Length of hospitalization is associated with selected biomarkers (albumin and lymphocytes) and with co-morbidities: study on 4000 patients
© The Author(s). 2017
Received: 13 December 2016
Accepted: 6 March 2017
Published: 21 March 2017
Low albumin levels and low lymphocyte counts are intra hospital conditions that exert a negative influence on prognosis, healing and length of hospitalization. The study aimed to analyze the correlation between low blood levels of albumin, low lymphocytes, and length of stay. The secondary aim was to identify other co-morbidities associated with prolonged hospital stay.
Retrospective pilot study was conducted by analyzing anamnestic and biochemical data, related to 4038 patients admitted to ten wards of Hospital San Paolo (Milan), collected from July 1st 2012 to December 31st 2012. A statistical analysis was carried out using the Correlation method, Multivariate Analysis and Regression. Lymphocyte count and co-morbidities were evaluated in the whole cohort, albumin levels in 1437 patients.
In the whole sample, low albumin levels and low lymphocyte counts were directly correlated to longer hospitalizations. The stratification of the results by department and diagnosis suggests that there is a higher correlation in certain subpopulations, and albumin shows a greater correlation with length of stay than lymphocytes. Also advanced age, high platelets, type of diagnosis, male gender and emergency admission led to longer hospitalizations.
A routine check of albumin, lymphocytes and a spectrum of significant variables can provide precious information which can eventually lead to a shorter hospital stay. Knowledge of the general health status of a patient and the possibility to estimate his/her length of hospital stay are essential information for Clinical Governance, and for the improvement of internal services of hospitals on a large scale.
KeywordsAlbumin Lymphocytes Length of stay Co-morbidities Screening method
Low levels of albumin and lymphocytes are highly correlated with prolonged hospitalizations.
Platelets, advanced age, number of co-morbidities, diagnosis, gender, urgent admission are also associated with prolonged hospitalizations
This routine screening will improve the hospitals internal healthcare along with helping to better allocate hospital resources in terms of budget and personnel; even for a clinical audit.
According to recent studies low albumin levels and low lymphocyte counts are the frequent in hospitalized patients, representing negative conditions with a negative impact on prognosis and length of stay (LOS) [1, 2]. Actually, albumin and lymphocyte count are biochemical parameters successfully used in common clinical practices for highlighting and monitoring certain specific diseases . Because of their importance in human biology and the variety of biochemical processes in which they take part, these markers are indices of general organic damage, unfavourable prognosis and malfunction; even if their role in determining nutritional status and length of stay is still debated [2, 4–14]. The ultimate goal of this study is to raise awareness among physicians about the health status of hospitalized patients, based on lymphocyte count and albumin levels at admission.
The main objective is to verify the correlation between serum albumin levels, lymphocyte counts and length of stay in a vast hospital population, together with various blood parameters and patient history. We would like to create an innovative, economical and standardized screening method, based on albumin, lymphocyte count and an analysis of co-morbidities, in order to assess the organic status of patients and predict the length of recovery at admission. These informations would give the opportunity to improve the organization of hospitals internal services, giving patients better treatments and shortening hospitalizations and reducing social costs associated with long waiting times and incorrect diagnosis [15, 16].
Study design, setting and participants
This is a retrospective cohort study, which took place in Hospital San Paolo of Milan after the study protocol was approved by the local Ethics Committee. The study included all the patients in the following wards: Surgery (1st and 2nd ward), Gynecology, Obstetrics, Infectious Diseases, Medicine (1st, 2nd, and 3rd ward), Orthopedics, and Urology. The observation period was July 1st 2012 - December 31st 2012. Day Hospital patients were excluded from the study (since the study tested how low levels of albumin and lymphocytes influenced the length of stay). Data collection, through electronic charts, included recording of anamnestic data such as gender, age, date of admission and discharge, type of diagnosis, concomitant diseases (identified by the specific International Classification Code of Diseases) and biochemical indices like complete blood count with lymphocytes count and albumin measured during the first 24–48 h. Starting from electronic charts, we created an Excel database containing all informations registered for all patients, divided according to the ward of admission. Raw data was critically examined using the method of descriptive statistical analysis, and the results were stratified by type of admission (elective or urgent), by ward, and diagnosis.
The SAS 9.3 software and its related modules (SAS MACRO and SAS GRAPHS) were used for data cleansing, statistical models, descriptive statistics and graphs. JMP 11 was also used to enhance the models and the graphs. Using the Correlation method we studied the relationship between albumin, lymphocytes, and length of stay, verifying its extensibility in the various wards, then divided the patients by diagnosis and lastly studying the entire hospital population. To obtain a good statistical analysis we include the most popular wards. The sample was then divided into eight main “classes of diagnosis”, based on the main types of diseases observed in our hospital population: Malignant tumors, Benign tumors, Inflammatory diseases, Infections, Bleeding conditions, Fractures, Pregnancy/Childbirth and Other. Even in this case statistical analysis was performed in order to examine type and intensity of the relationship between the hospital stay and low albumin and lymphocytes levels. At a later stage we used Regression analysis to highlight which other factors could influence length of stay, using Generalized Linear Models method (GLM). Finally, we studied the behavior of the variable “days of hospitalization” as a function of the number of co-morbidities. Correlation was evaluated using Pearson’s parametric coefficient while bivariate distribution was graphically represented using scatter plots.
For a more detailed and complete analysis we evaluate if there is a difference between two particular subgroups of the test sample: patients in which the albumin was measured and patients who do not present the value. The methodologies used to study the two groups were the Discriminant function analysis and the Multivariate stepwise method.
Analysis on the entire sample
Evaluation of lymphocytes and albumin performed within 24–48 h of admission
Main patient’s characteristics
63.95 ± 19.67
66.58 ± 17.80
49.72 ± 16.58
36.17 ± 6.93
55.57 ± 17.04
80.29 ± 14.61
79.59 ± 14.92
79.57 ± 15.91
68.01 ± 21.88
67.74 ± 16.13
60.27 ± 22.90
Frequency of albumin and lymphocytes cases within normal range of laboratory
Within normal range
% Normal range
Within normal range
% Normal range
Correlations between albumin, lymphocytes, co-morbidities, and length of hospital stay
Stratification of results by hospital ward
Correlation between albumin and lymphocytes and length of hospital stay, by ward
Stratification of results by diagnosis
Correlation between albumin and lymphocytes and length of hospital stay, by diagnosis
Multivariate Analysis and Regression
Regression analysis – estimates of maximum likelihood
Lim. Conf. < 95%
Lim. Conf. > 95%
x 2 Wald
Pr > x 2
Number of Comorbidities
Red Blood Cells
Pregnancy and childbirth
Likelihood ratio – significance analysis
Pr > X 2
Number of Co-morbidities
Inflammatory diseases excluded
Stepwise selection for patients with albumin value
Summary of stepwise selection
Pr > F
Pr < Lambda
Average Squared Canonical Correlation
Pr > ASCC
Age at recovery
Days of recovery
White blood count (WBC) 10^3/ul 4.0 – 10.0
Monocytes (absolute nr) 10^3/ul 0.2 – 1.0
Mean corpuscular hemoglobin concentration (MCHC) g/dl 31.5 – 34.5
Platelets (PLT) 10^3/uL 150 – 450
Eosinophils (absolute nr) 10^3/ul 0.0 – 0.5
Summary: aims and main results
The correlation between reduced albumin levels and prolonged hospitalization applied to the entire sample and to almost all hospital wards (except for gynecology and obstetrics), and also to certain diseases like benign tumors and inflammatory diseases. Even though a low blood lymphocyte count was associated with longer LOS in the entire sample, the results were only significant in the ward of orthopedics and surgery. Only for the diagnosis of certain clinical conditions like infectious diseases, fractures and pregnancy/childbirth, a low blood lymphocyte count correlated with prolonged hospital stay. Using the regression method platelets, advanced age, number of co-morbidities, diagnosis, gender and type of admission were significant variables associated with prolonged hospital stay, yielding important information that could be used to improve current nutritional screening tools.
Possible mechanisms and explanations for the findings
Our results indicate that low albumin levels have a close correlation with longer hospital stays, while the relationship with lymphocyte count is only marginal, in accordance with previous studies . Low lymphocyte counts lead to prolonged hospitalization mainly in the presence of infectious diseases, probably because lymphocytes play a critical role in the immune response against the pathogens involved. In the orthopedics ward, a decreased lymphocyte count leads to a significant increase in hospital days, mainly due to trauma and/or inflamation [7, 18, 19]. ACTH, corticosteroids, catecholamines, cytokines, chemokines and allarmines play an important role in the initiation and maintenance of the inflammatory response to injury, and also in the regulation of the albumin gene expression . The complex network of cytokines appears to be disrupted, especially after surgery . Interleukin-1β, -6, -8 and TNF-α, some suppressive cytokines such as Interleukin-10, -4 and Interleukin-1 receptor antagonist significantly increase just after the beginning of surgery, while Interferon-γ and Interleukin-2 are markedly reduced . This imbalance alters the immune response and may in part explain the correlation between low levels of lymphocytes and length of stay found in surgery ward I.
Strengths and limitations of the study
The main strengths of this study consist in the large amount of data at our disposal, and in the homogeneity of the sample, obtained through the standardization linked to the use of patient electronic charts; this allowed to identify various pathologies and co-morbidities through the use of international codes. The results obtained confirm the hypothesis that low albumin levels and low lymphocyte counts are associated with increased length of stay; the relationship applied to the entire sample examined, and the strength of correlation was higher in some wards, and might be applied to any kind of hospital.
This study has also highlighted some critical points of the clinical approach: limited evaluation of albumin at admission, and inability to trace the anthropometric data of patients. Anthropometric data and albumin levels were regularly measured before surgical procedures, in order to properly administer general anesthesia, antibiotics, or chemotherapeutic drugs, but not to determine the patient general health status. Clinicians carelessness about nutritional status has led to a general disinterest for important parameters such as weight, height, BMI and selected biochemical markers [21, 22]. Albumin measurement is an important low-cost instrumental exam, still marginally used in hospitals. Also anthropometric data are important for the assessment of nutritional status, but they are rarely measured, even though recent studies confirmed that these parameters represent the most predictive factor in determining the risk of complications: for instance, BMI values below 20 kg/m2 determine hospital stays 2.1 times longer compared to hospitalization for BMI within normal range; albumin and lymphocytes severely affect the length of hospitalization [23–26].
The importance of an early assessment of albumin and lymphocytes
The present study has highlighted the importance of an early assessment of albumin levsls. Low levels of albumin can be caused by various factors, like decreased food and calorie intake due to hospitalization , prolonged fasting , surgical operations , postural changes , cytokines , drugs , hormonal therapies , inflammatory diseases, liver and kidney diseases, cancer, infections and all medical conditions characterized by high metabolic energy requirement. Sepsis, for instance, can influence synthesis, consumption, and distribution of albumin between intra and extravascular compartments [11, 12, 18]. Rapid changes in albumin levels are common after admission, and the “sink rate” is very rapid especially after admission. Researchers have suggested that the sink rate is too fast to be associated only with patients nutritional deterioration . Posture modification, from standing to reclined position, was shown to cause a decrease in serum albumin: the production of TNF-α, Interleukin-2 and -6, inhibits the synthesis of albumin by acting on its gene expression, through a down-regulation process . Since lymphocytes are involved in the immune response, decreased lymphocyte counts are considered an indicator of the general decline of physiological functions, and factors of poor prognosis in hospitalized patients .
Clinical implications and future perspectives
With this research we intended to raise clinicians attention to the importance of albumin and lymphocytes to assess the status of hospitalized patients. It would have been useful and important to evaluate also patient anthropometric parameters which would have given the study a more complete analysis. These health indices, once routinely recorded by nursing staff, are now considered as the major reason of wasting time dedicated to more invasive clinical procedures. Therefore in light of the fact of there being no screening method universally accepted, we aim to provide guidelines for the assessment of patients health status in different contexts (community, hospitals, patients with specific diseases, etc). Low albumin levels and low lymphocytes count are directly related to longer hospital stays, and therefore the alteration of these markers causes a further deterioration of the nutritional status, thus promoting a cycle of malnutrition-infection leading to the onset of protein-energy malnutrition, a self-perpetuating process with a strong influence on patient outcomes (poor wound healing, loss of muscle strength, decreased mobility, increased risk of thromboembolic complications [27, 28]), length of stay and associated costs [29, 30].
Our challenge for the future is to convince clinicians on the importance of assessing albumin and lymphocytes and eventually doing a whole nutritional assessment of the single patient.
We can conclude portraying the data of a study conducted in 2003 in which it has been described that with a reduction of 1 g/dl in serum albumin, hospital days had increased by 71% . This finding grabbed our attention; in our study 924 patients had an albumin concentration below the lower limit (3.5 g/dl) of which 750 with a reduction of 1 g/dl, 169 with a decrease of 2 g/dl and 5 with less than 3 g/dl. Considering that for each gram lost of albumin there is a theoretical probability 71% increase in longer hospitalization and that albumin in our sample was evaluated in only 36% of our cases, and assuming that the distribution of the decline of albumin may be similar even in the population which albumin has not been evaluated, there are three questions to be asked: how many days patients have unnecessarily spent in hospital? How much have these additional days of hospitalization weighed, from an economic point of view, in the absence of albumin assessment? And more important, how much the extra days of hospitalization would have not economically impacted the hospital with an appropriate nutritional assessment? Exploiting new clinical knowledge and investing time to ensure maximum therapeutic benefit for each patient means to act in the interest of the community. One should invest time and resources during the first steps of admission, in order to assess patients real health status, and to create a personalized plan for recovery. This important concept is the rationale that guided us to conduct this research, but it should also be the reason that accompanies any decision of each health care professional in his profession.
Body impedance assessment
Generalized linear models
Length of stay
We thank Dr. Gerardo Cioffi, native speakers, for reviewing the English language
No source of funding has a role in the study’s design, conduct, and reporting.
Availability of data and materials
“Availability of data and materials” supporting their findings can be found.
All those designated as authors meet all four criteria for authorship having covered a specific role in writing the manuscript, as stated in the ICMJE Recommendations. AEP designed research; MR, LL, FR and AB conducted research and wrote the paper; LF reviewed the manuscript; EDP analyzed data and reviewed statistical section; each Author had a specific responsibility for final content, LF, MDS and UC reviewed the manuscript, analyzed data and reviewed statistical section; each Author had a specific responsibility for final content. All Authors read and approved the final manuscript.
We confirm that there are no known conflicts of interest associated with this work and there has been no significant financial support that could have influenced its outcome.
Consent for publication
Written informed consent was obtained from the patients of this study for the publication of personal data and images
Ethics approval and consent to participate
This retrospective study took place in Hospital San Paolo of Milan after the study protocol was approved by the local Ethics Committee.
Written informed consent to participate was obtained from the patients included in the study.
We provide as attachments the database containing all the information collected to perform the study and all documents related to it (Additional file 1) (Ethics Committee approval, informed consent, consent for the processing of personal data, study protocol and synopses).
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