Slijepcevic J*, Koncar M, Friganovic A, Mestrovic M, Draganic S and Slijepcevic V
University Hospital Center, Zagreb, Croatia
Background: In the least developed countries, sepsis remains the leading cause of death. This Research will show the occurrence of sepsis and septic shock in critically ill patients 10 years after the first attempts of researching incidence of sepsis in Croatia, and give us a better insight into the types of microorganisms that are found in septic patients.
Objective: Determine the number of morbidity and mortality of patients from sepsis, severe sepsis and septic shock in 3 ICUs in Clinical Hospital Centre Zagreb.
Hypothesis 1: Gram-negative bacteria are the leading cause of infection in patients with sepsis.
Hypothesis 2: Number of patients suffering from sepsis, severe sepsis, septic shock and their deaths is less than in the other countries with available data on morbidity and mortality.
Methods: The study was conducted with a specially designed form for data collection, made by researchers, and was approved by the Ethics Committee. As a measuring instrument, researchers used criteria for sepsis, severe sepsis and septic shock defined by the Surviving Sepsis Campaign. Included were 3169 patients. Demographic, clinical and microbiology data were collected prospectively.
Results: The total number of patients admitted was 3169. Sepsis and severe sepsis occurred in 67 patients, while the septic shock affected 16 patients. Total number of ICU patient deaths was 127, of which 31 patients died from the direct consequences of sepsis, severe sepsis and septic shock. In patients with sepsis, the lungs were the most common site of infection (67%). The most common microorganisms were Pseudomonas aureginosa (46%).
Discussion: We confirmed both hypotheses. Gram negative bacteria were the leading microorganism. Morbidity and mortality from sepsis is less than in the other countries with available data. This research shows that Croatian Hospital Centre Zagreb has lower occurrence of sepsis and septic shock than most ICUs in the world.
Sepsis, Septic shock, Microorganism, Morbidity, Mortality, Intensive care unit
Sepsis is a systemic response of the host to infectious stimuli, which consists of clinical, hemodynamic, biochemical, and inflammatory components , but according to the new definition, sepsis should be defined as life-threatening organ dysfunction caused by a dysregulated host response to infection . During this research, the new definition of sepsis was not applied because it was published in February 2016. The number of deaths from sepsis in the U.S. increased from 154.159 in 2000 to 207.427 in 2007 , and the numbers of hospitalizations with sepsis have overtaken those from cardial infarction . In the U.S, sepsis accounts for far more deaths than the number of deaths from prostate cancer, breast cancer and AIDS combined. Sepsis strikes an estimated 30 million people worldwide every year. The sepsis syndrome, severe sepsis, and septic shock represent a major therapeutic and economic problem .
Literature review showed two large investigations of sepsis occurrence were performed in Croatia. In one study, 314 sepsis episodes that occurred between 2000 and 2005, analysis has shown that the number of admitted patients to ICUs was increased from 3.7% in 2000 to 11.7% in 2005, while the recorded mortality was 14.2% in 2000 and 20.3% in 2005 . Second study conducted on 24 ICUs from a 1-year period (November 2004-October 2005) has shown that overall 8.6% of patients hospitalized in ICUs that were treated for septic syndrome or heavy sepsis what makes sepsis the third reason in occurrence for hospitalization in ICUs. Mortality was 29% for septic syndrome, 35% for heavy sepsis and 34% for septic shock . Both surveys were performed before 10 years and more, so our research gives us new insights about epidemiology of sepsis. Looking at previous studies that show that the incidence of sepsis is growing in Croatia, but our research denies that. The reduced mortality may be due to changes in the definition of sepsis, better detection and treatment of the underlying infection, or improved supportive care, after all, 10 years has passed and something has changed given the continuous progress in medicine. Because of these new results, there was a need to describe the particularities of medical/health situation in Clinical Centre Zagreb, nursing at nursing field and infection control that could be important/relevant connection with results. Croatian Nurses Society of Anesthesia, Reanimation, Intensive Care and Transfusion (CNSARICT), one of the largest nurse’s societies in Croatia, is a part of a Global Sepsis Alliance and they had recognized the need to carry out this investigation about morbidity, mortality and other characteristics related to sepsis. Inside CNSARIST there's a Commission for intensive care that has initiated and developed this research. High number of members come from Clinical Hospital Centre Zagreb, where the research was conducted.
Clinical Hospital Centre Zagreb, in the end of April 2016, had over 3215 employed health workers and 1,795 beds in accordance with the National Plan of the Ministry of Health . We know that optimal number of nurses is a prerequisite for the quality of health care. Increase in the number of elderly patients with multiple comorbidities who are admitted to ICU, leads to development of new therapeutic methods which increase nursing workload . Optimal ratio of nurses ideally required in ICU is 1:1. Although there is progress towards establishing such working conditions, we are unable to achieve these criteria at this point. In complex situations that may require two nurses per patient, in our conditions we can provide only one nurse per 2,5 patients. In attempt to control infections, cooperation with the Clinic of Microbiology and Clinic of Pharmacology is of great importance. Department for Anesthesia every week has a meeting with microbiologists to detect patients with infections and pharmacologists to evaluate the best antibiotic therapy. Such medical meetings are conducted in presence of microbiologists, pharmacologists, intensive care specialists and team – leader nurse. ICU is department of higher risk, and that's why the Hospital Infection Control carried out numerous inspections, for example, every day one infection control nurse visits all ICUs and monitors all patients who remain more than 3 days in ICU. That kind of supervision is the part of European Surveillance of ICU acquired infections . Furthermore, the inside Hospital Infection Control conducted quarterly reports about type of microorganism in each ICU; place of sampling; antibiotic consumption and other relevant data. There are numerous other monitoring carried out by nurses and doctors in Hospital Infection Control. With constant surveillance, we can recognize with which bacteria we have a problem and what measures we need to take to put it under control. As for working with septic patients, in Croatia doctor and nurses follow the leading guidelines. For doctors that is Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock , and for nurses that is 63 recommendations World Federation of Critical Care Nurse , that was translated by CNSARICT to Croatian language and was published on the official web site of CNSARICT, and delivered in every ICU in Croatia.
The study was a prospective, observational study, designed to define the epidemiology of sepsis and septic shock, and other clinical and microbiological characteristics of ICU surgical patients in 3 intensive care units and was approved by the Ethics Committee Clinical Hospital Centre Zagreb. Informed consent was not required because there was no deviation from routine medical practice and the personal data of patients was not shown in the research and they are protected by the Law on the Protection of Patients. The sample included all admitted ICU patients between January 1st and December 31st in 2015. The study followed up all patients (>0 yrs) until death or ICU discharge. Occurrence of sepsis and septic shock was monitored using criteria defined by Surviving Sepsis Campaign (Appendix 1 and 2). Sepsis was defined as the presence (probable or documented) of infection together with systemic manifestations of infection. Severe sepsis was defined as sepsis plus sepsis-induced organdys function or tissue hypo- perfusion. Septic shock was defined as sepsis-induced hypotension persisting despite adequate fluid resuscitation. Sepsis-induced tissue hypo-perfusion was defined as infection-induced hypotension, elevated lactate, or oliguria. The term sepsis includes sepsis and severe sepsis for easier management of data. Fungal infection was diagnosed when a fungus was isolated in any sterile sample. Documented sepsis was considered when a relevant microorganism was isolated from blood and a suspected focus (urine, or quantitative tracheal aspirate in intubated patients), or when the patient has 2 or more clinical signs of systemic inflammation according to Surviving Sepsis I Campaign Guidelines 2012. A special form was made for the purpose of the research to collect data, and was approved by the Ethics Committee Clinical Hospital Centre Zagreb. The form collected following information: type of ICU; name of the patient; date and year of birth; patient identification number; sex; input SAPS score I; referral diagnosis; proven cause of infection; name of infectious agents; isolate of microorganism; diagnosis of sepsis, severe sepsis and septic shock; condition on the day of discharge from ICU; output SAPA score II. This form was used in general, cardiac and neurosurgical intensive care units in Clinical Hospital Center Zagreb. Since epidemiology, microbiology and surveillance data is a little different between these 3 surgical ICUs, each ICU was processed separately and mutually compared. Six investigators collected data throughout the study period, 2 per each ICU. All data was revised by two senior investigators in situations when data values were either questionable or missing for required fields.
Data was analyzed descriptively and results for continuous variables with normal distribution were presented as means ± standard deviation (± SD). Clinical data was presented as the observed proportion with 95% confidence intervals and the p<0.05 was considered to be statistically significant. For clinical characteristics of the study groups (SAPS), differences between groups were assessed using a Student’s t-test. Data was analyzed in Excel (Microsoft) and SPSS 11.0 for Windows. Variables that were clinically significant were presented with odds ratio (OR) and 95% confidence interval (CI). We also used MedCalc (MedCalc Software) software for analyses.
Through one-year period, a total of 3169 patients were hospitalized in the 3 ICUs; general, cardiac and neurosurgical intensive care unit in Clinical Hospital Center Zagreb. Of the total number of admitted patients 126 of them had a condition as bacteremia, sepsis, severe sepsis and septic shock. Table 1 shows the frequency of individual diagnoses in three ICUs. Obtained data shows the highest representation of sepsis and severe sepsis (53.96%), followed by bacteremia (33.33%) and septic shock placed in third place (12.69%). Of 126 infection affected patients, 83 (65.87%) were male, 43 (34.12%) were female. The median patient age was 65 Years (mean ± SD, 62.2 ± 15.7). There were 3042 (96%) ICU survivors, and 127 (4%) ICU non-survivors. Of 127 deceased patients, 31 (24.40%) of them died of infectious complications.
|Bacteremia||12 (48%)||0||30 (45.45%)||42 (33.33%)|
|Sepsis & Severe sepsis||12 (48%)||22 (63%)||34 (51.51%)||68 (53.96%)|
|Septic shock||1 (4%)||13 (37%)||2 (3%)||16 (12.69%)|
Table 1: Frequency of individual diagnoses in three ICUs.
There was a difference in ICU mortality in patients who died from infections complications (neurosurgical 6.4%, general 74.1% and cardiac 19.3%). Figure 1 shows relationship between intensive care unit morbidity and mortality rates of patients with sepsis, severe sepsis and septic shock in 3 ICUs. Cardiac ICU had the largest number of patients suffering from sepsis, severe sepsis and septic shock (52.3%), but only 4.7% of them died. Characteristics of all 126 patients with bacteremia, sepsis, severe sepsis and septic shock are shown in Table 2. From 126 patient who had sepsis, sever sepsis or septic shock, we isolated 418 positive cultures of various microorganisms. Table 3 shows the type of microorganism distributed in 3 ICUs. The microorganism was considered once per patient even if present in more than one site. The most common type of microorganism was gram negative bacteria. In 418 positive cultures, 216 (51.6%) were gram negative. Pseudomonas were the most common Gram-negative microorganism, found in 58 isolates in all 3 ICUs, followed by the Gram positive micro-organism Staphylococcus, found in 52 isolates. The third most common microorganism was Candida albicans, found in 51 isolate.
|ICU||No. of patients||No. of infective patients||SAPS I Score Mean ± SD||SAPS II Score Mean ± SD||Bacteraemia||Sepsis & Severe sepsis||Septic shock||ICU Mortality||ICU Mortality from sepsis, severe sepsis and septic shock|
|Neurosurgical||736||25||43.6 ± 14.1||32.7 ± 12.2||12||12||1||26||2|
|General||1267||35||47.8 ± 15.1||29.5 ± 12.8||0||22||13||75||23|
|Cardiac||1166||66||41.1 ± 16.8||21.0 ± 12.7||30||34||2||26||6|
|Total||3169||126||44.1 ± 15.3||27.7 ± 12.5||42||68||16||127||31|
Table 2: Number of patients, number of infective patients, Simplified Acute Physiology Score (SAPS I – II), frequency of bacteremia, sepsis, severe sepsis and septic shock, ICU mortality rates, and ICU mortality from sepsis, severe sepsis and septic shock according to ICUs.
|Variables||General ICU||Cardiac ICU||Neurosurgical ICU||Total No.|
|MRSA||3 (37.5%)||4 (50%)||1 (12.5%)||8|
|Staphylococcus aureus||3 (21.4%)||6 (42.8%)||5 (35.7%)||14|
|Staphylococcus, others||19 (36.5%)||28 (53.8%)||5 (9.6%)||52|
|Streptococcus pneumoniae||0 (0%)||1 (50%)||1 (50%)||2|
|Streptococcus others||1 (12.5%)||5 (62.5%)||2 (25%)||8|
|Escherichia coli||9 (37.5%)||12 (50%)||3 (12.5%)||24|
|Klebsiella||3 (13.0%)||16 (69.5%)||4 (17.3%)||23|
|Enterobacter||19 (38.7%)||24 (48.9%)||6 (12.2%)||49|
|Pseudomonas||17 (29.3%)||31 (53.4%)||10 (17.2%)||58|
|Haemophilus||0 (0%)||1 (50%)||1 (50%)||2|
|Acinetobacter||12 (48%)||12 (48%)||1 (4%)||25|
|Stenotrophomonas maltrophiia||3 (14.2%)||18 (85.7%)||0 (0%)||21|
|Proteus||5 (35.7%)||6 (42.8%)||3 (21.4%)||14|
|Candida albicans||21 (41.1%)||30 (58.8%)||0 (0%)||51|
|16 (36.3%)||26 (59%)||2 (4.54%)||44|
|Aspergillus||9 (39.1%)||14 (60.8%)||0 (0%)||23|
Table 3: Distribution of microorganisms in 3 ICUs. Total number of micro-organisms findings was 418. Gram-negative bacteria were present in 216 isolates. Microorganism was considered once per patient even if present in more than one site.
We tested odds ratio between patients from whom we isolated gram negative, gram positive bacteria and patients who died from sepsis, severe sepsis and septic shock and had a gram positive or gram-negative bacterium (Table 4). We found no connects ion between those who had gram negative bacteria and died, and those who had gram positive bacteria and died.
|95% CI:||0.7711 to 2.2049|
Table 4: OR, odds ratio; CI, confidence interval and p Value between those who had gram-negative bacteria and died and those who had gram-positive bacteria and died.
The lung was the most common site of infection (67%), followed by the blood (48%) and urinary tract (46%) as we can see in Table 5. T test was used to test the difference between individual ICUs due to the input and output SAPS score of patients who suffered from sepsis, severe sepsis and septic shock (no=126), and we found significant differences between the intensive care units (Tables 6 and 7). T test shows difference in the output SAPS score II between cardiac and general ICU, t=2.06, p=0.43. The input SAPS score I has shown no difference between ICUs. The OR was calculated for each ICU regarding to the number of patients (Table 8).
|Site of infection/ICU||General ICU=35||Cardiac ICU=66||Neurosurgical ICU =25||Total =126|
|Respiratory||23 (66%)||45 (68%)||16 (64%)||84 (67%)|
|Bloodstream||12 (34%)||38 (58%)||11 (44%)||61 (48%)|
|Urinary||20 (57%)||32 (48%)||6 (24%)||58 (46%)|
Table 5: Site of infection in ICUs.
|Department||N||Mean||Std. Deviation||Std. Error Mean|
|SAPS score II||Cardiac ICU||54||21.0626||12.77714||1.73875|
|SAPS score I||Cardiac ICU||66||41.1364||16.83027||2.07166|
Table 6: Mean and SD for cardiac, general and neurosurgical ICU.
|Independent Samples test|
|Variables||Levene's Test for Equality of Variances||T-test for Equality of Means|
|95% Confidence Interval of the Difference|
|SAPS score II||Equal variances assumed||0.035||0.853||-8.40741||4.08108||-16.56030||-0.25451|
|Equal variances not assumed||-2.054||16.212||.056||-8.40741||4.09367||-17.07636||0.26154|
|SAPS score II||Equal variances assumed||0.062||0.804||-6.72078||3.40138||-13.46985||0.02830|
|Equal variances not assumed||-2.042||76.112||.045||-6.72078||3.29138||-13.27598||-0.16558|
*Mean:Cardiac ICU input SAPS score I: 41.1364; SD:16.83027
General ICU input SAPS score I: 47.8571; SD: 15.13108; t: 2.06; p: 0.43
Table 7: Independent Sample Test. T test of input SAPS score I and output SAPS score II between cardiac and general ICU.
|Department||Infected||Deceased||Survived||% mortality of infected patients||OR||CI||p-value|
|General ICU||35||23||12||66%||5.8737||2.6204 – 13.1661||<0.0001|
|Cardiac ICU||66||6||60||9%||0.3065||0.1207 – 0.7783||0.0129|
|Neurosurgical ICU||25||2||23||8%||0.2665||0.05942 – 1.1951||0.0841|
*Patients with sepsis in General ICU have 5.8 times higher mortality.
Table 8: OR for all ICUs, calculated on the number of patients with sepsis, severe sepsis and septic shock.
The primary purpose of our study was to document morbidity and mortality from sepsis, severe sepsis and septic shock in three ICUs in Zagreb, Croatia. From this data, we documented much less episodes of sepsis, severe sepsis and septic shock than in previous Croatian studies. Compared with previous Croatian studies performed in 2004/2005  and 2006 , our data suggests that in period of 10 years, incidence of sepsis was in fall. In research of Gašparović et al.7 in 5293 patients treated in 24 ICUs from November 1 in 2004, to October 31 in 2005, 456 (8.6%) were treated for sepsis syndrome or severe sepsis. In our research, total number of patients admitted in general, cardiac and neurosurgical intensive care unit in Clinical Hospital Center Zagreb in 2015 was 3169. Sepsis and severe sepsis occured in 67 (2.11%) patients, while the septic shock was affecting 16 (0.50%) patients. Total number of patient deaths was 127 (4%) of which 31 (0.97%) patients died from the direct consequences of sepsis, severe sepsis and septic shock. In different European and USA studies, the collected data shows unacceptably high mortality rate of sepsis ,-.
Large European SOAP study performed in 2002 provided extensive comparative data on sepsis syndrome in European ICUs and shown that 777 (24.7%) of 3,147 admitted patients had sepsis on admission -. In the past ten years, the high incidence of sepsis we can primarily attribute to hospital reorganization (closure of respiratory
ICU),but also to the implementation of critical pathways for detecting and managing patients with sepsis with increased awareness and sensitivity for the diagnosis, continuous educational efforts for ICU staff and non-ICU staff physicians, better detection (microbiological and clinical) and treatment of the underlying infection, improved supportive care, and it can be related to the increasing number of elderly and immunocompromised patients.
However, we found some new studies that concluded that the incidence of sepsis mortality is decreasing ,. Increasing awareness about sepsis, it's term and need for much better treatment has developed guidelines for sepsis. First guidelines were published 2004 , second 2008 , and third 2013 . Use of guidelines has brought to fall in mortality from sepsis. In his research, Castellanos-Ortega found that hospital mortality of adult patients with septic shock was decreasing from 57.3% to 37.5% .
Median age in European SOAP study was 64 , and in our it is 65. According to Centers for Disease Control and Prevention, the growth in both the number and proportion of older adults is unprecedented. Life expectancy continues to increase while the baby boomer generation ages. It is estimated that the number of Americans 65 years and older will double over the next 25 years .
Among the top 5 admitting diagnoses for older adults was infection (pneumonia) and sepsis . We can connect with these arguments because the average age in our research is higher than in other studies, and the lungs are the most vulnerable. The most common infection site in European SOAP study were the lungs (68%) and the abdomen (22%), while the most common causative agents were Staphylococcus aureus, in common to our research where the
While our survey in 3 ICUs isn't providing a valid and representative picture of the global pattern of sepsis, severe sepsis and septic shock in Zagreb, Croatia, we still have a new input regarding morbidity and mortality of sepsis which represents a significant decrease in both. Our results can contribute to the ICU management and performance with fully trained specialists, residents and intensive care nurses in intensive care medicine who are able to perform early recognition, aggressive resuscitation and promptly administer appropriate empirical antimicrobial treatment of patients with sepsis.
Our medical staff was leading with SSC bundles and with 63 recommendations from WFCCNa what shows significance in lower morbidity and mortality of sepsis. Although our methodology was strong, our study had limitations. We studied only patients treated in ICU during their ICU admission, and we excluded variable like Acute Physiology and Chronic Health Evaluation (APACHE II), and instead we used Simplified Acute Physiology Score (SAPS I and II).
Predictors of mortality in sepsis are interesting in studies like this one, but our aim was not focused on that. We can say that older age, male gender and Pseudomonas infection can be used as a mortality predictor based on the results, but no testing was used to prove that -. In our Department of Anesthesia and Intensive Care at Clinical Hospital Center Zagreb, we don't have a special sepsis team with more competence and knowledge about sepsis treatment, but in further our plan is to train several intensive care nurses to be specialists for the sepsis issue. We think that the early recognition sign of sepsis, that nurses see first, is the key for successful treatment and is lifesaving. The optimum treatment of severe sepsis and septic shock is a dynamic and evolving process and regarding that fact, we will enroll our further interventions (establish register for sepsis, educate nurse experts for sepsis and persist on standard numbers of nurses and doctors needed per patients in ICU) .
Given the importance of sepsis as a big ICU morbidity and mortality issue, for further study it will be interesting to follow mainly nurse activities and interventions to see how much effect can nursing have on morbidity and mortality of sepsis.
• This first research performed on Department of Anesthesia and Intensive Care at the largest Clinical Hospital Center in Zagreb, shows a low morbidity and mortality from sepsis, severe sepsis and septic shock than in other ICUs in different countries.
• Gram-negative microorganism persisted as a leading microorganism isolated from septic patients.
• Use of SSC guidelines and 63 recommendations for nurses, we achieve envious level of good practice in treating sepsis.
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