Management of Septic Shock According to SSC 2016 in Post Laparotomy Exploration due to Gastric Perforation

According to International Guidelines for Management of Sepsis and Septic Shock 2016, sepsis was defined as life threatening organ dysfunction caused by a dysregulated host response to infection. Sepsis and septic shock are major healthcare problems and the incidence increased by year. Septic Shock was defined as subset of sepsis in which underlying circulatory and cellular metabolism abnormalities are profound enough to substantially increase mortality and can be identified with persisting hypotension requiring vasopressors to maintain MAP&gt;65mmHg and having serum lactate level &gt; 2 mmo/L despite adequate volume resuscitation. Intraabdominal infection was reported as contributor to a high mortality rate for infection case in intensive care units. We reported a case of a patient with sepsis and septic shock caused by intraabdominal infection post laparotomy exploration ec gastric perforation. The patient was monitored prospectively, received antibiotics, hemodynamic support and mechanical ventilation support while being treated in the ICU. On the sixth day, the patient was transferred to ward.


Introduction
Sepsis was defined as life threatening organ dysfunction due to dysregulation or disproportion of immune response to infection, a major health problem and reported incidence continue to increase. 1 Several studies reported sepsis as the leading cause of death in critically ill patients throughout the world, in spite of its uncertain incidence. Septic shock is defined as subset of sepsis in which underlying failure in notably circulatory and cellular metabolism which may significantly increase mortality. Septic shock is characterized by persisting hypotension requiring vasopressors to maintain MAP≥65mmHg and having serum lactate level > 2 mmo/L despite adequate volume resuscitation with mortality reaching 40%. 1 Sepsis is the main cause of death in the Intensive Care Unit (ICU), with almost 15% diagnosed sepsis and twothirds of these fall in septic shock. Sometimes patients treated in the ICU also have accompanying diseases which aggravate their condition and organ failure which increases mortality. A study stated 60% of 305 patients with severe sepsis experienced lung infection followed by 39% due to abdominal infection. In an observation conducted by the Complicated IAI Observational World (CIAOW) in 2014 stated that the source of infection were intraabdominal infection, as much as 14.3%, ranks third, after appendix 34.6% and cholecystitis 14.8%, as for mortality due to Intraabdominal Infection (IAI) reached 10.7%. Etiology of IAI mostly includes gramnegative Escheria coli bacteria and gram-positive Enterococus faecalis. 2 Management of sepsis based on International Guideline for Management of Surviving Sepsis Campaign (SSC) 2016 includes crystalloid fluid resuscitation for at least 30 mL/kg iv in the first three hours to overcome hypoperfusion caused by sepsis. Additional fluid can be administered after reevaluation of hemodynamic status, whether pulse, blood pressure, arterial oxygen saturation, breathing frequency, temperature, urine output, etc., with invasive or non-invasive devices as available. Assess cardiac function, predict fluid responsiveness, maintain MAP 65 mm Hg with vasopressors, normalize lactate, take microbiological culture samples, and give antibiotics immediately after diagnosis of sepsis within the first 1 hour. 3 Patients who experienced sepsis after intraabdominal infection should get their source of infection controlled, treated in the ICU and get correct antibiotics to avoid complication towards better improvement.

Case Report
A 68 year old woman from a private hospital presented to the emergency department of Hasan Sadikin General Hospital Bandung with generalized abdominal tenderness and difficulties to defecate since two days prior admission, it was accompanied with epigastric pain two weeks prior admission aggravated by pressure but without vomiting. She admitted taking medicine and herbs for back pains and a year history of uncontrolled hypertension, with highest systolic blood pressure 160 mmHg but unknown diastolic pressure.

Figure 1 Electrocardiogram in emergency department
Source: private documentation Electronic copy available at: https://ssrn.com/abstract=3588997 Patient was priorly diagnosed as diffuse peritonitis due to Suspected Hollow Viscus Perforation; Suspected Gastric Perforation; Hypertensive Heart Disease; Stage I Acute Kidney Injury, was given 1800 cc NaCl 0.9% intravenous fluid in the first 6 hours and continued by 1800 cc for 18 hours; combination of intravenous antibiotics including ceftriaxone two grams every 24 hours and metronidazole 500 mg every eight hours, also planned to have laparotomy exploration.
Surgery was done with general anesthesia. Perforation in pre-pyloric area with diameter of 1 cm was fixed by primary suture, omental patch and done biopsy. During operation, patient received 900 cc of crystalloid solution with average blood loss of 150 cc and urine output 200cc. Hemodynamic status during the two hour surgery using norepinephrine 0,05-0,2μg/kg/m had an average systolic pressure 90-140 mmHg, diastolic 60-78 mmHg and heart rate 78-130x/min. After surgery, patient was transferred to Intensive Care Unit (ICU).
On the sixth day, laboratory results showed FBG 159, Na 139, K 4.0, Cl 105, Mg 1.9, Ca 4.83, patient was moved to High Care Unit (HCU). Patient was given RL solution 500 cc/24 hours, liquid diet with calory needs of 1500 to 2400 kkal. Urine production shown >0.5-1 cc/kg/hour with cumulative balance of -2778 cc.

Discussion
The word sepsis derives from the Greek word "sepo" which means "I rot" and was first mentioned in the poems of Homer (18 th century BC). In 1914, Hugo Schottmuller formally defined "septicaemia" as a disease caused by microbial blood stream invasion. Despite its definition, terms such as septicaemia, sepsis, toxemia and bacteremia were often overlapped.
Sepsis is now known as a condition involving early activation of pro-inflammatory and anti-inflammatory response in the body. Along with this condition, circulatory abnormalities such as decreased intravascular volume, peripheral vascular vasodilation, myocardial depression, and increased metabolism generate an imbalance between systemic oxygen delivery and oxygen demand which will lead to systemic tissue hypoxia. The pathophysiology of this condition starts with reactions to infection which will trigger neurohumoral response in the presence of pro-inflammatory and anti-inflammatory responses, starting with cellular activation of monocytes, macrophages and neutrophils that interact with endothelial cells. Subsequent bodily responses include mobilization of plasma contents as a result of cellular activation and endothelial disruption. Plasma contents include cytokines such as tumor necrosis factor, interleukin, caspase, protease, leukotriene, kinin, reactive oxygen species, nitric oxide, arachidonic acid, platelet activating factor, and eicosanoids.
Proinflammatory cytokines such as tumor necrosis factor α, interleukin-1β, and interleukin-6 will activate the coagulation chain and inhibit fibrinolysis. Activated Protein C (APC) is an important modulator of the coagulation and inflammatory chains that enhances the process of fibrinolysis and inhibits the process of thrombosis and inflammation. Activation of the complement and the coagulation chain help strengthen the process. The interaction dominantly occurs in vascular endothelium and as a result microvascular injury, thrombosis and capillary leakage will follow and leads to tissue ischemia. This endothelial disorder plays a role in the occurrence of organ dysfunction and global tissue hypoxia.

Figure 3 Coagulation Chain started with inflammatory response, thrombosis and fibrinolysis as response to infection.
Source: Bernard GR,Vincent JL,et al. 9 According to a study in 2014 that explains the wide pathophysiology of sepsis, identification of sepsis with SIRS criteria is no longer appropriate because SIRS indirectly stated dysregulation of body response to infection. 4 An amount of patients were admitted to the hospital with SIRS criteria but ultimately without evidence of infection. Pathological condition in the state of sepsis affects almost every component of micro-circulating cells including endothelial, smooth muscle cells, leucocyte, erythrocyte and tissues. Microcirculation determine oxygen availability for each cell and tissues which ensures organ functions properly and if not corrected properly may cause respiratory distress in tissues and cells and leads to macro circulation dysfunction and finally results in one and multiple organ failure.
Management of sepsis based on Surviving Sepsis Campaign (SSC) guideline were implemented to sepsis bundles with revised consensus that issued hour 1 bundle with the aim of providing resuscitation and sepsis management as soon as possible, to prevent subsequent organ dysfunction, in the first hour after patient was identified as having organ dysfunction with Quick SOFA (qSOFA) criteria that includes 2 out of three following criterias: Respiratory rate ≥22 x/min, loss of consciousness and systolic blood pressure of ≤ 100 mmHg, make sure hour 1 bundle is carried out as the main priority that is to measure of lactate levels, re-measuring if previous lactate levels >2 mmol/L, blood culture examination before administration of antibiotics, administration of broad-spectrum antibiotics, administration of crystalloid fluids 30 cc/kg if there is hypotension or lactate levels ≥ 4 mmol/L, administer vasopressors if hypotension occurs either during or after fluid resuscitation, to maintain the MAP value ≥ 65 mmHg. 3 In this patient, before surgery was planned, qSOFA score was found ≥3 including loss of consciousness with glassglow coma scale from 15 to 14, respiratory rate 24x/min and decreasing SBP 90 mmHg. In accordance with one hour bundle, lactate levels were examined and showed 3.0 mmol/L, but in the next 2 hours no lactate examination was done, a study stated that using lactate levels as a guide in resuscitation, decreased mortality rates. She was then given 2000 cc intravenous Ringer Lactate crystalloid fluid for resuscitation, broad spectrum intravenous antibiotic Ceftriaxone 2 gram every 24 hours and Metronidazole 500 mg every eight hours, vasopressor norepinephrine was used starting 0.05μg/kg/min. Blood culture was obtained after surgery in the ICU.
Next management focused on controlling the source of infection where most sepsis diagnosis may need emergency operation for diagnostic and infection source control. Laparotomy exploration was done for suspected gastric perforation in this patient. Empirical antibiotics with adequate concentration in the first hour after diagnosis were given. Administration of antibiotic must be evaluated everyday to prevent antibiotic deescalation. Use combination of antibiotics for septic shock patients, neutropeni patients and patients with multi drug resistant pathogen microbial infection. Duration of therapy may range from 7-10 days, longer usage may be given to delayed clinical response patients, S. aureus bacteremia, fungal infection, viral infection or immunological deficiency. Low procalcitonin levels may be used for guidance to stop antibiotic therapy in patients earlier with sepsis.
Abdominal sepsis is sepsis due to in intra-abdominal infections with or without peritoneal involvement, intraabdominal infection is divided into Community Acquired IAI (CCA-IAI) and Health Care Acquired IAI (HC-IAI). Based on the extent of the infection, it is divided into Uncomplicated IAI, which is a one organ infection without damage of intra-abdominal organs and Complicated IAI, which is an infection that extends from the source of the infectious organ into the peritoneum through the perforated viscus. 6 Guidelines issued by IDSA regarding diagnosis and management of intra-abdominal infections in 2010 recommend the administration of broad-spectrum empirical antibiotics to overcome the activity of gram-negative bacteria including meropenem, imipenem-cilastatin, doripenem, piperacillin-tazobactam, ciprofloxacin or levofloxacin in combination with metronidazole, or administration of ceftazidime, or cefepime in combination with metronidazole for high-risk community acquired IAI patients (late intervention> 24 hours, APACHE II score ≥15, extreme age, comorbid organ dysfunction, and low albumin). 7 In this patient, intravenous empirical antibiotic meropenem was given 1 gram every 8 hours and metronidazole 500 mg every 8 hours. Blood culture and sputum examination were also obtained but resulted no growth of microorganism.
Patient was treated in the ICU post operatively and given mechanical ventilation support with consideration of having major surgery, geriatrics with unstable cardiovascular condition, as previously seen VES unifocal infrequent + AF RVR on echocardiogram and received Digoxin during operation and on the first day of ICU hospitalization, as seen clinically, no lung problems was found but chest X-ray revealed minimal pleural effusion. Ventilator weaning gradually went well every day until patient was extubated. In accordance with the 2016 SSC recommendations, the use low tidal volume is reecommended in adult patients with respiratory failure induced by sepsis without ARDS, by giving tidal volume 4-6 cc/kg may offer good results, reduce the duration of mechanical ventilation usage, reduce the incidence of subsequent ARDS, and, in sepsis patients with abdominal surgery, the use of low tidal volume may reduce the incidence of respiratory failure and decrease the length of stay in the ICU. 1 Enteral nutrition in the first 24-48 hours of treatments in the ICU was recommended as nutritional management in sepsis and septic shock patients. 1 Administration of only parenteral nutrition or combination of parenteral and enteral nutrition is not recommended in patients that are able to be given enteral nutrition. Parenteral nutrition is more invasive, increases the risk of infection, does not reduce mortality, and is high cost. ⁸ In this patient, on the first day of ICU treatment, parenteral nutrition is given directly without combination with enteral, because patient fasted until the 5th postoperative day.
During treatment at the ICU, hemodynamic monitoring, hemodynamic support, urine production and fluid balance monitoring, empirical antibiotics, mechanical ventilation, sedation, analgesia, with the aim of giving better tissue perfusion. On the fifth day of treatment at the ICU, the patient was transferred to the ward in a stable condition.

Conclusion
Septic shock is a part of sepsis based on circulatory and cellular metabolic failure that may increase mortality significantly. Early and adequate diagnosis of sepsis since patient was admitted to emergency department, accompanied by appropriate management of sepsis such as fluid resuscitation, hemodynamic support, source control surgery, specific antibiotic administration will improve patient's outcome and reduce morbidity as well as mortality.