Intravascular Hypovolemia Research Articles

Nephrotic Syndrome: From Pathophysiology to Novel Therapeutic Approaches.

Nephrotic edema stands out as one of the most common complications of nephrotic syndrome. The effective management of hypervolemia is paramount in addressing this condition. Initially, "the underfill hypothesis" suggested that proteinuria and hypoalbuminemia led to fluid extravasation into the interstitial space, causing the intravascular hypovolemia and activation of neurohormonal compensatory mechanisms, which increased the retention of salt and water. Consequently, the recommended management involved diuretics and human-albumin infusion. However, recent findings from human and animal studies have unveiled a kidney-limited sodium-reabsorption mechanism, attributed to the presence of various serine proteases in the tubular lumen-activating ENaC channels, thereby causing sodium reabsorption. There is currently no standardized guideline for diuretic therapy. In clinical practice, loop diuretics continue to be the preferred initial choice. It is noteworthy that patients often exhibit diuretic resistance due to various factors such as high-sodium diets, poor drug compliance, changes in pharmacokinetics or pharmacodynamics, kidney dysfunction, decreased renal flow, nephron remodeling and proteasuria. Considering these challenges, combining diuretics may be a rational approach to overcoming diuretic resistance. Despite the limited data available on diuretic treatment in nephrotic syndrome complicated by hypervolemia, ENaC blockers emerge as a potential add-on treatment for nephrotic edema.

Hepatorenal syndrome misdiagnosis may be reduced using inferior vena cava ultrasound to assess intravascular volume and guide management

Hepatorenal syndrome (HRS) is a diagnosis of exclusion defined as acute kidney injury (AKI) with cirrhosis and ascites, with serum creatinine unresponsive to standardized volume administration and diuretic withdrawal. Persistent intravascular hypovolemia or hypervolemia may contribute to AKI and be revealed by inferior vena cava ultrasound (IVC US), which may guide additional volume management. Twenty hospitalized adult patients meeting HRS-AKI criteria had IVC US to assess intravascular volume after receiving standardized albumin administration and diuretic withdrawal. Six had IVC collapsibility index (IVC-CI) ≥50% and IVCmax ≤0.7 cm suggesting intravascular hypovolemia, 9 had IVC-CI <20% and IVCmax >0.7 cm suggesting intravascular hypervolemia, and 5 had IVC-CI ≥20% to <50% and IVCmax >0.7 cm. Additional volume management was prescribed in the 15 patients with either hypovolemia or hypervolemia. After 4–5 days, serum creatinine levels decreased ≥20% without hemodialysis in 6 of 20 patients – 3 with hypovolemia received additional volume, and 2 with hypervolemia plus one with ‘euvolemia’ and dyspnea were volume restricted and received diuretics. In the other 14 patients, serum creatinine failed to persistently decrease ≥20% or hemodialysis was required indicating that AKI did not improve. In summary, fifteen of 20 patients (75%) were presumed to have intravascular hypovolemia or hypervolemia by IVC ultrasound. Six of the 20 patients (40%) improved AKI by 4-5 days of follow-up with additional IVC US-guided volume management, and thus had been misdiagnosed as HRS-AKI. IVC US may more accurately define HRS-AKI as being neither hypovolemic nor hypervolemic, and guide volume management, decreasing the frequency of HRS-AKI misdiagnosis.

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.

Hypothermia and Cold Injury in Children.

Hypothermia and Cold Injury in Children.

SIADH (Syndrome of Inappropriate ADH Secretion): Perplexing Look of Dengue Fever

Dengue is a mosquito-borne disease (female mosquitoes of the Aedes genus, principally Aedes aegypti) caused by any one of four closely related dengue viruses. It is endemic in tropical and subtropical continent. World health organization (WHO) currently estimates there may be 50 -100 million dengue infections worldwide every year with over 2.5 billion people at risk of dengue. Symptomatic dengue virus infection may manifests as undifferentiated fever, classical dengue fever (with or without unusual hemorrhages), and dengue hemorrhagic fever (with or without shock). Isolated organopathy or expanded dengue syndrome (EDS) was coined by WHO in the year 2012 to describe cases, which do not fall into either dengue shock syndrome or dengue hemorrhagic fever. The atypical manifestations noted in expanded dengue are multisystemic and multifaceted with organ involvement, such as liver, brain, heart, kidney, central/peripheral nervous system, gastrointestinal tract, lympho reticular system. Dengue virus has long been considered as a non-neurotropic virus, as animal studies have shown that virus does not cross blood brain barrier. Hyponatremia may be found in association with dengue fever and is thought to be caused by peripheral fluid extravasation and resulting intravascular hypovolaemia. But hyponatremia due to syndrome of inappropriate secretion of anti-diuretic hormone (SIADH) in Dengue fever is rare. We report a 40 years old male who was diagnosed as Dengue fever (Dengue Ns1Ag positive) with thrombocytopenia and hyponatremia. He was admitted and further investigations revealed SIADH. He responded well to cautious sodium replacement and addition of tolvaptan. He recovered completely and was discharged after one week. Thus, all clinicians should keep in mind the possibility of SIADH as a part of expanded dengue syndrome.

Diagnosing capillary leak in critically ill patients: development of an innovative scoring instrument for non-invasive detection

BackgroundThe concomitant occurrence of the symptoms intravascular hypovolemia, peripheral edema and hemodynamic instability is typically named Capillary Leak Syndrome (CLS) and often occurs in surgical critical ill patients. However, neither a unitary definition nor standardized diagnostic criteria exist so far. We aimed to investigate common characteristics of this phenomenon with a subsequent scoring system, determining whether CLS contributes to mortality.MethodsWe conducted this single-center, observational, multidisciplinary, prospective trial in two separately run surgical ICUs of a tertiary academic medical center. 200 surgical patients admitted to the ICU and 30 healthy volunteers were included. Patients were clinically diagnosed as CLS or No-CLS group (each N = 100) according to the grade of edema, intravascular hypovolemia, hemodynamic instability, and positive fluid balance by two independent attending physicians with > 10 years of experience in ICU. We performed daily measurements with non-invasive body impedance electrical analysis, ultrasound and analysis of serum biomarkers to generate objective diagnostic criteria. Receiver operating characteristics were used, while we developed machine learning models to increase diagnostic specifications for our scoring model.ResultsThe 30-day mortility was increased among CLS patients (12 vs. 1%, P = 0.002), while showing higher SOFA-scores. Extracellular water was increased in patients with CLS with higher echogenicity of subcutaneous tissue [29(24–31) vs. 19(16–21), P < 0.001]. Biomarkers showed characteristic alterations, especially with an increased angiopoietin-2 concentration in CLS [9.9(6.2–17.3) vs. 3.7(2.6–5.6)ng/mL, P < 0.001]. We developed a score using seven parameters (echogenicity, SOFA-score, angiopoietin-2, syndecan-1, ICAM-1, lactate and interleukin-6). A Random Forest prediction model boosted its diagnostic characteristics (AUC 0.963, P < 0.001), while a two-parameter decision tree model showed good specifications (AUC 0.865).ConclusionsDiagnosis of CLS in critically ill patients is feasible by objective, non-invasive parameters using the CLS-Score. A simplified two-parameter diagnostic approach can enhance clinical utility. CLS contributes to mortality and should, therefore, classified as an independent entity.Trial Registration: German Clinical Trials Registry (DRKS No. 00012713), Date of registration 10/05/2017, www.drks.deGraphical

Effects of Body Position and Hypovolemia on the Regional Distribution of Pulmonary Perfusion During One-Lung Ventilation in Endotoxemic Pigs

Background: The incidence of hypoxemia during one-lung ventilation (OLV) is as high as 10%. It is also partially determined by the distribution of perfusion. During thoracic surgery, different body positions are used, such as the supine, semilateral, lateral, and prone positions, with such positions potentially influencing the distribution of perfusion. Furthermore, hypovolemia can impair hypoxic vasoconstriction. However, the effects of body position and hypovolemia on the distribution of perfusion remain poorly defined. We hypothesized that, during OLV, the relative perfusion of the ventilated lung is higher in the lateral decubitus position and that hypovolemia impairs the redistribution of pulmonary blood flow.Methods: Sixteen juvenile pigs were anesthetized, mechanically ventilated, submitted to a right-sided thoracotomy, and randomly assigned to one of two groups: (1) intravascular normovolemia or (2) intravascular hypovolemia, as achieved by drawing ~25% of the estimated blood volume (n = 8/group). Furthermore, to mimic thoracic surgery inflammatory conditions, Escherichia coli lipopolysaccharide was continuously infused at 0.5 μg kg−1 h−1. Under left-sided OLV conditions, the animals were further randomized to one of the four sequences of supine, left semilateral, left lateral, and prone positioning. Measurements of pulmonary perfusion distribution with fluorescence-marked microspheres, ventilation distribution by electrical impedance tomography, and gas exchange were then performed during two-lung ventilation in a supine position and after 30 min in each position and intravascular volume status during OLV.Results: During one-lung ventilation, the relative perfusion of the ventilated lung was higher in the lateral than the supine position. The relative perfusion of the non-ventilated lung was lower in the lateral than the supine and prone positions and in semilateral compared with the prone position. During OLV, the highest arterial partial pressure of oxygen/inspiratory fraction of oxygen (PaO2/FIO2) was achieved in the lateral position as compared with all the other positions. The distribution of perfusion, ventilation, and oxygenation did not differ significantly between normovolemia and hypovolemia.Conclusions: During one-lung ventilation in endotoxemic pigs, the relative perfusion of the ventilated lung and oxygenation were higher in the lateral than in the supine position and not impaired by hypovolemia.

Phase 1 trial of anti-CD22 recombinant immunotoxin moxetumomab pasudotox combined with rituximab for relapsed/refractory hairy cell leukemia.

7036 Background: Anti-CD22 recombinant immunotoxin moxetumomab pasudotox (Moxe) is FDA-approved for hairy cell leukemia (HCL) patients who have received at least two prior systemic therapies including a purine nucleoside analog. In phase 3 testing the complete remission (CR) rate was 41%, and response was higher in patients with lower tumor burden and lower titers of antidrug antibodies (ADA). Phase 1 testing indicated that most CRs were without minimal residual disease (MRD) and eradication of MRD was associated with prolonged CR duration. Monoclonal antibody (Mab) rituximab binds to CD20 on HCL cells and induces apoptosis or immune-mediated killing, but as a single-agent achieved only 13% CRs in relapsed HCL requiring therapy. In a phase 1 trial to determine safety, rituximab was combined with Moxe, with the goal to help reduce tumor burden and to prevent or delay ADA by killing normal B-cells. Methods: To allow rituximab sufficient time to accomplish both goals, it was infused 3 days before day 1 of cycle 1 at 375 mg/m2, and Moxe was given by 30-minute infusion on days 1, 3 and 5. On repeat cycles of Moxe days 1, 3 and 5, rituximab was given on day 1. Cycles were generally spaced 4 weeks apart. Moxe was begun at a lower dose, 30 rather than the 40 mcg/kg dose used in phase 3 in case the rituximab would increase its toxicity. Bone marrow aspirate flow cytometry, which can detect 0.002% HCL cells, was the most sensitive test used for MRD detection, much more sensitive than BRAF V600E digital droplet PCR (ddPCR) or bone marrow biopsy immunohistochemistry (IHC). Patients could receive 4 cycles past MRD-free CR, but not more than 8 cycles. Results: Three patients received Moxe at 30 mcg/Kg/dose and 6 received 40 mcg/Kg/dose, all without dose limiting toxicity (DLT). There was no evidence of hemolytic uremic syndrome or capillary leak syndrome. To prevent intravascular hypovolemia due to expected third spacing, patients were encouraged to drink one cup per hour of water or other fluid from days 1 to 8 and take dexamethasone 4 mg orally if headache or nausea prevented good oral hydration. Of the 9 patients, 7 (78%) achieved CR after 2 (n = 6) or 3 (n = 1) cycles, and achieved MRD-free CR after 2 (n = 3), 4 (n = 3) or 6 (n = 1) cycles. No patients became infected with COVID-19. Conclusions: This phase 1 trial met its primary endpoint of determining whether rituximab could be safely combined with Moxe and will enroll 4 additional patients to further access clinical activity. Further testing will determine whether addition of a CD20 Mab to Moxe significantly improves clinical outcome compared to Moxe alone, particularly long-term MRD-free CR rate. Clinical trial information: NCT03805932.

Comparative effects of flow vs. volume-controlled one-lung ventilation on gas exchange and respiratory system mechanics in pigs

BackgroundFlow-controlled ventilation (FCV) allows expiratory flow control, reducing the collapse of the airways during expiration. The performance of FCV during one-lung ventilation (OLV) under intravascular normo- and hypovolaemia is currently unknown. In this explorative study, we hypothesised that OLV with FCV improves PaO2 and reduces mechanical power compared to volume-controlled ventilation (VCV). Sixteen juvenile pigs were randomly assigned to one of two groups: (1) intravascular normovolaemia (n = 8) and (2) intravascular hypovolaemia (n = 8). To mimic inflammation due to major thoracic surgery, a thoracotomy was performed, and 0.5 μg/kg/h lipopolysaccharides from Escherichia coli continuously administered intravenously. Animals were randomly assigned to OLV with one of two sequences (60 min per mode): (1) VCV–FCV or (2) FCV–VCV. Variables of gas exchange, haemodynamics and respiratory signals were collected 20, 40 and 60 min after initiation of OLV with each mechanical ventilation mode. The distribution of ventilation was determined using electrical impedance tomography (EIT).ResultsOxygenation did not differ significantly between modes (P = 0.881). In the normovolaemia group, the corrected expired minute volume (P = 0.022) and positive end-expiratory pressure (PEEP) were lower during FCV than VCV. The minute volume (P ≤ 0.001), respiratory rate (P ≤ 0.001), total PEEP (P ≤ 0.001), resistance of the respiratory system (P ≤ 0.001), mechanical power (P ≤ 0.001) and resistive mechanical power (P ≤ 0.001) were lower during FCV than VCV irrespective of the volaemia status. The distribution of ventilation did not differ between both ventilation modes (P = 0.103).ConclusionsIn a model of OLV in normo- and hypovolemic pigs, mechanical power was lower during FCV compared to VCV, without significant differences in oxygenation. Furthermore, the efficacy of ventilation was higher during FCV compared to VCV during normovolaemia.

Pulse oximetry-based capillary refilling evaluation predicts postoperative outcomes in liver transplantation: a prospective observational cohort study

BackgroundCapillary refill time (CRT) is a non-invasive technique to evaluate tissue perfusion, and quantitative CRT (Q-CRT) adapted to pulse oximetry was developed with patients with sepsis and compared to blood lactate and sepsis scores. In post liver transplantation, large amounts of fluid administration are necessary for maintaining tissue perfusion to grafted liver against intravascular hypovolemia. This study aimed to evaluate whether Q-CRT can predict poor outcomes by detecting peripheral tissue perfusion abnormality in patients with liver transplantations who were treated with massive fluid administration.MethodsIn this single-center prospective cohort study, we enrolled adult patients with liver transplantations between June 2018 and July 2019. Measurement of Q-CRT was conducted at intensive care units (ICU) admission and postoperative day 1 (POD1).ResultsA total of 33 patients with liver transplantations were enrolled. Significant correlations of Q-CRT and ΔAb, a tissue oxygen delivery parameter calculated by pulse oximetry data, at ICU admission with the postoperative outcomes such as length of ICU and hospital stay and total amount of ascitic fluid discharge were observed. Quantitative CRT and ΔAb at ICU admission were significantly associated with these postoperative outcomes, even after adjusting preoperative and operative factors (MELD score and bleeding volume, respectively). However, quantitative CRT and ΔAb at POD1 and changes from ICU admission to POD1 failed to show significant associations.ConclusionsQ-CRT values were significantly associated with postoperative outcomes in liver transplantation. Although the mechanisms of this association need to be clarified further, Q-CRT may enable identification of high-risk patients that need intensive postoperative managements.

Venous Waveform Analysis Correlates With Echocardiography in Detecting Hypovolemia in a Rat Hemorrhage Model.

Assessing intravascular hypovolemia due to hemorrhage remains a clinical challenge. Central venous pressure (CVP) remains a commonly used monitor in surgical and intensive care settings for evaluating blood loss, despite well-described pitfalls of static pressure measurements. The authors investigated an alternative to CVP, intravenous waveform analysis (IVA) as a method for detecting blood loss and examined its correlation with echocardiography. Seven anesthetized, spontaneously breathing male Sprague Dawley rats with right internal jugular central venous and femoral arterial catheters underwent hemorrhage. Mean arterial pressure (MAP), heart rate, CVP, and IVA were assessed and recorded. Hemorrhage was performed until each rat had 25% estimated blood volume removed. IVA was obtained using fast Fourier transform and the amplitude of the fundamental frequency (f1) was measured. Transthoracic echocardiography was performed utilizing a parasternal short axis image of the left ventricle during hemorrhage. MAP, CVP, and IVA were compared with blood removed and correlated with left ventricular end diastolic area (LVEDA). All 7 rats underwent successful hemorrhage. MAP and f1 peak amplitude obtained by IVA showed significant changes with hemorrhage. MAP and f1 peak amplitude also significantly correlated with LVEDA during hemorrhage (R = 0.82 and 0.77, respectively). CVP did not significantly change with hemorrhage, and there was no significant correlation between CVP and LVEDA. In this study, f1 peak amplitude obtained by IVA was superior to CVP for detecting acute, massive hemorrhage. In addition, f1 peak amplitude correlated well with LVEDA on echocardiography. Translated clinically, IVA might provide a viable alternative to CVP for detecting hemorrhage.

Severe ovarian hyperstimulation syndrome with with pleural and pericardial effusion

As the number of couples receiving infertility treatment using assisted reproductive technology increases, it is important to be aware of the risks, one of the most serious being the hyperstimulation syndrome. Ovarian hyperstimulation syndrome (ОHS) is an iatrogenic condition resulting from the use of exogenous gonadotropins to induce the production of multiple eggs. Although the occurrence of this disorder is rare, it can be potentially life-threatening in its most severe forms. It is characterized by increased capillary permeability and fluid retention in the third space, nausea, vomiting, bloating, abdominal pain, tachycardia, tachypnea, and shortness of breath. Massive extravascular exudation leads to intravascular hypovolemia with the development of edema, ascites, pleural and pericardial effusion, hypovolemic shock, oliguria and electrolyte imbalance. Induced hemoconcentration leads to hypercoagulation and carries a risk of life-threatening thrombosis. We present a case of a woman admitted to an emergency room with shortness of breath and fainting, ascites, pleural effusions and pericardial effusion and subsequently diagnosed with severe ovarian hyperstimulation syndrome and taken to the intensive care unit. Early recognition, diagnosis and treatment of the syndrome reduces the risk of developing complications. This condition is life-threatening and patients need hospital treatment. The purpose of this publication is to raise awareness of this rare clinical condition.

Thrombotic microangiopathy and liver toxicity due to a combination therapy of leflunomide and methotrexate: a case report

BackgroundTreatment of active rheumatoid arthritis may necessitate a methotrexate mono- or combination therapy. As in the present case, novel side effects may occur, when escalating therapy.Case presentationA 63-year-old Caucasian female patient with rheumatoid arthritis on methotrexate for 8 years and on leflunomide for 6 years was admitted for weakness, edema, ascites, and petechiae of the lower legs. Comorbidities included a urinary tract infection, metabolic syndrome with obesity, type-2 diabetes without necessity for insulin or oral antidiabetics, and non-alcoholic fatty liver disease. Laboratory results showed acute liver failure, oliguric acute kidney injury, thrombocytopenia, and schistocyte-positive, Coombs-negative hemolytic anemia. On admission, her ADAMTS13 activity was decreased, and her leflunomide plasma level was elevated (120 μg/l). Due to severe hypoalbuminemia, an intravascular hypovolemia, and severe metabolic alcalosis with hypokalemia were found.For the newly diagnosed thrombotic microangiopathy, leflunomide and methotrexate were discontinued, and 4 units of fresh-frozen plasma were given. Steroid therapy was administered for 5 days, until thrombotic thrombocytopenic purpura was excluded. Intravenous human albumin, oral vitamin K, and cholestyramine were administered for liver failure and leflunomide overdosage, respectively. Liver biopsy revealed a non-alcoholic fatty liver disease transforming into liver cirrhosis. After 2 weeks, our patient was discharged. However, within 3 weeks after discharge, our patient was rehospitalized for a relapse of acute liver failure, urinary tract infection, and influenza. Leflunomide and methotrexate were not reintroduced before or thereafter. Over a period of 11 months after discharge, her thrombotic microangiopathy subsided, and her renal and liver function fully recovered.ConclusionsUnder a combination of leflunomide and methotrexate, liver toxicity and, for the first time, thrombotic microangiopathy occurred as side effects. Non-alcoholic fatty liver disease may have predisposed for the drug-induced liver toxicity.

Dialysis disequilibrium syndrome revisited: Feeling “Disequilibrated” due to inner ear dyshomeostasis?

Dizziness is one of the most common hemodialysis-associated symptoms, and has been thought to be caused by cerebral edema or intravascular hypovolemia. However, the possibility of a peripheral vestibular disturbance due to hemodialysis has not been addressed as a cause of hemodialysis-associated dizziness. In the present study, we propose a new hypothesis accounting for hemodialysis-associated dizziness, i.e., the decrease in serum osmolality due to rapid removal of urea during dialysis causes inner ear fluid dyshomeostasis, leading to density difference between perilymph and endolymph.

Attention to Detail.

Attention to Detail.

Abstract 16611: Higher Total Ultrafiltration Volume During Infant Cardiac Surgery is Associated With Acute Kidney Injury

Introduction: Many congenital heart centers use intraoperative ultrafiltration (UF) for fluid removal during and after infant cardiopulmonary bypass (CPB) surgery to reduce fluid overload. Excessive UF may result in intravascular hypovolemia. Postoperative acute kidney injury (AKI) is multifactorial, but little is understood about the role of UF on hypovolemia and postoperative AKI. Methods: This is a single center, retrospective review of infants receiving UF associated with CPB surgery. Patients requiring ECMO were excluded. UF volume (ml) was indexed to weight (kg). AKI was determined using the serum creatinine ‘Kidney Disease Improving Global Outcome (KDIGO)’ criteria or neonatal KDIGO (≤ 30 days of age) criteria. Multivariable logistic regression was used to adjust for multiple covariates associated with AKI. Results: From 6/2013 to 4/2015, 532 subjects &lt;1 year of age underwent CPB-assisted congenital heart surgery with UF. Sixty-four (12%) subjects developed postoperative AKI. No patients required renal replacement therapy. Higher total indexed UF volume was associated with AKI (median 119 ml/kg [IQR 92-164 ml/kg] versus 97 ml/kg [72-128 ml/kg], p=0.001). Other univariate associations with AKI are listed in table 1. After adjusting for multiple covariates, higher indexed total UF volume was associated with increased AKI risk (OR 1.1, CI 1.03 - 1.17, p=0.005) for each additional 10 ml/kg UF volume. The only additional independently associated factor with AKI was higher vasoactive inotrope score on post-operative day 2 (OR 1.1, [1.04-1.17], p&lt;0.001). Conclusions: While few patients developed postoperative AKI, higher intraoperative UF volume is associated with AKI risk. Postoperative hypovolemia due to excessive UF may be a modifiable AKI risk factor. Judicious use of postoperative UF may reduce AKI risk.

The effects of major burn related pathophysiological changes on the pharmacokinetics and pharmacodynamics of drug use: An appraisal utilizing antibiotics.

Patients suffering major burn injury represent a unique population of critically ill patients. Widespread skin and tissue damage causes release of systemic inflammatory mediators that promote endothelial leak, extravascular fluid shifts, and cardiovascular derangement. This phase is characterized by relative intra-vascular hypovolaemia and poor peripheral perfusion. Large volume intravenous fluid resuscitation is generally required. The patients' clinical course is then typically complicated by ongoing inflammation, protein catabolism, and marked haemodynamic perturbation. At all times, drug distribution, metabolism, and elimination are grossly distorted. For hydrophilic agents, changes in volume of distribution and clearance are marked, resulting in potentially sub-optimal drug exposure. In the case of antibiotics, this may then promote treatment failure, or the development of bacterial drug resistance. As such, empirical dose selection and pharmaceutical development must consider these features, with the application of strategies that attempt to counter the unique pharmacokinetic changes encountered in this setting.

Dengue in children: Issues in critical care settings

Dengue infection is an important tropical infection that can be responsible for serious illness and intensive care admission in children. Dengue virus belongs to Flavivirus genus and is transmitted by Aedes aegypti and Aedes al- bopictus mosquito. New World Health Organisation classification for the disease into dengue with/ without warning signs and severe dengue better identifies patients requiring in-hospital treatment and classifies atypical cases with severe end organ system involvement (liver, brain, heart, etc.) without shock or bleeding diathesis. Point of care tests for Non-Structural Protein 1 antigen and IgM based immuno-assay are important adjuncts to early diagnosis in emergency wards. Capillary leak and bleeding are central mechanism of manifestations of severe dengue. Severe capillary leakage creates intravascular hypovolemia which needs correction with aggressive but not over-jealous fluid therapy with timely tapering of high fluid rates, to maintain a fine balance of adequate resuscitation and preventing fluid overload at the same time. Indication for use of colloids upfront especially in patients with evidence of severe plasma leakage needs further evaluation. Transfusion of fresh whole blood or fresh packed red cells is important in patients with suspected severe bleeding. In view of recent evidence, prophylactic transfusion of platelets is going out of favour and platelets should be transfused for severe bleeding irrespective of platelet counts. Echocardiography and central venous pressure based fluid status evaluation act as precious adjuncts to for better assessment of intravascular volume. Atypical manifestation like neurological manifestations, renal failure, abdominal compartment syndrome, hemophagocytic lymphohistiocytosis need further documentation for better management of critically ill patients. Outcomes worldwide are improving with structured protocol based management.

Serum lactate as predictor and diagnostic biomarker of plasma leakage in adult dengue patients

Background &lt;br /&gt;Dengue fever (DF) and dengue hemorrhagic fever (DHF) are differentiated by the occurrence in DHF of plasma leakage into the interstitial space as shown by pleural and peritoneal effusion, hemoconcentration, and intravascular hypovolemia. Perfusion dysfunction causes anaerobic metabolism, which leads to increased serum lactate. This study was to determine serum lactate as prognostic predictor and diagnostic biomarker of plasma leakage in adult dengue patients.&lt;br /&gt;&lt;br /&gt;Methods &lt;br /&gt;A cross-sectional retrospective cohort study was conducted on 57 adult dengue patients hospitalized in the internal medicine ward of Cipto Mangunkusumo Hospital and Persahabatan Hospital in Jakarta. Serum lactate was examined to determine its mean difference between DF and DHF. The data was analyzed by independent t-test and the cut-off points were identified for presence as well as absence of plasma leakage, then the receiver operating characteristics (ROC) curve was used to determine sensitivity and specificity.&lt;br /&gt;&lt;br /&gt;Results &lt;br /&gt;Mean serum lactate was significantly higher in DHF than in DF. From the ROC curve, the cut-off point for serum lactate as prognostic predictor on day 3 of fever was ³2.65 mmol/L with AUC of 0.626 (95% CI 0.480-0.772; p=0.108). The cut-off point for diagnostic biomarker of plasma leakage on day 5 of fever was ³2.55 mmol/L with sensitivity 66.6%, specificity 54.2%, and AUC 0.668 (95% CI 0.550-0.826; p=0.016).&lt;br /&gt;&lt;br /&gt;Conclusion &lt;br /&gt;There was a significant difference in serum lactate between DF and DHF. In the critical phase, serum lactate of ³2.55 mmol/L could be used as plasma leakage diagnostic marker of low accuracy.

Dynamic Measurement of Hemodynamic Parameters and Cardiac Preload in Adults with Dengue: A Prospective Observational Study.

Few previous studies have monitored hemodynamic parameters to determine the physiological process of dengue or examined inferior vena cava (IVC) parameters to assess cardiac preload during the clinical phase of dengue. From January 2013 to July 2015, we prospectively studied 162 hospitalized adults with confirmed dengue viral infection using non-invasive cardiac output monitoring and bedside ultrasonography to determine changes in hemodynamic and IVC parameters and identify the types of circulatory shock that occur in patients with dengue. Of 162 patients with dengue, 17 (10.5%) experienced dengue shock and 145 (89.5%) did not. In patients with shock, the mean arterial pressure was significantly lower on day 6 after fever onset (P = 0.045) and the pulse pressure was significantly lower between days 4 and 7 (P<0.05). The stroke volume index and cardiac index were significantly decreased between days 4 and 15 and between days 5 and 8 after fever onset (P<0.05), respectively. A significant proportion of patients with dengue shock had an IVC diameter <1.5 cm and IVC collapsibility index >50% between days 4 and 5 (P<0.05). Hypovolemic shock was observed in 9 (52.9%) patients and cardiogenic shock in 8 (47.1%), with a median (interquartile range) time to shock onset of 6.0 (5.0–6.5) days after fever onset, which was the median day of defervescence. Intravascular hypovolemia occurred before defervescence, whereas myocardial dysfunction occurred on the day of defervescence until 2 weeks after fever onset. Hypovolemic shock and cardiogenic shock each occurred in approximately half of the patients with dengue shock. Therefore, dynamic measures to estimate changes in hemodynamic parameters and preload should be monitored to ensure adequate fluid therapy among patients with dengue, particularly patients with dengue shock.