Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Albumin is a transparent or slightly opalescent solution which may have a greenish tint or may vary from pale straw to amber color. Albumin may be given undiluted. Acceptable diluents include 0. Do not mix or add with other medicinal products including blood and blood components, protein hydrolysates, or solutions containing alcohol.
Do not add supplementary medication. Storage: Administer within 4 hours of entering the container. More rapid administration can cause circulatory overload and pulmonary edema. Generic: - Store below 86 degrees F Albuked : - Avoid temperatures above 86 degrees F - Discard product if it contains particulate matter, is cloudy, or discolored - Discard unused portion.
Do not store for later use. Albumarc: - Avoid temperatures above 86 degrees F - Discard product if it contains particulate matter, is cloudy, or discolored - Discard unused portion. Albuminar: - Discard product if it contains particulate matter, is cloudy, or discolored - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F Albuminex: - Avoid temperatures above 86 degrees F - Discard product if it contains particulate matter, is cloudy, or discolored - Do not freeze - Protect from light - Store in carton AlbuRx : - Discard product if it contains particulate matter, is cloudy, or discolored - Store at room temperature not exceeding 86 degrees F Albutein: - Avoid temperatures above 86 degrees F - Discard product if it contains particulate matter, is cloudy, or discolored - Discard unused portion.
Buminate: - Avoid temperatures above 86 degrees F - Discard product if it contains particulate matter, is cloudy, or discolored - Discard unused portion. Flexbumin: - Discard product if it contains particulate matter, is cloudy, or discolored - Discard unused portion. Macrotec: - Refrigerate between 36 and 46 degrees F Plasbumin: - Avoid temperatures above 86 degrees F - Discard product if it contains particulate matter, is cloudy, or discolored - Discard unused portion.
Use of albumin is contraindicated in patients with a history of albumin hypersensitivity or hypersensitivity to any of the excipients. Discontinue administration immediately and institute appropriate medical treatment if a hypersensitivity reaction is suspected.
Albumin is contraindicated in patients with severe anemia or heart failure with normal or increased intravascular volume. Monitor coagulation and hematology parameters when large volumes are replaced.
Ensure adequate substitution of other blood constituents e. Monitor electrolyte status and take appropriate steps to address electrolyte imbalance. Discontinue albumin administration at the first sign of cardiovascular overload e. Albumin increases plasma volume and can cause vascular overload, especially after rapid infusion.
Monitor blood pressure in trauma and postoperative surgery patients in order to detect rebleeding secondary to clot disruption. Closely monitor hemodynamic parameters for evidence of increased intracranial pressure and cardiac, respiratory, or renal failure in all patients.
Accumulation at concentrations associated with central nervous system and bone toxicity is more likely to occur in patients with renal disease or in premature neonates with immature kidneys. Albumin is a derivative of human blood. As with other products derived from or purified with human blood components, the remote possibility of contamination with Creutzfeldt-Jakob disease CJD or other viral infections exists in patients receiving albumin.
The manufacturing processes are designed to reduce the risk of transmitting viral infection. No cases of transmission of viral illness or CJD have ever been identified for albumin. Report all infections thought to have been transmitted by albumin to the manufacturer. Patients with marked dehydration require the administration of additional fluids when treated with concentrated albumin.
Monitor patients carefully to guard against circulatory overload and hyperhydration. It is not known whether albumin products can cause fetal harm or affect reproductive capacity when administered to a pregnant woman. No human or animal data are available to indicate the presence or absence of drug-associated risk with albumin use during pregnancy.
It is not known whether albumin is excreted in human milk. No human or animal data are available to indicate the presence or absence of drug-associated risk with albumin use while breast-feeding. Exogenously administered albumin increases the oncotic pressure of the intravascular system, pulling fluids from the interstitial space, thereby decreasing edema and increasing the circulating blood volume.
This increase in volume reduces the concentration and viscosity of blood in patients with decreased circulating blood volume and also maintains cardiac output in shock.
In dehydrated patients, albumin has little or no clinical effect on circulating blood volume. Albumin is also used to replace protein in patients with hypoproteinemia until the cause of the deficiency can be determined. In addition, exploratory analyses are planned. These analyses include measurement of effects of the different infusion rates on plasma concentration of markers of endothelial damage and on hormones involved in fluid homeostasis.
The dose administered to each patient is recorded in the case report form CRF, Additional file 4. The dose in the syringes is determined from their increased weight multiplied by an activity concentration from a standard.
This standard was prepared from a small sample from the I-HSA vial added to a test tube and measured for both activity and weight. Injected doses are corrected for remaining activity in the syringes. Haematocrit is measured by colorimetric analysis using a blood gas analyser Radiometer ; Radiometer, Copenhagen, Denmark. Assuming that no blood loss occurs during the study period, changes in haematocrit will reflect changes in plasma volume.
By this methodology, plasma volumes can be estimated every half-hour during the infusion of albumin. By measuring plasma volume with I-HSA at three different points in time, the potential effect of alterations in small- to large-vessel haematocrit can be corrected [ 19 ]. The area under the plasma volume curve will then be calculated for each patient plasma volume over time. The TER for albumin is a measure of leakage of albumin from microvessels into the microvasculature.
Changes in TER reflect changes in microvascular permeability and changes in parameters influencing convective transport of albumin such as transvascular hydrostatic pressure. Plasma concentration of I-HSA is measured at 10 minutes, 30 minutes, 45 minutes and 60 minutes after the last injection of the tracer.
Plasma concentration of I-HSA as a function of time will be plotted in a log-linear plot. The slope of the line represents TER and will be expressed as the percentage decrease in plasma concentration of I-HSA per hour [ 20 — 22 ].
For a summary of measurements, please see Fig. All study data will be recorded in CRFs for each patient, which are kept at the study site. Information on co-morbidities, medications, results of pre-operative physical examinations, routine laboratory analysis results, American Society of Anesthesiologists physical status classifications, Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity and Revised Cardiac Risk Index will be collected from the hospital electronic chart system.
Peri-operative data will be collected from the anaesthesia chart, and data that will be registered include anaesthesia methods and drugs, type and volume of fluids, peri-operative bleeding, and diuresis. Inclusion criteria will be registered in CRFs before randomisation. Clinical haemodynamic evaluation will be performed and recorded at inclusion and at minutes after the start of albumin infusion.
Members of the research team have unlimited access to study data. The data collected in the present study will be available from the corresponding author on reasonable request.
The auditing see below will include source data verification. In the present study, we wish to compare differences in changes in plasma volume, and it is reasonable to assume that the SD is in the lower part of this range. To adjust for a slightly lower than expected treatment effect and for the possibility that patients may not complete the protocol, we intend to include a total of 70 patients: 35 patients in each arm. The study will continue until the planned number of patients has been included, unless the interim analysis indicates that the study should be stopped.
Results will be unblinded when all data have been collected. The investigating team will perform the statistical analyses. Baseline variables of patients fulfilling study protocol in the two study arms will be tabulated. Discrete variables will be reported as frequencies and percentages, and continuous variables will be reported as either means with SDs or medians with interquartile ranges.
In the event of no difference between the groups with regard to primary outcome and a difference in the secondary outcome of plasma volume over time, we will interpret these results as supporting our hypothesis but that confirmatory studies are needed. With the exception of number of complications, all other outcomes are regarded as exploratory, and no emphasis will be placed on differences between the treatment groups, should the primary outcome and plasma volume over time outcome be negative.
A sensitivity analysis using multivariate regression will be performed to assess if treatment effect is dependent on type of surgery and baseline plasma volume. The purpose of auditing and quality control is to ensure scientific integrity, data quality, the safety and integrity of the participating subjects, and that the study is compliant with the current versions of the Declaration of Helsinki, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, good clinical practice and national regulations.
Considering that the patients will be treated according to normal routine during major abdominal surgery, that the infusion rates and volumes are within the normal range, and the low frequency of adverse events AEs in an earlier large prospective randomised clinical trial comparing albumin with normal saline in an ICU setting, the study will be performed without the use of a data monitoring board [ 23 ]. An independent statistician will perform an interim analysis for assessment of efficacy and futility after 36 patients have completed the protocol.
The Haybittle-Peto approach will be used when testing for efficacy. The results of each simulation will be combined with the obtained data.
Should the observed SD in interim analysis be higher than that used in the power calculation, the higher number will be used for the simulation. The principal investigator has the authority to stop the trial. A SAE is defined as an event that fulfils one or more of the following criteria: results in death, is life-threatening, requires prolongation of hospitalisation, results in persistent or significant disability or incapacity or any other important medical event.
Depending on the nature of the AE or SAE, the treatment will take place at either the trial centre, the local hospital or as an outpatient. Following completion of the trial, the main manuscript will be submitted to a peer-reviewed journal, regardless of the trial outcome. The diagram will include the number of screened patients, the number of patients giving consent, the number of patients meeting all inclusion criteria, the number of patients randomised to each of the two treatment arms, and the number of patients completing the protocol in each of the treatment groups.
The second figure will depict plasma volumes in the respective groups at baseline and at 30 minutes and minutes after the start of albumin infusion. The first table will describe baseline demographics as detailed above. The second table will describe secondary outcomes.
Authorship will be granted according to the criteria described by the International Committee of Medical Journal Editors [ 24 ]. Other than funding, the funders have no role in any aspect of the trial. The AIR study will provide clinical data on the importance of infusion rate for the plasma volume-expanding effect of colloids in patients with suspected hypovolaemia after major abdominal surgery.
The decision to include patients subjected to a Whipple procedure or major gynaecological surgery is based on the clinical experience that these patients often appear hypovolaemic in the immediate post-operative period and thus are likely to require fluid resuscitation. Post-operative hypovolaemia in these patients is at least partly due to vascular leak secondary to the systemic inflammatory response initiated by the operation, and these patients are therefore likely to share pathophysiological mechanisms with other critically ill patients requiring fluid resuscitation [ 25 ].
Given the transient nature of the need for fluid resuscitation in the majority of these post-operative patients, the immediate post-operative period was believed to represent the optimal time point for our purposes. Albumin is chosen as the study colloid because albumin is a naturally occurring colloid with very few contraindications in the current setting and with an excellent safety record [ 23 ]. The rates of infusion are chosen to differ as much as possible within the range of clinical practice for this patient category.
Plasma volume measurement using I-HSA is considered to be the gold standard for measurement of plasma volume and is used clinically in many hospitals worldwide. The radiation dose received by the patients due to participation in the study is approximately 0. Therefore, in accordance with World Health Organisation guidelines, patients will not receive treatment with potassium iodide to block thyroid uptake of radiolabelled iodine.
Measurement of TER for albumin is commonly used to evaluate vascular leak of albumin. After a bolus dose of I-has, there is a steep decline in plasma concentration during the first 10 minutes, which is thought to represent mixing and distribution into a rapidly equilibrating space. After the first 10 minutes, the rate of decline in plasma concentration of I-HSA reflects extravasation and a gradual increase in lymphatic return of the tracer.
To minimize the influence of lymphatic return on the decrease in in plasma concentration of tracer, TER is measured during the first hour after injection. It could be argued that recirculation of I-HSA from the two preceding plasma volume measurements see Fig.
On the basis of these assumptions, it can be estimated that recirculation will have a negligible influence on a difference in TER between the two treatment groups Additional file 5. This conclusion aligns with results from a similar analysis concerning repeated TER measurements in patients with sepsis [ 28 ].
Recruitment has been completed. The interim analysis has been performed, and no reason to halt the study has been found. No SAEs have been registered to date. Andersson at the Department of Laboratory Medicine for valuable assistance in various aspects of study conduct.
SS was responsible for study design, study coordination and conduct, and manuscript preparation. JB was responsible for study conduct and manuscript preparation. BB was responsible for study design and manuscript preparation. EL was responsible for study conduct and manuscript preparation.
PK was responsible for study design and conduct as well as manuscript preparation. BT was responsible for study design, study conduct and manuscript preparation. PB was the principal investigator and sponsor and was responsible for study design, study coordination and conduct, and manuscript preparation. All authors read and approved the final manuscript. The trial will be conducted in accordance with the protocol, applicable regulatory requirements, the principle of good clinical practice and the Declaration of Helsinki.
All patients will be given the opportunity to ask questions about the study and will also be given sufficient time to decide whether to participate in the study. Patients will be informed of their right to withdraw from the study at any time.
As a consequence of participation in the study, the patients will be subjected to a blood loss of 86 ml. DOC 99 kb. Effect of tracer recirculation on measuremnet of transcapillary escape rate for albumin.
DOCX kb. Svajunas Statkevicius, Email: es. Johan Bonnevier, Email: es. Bark, Email: es. Erik Larsson, Email: es. Carl M. Bobby Tingstedt, Email: es. National Center for Biotechnology Information , U. Journal List Trials v. Published online Dec 7. Bark , 1 Erik Larsson , 2 Carl M. Author information Article notes Copyright and License information Disclaimer. Corresponding author. Received Dec 6; Accepted Nov This article has been cited by other articles in PMC. Abstract Background Administration of fluids to restore normovolaemia is one of the most common therapeutic interventions performed peri-operatively and in the critically ill, but no study has evaluated the importance of infusion rate for the plasma volume-expanding effect of a resuscitation fluid.
Discussion The present study is the first clinical investigation of the importance of infusion rate for the plasma volume-expanding effect of a resuscitation fluid. Trial registration EudraCT identifier: Electronic supplementary material The online version of this article doi Background Major surgery initiates a systemic inflammatory response syndrome SIRS , which disrupts the normal regulation of transcapillary fluid exchange with tissue oedema and hypovolaemia as a consequence. Open in a separate window.
Exclusion criteria Patients fulfilling any of the following criteria will be excluded from the study: Hypersensitivity to the active drug or the tracer Signs of post-operative bleeding History of heart failure The physician caring for the patient considers that there are strong reasons to administer another fluid, or the same fluid but in another way or in a different volume than stated in the protocol Pregnancy Clinical judgement by the investigator or the treating physician that the patient should not participate in the study for reasons other than described above.
Informed consent and withdrawal Patients scheduled for the operative procedures described above will be assessed for inclusion. Intra- and post-operative care of the patients Eligible patients who have given consent to participate in the study will receive routine pre- and intra-operative care. Randomisation and blinding Patients are screened for indications for fluid administration during the first 5 h after admission to the PACU as described above.
Primary outcome The primary outcome in the study is change in plasma volume minutes after the start of the albumin infusion. Secondary outcomes Secondary outcomes are differences in plasma volume over time integral of plasma volume over time from the start of albumin infusion from plasma volume PV1 to PV3 and incidence of post-operative complications up to 30 days post-operatively see Additional file 3 for definitions of complications.
Data collection and management All study data will be recorded in CRFs for each patient, which are kept at the study site. Statistical analysis plan The study will continue until the planned number of patients has been included, unless the interim analysis indicates that the study should be stopped. General analytical principles Analysis will be performed on a per-protocol basis.
All hypothesis tests will be two-sided, with a maximal type I error risk of 0. Subgroup analysis will be performed regardless of overall treatment efficacy. Imputation will not be used to correct for missing data in the analysis. Assessment of baseline variables Baseline variables of patients fulfilling study protocol in the two study arms will be tabulated. Subgroup analysis A sensitivity analysis using multivariate regression will be performed to assess if treatment effect is dependent on type of surgery and baseline plasma volume.
Auditing The purpose of auditing and quality control is to ensure scientific integrity, data quality, the safety and integrity of the participating subjects, and that the study is compliant with the current versions of the Declaration of Helsinki, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, good clinical practice and national regulations.
Interim analysis An independent statistician will perform an interim analysis for assessment of efficacy and futility after 36 patients have completed the protocol. Discussion The AIR study will provide clinical data on the importance of infusion rate for the plasma volume-expanding effect of colloids in patients with suspected hypovolaemia after major abdominal surgery.
Trial status Recruitment has been completed. Competing interests The authors declare that they have no competing interests. Ethics approval and consent to participate The trial will be conducted in accordance with the protocol, applicable regulatory requirements, the principle of good clinical practice and the Declaration of Helsinki.
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