IMPACT OF PERIOPERATIVE FOCUSED TRANSTHORACIC ECHOCARDIOGRAPHY ON THE OUTCOMES OF PATIENTS WITH INTRA-ABDOMINAL SEPSIS

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LITHUANIAN UNIVERSITY OF HEALTH SCIENCES MEDICAL ACADEMY

Asta Mačiulienė

IMPACT OF PERIOPERATIVE

FOCUSED TRANSTHORACIC

ECHOCARDIOGRAPHY ON THE

OUTCOMES OF PATIENTS WITH

INTRA-ABDOMINAL SEPSIS

Doctoral Dissertation Medical and Health Sciences,

Medicine (M 001)

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This dissertation has been prepared at the Department of Anesthesiology of the Medical Academy of Lithuanian University of Health Sciences in 2015– 2020.

Scientific Supervisor

Prof. Dr. Andrius Macas (Lithuanian University of Health Sciences, Medical and Health Sciences, Medicine – M 001).

Consultant

Prof. Habil. Dr. Jolanta Justina Vaškelytė (Lithuanian University of Health Sciences, Medical and Health Sciences, Medicine – M001). The dissertation is defended at the Medical Research Council of the Medical Academy of Lithuanian University of Health Sciences:

Chairperson

Prof. Habil. Dr. Virgilijus Ulozas (Lithuanian University of Health Sciences, Medical and Health Sciences, Medicine – M 001).

Members:

Assoc. Prof. Dr. Vaidas Matijošaitis (Lithuanian University of Health Sciences, Medical and Health Sciences, Medicine – M 001);

Prof. Dr. Kristina Žvinienė (Lithuanian University of Health Sciences, Medical and Health Sciences, Medicine – M 001);

Prof. Dr. Jelena Čelutkienė (Vilnius University, Medical and Health Sciences, Medicine – M 001);

Prof. Dr. Osvaldas Pranevičius (New York – Presbyterian Hospital (USA), Medical and Health Sciences, Medicine – M 001).

The dissertation will be defended at the open session of the Medical Research Council of Lithuanian University of Health Sciences on 30th_April 2020 at 2:00 p.m. in the Pediatric Auditorium of the Hospital of Lithuanian University of Health Sciences Kauno klinikos.

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LIETUVOS SVEIKATOS MOKSLŲ UNIVERSITETAS MEDICINOS AKADEMIJA

Asta Mačiulienė

TIKSLINĖS PERIOPERACINĖS

TRANSTORAKALINĖS

ECHOKARDIOGRAFIJOS VERTĖ

SKUBIOJE PILVO CHIRURGIJOJE

SEPSIU SERGANTIEMS PACIENTAMS

Daktaro disertacija Medicinos ir sveikatos mokslai,

medicina (M 001)

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Disertacija rengta 2015–2020 metais Lietuvos sveikatos mokslų universitete Medicinos akademijos Anesteziologijos klinikoje.

Mokslinis vadovas

prof. dr. Andrius Macas (Lietuvos sveikatos mokslų universitetas, medi-cinos ir sveikatos mokslai, medicina – M 001).

Konsultantė

prof. habil. dr. Jolanta Justina Vaškelytė (Lietuvos sveikatos mokslų universitetas, medicinos ir sveikatos mokslai, medicina – M 001). Disertacija ginama Lietuvos sveikatos mokslų universiteto Medicinos akademijos medicinos mokslo krypties taryboje:

Pirmininkas

prof. habil. dr. Virgilijus Ulozas (Lietuvos sveikatos mokslų universite-tas, medicinos ir sveikatos mokslai, medicina – M 001).

Nariai:

doc. dr. Vaidas Matijošaitis (Lietuvos sveikatos mokslų universitetas, medicinos ir sveikatos mokslai, medicina – M 001);

prof. Dr. Kristina Žvinienė (Lietuvos sveikatos mokslų universitetas, medicinos ir sveikatos mokslai, medicina – M 001);

prof. dr. Jelena Čelutkienė (Vilniaus universitetas, medicinos ir sveikatos mokslai, medicina – M 001);

prof. dr. Osvaldas Pranevičius (Niujorko presbiterionų ligoninė (JAV), medicinos ir sveikatos mokslai, medicina – M 001).

Disertacija ginama viešame Medicinos mokslo krypties tarybos posėdyje 2020 m. balandžio 30 d. 14 val. Lietuvos sveikatos mokslų universiteto ligo-ninės Kauno klinikų Vaikų ligų klinikos auditorijoje.

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ABBREVIATIONS

APACHE II – a severity of disease classification system AUC – area under the curve

BMI – body mass index CI – confidence interval CIn – cardiac index CRP – C-reactive protein ICU – intensive care unit

d – days

EHM – extended hemodynamic monitoring EGDT – early goal directed therapy

H – hours

INR – international normalized ratio IVC – inferior vena cava

IVC max – the largest diameter of inferior vena cava IVC min – the smallest diameter of inferior vena cava LSMU – Lithuanian University of Health Sciences LVOT – left ventricle outflow tract

MAP – mean arterial blood pressure MPI – Mannheim peritonitis index

NR – non-responder

OR – odds ratio

PLT – platelet count

qSOFA – quick sepsis-related organ failure assessment

R – responder

ROC – receiver operating characteristic RM – routine monitoring

SBP – systolic blood pressure ScvO2 – central venous saturation SD – standard deviation

SOFA – sequential (sepsis-related) organ failure assessment

SV – stroke volume

T – temperature

TTE – transthoracic echocardiography VTI – velocity time integral

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1. INTRODUCTION

Sepsis is a systemic inflammatory response caused by an infection and is a life-threatening condition with a high morbidity and mortality rate [1–3]. It is the leading cause of death in intensive care units (ICU) in Western countries and is associated with increased healthcare costs and long-term morbidity. Mortality in patients with sepsis ranges from 28% to 50% worldwide [4, 5]. Abdominal sepsis is the host’s systemic inflammatory response to bacterial or yeast peritonitis [6]. The overall mortality rate of intra-abdominal sepsis is reported to be up to 10.5%. The subgroup of patients with septic shock demonstrates a mortality rate of about 36.5% [7]. Treating intra-abdominal sepsis involves a complex set of decisions. Appropriate oxygenation, anti-biotic therapy, cardiovascular support to maintain organ perfusion and surgical intervention are required as a specific treatment of the underlying disease. Even though sepsis and septic shock are medical emergencies that require immediate treatment [8], these pathologies remain undiagnosed in about 41% of cases prior to admission to ICU [4]. Early identification and treatment of sepsis have already been shown to improve the survival rate [9]. Undiagnosed sepsis is a huge problem that leads to delayed treatment, lost “golden hour” and dramatically decreased survival rate. It is crucial to identify the intra-abdominal sepsis patients as soon as possible to start the adequate treatment. More knowledge is required regarding the factors that increase the risk of death from intra-abdominal sepsis.

There is a number of perioperative risk scoring tools which can be used to calculate the risk of mortality and morbidity accurately [10–12]. Periopera-tive risk assessment has a significant influence on patient outcomes by improving multi-disciplinary decision-making, allocation of critical care resources, surgical source control management and communication with patients [12]. Urgent laparotomy is associated with an increased risk of mortality, which is approximately 15% [13, 14]. In combination with sepsis the mortality rate increases [15].

The strategy of intravenous fluid resuscitation for sepsis patients is often discussed. Most studies compare patients with different origins of sepsis, thus making it difficult to interpret the results. While some authors emphasize the importance of early goal-directed fluid therapy for sepsis patients to improve the outcomes [16], others claim liberal infusion therapy to be harmful and leading to increased mortality and hence they prefer the restrictive one [17, 18]. Fluid resuscitation limits the sepsis-induced tissue damage and prevents the overstimulation of endothelial activity [6]. On the other hand, aggressive fluid resuscitation in patients with acute peritonitis may be harmful as it may

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cause an increase of intra-abdominal pressure and worsen the inflammatory response. Fluid overload causes bowel edema [19]. Forced closure of the abdominal wall may induce intra-abdominal hypertension and abdominal compartment syndrome, which can consequently modify the physiology of other systems, causing significant morbidity and mortality [19]. Individuali-zation of the treatment approach could improve the results.

Focused TTE is valuable in the perioperative period for patients under-going elective non-cardiac surgery [20–24]. Focused TTE performed before elective non-cardiac surgery seems to be cost-effective compared to compre-hensive TTE. Estimated cost savings per person is $227.72, which includes fewer arterial and central catheters inserted, not performed comprehensive TTE, fewer postoperative admissions to ICU and fewer canceled surgeries [25]. Reports of a significantly changed patient management after focused TTE varies from 54 to 82% [20–24]. A strong agreement (97.8%) is found between the interpretation of echocardiography data assessed by a cardio-logist and anesthesiocardio-logist [26]. For more than a decade, fluid resuscitation in sepsis was based on an “early goal-directed therapy” (EGDT) whose targets are: central venous pressure (CVP) 8–12 mmHg, mean arterial pressu-re (MAP) > 65 mmHg, central venous oxygen saturation (ScvO2) > 70 % [27]. Recently, ProCESS, ARISE and ProMISe studies have reported no improvement in sepsis outcomes with EGDT [28]. Focused TTE is a pro-mising method to assess fluid responsiveness as various echocardiographic parameters were described as reliable to assess fluid responsiveness [29–37]. Focused TTE measured and stroke volume (SV) guided fluid management could be beneficial in patients with intra-abdominal sepsis.

1.1. Aim of the study

The aim of this study was to find out if stroke volume (SV) (obtained by focused TTE) guided fluid resuscitation has an impact on perioperative fluid management and improves intra-abdominal sepsis outcomes.

1.2. Objectives of the study

• To evaluate the feasibility of focused echocardiography monitoring in the postoperative unit and to assess the diagnostic value of dif-ferent parameters obtained by transthoracic echocardiography (TTE) to control non-cardiac patients’ postoperative fluid management. • To evaluate the predictive factors associated with 30-day in-hospital

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• To assess the incidence of unrecognized sepsis in patients under-going urgent abdominal surgery due to acute peritonitis.

•_{To find out if stroke volume (SV) (obtained by focused TTE) guided} fluid resuscitation changes perioperative fluid management.

• To evaluate the 30-day in-hospital mortality rate in different intra-abdominal sepsis patient groups (RM vs EHM group).

1.3. Relevance and novelty of the study 1.3.1. Relevance of the study

Management of sepsis and septic shock has been a hot topic over the last few years as sepsis is a major public health problem. Sepsis is a polymorphic pathobiological syndrome related to high morbidity and mortality worldwide [4, 5]. The new definitions of sepsis and septic shock were announced at the 45th_{Critical Care Congress in 2016 [8]. In Sepsis-3 the definitions of sepsis} and septic shock have been revised and major changes have been made. The definitions of systemic inflammatory response syndrome and severe sepsis have been ruled out. A more abstract definition of sepsis has been suggested. These changes have been made in order to increase the vigilance of doctors to suspect sepsis. According to Sepsis-3 definition, sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection [8]. Septic shock was defined as sepsis with a need for norepinephrine to maintain mean arterial pressure (MAP) above 65 mmHg despite fluid resuscitation in presence of lactic acidosis (serum lactate levels ≥ 2 mmol/L) [8]. Accu-mulating evidence clearly shows that doctors and scientists are searching for tips on how to reduce the morbidity and mortality from sepsis.

According to the literature, mortality from peritonitis due to intestinal perforation ranges from 3.6% to 41.7% in different hospitals [38]. Several studies have described mortality risk factors for peritonitis [1, 4, 39]. However, there are scarce data regarding the predictors of complications during and after a peritonitis episode. The aim of the second part of the study was to determine the incidence and the risk factors of 30-day in-hospital mortality in intra-abdominal sepsis patients and to analyze predictors of peritonitis-related outcome. There is no official register in Lithuania of intra-abdominal sepsis incidence and patients’ outcomes.

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11 1.3.2. Novelty of the study

Contemporary cardiology is inconceivable without echocardiography. Recently, echocardiography has been used more and more in urgent medi-cine: anesthesiology, intensive care and emergency medicine. The goals and objectives of echocardiography in anesthesiology or intensive care medicine are quite different from those in cardiology. The first part of the study was devoted to evaluate the feasibility of extended hemodynamic monitoring by focused assessed TTE in the perioperative period in patients undergoing non-cardiac surgery, which is new in Lithuania. We assessed the feasibility of this method in the perioperative period and identified the possible echocardio-graphic parameters to assess the fluid responsiveness.

One more topic of discussion with no clear consensus is fluid resusci-tation strategy in sepsis patients. Evidence shows early goal-directed therapy (EGDT) for sepsis patients to improve the outcomes [16]. In 2001 Rivers et al. [27] announced their study results showing that protocolized fluid resuscitation (EGDT) is associated with a significant increase in sepsis survival rate compared to standard care. Since then there have been many other observational and randomized controlled studies that included more than 70,000 patients and showed EGDT to be beneficial in sepsis manage-ment [28]. EGDT protocol is included in the sepsis managemanage-ment recommend-dations for the first 6 hours [16]. However, several recent studies (ProCESS, ARISE and ProMISe) report of no improvement in sepsis patients outcomes with EGDT [28]. What is more, the results of these studies show massive infusion therapy to be harmful and leading to increased mortality [17, 18]. Some of these studies suggest starting vasopressors early. Septic shock may be resulting in low cardiac output caused by different mechanisms. Reduced CO in sepsis patients might be due to septic shock with severe hypovolemia or septic shock with sepsis-induced cardiomyopathy [28]. Management of these cases should be different.

The last part of the study involved a comparison between two strategies of fluid resuscitation in intra-abdominal sepsis patients. The new fluid management strategy, based on focused echocardiography data, statistically changes the management of fluid resuscitation in patients undergoing elective noncardiac surgery [20, 21, 40], still, there are not so many studies including urgent cases. To our best knowledge, there are no studies that evaluated the influence of extended hemodynamic monitoring by focused TTE-based fluid resuscitation in intra-abdominal patients.

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2. REVIEW OF LITERATURE

2.1. Sepsis

Despite the advances in modern medicine, the problem of sepsis has not been solved yet. The number of sepsis cases is constantly increasing [9, 41]. This increase is linked to the aging population, severe chronic diseases, immune system impairment, increase in antibiotic-resistant infections and malnutrition [4, 41, 42]. Sepsis is a leading cause of death in intensive care units [4]. The most common causes of sepsis are pneumonia, intra-abdominal and urinary tract infections [41]. A wide variety of clinical features of sepsis depends on multiple factors such as characteristics of the host, site of the infection and time of the infection, which leads to numerous cases of misdiag-nosed sepsis [4]. Annual sepsis-related health care expenses are 24 billion dollars in the United States of America [9].

The Third International Consensus on the Diagnosis of Sepsis and Septic Shock was published in 2016. In Sepsis-3 the definitions of sepsis and septic shock have been revised and major changes have been made. Systemic inflammatory response syndrome and severe sepsis definitions have been ruled out. A more abstract definition of sepsis has been suggested. These changes have been made in order to increase the vigilance of doctors to suspect sepsis. According to Sepsis-3 definition, sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection [8]. Septic shock was defined as sepsis with a need for norepinephrine to maintain mean arterial pressure (MAP) above 65 mmHg despite fluid resuscitation in presence of lactic acidosis (serum lactate levels ≥ 2 mmol/L) [8].

Organ dysfunction is described as an increase in total Sequential Organ Failure Assessment (SOFA) score of two points [16]. SOFA score has shown to have greater statistical predictive validity compared to SIRS criteria [43]. Sepsis-3 suggested a new bedside scoring system called quick SOFA (qSOFA) to identify patients with underlying infection who are more likely to develop sepsis. This scoring system seems to be reliable outside the ICU to identify possible septic patients. However, the predictive validity for in-hospital mortality is higher for full SOFA score compared with qSOFA [43], so SOFA score of > 2 is assessed as a criterion of sepsis.

Sepsis management is a multidiscipline challenge. It consists of fluid resuscitation, antibiotics therapy and source control. The key recommenda-tions of the surviving sepsis campaign are represented in Table 2.1.1.

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Table 2.1.1 Main recommendations of Surviving Sepsis Campaign 2016

6 hours bundle: the goals of initial resuscitation should include the following parameters: CVP 8–12 mmHg; MAP ≥ 65 mmHg; Urine output ≥ 0.5 mL/kg/h; ScvO2 ≥ 70%

Intravenous antibiotics should be started within 1 hour of sepsis recognition

Fluid resuscitation of at least 30 mL/kg of crystalloid within 3 hours for patients with hypoperfusion

Vasopressors to maintain MAP above 65 mmHg should be started for patients who remain hypotensive despite fluid resuscitation

Norepinephrine is the first-choice vasopressor. Vasopressin or epinephrine can be added. For patients who remain unstable, dobutamine is recommended.

200 mg/day of intravenous hydrocortisone is suggested for hemodynamically unstable patients despite fluids and vasopressors

Blood transfusion is indicated for patients with a hemoglobin concentration of less than 70 g/L

Platelets should be transfused when the platelet count is less than 10 000/mm3_or

less than 20 000/mm3_{with bleeding.}

Sodium bicarbonate should not be used for most patients with pH ≥ 7.15 Source control within the first 12 hours after the diagnosis is made

One of the keys to successful sepsis treatment and management is monitoring of sepsis patients. Generally, monitoring of sepsis patients can be divided into the following groups: non-invasive and invasive monitoring, laboratory findings and biomarkers. Usually, hemodynamic monitoring of sepsis patients includes ECG, invasive arterial blood pressure monitoring, central venous pressure monitoring and may include pulmonary artery cathe-terization, which is the golden standard for CO monitoring. Due to the risk to the patient and the daily care cost, this method is not routinely used for monitoring in our country. An additional non-invasive method such as focu-sed TTE may be beneficial in sepsis management as it provides very important information concerning fluid responsiveness and cardiac status [44, 45]. The central venous preasure monitoring helps to evaluate RA pressure. The central venous line catheter is an access to administer intravenous fluids and vasoactive agents and to take samples of central venous oxygen satura-tion. Invasive ABP reflects changes in systemic arterial blood pressure in real-time. Arterial line placement allows to take blood gas samples more conve-niently [16, 46]. End organ perfusion can be monitored by serum lactate levels, ScvO2 and other markers of organ dysfunction, for example, urine output and renal markers [16]. It is notable that all measurements and laboratory data require continuous reassessment.

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2.2. Acute peritonitis complicated with sepsis

Infectious peritonitis is an inflammation of the peritoneum cavity. It can be classified as primary peritonitis (diffuse bacterial infection without intact integrity of the gastrointestinal tract), secondary peritonitis (peritoneal cavity infection caused by perforated gastrointestinal tract), and tertiary peritonitis (a peritoneal infection which persists or recurs after more than 48 hours after successful and adequate surgical source control of secondary peritonitis) [47, 48]. Complicated intra-abdominal infection may progress into sepsis in about 40% of cases [47]. The intra-abdominal infection causes about 25% of sepsis and septic shock [49] and it is the second common cause of sepsis after pulmonary causes [49–51]. Acute peritonitis remains an important cause of morbidity and mortality in emergency abdominal surgery [39]. According to WISS study, sepsis significantly influences acute peritonitis patients’ morta-lity rate, which is 4.4% when sepsis is present. Mortamorta-lity rate increases by up to 71.8 % when septic shock occurs [52].

It is very important to assess the severity of a patient's condition and start the treatment immediately. Patients' outcomes depend on successful case ma-nagement, patients’ related characteristics and health system factors [13, 38].

The fundamental management of intra-abdominal sepsis/septic shock treatment is source control and antimicrobial therapy [38, 39, 47, 48]. Sepsis guidelines suggest effective source control as soon as possible, which is declared as ungraded strong recommendation [16]. However, some studies discuss which one – the source control or antibiotics – should be the first [1]. Surviving sepsis campaign guidelines recommend to start administration of intravenous antimicrobials as soon as possible after recognition and within 1 hour for both sepsis and septic shock, which is a strong recommendation [5, 8]. According to the literature, mortality rate is lower when appropriate antibiotic therapy is started early [38].

Recently, more data have occured allowing to criticize the protocolized fluid resuscitation in sepsis patients. Since the study of Rivers et al. [27] in 2001 EGDT seemed to be associated with a significant increase in sepsis outcome compared to standard care. ProCESS, ARISE and ProMISe studies did not find improvement in sepsis patients outcomes with EGDT [28]. In spite of that, some studies show aggressive infusion resuscitation to be harm-ful and leading to increased mortality [17, 18]. There is a hypothesis that early norepinephrine administration might be an alternative for fluid resuscitation [53] and can be used as a faster control of septic shock [54]. A critical attitude is needed in this discussion as most of the research on sepsis involved patients with different origins of sepsis. Pathophysiology of peritonitis is related to a

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large amount of exudate released into the peritoneal cavity due to intravascu-lar fluid and protein displacement [55]. Immunologic reactions and endothe-lial cell dysfunction [46] have effects on additional fluid shifts. These mecha-nisms make peritonitis-induced sepsis quite different from sepsis of other origins that lead to sepsis with severe hypovolemia.

A variety of risk factors for mortality risk in acute peritonitis patients have been identified, however, preoperative sepsis with associated organ dysfunctions and septic shock were associated with the highest risk [56]. Patient-related factors associated with the increased mortality rate in intra-abdominal sepsis patients are cardiovascular disease, malignancy, decreased blood oxygen saturation level, severe chronic kidney disease, reduced systolic blood pressure, increased respiratory rate and age [57].

Urgent laparotomy is associated with a significantly increased risk of mortality, which is approximately 15% [13, 14]. However, this number may vary and depends on the indication, specific patient’s characteristics and health system factors [13, 20, 22, 24]. Acute peritonitis remains an important cause of morbidity and mortality in emergency abdominal surgery [39]. Mortality in intra-abdominal sepsis ranges from 28 to 47% [38, 42, 58]. Sepsis is a life-threatening complication [13, 21] of peritonitis. Early diagnosis, adequate source control, appropriate antimicrobial therapy based on local epidemiology and patient dependent factors, fluid resuscitation are the cornerstones in the management of patients with complicated intra-abdominal infection [59]. Renewed recommendations of management of intra-abdominal infections by the WSES 2016 consensus conference were published in 2017. The recommendations consist of 47 statements that discuss the following topics: optimal methods in diagnosing intra-abdominal infec-tion, patient risk factors, the impact of prognostic scores in clinical practice, source control management, the strategies of relaparotomy, strategy of perito-neal specimens sampling, principles of antimicrobial therapy, identification of inflammatory mediators that are involved in intra-abdominal sepsis, impact of these markers in clinical practice. Early clinical assessment and a step-up approach beginning with clinical and laboratory examination and progressing to imaging examinations are relevant for diagnosing intra-abdominal infec-tions [19]. According to the guidelines, most of the patients with complicated intra-abdominal infection should be scheduled for an urgent source control surgery, which can be delayed in less ill patients under appropriate circum-stances. There is a strong recommendation (1A) not to perform a planned relaparotomy as a general strategy in patients with secondary peritonitis [19]. Intraperitoneal specimens from the site of infection are mandatory and should be collected in every re-operation. The samples should undergo Gram stain, aerobic and anaerobic culture as well as antibiotic susceptibility testing [19].

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Antibacterial treatment recommendations are similar to Sepsis-3 recommen-dations and the empirical antibiotic therapy should be based on local epidemiology, individual patient risk factors, the severity and source of the infection. De-escalation is mandatory when the results of microbiological testing are available [16, 19]. If the intra-abdominal infection is not compli-cated and adequate source control is provided, a short course postoperative antibacterial therapy (3–5 days) is suggested. For complicated cases, the decision to continue, revise or stop antimicrobial therapy is based on clinical and laboratory data [19]. Early identification of sepsis, adequate fluid resusci-tation and vasopressors to maintain MAP of 65 to 70 mmHg is noted in the recommendations. It is highly recommended to avoid fluid overload in patients with generalized peritonitis [19].

There are various possible tools to assess perioperative risk such as Physiological and Operative Severity Score for the enUmeration of Mortality and Morbidity (POSSUM), Surgical Outcome Risk Tool (SORT), the risk calculator of the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP), etc. All these scoring systems are quite complex and time-consuming and each has its pros and cons. For instance, the APACHE II score, POSSUM and ACS-NSQIP provide the individual risk of morbidity and mortality [11, 12, 60, 61] while the SORT score is not patient-specific and only provides a general risk of the procedure [62]. ACS-NSQIP tool does not account for the urgency of the procedure and is not validated for emergency surgery. Mannheim Peritonitis Index (MPI) is a specific score for peritonitis patients, which is highly accurate to predict the outcomes in patients with peritonitis [63]. Basically, these scores are valuable due to the prediction of outcomes, the guidance of case management strategy, comparative audit and stratification in clinical trials [19].

2.3. Extended hemodynamic monitoring by focused transthoracic echocardiography

2.3.1. Point-of-care ultrasonography

Point-of-care ultrasonography can answer very specific questions. It is a rapidly expanding diagnostic tool in anesthesiology, emergency and intensive care medicine. There are many ultrasound protocols designed for a fast eva-luation of the patient’s condition deterioration. According to the European Association of Cardiovascular Imaging recommendations, focused echocar-diography can be performed by non-cardiologists, however, the investigator must be educated for that [64]. According to the data, mortality in patients who are already hypotensive when entering the emergency department is

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high. Identification of the etiology of hypotension and optimal treatment is essential for these patients [65, 66]. Research shows that hemodynamic evaluation based only on a clinical investigation is not accurate enough [20, 40]. Some studies demonstrate that focused TTE performed by a non-cardiologist has a great influence on a patient’s management. The significant changes in patient management after focused TTE has been reported in several studies. Breitkreutz R et al evaluated patients' ongoing cardiac arrest or those who were in a shock. They found that focused TTE findings changed patient management in 78% of cases. Canty DJ et al [67] found that periope-rative management of the patient’s undergoing elective noncardiac surgery was changed in 54% cases after focused TTE. Cowie B et al reported the change of 82% of patient management after focused TTE [20]. Focused TTE performed by an anesthesiologist in the perioperative period has a great influence on patient’s management. It allows more accurate risk evaluation with alterations in invasive monitoring, anesthesia management and postope-rative care plan [20, 67]. Early TTE performed by non-cardiologists increases the probability to detect the correct etiology of hypotension in non-traumatic patients from 50% to 80%. Furthermore, focused TTE assists rational and personalized administration of intravenous fluids and vasoactive drugs. [22]. One study found lower mortality in patients undergoing hip fracture surgeries, if focused TTE was performed before the surgery, not only 30 days post-surgery (4.7% vs 15.2%) but also 12 months post-post-surgery (17.1% vs 33.3%) [40]. Patients after focused TTE received a better management of underlying cardiovascular condition which may cause better outcomes in the focused TTE group.

2.3.2. Focused transthoracic echocardiography

Usually, focused TTE is performed in the supine position [68]. The basic echo windows are described below.

2.3.2.1. Subcostal four-chamber view

The transducer probe is put below the left rib arch so that the ultrasound beam would be oriented directly toward the patient’s left shoulder. The transducer orientation marker (OM) should be oriented to the patient’s left and rotated caudally until a four-chamber view is obtained [68]. To get the inferior vena cava image, the right atrium should be at the center of the image. The transducer is rotated counterclockwise and the ultrasound beam is oriented to the patient’s right. IVC will be seen in a long-axis view. The measurement of IVC is taken in M-mode 1 cm below the confluence of the

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hepatic veins [69, 70]. The subcostal four-chamber view is presented in Fig. 2.3.2.1.1. IVC image is shown in Fig. 2.3.2.1.2.

Fig. 2.3.2.1.1. Subcostal four-chamber view

Fig. 2.3.2.1.2. Inferior vena cava, subcostal long-axis view

2.3.2.2. Apical four and five-chamber view

The transducer is placed near the heart beam, approximately in the fifth or sixth intercostal space so that OM is pointed towards the patient’s left. The ultrasound beam is oriented to the patient’s right shoulder along the heart’s long axis. The five-chamber view is obtained by tilting transducer anterior toward the chest wall. Left ventricle outflow tract (LVOT) velocity time

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integral (VTI) is calculated by placing the pulsed wave Doppler cursor in the LVOT below the aortic valve [71]. Blood velocity is recorded through the aortic valve and integrated in time. VTI is used in stroke volume calculations, which correlates with invasive cardiac output measurement methods [71, 72]. The calculation of SV includes LVOT VTI and LVOT diameter. Stroke volume is a product of cross-sectional area and VTI: (SV) = cross-sectional area of the LVOT × VTI [72, 73]. The apical five-chamber view is presented in Fig. 2.3.2.2.1.

Fig. 2.3.2.2.1. Apical five-chamber view

2.3.2.3. Parasternal long and short axis view

To obtain the parasternal long-axis view transducer is placed in the third to fifth intercostal space near the left sternum side so that OM would be pointed to the patient’s right shoulder. To obtain the parasternal short-axis view the transducer is rotated 90° clockwise so that OM would be oriented to the patient’s left shoulder [68]. The cross-sectional area of the LVOT is measured in the parasternal long-axis view using the zoom to get accurate measurements. The parasternal long-axis view is presented in Fig. 2.3.2.3.1.

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Fig. 2.3.2.3.1. Parasternal long-axis view.

White line marks the measurement of LVOT diameter

2.3.3. TTE for sepsis patients. Possible findings

Both hyperdynamic (warm) and hypodynamic (cold) shock can be seen in sepsis patients [74]. In early stages, sepsis results in elevated catecholamine levels, which most likely cause an a-adrenergic response, which is seen as an augment in cardiac contractility and heart rate [75]. Hyperdynamic shock is described by increased CO, reduced peripheral resistance and warm extre-mities. However, adaptive response eventually becomes non-effective as excessive stimulation of cardiac βARs receptors causes myocardial damage [74]. Finally, hypodynamic, or cold, shock occurs with a low cardiac output, reduced peripheral perfusion and cool extremities [74, 76]. In most cases, normal or increased cardiac output in sepsis patients is seen in the first phases due to the hyperdynamic left ventricle. However, only 65% of patients with sepsis have increased CO. More than one third of sepsis patients have reduced CO less than (< 3 L/min) and hypokinetic left ventricle with reduced ejection fraction (mean EF of 38±17%) [77]. Different pathophysiological mecha-nisms are seen in sepsis patients, which requires different management (inotropes, vasoactive drugs, fluids) [74, 75, 77]. The main mechanism of cardiovascular failure in septic shock is presented in Fig. 2.3.3.1 [78].

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Fig. 2.3.3.1. Most common mechanisms of cardiovascular

instability in septic shock [78]

* LV – left ventricle, RV – right ventricle, SVR – systemic vascular resistance. Focused TTE allows us to assess the leading hemodynamic pathology and to administer adequate treatment. Focused TTE is suitable to guide hemo-dynamic management in sepsis patients due to the following reasons: non-invasive diagnostic method, repeatable, it is a rapid diagnostic tool in a trained physician’s hands, provides relevant information on cardiovascular status at the bedside [73].

Focused TTE is a tool to identify fluid responders, which makes fluid resuscitations individualized. The echocardiographic measurements of LVOT velocities are used to estimate SV [78]. For example, an increase in SV measured by TTE of at least 15% after a fluid bolus defines the patient as fluid responsive [17, 28]. A change in VTI of more than 15% after the fluid bolus predicts fluid responsiveness with high sensitivity and specificity (AUC = 0.92) [79]. Images of VTI changes post volume expansion are shown in Fig. 2.3.3.2.

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LV contractility assessment that shows hyperdynamic heart, “kissing” trabecular muscles of LV and small IVC diameter indicates hypovolemia and fluid responsiveness. Conversely, if reduced ejection fraction is present, patients could be at risk of fluid overload [80]. The patients with an increase in RV diameter after volume expansion but no increase in SV are not fluid responsive [80].

IVC variability index is a reliable measurement to evaluate fluid responsiveness for the patients under mechanical ventilation [81, 82]. Some studies show that IVC variability of more than 40% is suitable to predict fluid responders in spontaneously breathing patients [29, 82–85]. Fig. 2.3.3.3 de-monstrates images of IVC in M-mode, which is used to evaluate the variabi-lity of IVC.

The summary of possible TTE findings in septic shock patients is pre-sented in Table 2.3.3.1.

Table 2.3.3.1. Possible transthoracic echocardiography findings in septic

shock patients

Focused TTE findings Fluid responsiveness

Small LV and RV Yes

Hyperkinetic heart Yes

The collapse of the LV walls at end‐systole, “kissing LV walls” Yes Small IVC, which collapses during breathing Yes/No

Increase in VTI or SV of 15% Yes

Low ejection fraction No

Increase in RV diameter, no increase in SV No Paradoxical septal wall motion demonstrating high RV pressure No

RV – right ventricle; LV – left ventricle; IVC – inferior vena cava; VTI – velocity time integral; SV – stroke volume.

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Fig. 2.3.3.2. Changes in VTI post volume expansion in fluid responders:

A – before fluid bolus; B – increased VTI more than 15% post volume expansion

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Fig. 2.3.3.3. Inferior vena cava in M-mode: A – IVC collapses during

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3. METHODS

3.1. Ethics

Ethical approval for this study was provided by Kaunas Region Ethics Committee of Biomedical Surveys according to protocol No. BE-2-6 (session protocol No. BE-10-4). All patients gave their informed consent to participate in the study.

3.2. Progress towards building the clinical research for 2015–2020 Progress towards building the clinical research is schematically shown in Fig. 3.2.1.

Fig. 3.2.1. Progress of the research through 2015–2020

3.3. Assessment of fluid responsiveness. A pilot study 3.3.1. Study population

The group of subjects consisted of the patients referred for major abdominal surgery (gastric resection, gastrectomy, liver resection, pancreatic-duodenal resection, colorectal surgery) who had reduced mean arterial blood pressure (MAP) up to 30% from the baseline during the first-hour post-surgery. Exclusion criteria were: atrial fibrillation; severe cardiovascular or

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renal impairment; bad echocardiography image quality not suitable for further analysis. The prospective study was carried out in the Department of Anesthesiology, Lithuanian University of Health Sciences (LSMU) from May 1st_{to September 1}st_{, 2016.}

From all patients who were scheduled for major abdominal surgery during the study period, 45 patients were identified as eligible to participate in the study. Five patients were excluded due to the following reasons: one had severe contractility impairment, one had atrial fibrillation and the image quality of the rest was not suitable for accurate interpretation. The study flow chart is presented in Fig. 3.3.1.1.

Fig. 3.3.1.1. Flow chart of patient inclusion, follow up and analysis

3.3.2. Point-of-care transthoracic echocardiography assessment The echocardiography evaluation was performed in the supine position within one-hour post abdominal surgery. The standard transthoracic positions for TTE images (subcostal four-chamber view, apical four-chamber view, parasternal long-axis view and IVC echo windows) were taken for all patients.

TTE findings were assessed by two trained researchers. The intra- and inter-observer variability of operators for the stroke volume (SV) was 2.5 and 4%. SV of the patients was calculated before the fluid challenge and immediately after it. The patient was defined as a fluid responder if an increase in SV was at least 15% after the fluid expansion of 500 mL of

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crystalloids given over 15 minutes. The fluid challenge was stopped if SV was not improving. The calculation of SV included LVOT VTI and LVOT diameter. Stroke volume was defined as a product of cross-sectional area of LVOT and VTI: SV = cross-sectional area LVOT × VTI [72]. Patients were assigned to responders or non-responders in accordance with the increase of SV. The measurements of LVOT VTI and LVOT diameter were taken twice and average values were used for further calculations.

The following echocardiography measurements were taken before fluid expansion: mitral E and A waves, E/A ratio, LVOT VTI, IVCmax, and IVCmin diameters during breathing cycles. The IVC diameters were taken in M-mode 1 cm below the confluence of the hepatic veins [69]. The calculation of IVC variations was made by formula IVC index = (Dmax–Dmin)/Dmax. IVC index was expressed as a percentage [29, 84, 85].

The investigators had no influence on intraoperative fluid management. The doctor in charge was reported about focused TTE findings and made a further judgment on fluid management. Responders were continuously monitored by focused TTE.

3.4. Study of prediction of 30-day in-hospital mortality in patients undergoing urgent abdominal surgery due

to acute peritonitis complicated with sepsis 3.4.1. Study population

Sixty-seven patients, 36 men and 31 women, who had had signs of intra-abdominal sepsis (SOFA score 2 points or above) were recruited at the Department of Surgery, Lithuanian University of Health Sciences Hospital during the period from October 1st_{, 2016, to February 1}st_{, 2018.}

The inclusion criteria were: new arrivals, age ≥ 18 years, a signed written consent to participate in the study, urgent abdominal surgery due to acute peritonitis, SOFA score 2 points or above.

Exclusion criteria were: known pregnancy, acute mesenteric ischemia or thrombosis, intra-abdominal trauma, re-laparotomy.

The patients were followed for 30 days post-surgery or until a clinical event (death).

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Fig.3.4.1.1. Flowchart of patient inclusion, follow up and analysis

3.4.2. Assessment of the patients

The initial standard assessment of the patients was determined by the doctor in charge. Assessment of the patient’s pain location, character, onset, intensity, radiation, duration and progression, provocative and palliating factors and associated symptoms was performed. Past medical and surgical history, current medications and social history were taken. Physical exami-nation was performed and vital signs (mental status, body temperature, heart rate, not invasive arterial blood pressure, tachypnea, saturation, etc.) were evaluated. Blood samples (full blood count, urea, creatinine and electrolytes, liver function tests and serum amylase, prothrombin time, activated partial thromboplastin time, international normalized ratio, lactate, arterial blood gas) were taken. The following imaging tests were performed: chest X-rays, abdomen ultrasound examination and/or computed tomography scan. Fol-lowing their initial assessment, focused screening for sepsis by calculating SOFA score was performed by study investigators during the first-hour post-admission to the general surgery department. Sepsis was diagnosed if the Sequential (Sepsis-related) Organ Failure Assessment (SOFA) score was 2 points or above. Patients who had SOFA score of 2 or above and did not have documented diagnosis of sepsis at the time of focused screening were

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considered as not identified as septic by the doctor in charge. Full SOFA score was selected due to the higher predictive validity for in-hospital mortality (AUC ROC 0.74) compared with qSOFA (AUC ROC 0.66) [43]. The severity of the disease was evaluated by the APACHE II score and the Mannheim peritonitis index.

Old age was defined as age 70 years or above [86]. Body temperature on admission was used for calculations. Patients were divided into 3 groups according to body temperature: group I, t < 36 °C [87, 88], group II, t 36 °C – 38 °C and group III, t > 38°C [8]. During the first six hours from inclusion into the study urine output was monitored.

Coagulation impairment was appreciable if the international normalized ratio (INR) was ≥ 1.2 [89, 90].

Hypotension on admission was defined as systolic blood pressure < 90 mm Hg. Severe post-induction hypotension was defined as a drop in the MAP below 65 mmHg during the first 5 minutes post-induction of anesthesia. Septic shock was confirmed if norepinephrine was required to maintain mean arterial pressure (MAP) above 65 mmHg despite adequate fluid resuscitation [8].

3.4.4. Study endpoints

The primary endpoints included 30-day in-hospital mortality and asses-sment of mortality predictors in intra-abdominal sepsis patients. The secon-dary endpoint was to evaluate the incidence of undiagnosed sepsis during the preoperative period and risk factors of 30-day in-hospital mortality.

3.5. Study of the impact of stroke volume (obtained by focused TTE) guided fluid resuscitation on intra-abdominal sepsis outcomes 3.5.1. Study population

Two hundred sixty-five patients with acute abdominal pathology were identified during the period from October 1st_{, 2016, to February 1}st_{, 2018.} Finally, one hundred thirty-one were recruited at the Department of Surgery of the Hospital of Lithuanian University of Health Sciences Kauno klinikos and were involved in the case-control study and further analysis.

Patients were considered eligible for the study if they were 18 years or older, were new admissions scheduled for emergency surgery due to diffuse peritonitis, had SOFA score of 2 or above and signed a written informed consent to participate in the study. Exclusion criteria included local peritoni-tis, pregnancy, peritonitis due to acute mesenteric ischemia, thrombosis or trauma, terminal phase of malignant disease and re-laparotomy. One hundred

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thirty-one had a SOFA score of 2 or above and met the inclusion criteria. These patients were distributed into the RM (67 patients) and the EHM (64 patients) groups. The study flowchart is shown in Fig. 3.5.1.1.

Patients were distributed into two groups using numbered opaque envelopes containing grouping allocations: the routine monitoring and fluid resuscitation group (RM), and the extended hemodynamic monitoring (EHM) group, in which TTE-measured stroke volume-guided fluid management was performed. The distribution of the patients to the groups was completed within one hour after meeting the inclusion criteria.

Fig. 3.5.1.1. Flowchart of patient inclusion, follow up and analysis

3.5.2. Assessment of the patients

The initial standard assessment of the patients was determined by the physician in charge. Assessment of the patient’s pain location, type, onset, intensity, radiation, duration and progression, provocative and palliating factors and associated symptoms was performed. Past medical and surgical history, current medications and social history were taken. Physical examina-tion was performed and vital signs (mental status, body temperature, heart rate, not invasive arterial blood pressure, tachypnoea, saturation, etc.) were evaluated. Blood samples (full blood count, urea, creatinine and electrolytes,

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liver function tests and serum amylase, prothrombin time, activated partial thromboplastin time, international normalized ratio, lactate, arterial blood gas) were taken. The following imaging tests were performed: chest X-rays, abdomen ultrasound examination and/or computed tomography.

Patients who were admitted to the general surgery department due to peritonitis were screened for signs of sepsis by the study researchers. Sepsis was diagnosed if Sequential (Sepsis-related) Organ Failure Assessment score (SOFA) [91] was ≥ 2 points. SOFA score was chosen because the predictive validity for in-hospital mortality was higher for full SOFA score compared with qSOFA in peritonitis patients [43]. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) were used in this study. Septic shock was defined as sepsis with a need for norepinephrine to maintain mean arterial pressure (MAP) above 65 mmHg despite fluid resuscitation in presence of lactic acidosis (serum lactate levels ≥ 2 mmol/L) [8].

After patients were assigned either to the RM or the EHM group, the six-hour sepsis bundle started. Monitoring of the amount of infused crystalloids started in both groups. Central venous line and invasive arterial blood pres-sure (ABP) cannula were placed during the surgery. The target central venous pressure was 8–12 mmHg and the target MAP was > 65 mmHg as emphasi-zed in the Current Surviving Sepsis guidelines [16]. Routine monitoring group patients received standard monitoring and fluid resuscitation as determined by the physician in charge: a patient was considered to be fluid responsive if there was an increase in systolic blood pressure (SBP) of more than 10 mmHg after a fluid challenge of 4 mL/kg of crystalloids for over 10 minutes [17, 28] with urine output less than 0.5 mL/kg/h. In the EHM group a rapid 2-D echocardiography examination was repeatedly performed (for up to 6 hours after inclusion in the study) to assess fluid responsiveness. The first EHM evaluation was performed immediately after the patient was assigned to the EHM group. Fluid responders were defined by an increase in stroke volume (SV) of at least 15% after a fluid bolus of 4 mL/kg of Ringer lactate [17, 28] was given for over 10 minutes. Fluid administration was stopped if SV was not improving. Norepinephrine was administered to main-tain adequate tissue perfusion (MAP > 65 mmHg) for non-responders with MAP ≤ 65 mmHg.

All patients who required mechanical ventilation or norepinephrine infusion to maintain MAP ≥ 65 mmHg post-surgery were admitted to ICU.

Demographic and clinical characteristics, etiology of peritonitis, SOFA, APACHE II scores and the Mannheim peritonitis index were evaluated for all participants.

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3.5.3. Focused assessed transthoracic echocardiography

TTE was performed in the supine position for all EHM group patients. Two standard positions of TTE (apical five-chamber view and parasternal long-axis view) were used to assess fluid responsiveness. The apical view was obtained by placing the transducer above the cardiac apex beat in order for the ultrasound beam to be in parallel with the long axis of the heart. By tilting the transducer the apical five-chamber view was obtained [68]. Left ventricle outflow tract velocity time integral (LVOT VTI) measurements were calcula-ted by placing the pulsed Doppler sample volume below the aortic valve in the left ventricle outflow tract and recording velocity (cm/s) [71]. The first focused TTE was performed immediately after the patient was assigned to the EHM group. TTE was performed repeatedly for responders to guide fluid management after the fluid bolus. If a patient was not fluid responsive, focused TTE was stopped and additional TTE was done for the patients who experienced a drop of MAP to less than 65 mmHg (up to 6 hours after rando-mization). To get the parasternal long-axis view the transducer was placed in the third or fourth intercostal space near the left margin of the sternum so that the orientation marker (OM) would be pointed to the patient’s right shoulder [68]. LVOT diameter was measured from the white black interface of the septal endocardium to the anterior mitral leaflet parallel to the aortic valve plane and within 0.5–1.0 cm of the valve orifice [92]. LVOT diameter was measured once for all EHM group patients during the first assessment, as LVOT diameter is a constant in the same individual [93]. Stroke volume was defined as the product of the cross-sectional area and left ventricle outflow tract velocity-time integral [72]. Focused TTE was assessed by two investi-gators. The intra- and inter-observer variability of operators for the stroke volume (SV) was 2.5 and 4%.

3.5.4. Time

The following time points were noted: onset of abdominal pain (date, time), hospitalization (date, time), time of assignation to the RM or EHM group, surgery (date, time), duration of surgery, the commencement of antibiotics (date, time). After the assignation either to the RM or the EHM group, the six-hour sepsis bundle started. Detailed time points can be seen in Fig. 3.5.4.1.

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Fig. 3.5.4.1. The time points which were noted during the study period

3.5.5. Study endpoints

The following outcomes were registered: • 30-day in-hospital mortality;

• fluid therapy (ml) during the first six hours (post-assignation either to the RM or the EHM group up to 6 hours);

•_{hypotension (a drop of MAP to <65 mmHg) post-anesthesia} induc-tion (occurred during the first 5 minutes post-inducinduc-tion);

•_{the manifestation of septic shock (hemodynamic instability not} res-ponding to fluid administration, which requires norepinephrine infusion to maintain MAP ≥ 65 mmHg);

•_{admission to ICU post-surgery;}

3.6. Calculation of the study power

The statistical power within a given sample size is influenced by several factors: the effect size, sample size, and confidence interval.

For the assessment of fluid responsiveness study, the sample size was selected based on an assumption of 80% power to detect a variant at 5%

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significance. To detect the significant difference in mean values of the variability of VTI during breathing cycles for responders vs non-responders assuming significance level alpha=0.05 and power of the test=0.8, we should have at least 6 patients in each group.

For the study of prediction of 30-day in-hospital mortality, a minimal sample size of at least 60 patients to detect a significant difference in mortality regarding associated factors was determined to assume significance level alpha 0.05 and power of test 0.8.

According to the literature for the study of the impact of extended focu-sed hemodynamic monitoring guided fluid resuscitation on intra-abdominal sepsis outcomes, it was determined that at least 50 patients should be in each group to detect a significant difference in mortality of more than 10% [40] in routine monitoring group vs extended hemodynamic monitoring group by EHM, assuming that the significance level alpha=0.05 and power of the test=0.8.

The prior mentioned calculations were performed using a web-based calculator for sample size ClinCal.com.

3.7. Statistical analysis

3.7.1. Assessment of fluid responsiveness. A pilot study

All study participants were stratified into two groups: responders and non-responders. Data were analyzed using the SPSS 24.0 software. The Kruskal-Wallis tests were used for comparison of data distributions. A nonparametric χ2_{test was used for the analysis of nominal qualitative} data. The Mann-Whitney U test was used to compare the distributions of two samples. A significance level of 0.05 was considered for all tests. A recei-ver operating characteristic (ROC) curve was used to determine the threshold value of mitral E and A waves, E/A ratio, LVOT VTI variability, cardiac index (CIn) and IVC variations to predict fluid responsiveness, taking into account the increase of SV more than 15%. We defined the area under the curve (AUC) to be clinically relevant if AUC was more than 0.7. For defining the success rate of fluid responsiveness by different methods, Cochrane’s Q test was used.

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3.7.2. Study of prediction of 30-day in-hospital mortality in patients undergoing urgent abdominal surgery due to acute peritonitis complicated with sepsis

Data were processed using the SPSS 24.0 statistical analysis package. Kruskal-Wallis test was used for comparison of data distributions. A nonpa-rametric χ2_{test was applied for the analysis of nominal qualitative data.} Mann-Whitney U test helped to compare distributions of two samples. The receiver operating characteristic (ROC) curve was used to determine the threshold value for the prognostic ability of a binary classifier. We considered prognostic ability as clinically relevant when the area under the curve (AUC) was more than 0.7. Kaplan Meier estimator was used for survival statistics. Binary logistic regression was carried out to identify the risk factors associated with mortality of patients. A significance level of 0.05 was used for all tests. A minimal sample size of at least 60 patients to detect a signi-ficant difference in mortality in regard to associated factors was determined to assume significance level alpha 0.05 and power of test 0.8.

3.7.3. Study of the impact of extended focused hemodynamic monitoring guided fluid resuscitation on intra-abdominal sepsis outcomes

The data were processed using SPSS 24.0 statistical analysis package. Data normality was assessed by the Kolmogorov-Smirnov test. Data (age, BMI, in-hospital stay (overall, ICU), vasopressor administration (h)) are presented as mean values and confidence interval (CI) or standard deviation (SD). Means of the data were compared using paired or unpaired t-tests where appropriate. A nonparametric χ2_{test was used for the analysis of nominal} qualitative data. The Mann-Whitney U test was used to compare the distribu-tions of two samples. All tests have a 0.05 significance level selected. Kaplan Meier curves were used for survival statistics.

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4. RESULTS

4.1. Assessment of fluid responsiveness. A pilot study 4.1.1. Study population

Adequate IVC images from the subcostal window were obtained in 33 (76.7%) patients, for the rest 10 (23.3%) trans-hepatic acoustic window was used. The proportion of adequate view was significantly lower for the IVC echo window while trying to get the image from the subcostal long-axis view (p=0.046). The lower success rate of obtaining an adequate subcostal view was associated with experienced moderate (4–6 points according to Pain rating scale) postoperative pain (p=0.002). An adequate parasternal long-axis view was obtained in all 43 (100%) patients. Apical four and five chamber views were successfully obtained in 40 (93%) of the patients. In all 3 cases of bad quality images from the apical view, the patient was in the supine position, and the focused TTE protocol not to change the patient’s position was followed.

The detailed feasibility of TTE monitoring in perioperative period is presented in Table 4.1.1.1.

Table 4.1.1.1. Feasibility of focused transthoracic echocardiography in

post-operative period

Parameters patients, All n (%)

Image quality

p-value No image obtained or

bad quality, n (%) Good quality, n (%)

IVC (subcostal view)

IVC (trans hepatic view) 43 (100) 10 (23.3) 33 (76.7) 10 (100) 0.046*

Apical view 43 (100) 3 (7) 40 (93)

>0.05 Parasternal long and short

axes view 43 (100) 0 43 (100)

* – statistically significant difference.

Forty patients, 23 (57.5%) men and 17 (42.5%) women, who had reduced MAP from the baseline with suitable echo images, were included in the study. The mean age of the patients was 60.8 (56.9–64.78) years. Sixteen patients (40%) had ASA physical status II and 24 (60%) had physical status III. The median pre-investigational VAS measurement was 3 (min 2, max 7). Demo-graphic characteristics of responders and non-responders are presented in Table 4.1.1.2.

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Table 4.1.1.2. Baseline characteristics of the patients and comparison between

responders and non-responders

Responders Non-responders p-value

Patients, n (%) 12 (27.5%) 29 (72.5%) –

Age (y), mean (CI) 62 (57.22–66.78) 60.45 (55.2–65.68) 0.881 Gender:

Male, n

Female, n 9 2 14 15 0.55

Body mass index, n (SD) 25.44 (±3.8) 28.07 (±7.1) 0.131 ASA status:

II, n (%)

III, n (%) 3 (18.8%) 8 (33.3%) 13 (81.2%) 16 (66.7%) 0.425

Visual analogue scale 4 (3–5) 3 (1–6) 0.72

4.1.2. Identification of responders by changes in VTI after volume expansion versus changes in clinical parameters

The increase of SV of more than 15 % after volume expansion was found in 12 patients (30%) while the increase of SBP of more than 10 mmHg occurred only in 6 (15%) patients. Characteristics of the patients and compari-son between responders and non-responders are shown in Table 4.1.2.1. The identification of fluid responsiveness by the complex of clinical signs was significantly lower compared to echocardiography data (p=0.034).

Table 4.1.2.1. Characteristics of the patients and comparison between

responders and non-responders

Variables Responders Non-responders p-value

Heart rate 70 (±13) 71 (±12) 0.633

MAP, mmHg 62.9 (±7.91) 63.6 (±7.02) 0.78

Breathing rate 13 (±1.6) 14 (±2.5) 0.254

Urine flow rate, mL/kg/h 0.75 (±0.34) 1.25 (±0.38) <0.001*

VTI max 20.69 (±4.54) 22.73 (±4.16) 0.198

VTI min 17.57 (±4.25) 21.59 (±4.07) 0.018*

VTI variability, % 14 (±5.9) 6.48 (±12.9) <0.001* * – statistically significant difference.

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4.1.3. Possible echocardiographic parameters for identification of fluid responders

Variability of LVOT VTI during the breathing cycle was significantly higher in responders compared to non-responders, 14% (±5.9) and 6.48% (±12.9) respectively (p<0.001).

The mitral E wave velocity was 72.14 cm/s (±14.5) in responders compa-red to 89.7 cm/s (±17.2) in non-responders. ROC analysis showed AUC was 0.78 (95% CI 0.619–0.941, p=0.006), the best cut off value was 78.5 with 75% sensitivity and 82.1% specificity. The increase of mitral E wave after the fluid challenge was bigger in responders compared to non-responders, 9.28 cm/s (±5.9) and 2.64 cm/s (±2.84) (p=0.003). Calculation of ∆E is a suitable parameter to predict fluid responsiveness as AUC under the ROC curve was 0.893 (95% CI 0.794–0.992, p<0.001). The increase of E wave of more than 4 cm/s can predict fluid responsiveness with a sensitivity of 91.7% and specificity of 78.6%. The similar results were with A/E ratio: mean E/A ratio in responders was 0.87 (SD 0.096) and in non-responders it was 1.086 (±0.16), AUC was 0.868 (95% CI 0.755–0.98, p<0.001), the best cut off value 0.913 with 75% sensitivity and 89.3% specificity. The increase of E/A ratio after fluid bolus was bigger in responders compared to non-respon-ders 0.07 (±0.02) and 0.04 (±0.008) respectively (p=0.001). The AUC under the ROC curve was 0.878 (95% CI 0.76–0.995, p<0.001). The increase of E/A ratio of more than 0.07 can predict fluid responsiveness with a sensitivity of 83.3% and specificity of 85.7%.

Although cardiac index was lower in responders, 2.89 L/min/m2_(±1.06), compared to non-responders, 3.35 L/min/m2_{(±0.94), the difference was not} significant (p=0.214). According to ROC analysis, AUC was 0.622 (95% CI 0.424–0.82, p=0.82). CIn seemed to be not suitable for the prognosis of fluid responsiveness.

The variability of IVC was significantly higher in responders, 32.29% (±13.48), compared to 11.03% (±12.24) in non-responders (p<0.001). The AUC of the ROC curve for the IVC variability index was 0.878 (95% CI 0.768–0.988, p<0.001) and the best cut off value seemed to be 26.6% with 75% sensitivity and 82.8% specificity.

The results of ROC analysis are shown in Fig. 4.1.3.1 and Fig. 4.1.3.2. The individual values of these parameters for responders and non-responders are shown in Table 4.1.3.1 and graphic data are presented in Fig. 4.1.3.3.

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Table 4.1.3.1. Individual values of echocardiographic parameters in

respon-ders and non-responrespon-ders after fluid challenge

Variables Responders Non-responders p-value

Mitral E wave, cm/s (SD) 72.14 (±14.5) 89.7 (±17.2) 0.004

∆ E, cm/s (SD) 9.28 (±5.9) 2.64 (±2.84) 0.003

E/A ratio (SD) 0.87 (±0.096) 1.086 (±0.16) <0.001

∆ E/A (SD) 0.07 (±0.02) 0.04 (±0.008) 0.001

IVC index, % (SD) 32.29 (±13.48) 11.03 (±12.24) <0.001

Cardiac index, L/min/m2_(SD) _{2.89 (±1.06)} _{3.35 (±0.94)} _0.214

* – statistically significant difference.

Fig. 4.1.3.1. Receiver operator characteristic (ROC) curves for

echocardiographic data defining fluid responsiveness. The area under the curve (AUC) was considered to be clinically relevant if AUC was more than 0.7. Areas under the ROC curve: Mitral E wave velocity – 0.78

(95% CI 0.619–0.941, p=0.006); E/A ratio – 0.868 (95% CI 0.75–0.98, p<0.001); Cardiac index – 0.622 (95% CI 0.424–0.82, p=0.82)

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Fig. 4.1.3.2. Receiver operator characteristic (ROC) curves for

echocardiographic IVC index defining fluid responsiveness. The area under the curve (AUC) was considered to be clinically relevant if AUC was more

IMPACT OF PERIOPERATIVE FOCUSED TRANSTHORACIC ECHOCARDIOGRAPHY ON THE OUTCOMES OF PATIENTS WITH INTRA-ABDOMINAL SEPSIS

Asta Mačiulienė