Analysis of survival for patients in relation to central venous catheter and nosocomial blood stream infections : A case study

This study was focussed on survival rates of patients Background: admitted to acute care units who utilized medical devices known as central venous catheters (CVC). CVCs are useful devices in clinical care; however some infections such as central line associated bloodstream infections (CLABSI) may occur, which are associated with increased lengths of stay and costs as well as higher morbidity and mortality rates. The overall objective of the present study was to determine survival probabilities and hazard rates for patients who used CVC devices and compare the subgroups by infection status. The study was focused on all patients who were admitted to Methods: Critical Care Units between 8 December 2012 and 31 March 2016 and utilized CVC devices. It was a retrospective study. Survival analysis techniques, test of equality of proportions, Man-Whitney test and Chi–square test of independence were used. A total of 363 out of 1089 patients included in the study died Results: during hospitalization. 47 patients developed nosocomial CLABSI. The average duration was 18.19 days and median of 12 days for hospitalized patients who did not develop a nosocomial CLABSI compared to an average of 56.79 days and a median of 51 days for those who did. There was a significantly higher proportion of mortality of those who developed nosocomial CLABSI compared to those that didn’t (p-value=0.01379). The results indicate that there was a significant association between infection status and discharge status, and significant difference to the survival rates of the patients based on infection status. There is a significant impact on mortality and morbidity of Conclusions: patients who develop nosocomial CLABSI. The duration of hospitalization by patients who developed CLABSI was significantly higher compared to patients who did not. Increased length of stay leads to higher cost of hospitalization.


Introduction
Central line associated bloodstream infection (CLABSI) is a type of infection that affects patients who utilize central venous catheter (CVC) during their hospitalization. CVC refers to any central venous access device inserted into the internal jugular, subclavian or femoral vein that terminates in the inferior vena cava or right atrium 1 . CVCs are commonly used in wards and critical care units, such as the intensive care unit (ICU), and they are also referred to as central lines. In accordance with The Joint Commission (2012), CVCs are essential in health care provision as they facilitate administration of medications, intravenous fluids, and hemodialysis among other functions. CVCs are used both in the in-patient and out-patient clinical care management 2 .
According to The Joint Commission (2012), there are a variety of CVCs available in various sizes as well as different catheter materials, for example CVCs can be single or multi-lumen (double, triple or quadruple lumen). Another categorization by design classifies them as tunnelled catheters, non-tunnelled catheters, peripherally inserted central catheters and implantable ports 2 . The choice of catheter is as a result of defined need and preferences of the clinical care giver or the patient. Every catheter device carries with it some risk of infection, however, the extent of risk depends on the type of catheter used 3 .
Healthcare associated infection (HAI) refers to infections that occur in the course of healthcare management in any setting, more specifically, the infections acquired during hospitalization are referred to as nosocomial infections 2,4 . US Centers for Disease Control and Prevention (2016) observed that there was ~46% decrease in CLABSIs in hospitals across the U.S.A from year 2008 to 2013, whilst about 30,100 still occurred in critical care units and wards 5 . There was a declaration by the European Union that policy on HAI prevention be prioritized in 2008 6 .
Several studies have linked CLABSIs to prolonged hospitalization and increased health management cost, as well as increased morbidity and mortality 2,7-12 and 13. Morgan et al.
(2010) conducted a five year study, in which the authors established that HAIs, especially CLABSIs, contributed to about one third of unexpected in-hospital mortality 13 . Soufir et al. (1999) conducted a prospective, matched cohort study from 1 st January 1990 to 31 st December 1995, in two ICUs in Paris, France and deduced that for ICU survival rates, the risk of death was significantly increased in patients with catheter related septicaemia as compared to control patients who did not develop septicaemia, with a relative risk of 2.06 (95% CI, 1.16-3.68; p-value <0.05) 8 . Garnacho-Montero et al. (2008) found that the median time from insertion of the catheter to the development of bacteraemia was 10 days. Further, 18 out of 66 patients died in the ICU (27.3%) 10 .
However, various studies face a myriad of challenges which may be attributed to difficulties in estimating the mortality resulting from blood stream infections 8 (2007) observed that it may not be easy to determine the patients who die "with" CLABSI compared to those who die "because of" CLABSI 15 .
Very few studies have been carried out on CVC utilization or its relationship with CLABSI, in particular in developing countries. Methodologies utilised in some published studies are varied, with some facing validity problems, necessitating the need for more studies. Hospitals follow a distinct culture of patient safety programmes, which among other factors affect outcomes of hospitalized patients in different ways. Globally, the risk associated with nosocomial CLABSI is dire, and even though there has been application of various strategies to reduce the impact on patients, it remains a crucial problem.
This study was intended to provide results that explain survival for patients who used CVC devices and developed CLABSI during their duration of hospitalization and compare with those who do not develop the infection in Kenya. The conceptual framework as adopted from De Angelis et al., 2010 14 can be viewed in Figure 1.

Objectives
The overall aim was to determine the survival probabilities and hazard rates for patients who used CVC and establish factors affecting their survival and assess how they differ with the subset of the population that develops CLABSI. The specific objectives were as follows: i) to assess the survival probabilities for persons who utilized CVC during hospitalization; ii) to compare the survival time of patients' group with CLABSI and the group not infected; ii) to determine whether there is an association between infection status and mortality; iii) to determine whether mortality is significantly different between the two groups and to determine factors that affect survival of patients with CLABSI.

Study setting and participants
The study was conducted at critical care units of Aga Khan University Hospital, Nairobi, Kenya namely 11-bed medicalsurgical ICU, 6-bed coronary care unit, 4-bed cardiothoracic intensity care unit and 16-bed high dependency unit. The focus was on acute care admitted patients, who utilized CVC access devices between 8 th December, 2012 and 31 st March, 2016. The data was obtained retrospectively and included the following variables: patient's age, date of admission and discharge, discharge status, count of devices utilized, type of CVC device used, gender, infection status, event status and survival time in days. Data were obtained from the hospital's electronic database and infection control surveillance datasheets. Infection control team of specialized nurses were involved in data collection. A CLABSI was considered nosocomial if a recognized pathogen was isolated from one or more percutaneous blood cultures after 48hrs of vascular catheterization and was confirmed to be unrelated to an infection from a different site. Determination of the source of infection was determined by both intensivists and microbiologists through clinical evaluation.

Analytical methods
Data were extracted and exported into MS Excel 2010 where aggregation and organization was initially carried out. Data were then exported into Statistical Package for the Social Sciences (SPSS v.24), R GUI (R-3.1.1) and Stata (SE 11.1) for further data management, cleaning and analysis. Each statistical program was utilized to run suitable analyses as per the objectives of the study as well as for attainment of desired outputs.

Measures utilized
Both exploratory and inferential analyses were utilized. Kaplan Meier curves were used to assess the survival probabilities of exposed versus un-exposed. Log rank, Breslow, Tarone-Ware, Peto and Flemington-Harrington tests helped in testing whether the survival curves between groups differed significantly. Additional statistical tests utilized were Chi-Square test of association and test of equality of proportions, as well as Man-Whitney test.
Description of measure utilized Survival analysis is a group of statistical techniques used in analysis whereby outcome variable of interest is time taken until an event occurs. In this study the event of interest was death, which occurred among hospitalized patients who had utilized central line devices. In survival analysis time variable is referred to as survival time, in this study, the length of stay. Censoring was done when a patient did not die by the end of hospitalization, meaning he/she was either discharged alive or transferred to another facility (lost for follow-up). Censoring assumptions provided that there was independence, randomness and non-informative censoring 17 . In particular, right censoring was utilized.

Terminology and notation in survival analysis
Let T denote the random variable representing survival time where T≥ 0. The distribution of survival times is characterized by any of three functions: the survival function (S(t)), the probability density (f(t)) or the hazard function (h(t)). Equation (1) shows an expression of a survival function - The hazard function, h(t), presents instantaneous rate upon which events occur, provided no such previous events. The hazard function h(t) is portrayed in Equation (2), it can also be referred to as a conditional failure rate.
Hazard rate is used in providing information regarding conditional failures, in model identification and as a basis of expressing survival analysis math models.
Its cumulative function (Equation (3)) produces accumulated risk up to time t, Kaplan Meier function enables approximation of survival probabilities by use of the product limit formula. Kaplan Meier product limit formula is given by Equation (4)

Comparison of survival curves
The Log Rank Test is used to compare two or more Kaplan Meier Curves. The test is approximately Chi-Square particularly for large samples with G-1 degrees of freedom (df), where G is the number of groups involved as provided in Equation (5).
Log rank is used to test the null hypothesis that there is no significant difference between two survival curves. Similarly the alternative tests to Log rank are Breslow (Wilcoxon) and the Tarone-Ware; these tests apply different weights to i th failure time.
Breslow (Wilcoxon) test weights the observed minus expected score at time t i by the number at risk n i over all the groups at time t i . In this test the weights subjected at the earlier failure times are higher as compared to later failure times 17 .
The test statistic is as shown in Equation (6) Tarone-Ware test statistic applies more weight to the early failure times by weighting the observed minus expected score at time t(i) by i n , where n i refers to the number at risk.

S t
for entire data to determine its weights for the i th failure time.
Different choices of values for p and q can be done. Weights are computed as shown in Equation (7) whereas the test statistic is similar to Equation (6).
Test of equality of proportions We consider the difference in the two proportions to be given by = − , which is approximately normally distributed with mean zero and if the counts are binomially distributed with the same parameter.
The null hypothesis is such that P 1 = P 2 , the common estimate for the proportion Chi Square test of independence is used to determine whether there is a significant association between two categorical variables.
Chi square test statistic is as portrayed in Equation (9)

Results
A total of 1086 patients were included in the study; males 648 (59.7%). 363 patients experienced the event of interest (death). 47 patients developed nosocomial CLABSI during their hospitalization. Table 1 summarised the participant's demographics.   Test of association between infection status and event (discharge) status depict a χ 2 1 =6.868, p-value=0.009, which is significant at 5% level; therefore, there is a significant statistical association between the infection status and the event (discharge) status. Test of association between gender and event (discharge) status depict a χ 2 1 =0.705, p-value=0.401, which is not significant at 5% level; hence there is no significant association between the gender of the patient and the discharge (event) status at 5% level ( Table 3). Test of association between the gender of the patient and the infection status depict a χ 2 1 = 1.446, p-value=0.229, which is not significant at 5% level; hence there is no significant association between the patient's gender and the infection status at 5% level ( Table 3).
Test of equality of proportions of death between CLABSI infected and group not infected by CLABSI produced a P 1 =0.511 and P 2 =0.326 with χ 2 1 =6.0647, p-value=0.014, the 95% CI [0.02752, 0.34121]. This indicates that the proportions between the two groups are significantly different at 5% level. Hence, nosocomial CLABSI subjects a patient to a higher mortality rate as compared to a patient who does not get the infection during hospitalization.
Survival probabilities were assessed graphically as well by use of survival tables. Graphic assessment was done by use of Kaplan Meier (KM) curves for all subjects (see Figure 2), in the initial period of about 50 days after admission, survival probabilities decline at relatively more close ranges as compared to the period after 50 days. The overall mean time estimate was    Stratification by gender yielded the following survival curves for male and female, portrayed in Figure 3. The survival probabilities for the female subgroup were higher at the initial phase of about 40 days after admission after which the male's survival rates remained higher until the end. Tests on survival curves by infection status after adjusting for gender using the three tests displayed on Table 5 indicate that the survival curves were all significantly different at 5% level.
Tests on the survival curves with respect to gender adjusted for infection status; initially both male and female patients  indicate similar survival rates from the beginning of the admission period up to about the tenth day of admission. After approximately the tenth day the female subgroup seem to portray higher survival rates up to about 45 th day of admission. Stratification by patients who developed nosocomial CLABSI indicates that initially both male and female experienced similar survival rates up to approximately 6 days where the survival rates for male remain higher (see Figure 3). Three pair wise tests were conducted on survival curves with respect to gender after adjusting for infection status. Results indicate that all the three tests were not significant at 5% level.

Survival probabilities
This section portrays the survival tables for all the patients studied as well as for specific subgroups. The survival table for all the patients who were admitted into the critical care units and utilized CVCs, as provided in Table 6.
Survival table for the group who were infected by CLABSI is provided in Table 7.
The survival table for the patient group who did not get infected by CLABSI is shown in Table 8.
Assessment of the proportional hazards (PH) assumptions done using log minus log plots, observed versus expected and goodness of fit test. Assessment of the log minus log curves by infection status indicated that they were not parallel hence violating the PH assumption. Secondly, using Observed versus Expected plots; evaluated by comparing observed (KM survival estimates) versus expected (Cox adjusted) survival curve estimates plotted on the same graph with an anticipation that they would be as close to each other as possible. Results depicted a divergence between the two curves, hence violating the assumptions of PH. Lastly, using the goodness of fit test, the results depict that only the infection status doesn't violate the PH assumption. Age, gender and number of the devices used had p-values < 0.05 indicating that violation of the PH assumption (Table 9).

Discussion
Based on the results, we deduce that there is a significant difference between the lengths of stay by the patients who develop nosocomial CLABSI compared to that of patients who do not develop the infection. The patients who develop nosocomial CLABSI recorded a longer duration of stay in the hospital this in agreement with other studies conducted by 14,2,7-10 and 11.
The proportion of patients who died after developing the nosocomial CLABSI compared to the proportion of those who died having not developed the infection revealed that there is a significant difference in the two proportions at 5% level     =6.0647, p-value=0.01379). Consequently, indicating that mortality as well as morbidity is significantly increased when a patient develops the nosocomial CLABSI, similar studies by 2,7-10,14 and 11 made a similar conclusion.
In the index study, the survival curves between those who developed an infection and those that didn't were different. This difference was not due to gender or the discharge status (alive/ dead) of the patient. To the best of our knowledge no such findings have been documented in similar studies.

Recommendations
Since CLABSI infections have been found to elongate patient's length of stay, appropriate strategies such as implementation of and adherence to the CVC insertion and maintenance bundles would be ideal in order to reduce the infection rates. Further matched studies in relation to CVC utilization along specific age groups and in specific diagnoses is recommended. More survival analysis research is needed in developing countries in regard to CLABSI as well as in utilization of the CVCs.

Ethical consideration
Authority to conduct the study was issued by the Ethics and Research Committee (ERC) of the participating hospital. Ethical review was conducted by the Kenyatta National Hospital/ University of Nairobi ERC, who provided approval (Ref: KNH-ERC/A/381) and an affiliation letter. Participant consent was waived since it was a retrospective study. Privacy and confidentiality was maintained by ensuring the information gathered was not relayed to anyone, but used for this study only. Patients' names were not included in the data collected and only identification numbers utilized. No risks were subjected to the patients. Direct benefit was not intended for the study population; however the results are useful in terms of adding knowledge to the existing research.
Raw data were gathered electronically and the computer used in data analysis was personalized with limited access through password protection. No public computer was utilized in data aggregation or analysis.

Study limitations
The data having two subgroups that were considered in the study were disproportionate; the group (with the nosocomial CLABSI) had a very small proportion of 4.3% of the total number patients in the study compared to the proportion of the group that did not have the CLABSI infection during hospitalization. These disproportionate groups may not be very useful in survival model fitting. Searching for published journals from studies carried out in developing countries regarding survival analysis in relation to the use of CVC devices were not available.

Conclusions
The results reveal that there was a significant association between the nosocomial CLABSI infection status and the discharge status as well as the patient's length of stay. In addition, there is a difference between the survival rates of the patients who developed nosocomial CLABSI compared to those who did not. Mortality was higher among patients who developed nosocomial CLABSI compared to those who did not during their hospitalization. The duration of hospitalization (length of stay) by the patients who developed CLABSI was significantly higher compared with the duration taken (length of stay) by patients who did not develop CLABSI, which has a great impact on the financial burden the patients are subjected to due to added hospital bed days as well as medication administered.