains about progressive pain and numbness in lower limbs. In the hospital symptoms were rapidly progressing and patient developed asymmetrical painful tetraparesis (muscle strength in legs 0-1, muscle strength in arms 4). Systemic manifestations included hypotension, tachycardia, hemoconcentration, hypoalbuminemia, cardiac tamponade, crush syndrome. On 5th day from symptom onset treatment with intravenous immunoglobulin (IvIg) was started. After first IVIG treatment course systemic symptoms had resolved. Patient continued to receive IvIg monthly as a prophylactic treatment. After two courses of IvIg pain ceased, muscle strength improved (arm muscles 5, leg muscles 4). Patient died 20 months after symptom onset due to repeated systemic relapses. Electrodiagnostic study (EMG/NCS) was performed 3 times (on 3rd day from symptom onset, after first and second IvIg course). First EMG/NCS showed severe axonal motor and sensory neuropathy in legs, mild motor axonal damage in arms with massive spontaneous activity in all examined muscles. After repeated IvIg courses NCS in arms become normal, in legs tibial and peroneal MUAP remained absent, sural SNAP became normal; EMG showed slight evidence of reinnervation process without signs of active denervation. Conclusion. ISCLS can be considered in patients with rapidly progressive axonal polyradiculoneuritis with autonomic signs.

Autonomic biomarkers of shock in idiopathic systemic capillary leak syndrome.

ObjectiveThe term Idiopathic Systemic Capillary Leak Syndrome (ISCLS) refers to an uncommon condition of severe distributive shock, resulting from an abrupt shift of fluids and proteins from the intravascular to the interstitial compartment. We hypothesise that the autonomic nervous system (ANS) fails in regulating the response to hypovolemia in acute ISCLS and that ANS variables characterise the progression to the recovery.DesignProspective cohort study of patients admitted to ICU for severe ISCLS flares.SettingSingle, referral center in Italy for ISCLS.PatientsAnalysis of cardiovascular signals recorded during seven severe ISCLS attacks and one prodromal period in five patients.InterventionsANS was studied non-invasively by means of heart rate variability (HRV) and blood pressure variability analysis, as an estimation of vagal and sympathetic modulation directed to the heart and vessels. Heart rate and systolic arterial pressure (SAP) variability were also used to assess baroreflex sensitivity. ANS variables were measured during the subsequent phases which characterise ISCLS flares, namely the acute phase, the post-acute phase, and the recovery phase.Measurements and main resultsHRV was severely depressed during the acute phase accounting for the loss of ANS modulation during massive capillary extravasation. This phase was characterised by shock and impaired baroreflex control, which allowed SAP to oscillate driven by respiratory activity. Impending shock and transition from shock to a post-acute phase were marked by change of baroreflex spectral variables. The baroreflex control was fully restored during recovery.ConclusionsANS modulation and baroreflex control are severely impaired during the acute haemodynamic instability which characterises ISCLS crises and their progressive restoration may be a clue of improvement. ANS indices during ISCLS flares might serve as useful biomarkers, able to timely announce the transition from one phase to the subsequent one, thus helping to adapt therapy accordingly.

Idiopathic systemic capillary leak syndrome (Clarkson’s disease) presenting with recurrent hypovolemic shock

A 49-year old male with a past medical history of myocardial infarction and compartment syndromes requiring fasciotomies presented on five occasions with hypovolemic shock. We describe his admissions and presumptive diagnoses which required large volumes of intravenous fluids, admission to intensive care for vasopressors and renal replacement therapy. The presentations were always precipitated by a prodrome of fatigue and pre-syncopal episodes. On his last admission, a diagnosis of Idiopathic systemic capillary leak syndrome (ISCLS), also known as Clarkson’s Disease, was reached. He is currently receiving high dose intravenous immunoglobulins on a monthly basis.

Idiopathic systemic capillary leak syndrome - An often missed diagnosis.

Idiopathic systemic capillary leak syndrome (ISCLS) is a potentially fatal disorder characterised by 'attacks' of varying intensity of hypovolemic shock in association with haemoconcentration and hypoalbuminaemia. It is a disease of exclusion, and the severity of attacks may mimic sepsis at presentation. We report a case of a lady with recurrent attacks of ISCLS with at least two life-threatening episodes, having been treated elsewhere as a case of steroid insufficiency. The diagnosis is often challenging, and treatment of an acute episode involves the judicious use of fluids and vasopressors, as required. Prophylaxis to prevent further attacks is of varied success.

Genesis of Antibiotic Resistance LIII: “Virchow’s Triad” of Capillary (Vascular) Leak Syndrome (CLS) tethered Adverse Pressure Gradient exacerbated mortality rate in NCT01663701: A critical appraisal

Based on adverse effects of biosimilar(s), for oncological treatment modalities (radiation/chemotherapy), posted in FAERS and VigiBase, an effort has been made to derive a temporal correlation between CLS and hemodynamic (Fluid dynamic/mechanics properties) dysregulation lead exacerbated mortality rate in NCT01663701. Idiopathic (unknown etiology) systemic capillary leak syndrome (SCLS) or Capillary leak syndrome (CLS), also known as vascular leak syndrome (VLS), with clinical features such as leakage of the plasma (reversible plasma extravasation with fluid resuscitation), vascular collapse accompanied by a classic triad of hypoalbuminemia, hemoconcentration, and hypotension in the absence of secondary causes of shock with edema. Fluid management is an effective clinical management strategy for an improved prognosis (verbatim in part and modified from J Clin Med. 2018; seven (11); J Clin Med. 2019; 8(2)). The clinical presentation of CLS with a corollary of Virchow’s triad ( https://www.ncbi.nlm.nih.gov/books/NBK539697/) and the critical events for a laminar to turbulence transition ( ELTT) is systematically correlated. Virchow’s triad I ‐ Endothelial damage:ELTT 1. Region of instability of small wavy disturbances called Tollmien‐Schlichting wave ELTT 2. Periodicity accompanied by the appearance of vortices ELTT 3. Peak‐Valley development in vortices, ELTT 4. Vorticity concentration and shear layer development with inflectional profile appearance and disappearance in Tollmien‐Schlichting wave pattern, Virchow’s triad II ‐ Venous stasis: ELTT 5. Breakdown: evolution of a staggered vortex pattern twice the wavelength of Tollmien‐Schlichting waves ( a high frequency fluctuations of hairpin eddies ‐ eddy currents, disrupts the laminar flow of blood, bringing platelets in close contact with the vascular wallVirchow’s triad III ‐ Hypercoagulability: ELTT 6. Cascading of vortices and turbulent‐spot development, (spots of thrombus lead to increased turbulence thus reduction in blood flow. Infarction and ischemia Thrombi often result in reduced blood flow to tissue (ischemia) or complete obstruction (absolute irreversible stasis NFP=0 mmHG, ?) of blood flow leading to cell death(infarction) with concurrent impairment of global net filtration pressure (NFP) in mark transition of laminar to turbulent flow pattern. Taken together, herewith it is suggested that a better understanding of the components of multifactorial mode of turbulence modelling in particular on time scale, blood viscosity, velocity profile, NFP gradient, and structural integrity of blood vessels (endothelial damage) of the capillary bed in the context of thromboembolic events [DDx: ischemic stroke(CVA), disseminated intravascular coagulation (DIC), deep vein thrombosis (DVT), pulmonary embolism and CLS], would enable better stratification of clinical risk factors, precision in clinical decision making amalgamating differential diagnosis for an accurate prognosis in early resuscitation protocol on sepsis such as NCT01663701.Support or Funding InformationSupported by professional development funds by SWTJC to Subburaj Kannan

The effects of severe hemoconcentration on acid-base equilibrium in critically ill patients: the forgotten role of buffers in whole blood.

Idiopathic Systemic Capillary Leak Syndrome (ISCLS) is a paroxysmal permeability disorder characterized by abrupt onset of shock and hemoconcentration due to massive shift of fluids and proteins from the intravascular to the interstitial compartment. We hypothesize that increased hemoglobin concentration has a pivotal role in the acid-base imbalance during life-threatening crises. Analysis of the acid-base balance fluctuations during six severe ISCLS flares admitted to ICU of a referral center for ISCLS. Acid-base equilibrium was assessed for plasma and the whole blood by single and multicompartmental models. The acute phase of ISCLS was characterized by shock, hypoalbuminemia, severe hemoconcentration, and acidosis. The physical-chemical approach for plasma found a remarkable component of unmeasured anions (SIG) during the acute phase. After correction of the physical-chemical model for the whole blood, the SIG variations disappeared because the buffer role of hemoglobin was relevant. Hemoglobin has a remarkable role in buffering metabolic acidosis during the shock phase of ISCLS. In these circumstances, the assessment of acid-base equilibrium in plasma alone may overestimate unmeasured anions. On the contrary, the physical-chemical model corrected for whole blood better explains the metabolic component of acid-base imbalance when marked shift of hemoglobin concentration occurs.