Pulmonary edema may cause respiratory distress with a rapid, shallow breathing pattern and moist lung sounds heard on auscultation. Patients with evidence of heart disease murmur, gallop sounds or arrhythmias may have underlying heart pathology, which can exacerbate pulmonary edema due to fluid intolerance and low COP. Heart murmurs can also be heard due to severe alterations in blood rheology associated with anemia or low blood protein. Edema of the intestines may result in poor GI function, altered normal borborygmi, vomiting or diarrhea.
Peripheral edema is recognized first in body areas with thin skin, low muscle mass, and few fat stores, such as around the Achilles tendon or intermandibular space.
Conjunctival edema chemosis is an early sign of fluid intolerance, followed quickly by subcutaneous fluid accumulation around the head and neck and the distal limbs. Assessment of the patient for improvement or resolution of clinical signs associated with alterations in albumin and COP hypotension, edema, pleural effusion, ascites, and respiratory distress is an important monitoring tool throughout resuscitation and definitive treatment.
The minimum laboratory database blood samples should ideally be drawn prior to fluid resuscitation. The POC tests will include the packed cell volume PCV , total protein TP , blood glucose, blood urea nitrogen BUN , blood gas analysis, electrolyte panel, coagulation profile prothrombin time, activated partial thromboplastin time , platelet number estimation, and urinalysis.
A serum or plasma refractometer reading can provide a TP, which is a combination of albumin plus globulin and other blood proteins. A separate biochemical assay is required to determine the precise albumin and globulin concentration. An elevation in TP more commonly represents reduced plasma water but can be a consequence of an elevation in globulins. Synthetic colloids are not demonstrated on the refractometer and will dilute the concentration of albumin and other proteins [1].
Refractometer readings should be interpreted in light of evaluation of other microhematocrit levels, including PCV, serum color, and buffy coat; this may provide further insight into the underlying disease process. The BUN may be elevated with proteinuria from kidney disease or low with liver cirrhosis or failure, each a potential cause of hypoalbuminemia.
Hyperglycemia can alter the glycocalyx layer of the vasculature, increasing the permeability of the glomerular capillary wall to albumin [20]. A large proportion of serum calcium is bound to albumin in the blood. Measuring the ionized portion of calcium will allow for a more accurate assessment of serum calcium concentrations. Blood albumin concentrations can also affect the acid—base status of the patient.
Albumin acts as a weak acid, with hypoalbuminemia therefore having an alkalinizing effect with an increase in the base excess. Increases in blood albumin are associated with an acidifying effect. Treatment for either acid—base derangement involves specific therapy for the underlying disease. See Chapter 7 for further information.
Platelet numbers may decline and coagulation times increase with disseminated intravascular coagulation DIC , a common consequence of systemic inflammatory response syndrome SIRS diseases, to include sepsis. Increased vascular permeability leads to hypoalbuminemia. Loss of AT from the circulating blood can be a marker of a risk for thrombosis.
Administration of synthetic colloids may artificially raise urine specific gravity and should be considered when evaluating USG in critically ill animals. The urine sediment is examined for signs of a urinary tract infection as the cause of proteinuria or a focus of inflammation. Blood for a complete blood count CBC and serum biochemical profile is drawn prior to fluid resuscitation and submitted for analysis. Leukocytosis and leukopenia can each be a consequence of systemic inflammation or sepsis.
The biochemical profile is evaluated for evidence of underlying diseases that cause disorders of albumin and COP.
The serum albumin concentration will be reported. Hyperalbuminemia is almost always associated with dehydration, but other causes must be considered. Hypercholesterolemia, hypoglycemia, decreased BUN and prolonged clotting times, with or without elevated liver enzymes, are strongly suggestive of severe liver disease as the cause of hypoalbuminemia. Hypoalbuminemia is consistent with a low COP in patients that have not been treated with natural or synthetic colloids.
The COP can be calculated using serum albumin or total protein values; however, this method has been found to provide an inaccurate assessment of COP in the critically ill patient [21—24]. Additional testing might be required to find the underlying cause of albumin alterations, such as serology for infectious pathogens, culture and susceptibility of urine or fluids, urine protein:creatinine ratio, drug concentrations, bile acids, and histopathology of intestinal biopsies.
Diagnostic imaging begins with plain thoracic and abdominal radiographs. Thoracic radiographs are evaluated for pulmonary, cardiac or pleural space abnormalities.
The presence of pleural fluid will direct centesis for diagnostic sampling and relief of pleural pressure. The presence of pulmonary edema can be a consequence of hypoalbuminemia and a low COP, heart disease, acute lung injury or acute respiratory distress syndrome. Abdominal radiographs can demonstrate organ size, positioning, and shape as well as the presence of abdominal effusion. Ultrasound may provide a more detailed evaluation of organs for evidence of cysts, fluid, infiltrates, hemorrhage, edema or other anatomical abnormalities.
The aspiration of abdominal or pleural fluid can be guided by ultrasound with the fluid evaluated by culture, cytology, and biochemistry as indicated. Advanced imaging such as a portovenogram, nuclear scintigraphy, computed tomography or nuclear magnetic resonance imaging may be indicated to better define the extent and nature of a suspected or confirmed abnormality. Signs of poor perfusion, dehydration, peripheral edema, abdominal distension, and changes in breathing rate and effort can suggest fluid extravasation due to hypoalbuminemia and a lowered COP.
The refractometer is used to easily follow the trends of change in total protein. The results can indicate a likely rise or fall in COP when crystalloids have been used as the sole resuscitation and maintenance fluid.
However, direct measurement of the COP with a colloid osmometer is required after the administration of synthetic colloids since they are not measured by the refractometer.
Monitoring blood pressure and pulse oximetry can provide an early indication of pulmonary complications attributable to hypoalbuminemia and a low COP and show progress during treatment. Monitoring the blood pressure, blood lactate, and urine output can provide insight into the tissue perfusion of core organs. The electrocardiogram can help with early detection of cardiac edema or ischemia. Changes in serum albumin are the result of pathological events, not the cause of them.
Critically ill patients often have one or more underlying disease processes that contribute to alterations in blood albumin and ultimately a significant change in COP see Table 4. Both factors can have an important impact on the outcome of the patient. A high serum albumin is primarily a reflection of dehydration and is typically resolved through fluid therapy.
However, low serum albumin and the resultant decrease in COP can be a component of any critical illness. The resulting complications of hypoalbuminemia must be strategically managed for an optimal therapeutic outcome. Hypoalbuminemia is to be anticipated as a complication of any critical illness.
After a major insult, the serum albumin inevitably decreases and tends to increase slowly as the patient recovers. A clear association has been found between the albumin level and the severity of insult [26] but it is unclear whether there is a cause—effect relationship or whether it is just a marker of serious disease [27]. Hypoalbuminemia is associated with increased complications and reduced survival in critically ill humans, dogs, and cats [28—32]. Each 1. Loss of protein from the blood into the GI tract occurs due to mucosal disease with ulceration, obstruction of lymphatic flow, increased mucosal capillary permeability or a combination of these problems.
Chapter 15 provides more information pertaining to the impact of GI disease in the critical patient. Proteinuria occurs as the result of increased permeability of the glomerular filtration barrier, composed of the glomerular endothelial cell, the basement membrane, and the podocyte.
Abnormalities in one or more of these components can result in proteinuria and albuminuria. Chapter 13 provides options for the diagnosis and treatment of proteinuria. The resultant hypoalbuminemia contributes to the morbidity and mortality in both GI and renal disorders.
The vascular endothelium is one of the earliest targets for inflammatory mediators in SIRS diseases and sepsis [35]. Cytokines, proteases, histamine, and heparinase released in inflammation further degrade the EGL. The transcapillary escape of albumin has been demonstrated in septic patients [36]. The loss of circulating albumin accompanies the loss of the glycocalyx, lowering the COP and increasing fluid extravasation [37]. Low intravascular COP in trauma patients correlated well to EGL degradation and thrombin loss, which subsequently affected vascular permeability and coagulation [38].
These changes can have a devastating impact on the intravascular fluid volume and oxygen delivery to the tissues [39]. Hypovolemia is an anticipated consequence and can lead to inadequate oxygen delivery, increased lactate production, decreased adenosine triphosphate ATP production, cell membrane breakdown, cellular death, organ failure, and death.
Even a very minor intravascular volume deficit could lead to ischemia of splanchnic organs in the critical veterinary or human patient [40]. The onset and outcome of acute lung injury and acute respiratory distress syndrome are closely associated with hypoalbuminemia.
The clinical signs resulting from low albumin are most frequently due to the accompanying decrease in intravascular COP. In-vitro oxidized albumin showed significantly higher COP values than non-oxidized albumin at identical albumin levels.
In vivo, in hypoalbuminemic HD patients with the highest OS and inflammation, COP values were also higher than expected for the low albumin levels.
The contribution to COP by other prevalent plasma proteins, such as fibrinogen and immunoglobulins was negligible. We imply that the calculation of COP based on albumin levels should be revisited in face of OS and inflammation.
Hence, in hypoalbuminemic proteinuric patients with systemic OS and inflammation the assumption of low COP should be verified by its measurements. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: The authors have declared that no competing interests exist. Albumin is the most abundant protein in human plasma with remarkably diverse functions including antioxidant activity, buffering properties, binding and transport capacities for numerous substances free fatty acids, various ions, NO, bilirubin, peptides, uremic toxins and drugs.
The steady state concentration of albumin in plasma depends on the rates of biosynthesis and degradation, and on its inter-compartmental distribution.
In agreement with the established increase in OS in chronic kidney disease CKD patients [ 6 ], recent studies have shown that apparent hypoalbuminemia is partially due to oxidation of albumin which impairs its quantification by the standard laboratory assay using bromocresol-green BCG [ 4 , 7 ].
In pathologic conditions such as CKD or proteinuria, reactive oxygen species ROS that normally play important roles in normal cellular physiology are involved in various injurious consequences such as systemic inflammation and protein modifications.
The present study evaluated the impact of albumin oxidation on measurements of COP in proteinuric patients with various degrees of systemic inflammation and of hypoalbuminemia. Sixty two percent of the nephrotic syndrome patients were CKD, i. All patients and HC subjects had normal liver function and no evidence of infection or malignancy. Blood of HD patients was drawn from the arterial line before dialysis. The study was approved by the Helsinki Committee Institutional Review Board of Galilee Medical Center, Nahariya, Israel, in compliance with the declaration of Helsinki, and all subjects signed a written informed consent form.
Serum albumin was isolated by gel-filtration GF chromatography as described previously [ 4 , 7 ]. The albumin-detection index is defined as the ratio of the BCG read-out clinical assay to the total albumin concentration, as determined by OD [ 4 ] in the albumin-containing fractions. Levels of advanced oxidation protein products AOPP , a marker of protein oxidation, were measured in sera as described previously [ 8 ]. The minimal sample volume for determination of COP is 0.
Non-proteinaceous contents were removed by dialysis overnight membrane cutoff 12kDa. This step was repeated. After 10 min incubation the albumin samples were eluted by centrifugation 12,g, 1 min into a new collection tube. The resin bound immunoglobulins were discarded by centrifugation. As BCG-measured albumin levels in patients were lower than in HC, COP values could not be compared between these groups in the hypoalbuminemic range of albumin levels.
Therefore, albumin levels had to be decreased artificially in samples of HC sera, prior to COP measurement. Twenty HC sera were partially albumin-depleted using the same CB3GA procedure, except that the depletion step was performed only once and the column bound albumin was discarded. The obtained partially-albumin-depleted HC sera resulting albumin levels: 1.
Purification from sera yields albumin amounts that cannot meet these requirements. This step increased both the albumin level and COP value in each sample. Data parameters were analyzed by unpaired t-test, by linear regression analysis and by Wilcoxon Signed Ranks Test, as appropriate. The characteristics of HC subjects and patients are given in Table 1.
The reliability of the BCG assay for albumin quantification is markedly impaired by oxidation of albumin resulting in underestimation of its concentration [ 4 , 7 ]. Albumin correlated with the index values of all subjects Fig 1A insert. However, the regression lines in the HD group and in the proteinuria high inflammation group were clearly elevated compared to the regression lines in the proteinuria low inflammation and HC groups Fig 1B. In order to clarify the significance of these high COP values, and to examine the role of albumin modifications in this observation, two further types of experiments were performed: a COP measurements of in-vitro oxidized albumin; and b measurements of COP in albumin purified from patients' sera.
The separate regression lines are given for each subjects' group and for HC sera after partial albumin depletion Alb-depl. The BCG-measured albumin levels were also correlated with the albumin detection index insert in Fig 1A. Albumin was purified from HD and HC sera, diluted to give equal concentrations and used for COP measurements after addition of equal volume of each sample to a normal HC sample with known albumin level and index a single HC serum was used in each experiment.
In order to dismiss the confounding effects of albumin levels on the analysis, the samples for this correlation included selected patients' sera and partially albumin-depleted HC sera, all with albumin levels of 1. A significant inverse association was demonstrated between the index and the COP Fig 4.
The association of COP measured in serum with albumin detection index was analyzed using selected subject's sera with albumin levels within a narrow range of 1. HC sera with albumin levels within this range were obtained by partial albumin depletion Alb-depl. To investigate the potential contribution of other plasma proteins to the "oncotic gap" in HD patients, COP was measured in commercial preparations of purified human fibrinogen, albumin and immunoglobulins IgG , in physiological concentrations.
The calculated slopes of 0. Such potential increases in COP are considerably lower than the observed "oncotic gaps" of 5. This study highlights the possibly misleading decrease in albumin concentrations, when measured by BCG, which complicates the interpretation of hypoalbuminemia in epidemiological and clinical studies. In patients with varying degrees of inflammation and oxidative stress such as proteinurics and patients on chronic HD therapy, the albumin detection efficacy of the BCG assay is greatly decreased.
Consequently, the measured COP values are higher than expected for these "hypoalbuminemic" patients. The assumption that serum albumin levels are higher than measured was supported by COP measurements, used to indirectly assess albumin concentrations, in two types of experiments: in purified albumin from HD and HC subjects and in experiments where albumin was oxidized in-vitro.
It is postulated that the effect of "true" hypoalbuminemia on COP in acute illness is, at least in part, counterbalanced by an increase in the concentration of other plasma proteins, namely globulins and acute phase proteins [ 10 ]. Although COP in this study was measured in serum, where fibrinogen an established acute phase protein is theoretically absent, the coagulation abnormalities which exist in HD patients [ 11 ] may lead to some residual fibrinogen in sera.
Globulins — kDa are not acute phase proteins. However, in studies using mathematical calculations for assessment of COP, globulins have been suggested to play a role in maintaining COP [ 12 ]. We demonstrate that even a major increase of globulins, as shown in some clinical conditions [ 13 ], would add only 1. As patients with hyperglobulinemia were excluded from this study, there could not be a contribution of fibrinogen and IgG to the "oncotic gap".
Both OS and intracellular redox status are involved in inflammation and aging [ 14 ]. Hypoalbuminemia, inflammation and OS are biologically linked, as demonstrated by the correlations between the levels of inflammatory and OS biomarkers in hypoalbuminemic and normo-albuminemic HD patients [ 15 ]. This link is supported by the current study: the changes in the OS markers, AOPP and albumin detection index, are related to the degree of systemic inflammation Table 1. A potential weakness of the study is the lack of strict age-matched controls.
To assess the possible confounding effects of age on the index and on the associated COP, we investigated the correlations between these parameters and age in our HC group. Age did not correlate with the index nor with COP data not shown , thus ruling out age as a confounding factor. The existence of an "oncotic gap" between HD patients and proteinuric patients of similar ages further supports the notion that the oxidation of albumin, and not the subject's age, is a major contributor to this phenomenon.
This is explained by the differences in oxidative modifications between these samples. AGE-albumin is a single modification adduct, with a very dominant effect on the index [ 4 ]. In contrast, the purified HD-albumin contains various modifications such as AGEs, carbonyls, AOPP, oxidized thiols and other modifications [ 4 , 8 , 9 , 16 — 19 ], each with a different potential to decrease the index.
Hence, although index values and the albumin concentrations appear to be similar, COP values may differ. The effect of oxidative modifications on albumin aggregation [ 20 ] may also influence COP measurements by decreasing the number of molecules, i. This may be related to the absence of edema in these apparently hypoalbuminemic patients [ 21 ] and certainly deserves further investigation. Hypoalbuminemia associated with large urinary losses of protein, which decreases albumin levels, may also be associated with albumin modification and variability in the measurements by BCG [ 7 ].
Consequently, other methods for differentiation of true and apparent hypoalbuminemia are required. Other clinical methods include bromocresol-purple BCP and immuno-nephelometry. These methods are based on binding a reagent to the albumin molecule, and are compromised by oxidative modifications [ 4 ].
Moreover, a Bland-Altman analysis indicated a difference between BCG and immuno-nephelometry, that declines as albumin levels decrease, suggesting that these two methods show the highest similarity in the hypoalbuminemic range of albumin levels supplementary data, Pannel B in S1 Fig. Methods such as optical density OD and COP are insensitive to albumin oxidation, but are not albumin-specific, and the required albumin-purification steps limit their clinical use.
Yet, COP may be used potentially as a tool for "differential diagnosis" between true hypoalbuminemia states that originate from decreased albumin production or albumin loss to those originating from decreased detection.
The rate of albumin synthesis is influenced by multiple factors including nutrition, inflammation, hormone status, and oncotic pressure. Increased COP decreases albumin gene expression [ 1 , 22 ], and in healthy animals is a primary determinant of albumin synthesis rate [ 23 ]. Numerous studies have pointed the importance of hypoalbuminemia in cardiovascular disease CVD of HD patients, suggesting hypoalbuminemia BCG-measured as a predictor of vascular morbidity and mortality [ 24 ].
These mechanisms suggest oxidized albumin as a pathogenic factor with a potential to initiate and accelerate atherosclerosis. The fact that albumin levels are systematically underestimated is shown by normal COP values. Serum albumin levels are commonly used for epidemiological studies, although without knowledge about the oxidative stress of the patients it is impossible to distinguish between true and apparent hypoalbuminemia.
Since COP correlates with total serum albumin even when modified or oxidized, this measure has potential benefit in developing unique assays for improved assessment of true hypoalbuminemia. The Bland-Altman analysis B indicated a difference between the results of these assays. This difference declines as albumin levels decrease, suggesting that the highest similarity between these methods is in the hypoalbuminemic range of albumin levels.
0コメント