Sepsis Prevalnce in Jimma
Submitted By tadi
Prevalence, outcome and prognostic factors of sepsis in Jimma Specialized Hospital.
By Dr Tadiwos Hailu (M.D)
A Proposal Submitted to the Department of Internal Medicine, Jimma University, in Partial Fulfillment of The Requirement for a Specialty Certificate in Internal Medicine.
September, 2012 Jimma, Ethiopia
Prevalence, outcome and prognostic factors of sepsis in Jimma specialized hospital.
Dr Tadiwos Hailu By
Advisors: 1-Dr.Daniel yilma [M.D] 2-Birtukan Tsehayneh [Bsc. Msc.]
September, 2012 Jimma Ethiopia
Background: Sepsis is a final pathway of infectious disease in critically ill patients. It is highly fatal condition. Though many researches are undertake in pathophysiology, epidemiology and management of sepsis in developed nation ,very limited information is available in low incomes countries where infections are prevalent. Objective:
The objective of the study was to determine the prevalence and outcome of sepsis and its prognostic factors in patients admitted to Jimma University Specialized Hospital.
Method: Patients with systemic inflammatory response due to infections were studied using prospective cohort study design for four month period in Jimma University hospital. A structured questioner was used to collect data on socio demographic feature of the patient and clinical feature, outcome and prognostic factors . Data was cleaned, edited and entered to SPSS window for analysis. The survival analysis and determination of prognostic factors was done using Cox regression model. The value of p < 0.05 was considered statistically significant. Result: The prevalence of sepsis, severe sepsis, septic and refractory shock in the study population was 14%.7.8%,2.1% and 1.4% with their associated all cause mortality of at the end of 28 days are 35.8%,44.1%,68.8% and 88.9% respectively. The clinical variables that predict poor prognostic factor were temperature ([HR=0.76,(0.660.87),P=0.00]), neurologic infections[HR=3.5, (1.830-6.912),P=0.00], delayed capillary filling [HR=3.56,95 % CI (1.760 7.230),P=0.00] and change in mental status with GCS deterioration[HR=0.75, (0.68-0.82),P=0.00]. Co morbidities and the patient management factors were not shown to be significant predictors. Conclusion: The prevalence of sepsis in this study is lower than others study. The mortality of severe sepsis is comparable to other regional studies however septic shock mortality was found to be higher. Key words: Sepsis,Outcome,Prognostic factors
List of Acronyms
AIDS- Acquired Immune Deficiency Syndrome ARDS - Acute respiratory distress syndrome CBC-complete blood count
ICU-Intensive Care Unit HICs- High income countries HIV- human immune deficiency virus HIV Abs- HIV antibodies
LMICs -low-income and middle-income countries MAP –mean arterial blood pressure MODS- multiple organ dysfunction syndromes RBS-Random blood sugar SIRS-systemic inflammatory response syndrome SSA-Sub-Saharan Africa WBC count-white blood cell count
Table of Contents
Proposal summary ..................................................................................... ii List of acronyms ....................................................................................... iii Table of contents ....................................................................................... IV List of figures and tables……………………………………………………VI Chapter One: Introduction ......................................................................... 1 1.1 Background ..................................................................................... 1 1.2 Statement of the Problem ................................................................. 4 Chapter Two: Literature Review ............................................................... 5 2.1 Literature Review ............................................................................ 5 2.2 Significance of the Study ................................................................. 10 Chapter Three: Objectives ......................................................................... 11 3.1 General Objective ............................................................................ 11 3.2 Specific Objectives .......................................................................... 11 Chapter Four: Methods and Materials........................................................ 12 4.1 Study area and period ...................................................................... 12 4.2 Study Design ................................................................................... 12 4.3 Population ....................................................................................... 12 4.3.1 Source Population ................................................................ 12 4.3.2 Study Population/ Sample population ................................... 12 4.4- Inclusion and Exclusion Criteria ..................................................... 12 4.5- Sample size and Sampling technique .............................................. 13 4.6- Data collection and Measurement ................................................... 14 4.6.1 –Data Collection Process and Instrument ............................ 14 4.6.2- Variables ........................................................................... 14 iv 4.7-Operational Definitions ................................................................... 15 4.8-Data Analysis .................................................................................. 15 4.9-Data Quality Control ....................................................................... 15 4.10-Ethical Considerations .................................................................. 17 Chapter Five: Result………………………………………………….. …18 Chapter Six: Discussion…………………………………………………..25 Chapter Seven: Conclusion and Recomendation………………………….29 Chapter Eight: Project Budget Plan [ Budget Break Down ] ...................... 30 Chapter Nine: Research Work Plan [ Project time Plan / Gant chart ] ........ 31 Chapter Ten: References ........................................................................... 32 Annexes 1 – Questionnaires ..................................................................... 37 Annexes 2- Informed Consent Form [English]…………………………. 42 Annexes 3- Informed Consent Form [ Affan oromo ]………………… 43 Annexes 3- Informed Consent Form [ Amharic ]……………………….. 44 Annexes 4- Ethical Clearance Request Form …………………………... 45
List of figures and tables
Table 1. Socio demographic Charcterstics of sepsis patients -------------------------18 Table 2. The number of Co-morbid illness in of sepsis patients……………………………21
Table 3. The number of microorganisms isolated from sepsis patients……………………..21
Table 4.The number of prescribed medication…………………………………………………….22 Table 5. The Cox regression hazard ratio of dependent variables………………………..23 Table 6: Budget plan------------------------------------------------------------------------------30 Table 7: Work plan-----------------------------------------------------------------------------31 Figure 1 Kaplan mier survival analysis curve of severe sepsis ………………………………19 Figure 2 The percentage of anatomic site of infection ……..………………………………….20
Chapter one: Introduction
1.1 Back ground
Sepsis is a common, expensive and highly fatal clinical syndrome that is characterized by systemic inflammatory response syndrome due to infection. Although inflammation is an essential host response for infection, sepsis involves a dysregulation of the normal inflammatory process, including the possibility that a massive and uncontrolled release of pro inflammatory mediators, evokes wide spread tissue injury and dysfunction of multiple organs that are remote from infection. Sepsis syndrome is a spectrum of disease; SIRS [systemic inflammatory response syndrome] with possible infection in one end to severe sepsis, septic shock and multiple organ failure in the other end. It is a final common pathway of many infectious processes e.g. Bacterial, viral, fungal and parasitic infection in critically ill patients. The source of the infection can be known, such as pneumonia, urinary tract infection, or skin or soft tissue infection, or unknown [1-4]. Sepsis disproportionately affects the elderly and minority populations such as immunecompromised patients. In addition to its significantly associated morbidity, sepsis also has notable economic costs . After several failed attempts, there are recent progression in understanding and treatment of sepsis. Significant improvements in the outcomes of septic patients have been demonstrated using early goal directed therapy using bundle of sepsis management , the selected use of cortico-steroids , glycemic control , and activated protein C . Despite afro-mentioned success, little is known in low income countries, particularly in study region, with respect to the epidemiology and the practice in management of sepsis . Hence, this study plans to explore the current existing situation and give a baseline epidemiologic data to guide physicians in the timely institution of appropriate intervention measures and in the design of local intervention trials.
Definition After the initial attempt in 1991, the International Sepsis Definitions Conference that included the American College of Chest Physicians [ACCP] and Society of Critical Care Medicine [SCCM], American Thoracic Society [ATS], European Society of Intensive Care Medicine [ESICM], and Surgical Infection Society [SIS] arrived at consensus in defining systemic inflammatory response syndrome [SIRS], sepsis, severe sepsis, and septic shock in 2001. These definitions are provided below [10, 11,12]. Both SIRS and sepsis exist on a continuum of severity that ends with multiple organ dysfunction syndromes [MODS]. Infection is the invasion of normally sterile tissue by organisms.
Bacteremia is the presence of viable bacteria in the blood.
Systemic inflammatory response syndrome is the clinical syndrome that two or more of
the following abnormalities be present:
Temperature >38.5ºC or 90 beats/min;
Respiratory rate >20 breaths/min or PaCO2 12,000 cells/mm3, 10 percent immature [band] forms.
Sepsis is SIRS that has a proven or suspected microbial etiology. Severe sepsis refers to sepsis plus at least one of the following signs of hypo perfusion or organ dysfunction: Areas of mottled skin; Capillary refilling requires three seconds or longer; Urine output 2 mmol/L; Abrupt change in mental status; Abnormal electroencephalographic [EEG] findings; Platelet count 5 mcg/kg per min,
norepinephrine 80 mmHg if the patient has baseline hypertension] requires dopamine >15 mcg/kg per min, norepinephrine >0.25 mcg/kg per min, or epinephrine >0.25 mcg/kg per min despite adequate fluid resuscitation. Multiple organ dysfunction refers to progressive organ dysfunction in an acutely ill patient, such that homeostasis cannot be maintained without intervention.There are no universally accepted criteria for individual organ dysfunction in MODS. However, progressive abnormalities of the following organ-specific parameters are commonly used to diagnose MODS and are correlated with increased ICU mortality : PO2/FiO2 ratio; Serum creatinine; Platelet count; Glasgow coma score; Serum bilirubin;
Pressure-adjusted heart rate, defined by heart rate multiplied by the ratio of central venous pressure and mean arterial pressure.
2.2 Statement of the Problem
Sepsis is a leading cause of death and significant health-care burden worldwide [8, 10]. 10 % patients admitted to ICU worldwide are due to severe sepsis. Besides, Severe sepsis is such a fatal disease that its mortality rates reported to be 20–60% in several studies [4, 13, 16, 22, 23, 24, 27].
In united state, it was the tenth leading cause of death overall and its incidence and hospitalization rate was ever increasing. There trends were not limited to USA as European studies is also show similar observations. [12, 22].Though there is a prominent scarcity of data from developing countries, the Latin America study indicated the high rate of sepsis [96%], severe sepsis [62 %] and septic shock [45.6 %] among adult patients with infections and admitted to ten hospitals in the four main cities of Colombia for six month .
Though the burden of the sepsis in developing countries is expected to be heavy enough and also the likelihood of implementing internationally accepted management of septic patients in low income countries is questionable, only few studies were conducted in investigating the epidemiology and in providing viable alternative approaches, particularly in resources limited sub-Saharan countries . On the line of customizing universally accepted Surviving Sepsis Campaign recommendation to local setups, one should find out factors which predict mortality to allocate resources to selected patients who require aggressive management most. For instance, failure to promptly initiate effective antibiotics associated with increased morbidity and mortality [58, 59] that can be overcomed by assisting physicians to choose the right antibiotic regimen based on regularly updated epidemiologic data on antibiotic susceptibility and causative microorganisms related to that geographic area.
Chapter Two: Literature review
2.1 Literature review
Incidence, prevalence and mortality
Since the term sepsis is ever used by the Ancient Greeks, it still continues to be an important cause of morbidity, mortality and tremendous economic and social burden. It is also remains a major medical challenge to physicians all over the world. Worldwide, approximately 10% of patients admitted to the ICU presented with severe sepsis. Sepsis in high income countries [HICs] accounts for a significant burden of disease and mortality and has been implicated as the leading cause of non-cardiac death amongst critically ill patients in these settings [1, 4, 16] Artigas et al conducted a large cohort study in 14,364 unselected consecutive adult patients admitted to 28 ICUs in Europe, Canada and Israel from May 1997 to May 1998 and conclude the crude incidence of ICU infections remains high [21.1%]. About 28% of infections were associated with sepsis, 24% with severe sepsis and 30% with septic shock, and 18% were not classified. Crude hospital mortality rates ranged from 16.9% in non infected patients to 53.6% in patients with hospital acquired infections at the time of ICU admission and acquiring infection during the ICU stay . United state
The study conducted by Argus DC and coworkers indicated the annual incidence of Severe sepsis is 750,000 cases in the United States and is increasing by 9% each year . Sepsis is a major burden on the US healthcare system resulting in annual costs of $16.7 billion .It is responsible for 2% of all hospitalizations. . The incidence of sepsis varies among the different racial and ethnic groups, but appears to be highest among African-American males .
Europe This trend has also been noted outside of the United States.  Harrison and his colleagues demonstrated that severe sepsis accounts 27 % of hospital admission in the first 24hours and hospital mortality was 44.7% in 2004.  More recently, European study conducted in 198 ICU in 24 countries showed 32.2% mortality at 60 days of follow-up of patients with severe sepsis and 54% mortality in patients with septic shock .
The increasing incidence is thought to be a consequence of advancing age, immunosuppressant, and multidrug-resistant infection . Seasonal variation is likely, probably due to the increased likelihood of a respiratory source during the winter and the incidence is also greatest for severe sepsis arising from infections, such as community-acquired pneumonia. . Low and middle income countries Comparable epidemiologic data on the burden of sepsis and progress in addressing sepsis has not been reported from low-income and middle-income countries [LMICs] despite the high incidence of bacterial, parasitic, and HIV infection are substantial problems. In 2004,a prospective study conducted in brazil tertiary hospital ,showed SIRS, sepsis, severe sepsis and septic shock accounted 88.9%, 2.5% ,22.8%,21.6% of hospital admission respectively and mortality rates were 32.8%,49.9% and 72.7% were for sepsis, severe sepsis and septic shock  . The other multicenter prospective study by Rodriguez et al, published in this issue of Critical Care Medicine in 2001 , constitutes a remarkable effort to characterize the epidemiology of sepsis in a developing country. Over a 6-month period, the authors prospectively recruited 2681septic patients in ten hospitals of the four main cities of Colombia corresponding to a cumulative monthly incidence rate of sepsis of 3.61 per 100 admissions per hospital and rate of severe sepsis and septic shock, 62% and 45.6% were respectively.
Few researches have been conducted in sub Saharan countries. In a study of inpatients in Malawi, mortality was 18% among general medical admissions and 38% among patients with bacteraemia, with a strong correlation between HIV infection and bacteraemia .
In a Prospective observational Study of Management and Outcomes 380 severe sepsis patients in Uganda in 2006,Overall mortality was 43.0%, with 23.7% in-hospital mortality and 22.3% postdischarge mortality . Mortality
In general, despite technological and therapeutic advances, Sepsis has a high mortality rate, with estimates ranging from 20 to 60 percent [4, 16, 22, 23, 24, 27].From large epidemiologic studies, sepsis emerges as a common disorder and its frequency and mortality rate exceed the number of other diseases that hold a heightened public awareness such as AIDS and breast cancer .
Disease severity The severity of disease appears to be increasing. In one retrospective analysis, the proportion of patients with sepsis who also had at least one dysfunctional organ [i.e. severe sepsis] increased from 26 to 44 percent over a ten-year period [23, 24]. The most common manifestations of severe organ dysfunction were acute respiratory distress syndrome, acute renal failure, and disseminated intravascular coagulation .
Mortality rates increase stepwise according to disease severity. In one study, the mortality rate of SIRS, sepsis, severe sepsis, and septic shock was 7, 16, 20, and 46 percent, respectively .
RISK FACTORS and PROGNOSTIC FACTORS Certain groups of population are identified to be at risk of developing sepsis in large. These include patients with bacteremia, advanced age, comorbidites like neoplasms, renal failure, hepatic failure, AIDS and immunosuppressant medications. These factors are also important prognostic indicators for mortality [1,4,34]. At any given moment, approximately 50 percent of ICU patients have a nosocomial infection and, therefore, are at high risk for sepsis  Age The incidence of sepsis is disproportionately increased in older adult patients [≥65 years] account for nearly 60 percent of all episodes of severe sepsis in the United States and age above 40 years is an independent predictor of mortality due to sepsis. Moreover, older adult nonsurvivors tend to die earlier during hospitalization .Age is probably a risk factor for mortality because of its association with co- morbid illnesses, impaired immunologic responses, malnutrition, increased exposure to potentially resistant pathogens in nursing homes, and increased utilization of medical devices, such as indwelling catheters and central venous lines [1, 4]. AIDS HIV-positive individuals are at greater risk for sepsis because of their immunosuppression . In areas of high HIV prevalence, sepsis might contribute substantially to overall mortality. In a prospective study of consecutive HIV-seropositive patients admitted to an Ethiopian Black lion teaching hospital, sepsis and septic shock were among the most common causes of mortality. Several other studies from sub-Saharan Africa [SSA] reveal an association between HIV infection and an increased likelihood of bacteremia and mortality.In the Ugandan sepsis study, Most patients were also HIV-infected ( 84.9%)[21,32,33].
Site of infection
The site of infection is another important determinant of outcome in patients with sepsis. When the focus of infection is gastrointestinal, pulmonary or unknown, the mortality rate from sepsis is higher than urosepsis. As in one study found that the former group had mortality rate of 50 to 55 percent compared to only 30 percent when the source of infection was the urinary tract [36, 37].
Blood cultures Jones and his colleagues studied 270 blood cultures and they found out 95 percent of positive blood cultures were associated with sepsis, severe sepsis, or septic shock . Similarly, approximately 50 percent of patients with severe sepsis are bacteremic at the time of diagnosis according to one study . The incidence of positive blood cultures increased with the severity of sepsis syndrome. . However, the presence or absence of a positive blood culture does not appear to influence the outcome, suggesting that prognosis is more closely related to the severity of sepsis than the severity of the underlying infection .When bloodstream infections become severe [i.e. severe sepsis or septic shock], the outcome is similar regardless of whether the pathogens are gram-negative or gram-positive bacteria [40, 41].
Gram positive bacteria are most frequently identified in patients with sepsis in the United States, although the number of cases of Gram negative sepsis remains substantial. In a meta-analysis of 19 prospective studies on community-acquired bacteraemia in Africa, the most common organisms isolated were Salmonella spp [predominantly non-typhi], Streptococcus pneumoniae, and Gramnegative organisms such as Escherichia coli.11 Among cases for which mortality data were recorded, patients with bloodstream infections had an average mortality of 21.5%  .
Septic patients with Mycobacterium tuberculosis [MTB] bacteremia have higher in hospital mortality [21, 34].
Parasitic infections like Malaria and fungemia are also progress to sepsis [43, 44]. The incidence of fungal sepsis has increased over the past decade, but remains lower than bacterial sepsis .
Type of infection
Sepsis due to nosocomial pathogens has a higher mortality than sepsis due to communityacquired pathogens .Increased mortality is associated with bloodstream infections due to methicillin-resistant staphylococcus aureus, non-candidal fungus , candida, methicillin-sensitive staphylococcus aureus, and pseudomonas , as well as polymicrobial infections .
Failure to develop a fever [defined as a temperature below 35.5 ºC] and Leukopenia [a white blood cell count less than 4000/mm3] were also prognostic factors and they were more common among non-survivors of sepsis than survivors in studies [47, 48, 49].
The severity of sepsis and, therefore, the outcome are influenced by clinical characteristics like the host’s response to infection, the site and type of infection, and the timing and type of antimicrobial therapy. Antimicrobial therapy Several studies show that poor outcomes are e associated with inadequate or inappropriate antimicrobial therapy to which the pathogen is resistance. [50, 51] and the time to initiation of appropriate antimicrobial therapy is also the strongest predictor of mortality . Early initiation of antibiotic therapy is associated with lower mortality to extent of reduction of mortality by 50 % [52,53]. Restoration of perfusion Early goal directed therapy clearly showed that administration of large amount fluid within six hours has significant benefit and failure to aggressively restore perfusion early may also be associated with mortality . In Ugandan study, admission Glasgow Coma Scale and Karnofsky Performance Scale [KPS], tachypnea, leukocytosis and thrombocytopenia were significant predictors of in-hospital mortality.Median volume of fluid resuscitation within the first 6 hours of presentation was 500 mLs [IQR 250–1000 mls]. Fifty-two different empirical antibacterial regimens were used during the study . The results of self reported survey strongly suggest that the most recent Surviving Sepsis guide lines cannot be implemented in Africa, particularly in Sub-Saharan Africa, due to a shortage of required hosp ital facilities, equipment, drugs and disposable materials . Factors thought to contribute to poor outcomes of critically ill patients in these settings include limitations due to cost, deficiency of diagnostic laboratories, microbiologic and radiologic capabilities and delayed presentation of severely sick patients . Notably, a retrospective hospital chart review from Zambia revealed that 79 [86%] of 92 hypotensive patients with suspected sepsis received no intravenous [IV] fluid resuscitation . Additionally, a study of bacteremic children in Tanzania highlighted increased mortality when empiric antibiotics were discordant with antibiotic susceptibility profiles .
2.2 Significance of the study
As sepsis remains to be a significant cause of morbidity and mortality in hospitalized patients worldwide, epidemiology studies such as this are needed to be conducted to expose the healthcare burden from the disease. Particularly, in many LMIC health-care facilities where the lack of required diagnostic capability makes accurate diagnoses difficult and large percentage of patients with sepsis, as the result, might remain unrecognized [21, 23]. Despite international progress in successful mangent of sepsis, the Surviving Sepsis Campaign recommendations and the sepsis bundles are far from being implemented in LIC, as it is conveyed in one sub-Saharan countries survey.  This emphasis the importance of examining and comparing the current patient care approach effectiveness and efficiency. Unfortunately research efforts on sepsis are scarce or have been almost wholly confined to sepsis in maternal and pediatrics populations in developing countries like Ethiopia. Moreover, epidemiological Studies conducted on local, regional and national levels are important to guide physicians in the timely institution of appropriate intervention measures for management of patients and it gives a baseline data in the design of local intervention trials in the hierarchy of evidence-based medicine.
Chapter three: Objective
3.1 General Objective. To determine the prevalence, outcome of sepsis and its prognostic factors in patients admitted in Jimma university hospital. 3.2 Specific objectives.-
1. To determine the prevalence of sepsis in admitted patients. 2. To determine the mortality rate of sepsis patients
3. To assess the magnitude of the development of severe sepsis and septic shock.
4. To assess demographic and socioeconomic characteristics of sepsis patients. 5. To identify prognostic factors associated with morality of sepsis patients 6. To determine length of hospital stay of sepsis patients.
Chapter Four: Methods
4.1 Study area and period
The study was conducted in Jimma University specialized hospital, which is referral teaching hospital in the largest region of the country, serving nearly 15 million peoples. The study was e conducted from Yekatit 15 to Sene 15. 4.2 Study design Prospective cohort study was performed in single center. There was no interventions related to the study, and all patients were received the routine care following the hospital’s guidelines. 4.3 Study participants 4.3.1. Source population All adult patients admitted to Jimma University specialized hospital, internal medicine department during the study period. 4.3.2 Study population
All adult patients were be enrolled prospectively using the inclusion criteria from emergency outpatient department of internal medicine, medical ward and intensive care unit.
4.4 Inclusion and Exclusion Criteria. 4.4.1 Inclusion CriteriaAny adult patient over 18 yrs of age who presented to emergency department during the study period was screened to eligibility. Patients who were already admitted to ward or ICU and who develop the first episode of infection also included in the enrollment.
The inclusion criteria required the patient to: 1. meet the criteria for SIRS as defined by ACCP/SCCM consensus conference and there should be probable or confirmed diagnosis of infection according to medical record 2. be admitted hospital from the emergency ward or it has to the first episode of infection for the inpatient patients in wards or ICU.
4.4.2 Exclusion CriteriaThe patient excluded if: 1. They present as non medical illness like trauma and surgical emergencies. 2. They already recruited in the study and this is re-admission. 3. They refuse to participate. 4. The suspected or probable diagnosis of infection is later excluded during hospitalization 4.5 Sample size Calculation and sampling technique 4.5.1 The sample size is calculated using the formula n= [Zα/2] p [1-P] / d Where,
n= is the sample size
Zα /2= Standard normal variable at 95% confidence level [1.96]. P=Prevalence of sepsis in this set up is unknown [0.5 is taken]. d= Precision [marginal error] = 0.05.
2 2 n= [1.96] [0.5] [0.5] / [0.05]
Then, the sample size
n= 384 The final sample size is thus 384 patients.
Sampling technique Convenient sampling technique was used for all patients fulfilling the inclusion criteria until the study period completed or the total sample size is achieved [384 patients in this study]
4.6.1 Data Collection Process and Instrument.
Patient enrollment was the responsibility of the treating physician. The body temperature, heartbeat frequency and respiratory frequency of all patients was measured and recorded on arrival by the treating physician. The data was collected a few minutes after the patient arrived in the ward. The data collecting nurses was aware of the study and repeatedly reminded to obtain a full set of observations for all patients.
Demographic and socioeconomic characteristics, first admission diagnosis and co morbidities, clinical status as sepsis, severe sepsis or septic shock was recorded.
Follow up registration was performed on day 28, on discharge or during death by chart review. Clinical, laboratorial and microbiological data and the management details was extracted from the medical records. The further development of sepsis, severe sepsis or septic shock, length of hospital stay was documented. All research team was trained in process of data collection. All data was collected by standardized closed response questioner as data collection instrument. The enrollment, checking data accuracy and consistency as well as the patient’s diagnosis was supervised by an investigator. When patients were discharged from the hospital before 28 days, they were contacted patients by telephone for information regarding outpatient survival. 4.6.2 Variables in the study
Dependent Variables Status of the patient at 28-day mortality rate
Independent Variables Demographic characteristics [age, sex, educational level, occupation, marital status, ethnicity] The clinical feature of the patient [admission mean temperature, heart rate, respirator rate and WBC count, MAP]
Laboratory variables CBC HIV Abs CD4 count BUN/Creatinine RBS Bilrubin Malaria blood smear Radiology – chest x-ray Blood culture , Mycobacterium culture . Electrolyte [Na,K,Cl,]Serum bicarbonate and albumin, whole blood lactate are optional as treating physician demand Hospital length of stay, 4.7 Operational Definitions.
Infection was based on the clinical evaluation, including clinical examinations as well as radiological evaluation, and laboratorial investigation as indicated.
Infection sites was categorized as follows: pneumonia,peritonitis, urinary tract infection, exacerbation of chronic obstructive pulmonary disease, catheter-related infection,primary bacteremia [excluding untreated Staphylococcus epidermidis bacteremia],mis-cellaneous sites [mediastinitis, prostatitis, osteomyelitis, and others], and multiple sites.
Hospital-acquired infections was defined as those not present or incubating at the time of admission to the hospital, i.e., infections that become evident 48 hrs after admission. Early appropriate antimicrobial therapy was defined as effectiveness on the causative agent of at least one of the empirically selected antimicrobials on the day of the diagnosis of an episode of severe sepsis. Effectiveness of antimicrobials was assessed based on the culture results and known susceptibility of the organism to the antimicrobials used and on antimicrobial susceptibility testing. For undocumented infections, appropriateness of antimicrobial therapy was assessed based on published recommendations, depending on the infection site. Bacteremia was defined as bacterial isolation from one or more blood culture bottles. 4.8 Data Analysis The data was cleaned, edited and entered to SPSS window for analysis. The result was described as mean + standard deviation for normally distributed continuous variables. Numbers [percentages] was used for categorical variables. Survival analysis and predictors of mortality was analyzed by cox regression model The value of p < 0.05 was considered statistically significant. 4.9 Data quality Assurance.
The prepared questionnaire was pre tested on earlier on patients who were not part of the study before it was administered to the actual study group. The principal investigator trained the two nurses on filling the questionnaire and also supervised the completeness and relevance of the data collected daily on data collection days. Any inconsistency, inaccuracy, or missing data implied was returned for correction on same day of patient discharge.
4.10 Ethical Considerations This study did not involve any potentially harmful intervention to the patient and before official commencement of the data collection process, ethical clearance obtained from the ethical committee of Jimma University. Every participant in the study asked for his/her willingness to be involved in the study and consent would be obtained based on free will. The information collected from participants remained confidential. Communication of Results the results of this study was be submitted to the department of Internal Medicine, Jimma University and its publication will be worked on.
Chapter five: Result
4.1 The prevalence of sepsis and characteristics of sepsis patients During the study period of four month, from Feb 22 to June 23, a total of 750 of patients admitted to JUSH . Among these admissions, 106 of them fulfilled the inclusion criteria that are patients with SIRS and suspected infection, sepsis. Therefore the prevalence of sepsis among admitted patients in that particular period become 14%. Severe sepsis, septic shock and refractory shock consists of 59(7.8%), 16(2.1%) and 10(1.39%) patients respectively. The socio-demographic characteristics of the patients are listed in table 1. In general, the median age of the recruited patients was 36.5, with the range between 18 to 92. The number of male and female subjects were 49 (46.2 %) and 57(53.8%) respectively. Table 1 Socio demographic characteristics of sepsis patients
Socio demographic characteristics Age (median + S.D) Sex Male Female Out come at 28 day Alive 34.5+ 17.1 20(40.8%) 18(31.6%) 28 37.3%) 3(37.5%) 2 (18.2%) 3 (37.5%) 2 (50.0%) 18(43.9%) 1(25.0%) 4(50.0%) 0 (0%) 12(26.1%) 2(40.0%) 1(100%) Dead 38.0+ 15.8 29(59.2%) 39(68.4%) 47 (62.7%) 5(62.5%) 9(81.8%) 5(62.5%) 2 (50.0%) 23(56.1%) 3(75.0%) 4(50.0%) 1(100%) 34(73.9%) 3(60%) 0(0%) Total 36.5 + 16.29 49(46.2%) 57(53.8%) 75 (70.8%) 8 (7.5%) 11 (10.4%) 8 (7.5%) 4(3.8%) 41(38.7%) 4(3.8%) 8(7.5%) 1(0.9%) 46(43.4%) 5(4.7%) 1(0.9%)
Cannot read write and read grad1-7 grade8-12 grade >12 Farmer Government employee student
unemployed housewife private business others
Among the SIRS criteria to be fulfilled in these patients, tachycardia and tachypenia were both the commonest, 103(97.2%) and followed by fever, 64(60.4%) and hypothermia 13 (12.3%) respectively. Leckuocytosis and lecuopenia also consists of 39 (36.8%) and19 (17.9%). All of the criteria was met in 37 (34.9%) of them while 55(51.9%) fulfill three out of the four.
The median systolic and diastolic blood pressure at presentation was 100 mm hg & 60 mm hg respectively. 34 (32.1%) patents had SBP below 90 and 58(54.7%) had diastolic below 60. In 3(2.8%) of them, BP was unrecordable. 4.2 Mortality rate of sepsis patients Out 59 of severe sepsis patents, 26 are dead that make the mortality rate of severe sepsis calculated to be 44.1% and 11 out of 16 patient & 8 out of 9 patient was for septic shock and refractory shock respectively. The figure below depict the median survival time of 20 days in Kaplan-Meier survival analysis.
Figure 2 : Kaplan-Meier survival analysis of severe sepsis
4.3 The prognostic factors associated with morality of sepsis patients 4.3.1 Anatomic site of infection Respiratory system was commonest anatomic site of infection attributed to 65 (61.3%) patients, particularly severe community acquired pneumonia was leading diagnosis. Nervous system infection, gastro -intestinal involvement and genitourinary infection follow in order of importance respectively. See figure 1. All infections were acquired from community except two cases in which hospital infection considered
Figure 2 Percentage of anatomic site of infection.
4.3.2 Severity of the illness Severe sepsis 42 (39.6%) of the patients develop at presentation and the remaining, 17(16.3%), develop later after admission. Change in mental status (43, 40.6%) and Low platelet count (22, 20.8%) were the commonest manifestation followed by delayed capillary filling (15, 14.2%), molted skin (12,11.3%)and reduced urine output (4,3.8%). ARDS (7, 6.6%) and DIC (3, 2.8%) was also recorded in several patients. Septic shock was diagnosed in 16 (15.1%) of them. Of which, 14(87.5) are progressed from sepsis later on after presentation. Refractory shock also considered in 10 (9.4%) of cases. 20
4.3.3 Co morbidities Co morbidities was found in 75(70.8%) of the patients. Of which, CHF was the leading illness followed by 33 (31.1%). 27(25.5%) patients are HIV patients. Malaria was diagnosed only in 6 patients. Please see the remaining from the table below. Table 2 the number of co morbid illness in the sepsis patients
11(10.4%) 8(7.5% ) 1(0.9%) 5(4.7%)
Out come at 28 day Alive Total
6(5.7%) 16(15.1%) 6(5.7%) 27(25.5%)
3 4 5 6 7 8 9
CKD CLD Hematology Malignancy Solid malignancy Stroke Heart Failure COPD
5(4.7%) 1(0.9%) 8(7.5%) 1(0.9%) 6(5.7%) 20(18.9%) 1(0.9%)
13(12.3%) 2(1.9%) 13(12.3%) 1(0.9%) 7(6.6%) 33(31.1%) 1(0.9%)
4.3.4 Blood culture For 95(89.6%) patients, blood culture was done on aerobic media .Among these, only 16(16.8%) samples have grown microorganisms. These consists of gram positives (8, 8.4%) and negative (8,8.4%) bacteria . The isolated organisms are listed in table below. Table 3 Number of microorganisms isolated from the patients
S.No 1 2 3 4 5 6 7 8 9 Organisms Staphylococcus aureus Coagulase negative Staphylococcus Citrobacter Spps Escherichia coli Enterobacter Spps Klebsiella pneumonia Pseudomonas aeruginosa Salmonella Spps Serratia marcescens Total Number 6 2 1 2 1 1 1 1 1 16 Percent 37.5 12.5 6.25 12.5 6.25 6.25 6.25 6.25 6.25 100
4.3.5 Treatment related factors Nearly all (99, 93.4%) patients received antibiotics .Ceftrixone was given nearly for all those patients, 92 (92 %). Doxycycline (24), Metrinidazole(11) and vancomycine(2) were prescribed. The median time of initiation of the antibiotics was 4 hour after arrival to emergency OPD. The range varies with in several minutes up to 15 hrs. Only12 (11.3%) of patients took the antibiotics in the one hr. Ceftrixone was resistant12.5 % &57.1% for gram positive and negative. Out of 14 patients data available on culture and antibiotics, the empirical choice of the antibiotics was inappropriate to 4(28.5%) of them. Table 4 The number of prescribed medications
Medications name Ceftrixone Metrindazole Doxycyclin Cotrimoxazole Vancomycin CAF Gentamycin Ampicillin
Number of patients 92 11 24 3 2 1 1 4
S.no 9 10 11 12 13 14 15 16
Medications name Amoxicillin Cloxaciilin Norfloxacin Fluconazole Dexamethasone Hydrocortisone Dopamine Adrenalin
Number of patients 2 3 3 3 2 3 6 4
1 2 3 4 5 6 7 8
The number of patients who received fluid was 66 (66.2%) and the remaining, 39(36.8%) did not take fluid. Of 66, only 33% got more than 1500 mLs of IV fluid within the first 6 hours of presentation. The mean total amounts of fluid given at six and twelve hour are 2.4 & 3.5 liter respectively. Vasopressor (dopamine and adrenalin) was administered for 10 patients with septic shock. Hydrocortisone was given to 3 pts only with possible consideration of adrenal crisis. There is no records of blood transfusion or surgical procedures like abscess drainage in any of the patients. There is a record of insulin injections given for 3 patients despite 6 diabetic patients admitted. It was possible to confirm the health status of all patients in the study at hospital discharge and at the 28 day through telephone communication. No patients lost to follow up. At the end of the 28 day after recruitment, 38 (35.8%) become deceased and the rest, 68(64.2%), were survived to the end of the study period. Of 38 patients, 21 dead during hospitalization. The median lengths of hospital stay were 15 days though it ranges from 1 to 60 days. The median duration days of life in all patients were 28 + 8.8 days. However, it was 11.5 + 8.8 days in the dead patients. 22
Cox regression analysis was done to determine the risk of hazard for the possible prognostic factors included in the study. Though mortality showed to be reduce by 1% as age increase by one year and 64% by being male, none of them, including other socio demographic variables, found to affect statistically significantly the survival.
Table 5 Cox regression hazard ratio of the dependant variables
Variables Age Sex Temperature (c) Tachycardia(beat/min) Tachypenia (breath/min) Wbc(cells/mm3) Severe sepsis(Yes/no) Septic shock (yes/no) Refractory shock (yes/no) Progression of disease (yes/no) Comorbidity (yes/no) GCS Culture positivity (yes/no) Initiation time of antibiotics Antibiotics given (yes/no) Iv fluid given (yes/no) Vaso pressor given(yes/no) Level of Significance 0.372 0.56 0.00 0.739 0.562 .348 .045 .002 .000 .000 .736 .000 .133 .283 .291 .008 .001 .557 .440 .426 .000 .624 .038 Hazard ratio 0.99 0.36 0.76 0.996 0.988 1.000 2.011 3.057 4.800 4.365 1.132 .752 .332 .999 2.915 3.027 3.872 .824 21.199 1.373 3.556 .745 .287 Confidence interval 0.96-1.01 0.70-2.53 0.66-0.87 0.971-1.021 0.949-1.029 1.000-1.000 1.014-3.988 1.511-6.184 2.170-10.619 2.058-9.258 .550-2.332 .686-.824 .079-1.398 .997-1.001 .400-21.253 1.329-6.894 1.758-8.525 .433-1.570 .009-4.932 .629-2.996 1.830-6.912 .229-2.422 .088-.934
Treatment related factors
Anatomical site of infection
Severity of the disease
Respiratory Gastro intestine gentiourinary Nervous cardiovacular Skin/soft tissue
Among the inclusion criteria, only degree of temperature has significant relationship as it demonstrated to reduce the hazard risk by with one degree centigrade elevation of temperature. The failure to mount fever was poor prognostic factor because patients with hypothermia group comparing to those with fever, they have 92 percent increase in mortality [HR=4.926, C.I (2.259-10.743),p=0.00]. Otherwise respiratory rate, pulse rate and WBC count, be it leucocytosis or leucopenia, no association with survival statistically. Fulfilling all criteria or three among the four has no difference from the minimum to criteria set to diagnosis sepsis with respect to prognosis. Regarding, the site of infections, only nervous system infections were poor prognostic factor with the hazard ratio of 3.55 increasing mortality by 55%. The remaining are not as depicted in table 5. The severity of the illness also matter as the patients with septic shock and refractory shock have 3 times [HR=3.05, 95%CI(1.5-6.2),p=0.00]and 4.8[HR=4.36, 95%CI(2.059.25),p=0.00] times greater risk than patients without these stages. The progression of the disease to next severe stage was poor prognostic by increasing the risk of death 36% [HR=4.36, 95%CI(2.05-9.25),p=0.00] However, being in severe sepsis did not predict significantly. Mottled skin, capillary refilling and change in mental status were poor prognostic factors among the list of organ dysfunction signs in severe sepsis criteria with the hazard risk of 3.0, 3.5 and 3.8 respectively. Particularly the change in mental status in terms of GCS showed that for reduction by single value in the scale ,there is 25% increase mortality [HR=0.75,95 % CI (0.68-0.82),P=0.00] None of the co morbid illness has shown significant in prognostic factor. Neither administration of antibiotics nor the time and amount of fluid given show significance result. Though it is counter intuitive to the common sense, the administration of fluid was found to significantly increase the hazard [HR=3.02, 95%CI (1.32-6.89) P=0.008].
Chapter six: Discussion
This study is the first observational prospective evaluation of septic patients admitted to the internal medicine ward in a Jimma university specialized hospital with the objective of determining the prevalence and outcome of sepsis with its prognostic factors.
As there was no known figure on prevalence of sepsis patients in the country or nearby similar countries, it was planned to recruit nearly 377 patients using sample size calculation formula with prevalence of sepsis estimated to be 0.5 so that it can give the maximum sample size.
However with the study time of 4 month, only the 106 patients were diagnosed to have sepsis based on the presence of any 2 or more of the SIRS criteria as a result of infection, which was assessed to be either definite or probable. Unfortunately the investigator was not able to expand the time and place of research due to time and finance constraints. Despite this short coming, which requires vigilant interpretation of the study result, it is believed it can shine light on the matter. Comparing to one developing country study conducted for 6 month, the prevalence of sepsis in this study is lower (17% vs 25% ) among admitted patients. besides the sample size, other factors like seasonal variability may impact on variability of the finding. the prevalence of severe sepsis in our study (7.8%) also close to the world wide figure of prevalence of sepsis in icu admissions(10%) .
Sepsis affects a comparatively young (median age, 36 yr) unlike other studies conducted in high income countries where old age disproportionately suffered and become poor prognostic factors [1,4, 29]. Such difference probably explained by the fact that general population is younger in developing countries. Moreover results from this study compare favorably with data in Colombia where younger were affected and particularly Uganda in which the mean age was in thirties .
The mortality of severe sepsis (44.1%) was comparable to Ugandan study of severe sepsis (43%).It is also within the wide range of mortality reported (20 to 60 %) in the other studies [4, 16, 22, 23, 24, 27] However, once septic shock has ensued, fatality was 68.8% compared to reported rates of 40-60% in the developed countries.
Disease progression was also important in heralding the hazard of death. This finding goes with stepwise increase mortality rates according to disease severity in other research.(25)
Several important variables were identified in this investigation to as the predictor of worse outcome. Hypothermia is found to portend a poor prognosis in this study. This correlate with the finding in one study of 519 patients with sepsis in whom Failure to develop a fever (defined as a temperature below 35.5 ºC) was more common among non-survivors of sepsis than survivors (17 versus 5 percent)(48)
Unlike other studies, leucopenia or leukocytois,tachypenia or tachycardia does not show any prognostic value.(21,47,48,49).Most of the patients fulfilled either 2 or 3 of the SIRS criteria but there was no significant association between the number of criteria fulfilled and the outcome of sepsis(60)
Site of infection has prognostic value in some but not in the others studies (36,37).The lower respiratory tract infection was the most common site of infection in this study, which is consistent with several studies.(35,60) Moreover nervous system infection is found to be serious enough to signify mortality.
Among severity signs of sepsis, change in mental status and also specifically GCS < 15 portends poor prognosis. Similar results seen in the Uganda study (21).though their study also showed thrombocytopenia was also significant indicator, they used cut of point of less than 150,000 unlike this study. Comparing to the above similar study, large number of patients received more than 1500 mLs of IV fluid within the first 6 hours of presentation in our setup (33% vs 12%) .The median volume of IV crystalloid received within the first 6 hours was (2400 vs 500ml) and at 24 hours was (3500 vs1000 mL). Having in mind, aggressive fluid resuscitation is the recommendation in early goal directed therapy, it was better in this study comparing to the Uganda and Zambia study. (21,56 )
Despite the above argument, the mortality was seen higher in patients received IV fluid in this study which requires further study with cautious selection of patients since heart failure was the major co morbidity in this study.
The blood culture positivity was relatively low as 16.8% compared to 30% positivity in other series. Limitations of culture techniques and previous administration of antimicrobials may explain this .[38,60] Moreover the prevalence of bacteremia (18.9%) was closer to our figure in Uganda study. In contrast to their findings, Patients with bacteremia have no significant hazard to death which goes in line with other studies. (39,40,41)
The appropriateness of empiric antibacterial therapy is important deterministic factor in several studies. In this study, however, the complete data on the antibiotics and bactermia was too small (14) to comment on the issue. Regarding early initiation of antibiotics within one hour, this study found that there is delay in significant number even comparing with the Ugandan figure (11.3 vs 33%)
Chapter seven: Conclusion and recommendation.
The prevalence of sepsis, severe sepsis, septic and refractory shock in the study population was 14%.7.8%,2.1% and 1.4% with their associated all cause mortality of at the end of 28 days are 35.8%,44.1%,68.8% and 88.9% respectively. The median length of stay in hospital was 15 days. The prevalence of sepsis in this study is lower than others study. The mortality of severe sepsis is comparable to other regional studies however as the illness progressed to septic shock mortality was found to be higher.
Most of patients were younger with median age of 37 unlike developed countries. The clinical variables that predict poor prognostic factor were temperature (hypothermia), neurologic infections, delayed capillary filling and change in mental status with GCS deterioration.
Co morbidities and the patient management factors were not shown to be significant predictors.
As this study shined light in our knowledge sepsis and its outcome, we can see that the mortality of severe sepsis and septic shock is so higher that it demands treating physicians and other responsible vigilant attention and concern. Though the increase mortality associated with reperfusion therapy requires further in detail analysis, aggressive fluid management should be encouraged in selected patients according to sepsis mangent guidelines. Early initiation of antibiotics is recommended since the trend is lower than other comparable developing country. Proper documentation of the management, appropriate and routine blood culture and other investigation facilities, lack of alternative medications and complete ICU service and reluctance in staff cooperation was some of the limitation and difficulties.
Finally, using the input from such research as baseline epidemiological data, it strongly recommended conducting future intervention trials with careful designed methodology.
Chapter eight: Project Budget Plan
Table 6. Project Budget Plan.
Budget Category Unit Cost [Birr] Multiplying Factor Total Cost [Birr]
1-Training of Data Collectors 1.1 Data Collectors 1.2 Data clerk 1.3 supervisors Subtotal 2-Payments 2.1Data Collectors. At EOPD In the wards 5/patient 5/pateint 5*384 5*384 1920 1920 95/day 90/day 95/day 95*2*2 90*1*2 95*1*2 380 180 290 870
2.2 Data entry 2.3 Supervisor Subtotal 3- Phone cost 4- Materials and Supplies. 4.1 Computer Papers Subtotal 5- Typist 5.1 Per Diem Subtotal Grand Sum 6- contingency GRAND TOTAL
1920 1536 7296
500 500 9526
Chapter nine: Project work Plan
Table 7 -Project work Plan. List of Activities Responsible Person Proposal Development and Preparation of Questionnaire. Recruiting and Training Data Investigator Collectors. Data Collection and Data Entry Data collectors and Data Clerk Data Analysis. Report Writing. Submission of first Draft to an advisor. Submission of final Draft to an advisor. Investigator **** Investigator Investigator Investigator **** **** **** **** ** ** ** ** **** Investigator Sept Oct Nov. to Feb. April May
Chapter ten: References
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Annex 1. Questioner on prevalence, outcome and prognostic factors of sepsis in Jimma specialized hospital in 2005 e.c. PART I – Questions on patient eligibility to be include the study.
1. Does the patient has Temperature core >38.5ºC or 37.5 or < 35.5 axilliary] 2. Does the patient heart rate >90 beats/min 1. Yes 2. No Please, record the T _________centigrade 1. Yes 2. No Please, record the HR _______ beat /min
3. Does the patient has Respiratory rate >20 breaths/min 4. Does the patient has WBC >12,000 cells/mm3, 2 mmol/L? 1. Yes 2. No 19. Does the patient has Septic Shock [Severe sepsis and one of the following conditions ] 19.1 Systemic mean BP of 0.25 mcg/kg/min to maintain mean BP at >60 mm Hg [80 m Hg if previous hypertension] 1. Yes 2. No 22. Does the patient progress to severe sepsis, septic shock or refractory shock after presentation? 1. Yes 2. No
23. Does the patient has a terminal disease (defined as the physician’s judgment of a >50%
likelihood of mortality within 30 days of the index ED visit) or metastatic cancer?
1. Yes 2. No PART IV- Questions on prognostic factors? 24. Does the patient has any of the following Co-morbidities? 24.1Chronic renal failure, 1. Yes 2. No 24.2Chronic liver disease, 1. Yes 2. No 24.3Heart failure, 1. Yes 2. No 24.4Chronic obstructive pulmonary disease 1. Yes 2. No 24.5Stroke 1. Yes 2. No 24.6Diabetic 1. Yes 2. No 24.7Hematological malignancy 1. Yes 2. No 24.8Solid malignancies, 1. Yes 2. No 24.9AIDS 1. Yes 2. No 24.10 Immunosuppressant medications or long term steroids 1. Yes 2. No 24.11 Other (specify)__________ 25. What is admission GCS level? _______/15 26. Does urinary output of