sepsis update taiz univer 15-7-2024.pptx

the new suspected update in sepsis that change in surviving sepsis campaign

1. Update in Sepsis and Septic Shock management 2024 Anwar Yusr Critical Care Consultant University of Science and Technology Hospital 21-7-2024

2. In 1991 ,  sepsis  was first defined. SEPSIS 1 In 2001 , definitions were updated with clinical and laboratory variables. SEPSIS 2 In 2004 , the Surviving Sepsis Campaign guidelines adopted those definitions, which led to the development of a protocol-driven model for sepsis care used worldwide (2004 – 2008 – 2012- 2016-2021). In 2016 , the Sepsis-3 committee.

3. 2010 2014 2018 2006 2002 Declaration Barcelona 2004 Adult Guidelines 2008 Adult Guidelines 2021 Adult Guidelines 2016 Adult Guidelines 2002 SSC initiated between ESICM, SCCM & ISF 2010 Data published on 15,000 SSC database 20% RRR for patients from demonstrating death. 2013 sepsis metrics adopted by New York state, USA. 2017 Data from New York state published on 100,000 patients with 15.2% RRR for death. 2018 Hour-one bundle released. 2005 working with IHI to create first set of performance improvement bundles. 2008 SSC independent of industry funding and ISF no longer a partner 2018 Sepsis research priorities published 2020 SSC COVID- 19 Guidelines 2022 2012 Adult Guidelines 2014 Data published on 30,000 patients from SSC database demonstrating 25% RRR for death. Surviving Sepsis Campaign Timeline 3

4. Mortality  Sepsis : 30% - 50%  Septic Shock: 50% - 60% Why we are spe n ding t i m e on se p sis?

5. Sepsis 1 ACCP/SCCM 1991 consensus Conference

6. The Sepsis Continuum A clinical response arising from a nonspecific insult , with  2 of the following : T >38 o C or <36 o C HR >90 beats/min RR >20/min WBC >12,000/mm 3 or <4,000/ mm 3 or >10% bands SIRS = systemic inflammatory response syndrome SIRS with a presumed or confirmed infectious process Chest 1992;101:1644. Sepsis SIRS Severe Sepsis Septic Shock Sepsis with organ failure Refractory hypotension The Sepsis Continuum

7. SIRS Can be triggered by localized or generalized infection and Non-infection. Noninfectious process as a cause. Pancreatitis. Autoimmune disease. Vasculitis . Thromboembolism. Burns. Surgery/trauma. Pulmonary contusion. Approximately 10 - 12% of patients with sepsis in ICU do not have ≥2 SIRS criteria.

8. SEPSIS 2 IN 2001 SCCM,ESICM, ACCP, ATS and SIS the second consensus meeting and updated the criteria for sepsis .

9. IN 2001 SCCM,ESICM, ACCP, ATS and SIS the second consensus meeting and updated the criteria for sepsis . Definitions of sepsis, severe sepsis and septic shock which were stratified at the consensus meeting 10 years previously were modified. Signs and symptoms of sepsis were much greater in number and detail. The documented or suspected infection-specific findings were categorized as general , inflammatory , hemodynamic , organ dysfunction and tissue perfusion variations, biochemical indicators were considered. SEPSIS 2 (2001)

10. modified SIRS’ criteria The problems was that this was defined more for research protocols that clinical use. Even using the modified SIRS, you will miss 1 in 8 patients with severe sepsis.

11. What is wrong with these definitions Too sensitive A bad cold could be classified as sepsis Routine post op patients Too much variability in the definition which can affect reported outcome such as mortality

12. Sepsis Definition Surviving Sepsis Campaign 2012 Infection + SIRS 2. Inflammatory variables -WBC > 12,000, < 4,000 or Band > 10% - CRP > 2 times - Procalcitonin > 2 times 1. General variables -BT > 38 ° -HR > 90 bpm , Tachycardia - Alteration of consciousness -Positive fluid balance > 20 ml/kg/24hrs -BS > 140 mg% without DM 5. Tissue perfusion variables -Lactate > 1 mmol /L -Capillary refill prolong, skin mott 4. Organ dysfunction variables - PaO2/FiO2 < 300 -Urine < 0.5 ml/kg/ hr x 2 hrs -Cr rising > 0.5 mg/dl -INR > 1.5, aPTT > 60 second -Absent bowel sound -Platelet < 100,000 -TB > 4 mg/dl 3. Hemodynamic variables - Hypotension -SBP < 90 or Drop > 40 mmHg -MAP < 70

13. SEPSIS - 3 The third international consensus definitions for Sepsis and Septic shock FEB 2016

14. SEPSIS - 3 The new definition of sepsis is: “Life threatening organ dysfunction caused by a dysregulated host response to infection” ‘Infection with an increase of two or more SOFA points’

15. Sepsis definition 2016 Definition of sepsis: ‘a potentially life threatening organ dysfunction due to dysregulated host response to infection’. Does this provide a rapid screening or enable a definitive diagnosis?

16. The problem with these ‘definitions’ The issue with all the ‘sepsis’ definitions is that they are consensus definitions using what has been called “threshold decision making”. They use biomarkers to predict sensitivity and specificity. They do not actually define what sepsis is from a clinical basis. In many ways they are merely predictors of mortality.

17. The problem with these ‘definitions’

18. The problem with these ‘definitions’

19. Sepsis 3 In short, Sepsis 3 criteria really only increased the specificity of predicting mortality while decreasing sensitivity from SIRS. And overall sensitivity of Sepsis 3 for patients OUTSIDE of the ICU is less than 55%.

20. Lactate ? The authors of Sepsis 3 determine that lactate measurement did not improve the predictive validity of qSOFA but might be helpful in identifying patients at ‘intermediate risk ’?

21. Some of the problems with Sepsis 3 Fever and other SIRS criteria have a low specificity. There are no clinical signs of sepsis. Elderly, immunocompromised and malnourished patients often do not manifest signs of sepsis or SIRS. Some of the ‘clinical criteria’ apply to adult physiological variables. Actual infection may never be confirmed. qSOFA has never been prospectively validated.

22. Some of the problems with Sepsis 3 6. Increases in WBC is a marker of stress not just infection. 7. Biomarkers such as CRP, procalcitonin , IL-6 have limited sensitivity and specificity and cannot/should not be used in isolation.

23. Sepsis is a dynamic process Sepsis is a dynamic condition and none of the prior nor current ‘definitions’ account for change in time. As well, all the criteria for ‘diagnosing’ sepsis may not be present at a single time in any one patient.

24. Bottom line Consider sepsis as a possible cause whenever a patient develops new organ dysfunction. If you suspect sepsis, but qSOFA criteria are not met, do not withhold therapy. If qSOFA criteria are met, there should be prompt consideration of infection, further investigation and definite sepsis management initiated.

25. Sepsis Pathophysiology

26. Coagulation and Impaired Fibrinolysis In Severe Sepsis Reprinted with permission from the National Initiative in Sepsis Education (NISE). Endothelium Neutrophil Monocyte IL-6 IL-1 TNF-  IL-6 Inflammatory Response to Infection Thrombotic Response to Infection Fibrinolytic Response to Infection TAFI PAI-1 Suppressed fibrinolysis Factor VIIIa Tissue Factor COAGULATION CASCADE Factor Va THROMBIN Fibrin Fibrin clot Tissue Factor

27. Sepsis Pathophysiology

28. Modified from criteria published in: Balk RA. Crit Care Clin . 2000;16:337-352. Kleinpell RM. Crit Care Nurs Clin N Am 2003;15:27-34. Cardiovascular Tachycardia Hypotension Altered CVP and PAOP Renal Oliguria Anuria  Creatinine Hematologic  platelets,  PT/INR/  aPTT  protein C  D-dimer Hepatic Jaundice  Liver enzymes  Albumin CNS Altered consciousness Confusion Metabolic Metabolic acidosis  Lactate level  Lactate clearance Respiratory Tachypnea  PaO 2  PaO 2 /FiO 2 ratio Any Organ Can be Affected by Sepsis .

29. SEPSIS 2016 Septic Shock SEPSIS

30. New Definition of Sepsis 2016 Strange Mortality 10% Mortality 40% SEPSIS SEPTIC SHOCK Lactate Micro circulation Indicators ? Metabolic acidosis Tissue hypoperfusion

31. SEPSIS - 3 The new definition of septic shock is: “A subset of sepsis with particularly profound circulatory, cellular and metabolic abnormalities associated with an increased mortality than sepsis alone” “ Infection with hypotension requiring vasopressors to maintain MAP >65mmHg PLUS a Lactate of >2mmol/l”

32. SOFA SOFA Variables PaO2/FiO2 ratio Glasgow Coma Scale score Mean arterial pressure Administration of vasopressors with type and dose rate of infusion Serum creatinine or urine output Bilirubin Platelet count PaO2/FiO2 = P/F ratio: Normal = 100/0.21 = 476 ARDS Mild < 300 Moderate < 200 Severe < 100 Clinical Lab Treatment 6 variables 30 Scores CNS CVS ReS HeP ReN HeM

33. SO F A S c o r e Describe and quantify organ failure. Predict outcome. Proposed for use in triage strategies because it helps to quantify the principle of utility .

34. qSOFA : Clinical Dx . qSOFA (Quick SOFA) Criteria 1. Respiratory rate ≥ 22/min 2. Altered mentation 3. Systolic BP ≤100mmHg qSOFA Variables - Respiratory rate - Mental status -Systolic BP Altered mentation Cerebral tissue hypoperfusion Early Detection and Management 2/3

35. OUTLINE An initial SOFA score of < 9 predicted a mortality of < 33%. A SOFA > 11 predicted mortality of 95%

36. qSOFA (>2) : GCS<15 SBP < 100 RR > 22 Despite adequate volume: Vasopressors required for MAP > 65 Serum lactate >2

37. Shock = Tissue Hypoperfusion Brain -Cerebral hypoperfusion -Alteration of conscious Renal and Metabolism -AKI -Metabolic acidosis Heart -Myocardial depression -2 nd MI Endocrine -Hypo& Hyperglycemia Hematology -DIC Lung -ARDS GI and Liver - Shock liver Skin -Cool  Late - C apillary refill MODS

38. JAMA . 2016;315(8):762-774. doi:10.1001/jama.2016.0288 Suggested Clinical Criteria for Sepsis (if in ICU?) Infection + 2 or more SOFA points (above baseline) Consider Sepsis outside ICU if Infection + 2 or more qSOFA points

39. What you should/shouldn’t do… Do : MV (potentially) Minimal sedation/analgesia BG control (<180) CRRT for AKI VTE prophylaxis (LMWH/heparin) Stress ulcer prophylaxis (PPI/H2RA) Aspirin (probably) Don’t : Immunoglobulins Intensive insulin therapy Bicarb Immune stimulation Esmolol (who knows??) S S C r ec o mmend s A G A IN S T 2016

40. Screening for sepsis PICO Question 2021 Recommendation Recommendation Strength and Quality Change from 2016 In acutely ill patients should we use qSOFA criteria to screen for the presence of sepsis? We recommend against using qSOFA compared with SIRS, NEWS, or MEWS as a single- screening tool for sepsis or septic shock. Strong, moderate- quality E vidence New recommendation In summary, qSOFA should not be used as a single screening tool for sepsis. NEWS, MEWS, or SIRS may be more beneficial at this time.

41. ADMISSION TO INTENSIVE CARE Consultation with critical care services or transfer to ICU ideally within 6 hours either locally or through BC Patient Transfer Network.

42. Four phenotypes alpha phenotype (patients on lowest dose of a vasopressor) had the lowest mortality at 5 percent. beta phenotype (older patients with chronic illnesses and kidney dysfunction) had a mortality of 13 percent. gamma phenotype (patients with inflammation and pulmonary dysfunction) had a mortality of 24 percent. delta phenotype (patients with liver dysfunction and septic shock) had the highest mortality at 40 percent

43. WHO Health Emergencies program (WHE) Five principles of sepsis management (1/2) Recognize patients with sepsis and septic shock: Patients with sepsis have suspected or documented infection and acute life-threatening organ dysfunction . A subset of these patients, may have septic shock and show clinical signs of circulatory failure and hypoperfusion. Patients with sepsis and septic shock need treatment and resuscitation immediately!

44. WHO Health Emergencies program (WHE) Five principles of sepsis management (2/2) Give appropriate antimicrobials within 1 hour in shocked patients. Give a targeted resuscitation during the first 6 hours . Monitor-record-interpret-respond . Deliver quality care (later lecture). “As soon as sepsis is suspected the clock has started.”

45. FLAB in the first hour – Give F luids , Result Initial L actate , Give A ntibiotics after Drawing B lood Cultures

46. Culture We recommend that appropriate routine microbiologic cultures including blood ) be obtained before starting antimicrobial therapy in patients with suspected sepsis or septic shock and no substantial delay in the start of antimicrobials ( BPS ). Remarks : Appropriate routine microbiologic cultures always include at least two sets of blood cultures (aerobic and anaerobic). approximately one-half of cases of sepsis, an organism is not identified (culture negative sepsis)

47. A n t i b i o ti c s K U MA R 200 6: Effecti v e antim i c r obia l a d m i ni s tration w i thin the f irs t h ou r o f d o cumente d hypotension was as s ociated with inc r ease d su r vival to hospital dis c harge in a d ult p a tients with septic shock.  B L I S S 201 6: In c r it i cal l y i l l patient s with seve r e seps i s not rece i ving RRT, CI a d ministr at ion was a s s o ciated wi t h higher c l inica l cur e rates an d bet ter P K/ P D targ e t att a inm en t comp a red to IB do s ing for three co mmon beta-lacta m antibiotic s .  F E R R E R ( 201 4 ) : s i gn i ficant as s ociation betwee n dela y in antibiotic a d m i ni s tration ove r the first 6 hours an d inc r eas ing mortal i ty . ”  S TO P - IT (201 5 ) : In p a tients with in t ra abd omina l in f ec t io n s who had un d er g on e a n adeq uat e s o u rce c o n trol pro c edur e, the outco m e after fixe d-duration antibioti c therapy ( a p p roximatel y 4 day s ) w e re sim i la r to those afte r a lon g e r cour s e o f antibiot i c s ( a p p roximatel y 8 day s ) t hat extende d until afte r re s olution o f p h ys i olo g ica l a b normalit i es.  B. L : Wheth e r the r e e xi s ts a differ e nce betw e e n – 1 hour an d 1 – 2 hours could b e de b ate d , bu t g r eate r than 2 hours i s alm os t c ertain l y as s ociated with a higher rate o f hospital mo r talit y .

48. Initiation of antimicrobials For adults with possible septic shock or a high likelihood for sepsis , we recommend administering antimicrobials immediately, ideally within 1 hour of recognition. ( Strong recommendation, low QOE for shock, very low for sepsis without shock ). For adults with possible sepsis without shock , we suggest a time- limited course of rapid investigation and if concern for infection persists, the administration of antimicrobials within 3 hours from the time when sepsis was first recognized. ( Weak recommendation, low QOE ). Source control (surgical , minimally invasive ,removal of intravascular access devices that are a possible source of sepsis or septic shock after other vascular access has been established) . Selection of broad-spectrum antibiotics, including MRSA, MDRO and fungal coverage, should be based on local antibiograms and clinical indication (see SSCG 2021 ). Empiric antimicrobials should be discontinued if an alternative cause of illness is demonstrated or strongly suspected .

49. Main risk factors for multi-drug resistant pathogens MRSA Previous infection/colonization by MRSA in the last 12 months Hemodialysis or peritoneal dialysis Presence of central venous catheters or intravascular devices Administration of multiple antibiotics in the last 30 days (in particular with cephalosporins or fluoroquinolones ) Immunodepression Immunosuppressor treatments Rheumatoid arthritis Drug addiction Patients coming from long-term care facilities or who have undergone hospital stay in the last 12 months Close contact with patients colonized by MRSA

50. ESBL Previous infection/colonization with ESBL in the last 12 months Prolonged hospitalization (>10 days, in particular in ICU/hospice/long-term care facilities) Presence of permanent urinary catheter Administration of multiple antibiotics in the last 30 days (particularly with cephalosporins or fluoroquinolones ) Patients with percutaneous endoscopic gastrostomy

51. Pseudomonas aeruginosa Previous infection/colonization with P. aeruginosa in the last 12 months Administration of multiple antibiotics in the last 30 days ( particularly with cephalosporins or fluoroquinolones ) Pulmonary anatomic abnormalities with recurrent infections (e.g ., bronchiectasis) Elderly patients (>80 years) Scarce glycemic control in diabetic subjects Presence of permanent urinary catheter Prolonged steroid use (>6 weeks) Neutropenic fever Cystic fibrosis

52. Candida spp. 1. Immunodepression 2. Presence of central venous catheters or intravascular devices 3. Patients in total parenteral nutrition 4. Prolonged hospitalization (>10 days, particularly in an ICU) 5. Recent surgery (particularly abdominal surgery) 6. Prolonged wide-range antibiotic administration 7. Previous necrotizing pancreatitis 8. Recent fungal infection/colonization

53. A n t i b i o ti c s The optimal timing of source control is unknown but guidelines suggest no more than 6 to 12 hours after diagnosis since survival is negatively impacted by inadequate source control. Drainage (Percutaneous >> Surgical) of abscess. Remove IV access devices if found as source. In summary, the current recommendations for antibiotic coverage are based on suspicion for an acute bacterial process, and administration of a “broad” antimicrobial regimen is recommended within one hour of recognizing septic shock or within three hours in sepsis without shock.

54. Du r a ti o n a n d p r o c a l c i t o n i n A n timi c r ob ial t r e a tme n t du r a ti o n o f 7 – 10 d a y s is ad e qu a t e f or mo s t ser i ou s i n f e c ti o n s ass o ci a t ed with se p s is and se p ti c sh o ck ( w eak r e c ommend a ti on , l ow qua li ty o f e v i den c e ) Me a su r em e n t o f p r ocalci t onin l e v els c an b e use d t o supp ort sh o r t en in g t h e du r a ti o n o f a n timic r o b ial the r a p y in s e p s is p a ti e n ts ( w eak r e c ommend a ti o n , l ow qua li ty o f e v i den c e ). P r ocalci t onin l e v els c an b e use d t o supp ort the d i s c o n ti nu a ti o n o f emp i ric a n ti b i o tics i np a tie n ts who i n itially appe a r ed t o h a v e se p s i s , b u t su b sequ e n tl y h a v e limi t ed cli n i c al e v i den c e o f i n f e c ti on. For adults with suspected sepsis or septic shock, we suggest against using procalcitonin plus clinical evaluation to decide when to start antimicrobials , as compared to clinical evaluation alone. Weak recommendation, very low quality of evidence SSC 2021 Recommendation : • For adults with an initial diagnosis of sepsis or septic shock and adequate source control, where optimal duration of therapy is unclear, we suggest using procalcitonin AND clinical evaluation to decide when to discontinue antimicrobials over clinical evaluation alone .

55. Interventions to improve tissue perfusion Crystalloid fluids. Vasopressors. Inotropes. Packed red blood cell (PRBC) transfusion . Early identification of patients with sepsis and implementation of early, evidence-based therapies improves outcomes and reduces mortality : implementing the Surviving Sepsis Campaign International Guidelines for Management of Sepsis and Septic Shock ( 2021 ) saves lives.

56. Initial Resuscitation Goals within first 6 hours MAP ≥ 65 mm Hg. CVP 8-12 mm Hg . Urine Output ≥ 0.5 ml/kg/hr . Central Venous ( SVC ) or Mixed Venous Oxygen Saturation 70% or 65% respectively . In patients with elevated lactate, target to decrease lactate .

57. Changing Paradigm: Septic Shock Management ProCESS trial – randomized, 31 centers, 1,341 patients ARISE trial – randomized, 51 centers (mostly Australia and New Zealand), 1,600 patients ProMISe – randomized, UK, 56 centers, 1,260 patients

58. Results of Three International Studies (2014-2015) ARISE and ProMISe had two groups: EGDT * and usual care ProCESS had three groups: EGDT, structured resuscitation and usual care Before randomization, all patients received antibiotics and an average of 2500 mL of NS (equal to 30 ml/kg), had blood cultures and lactate drawn No statistically significant difference in mortality between groups Mortality rate 18 percent for ARISE & ProCESS Mortality rate 30 percent for ProMISe *EGDT – Early goal-directed therapy

59. 3723 patients at 138 hospitals in seven countries (all patients from the ProCESS, ProMISe and ARISE trials) Prior to randomization >92 percent of patients were identified early and provided the 3-hour bundle (including 2L of fluid and antibiotics-given within 70 minutes of presentation to ED) No difference in 90-day mortality between EGDT and usual care groups Authors stated: “It remains possible that general advances in the provision of care for sepsis and septic shock, to the benefit of all patients, explain part or all of the difference in findings between the trial by Rivers et al. and the more recent trials.”

60. In 2013 , New York began requiring hospitals to follow protocols for the early identification April 2014 to June 30, 2016 49,331 patients at 149 hospitals 82.5 percent had the three-hour bundle completed within three hours (median time was 1.3 hours) Longer time to completion of the three-hour bundle was associated with higher risk-adjusted, in-hospital mortality as well as longer time to administration of antibiotics (14 percent higher for both)

61. KEY TRIALS – THE TRILOGY

62. PICO Question 2021 Recommendation Recommendation Strength and Quality Change from 2016 In patients with known or suspected infection and hypotension and / or an elevated lactate should we administer 30mL/Kg BW of crystalloids or a rapid small volume fluid challenge and re- assess? For patients with sepsis induced hypoperfusion or septic shock we suggest that at least 30 mL/kg of IV crystalloid fluid should be given within the first 3 hr of resuscitation. Weak , low quality of evidence Downgraded from Strong, low Q uality of evidence “We recommend that in the initial resuscitation from sepsis- induced hypoperfusion, at least 30 mL/kg of IV crystalloid fluid be given within the first 3 hr” Initial Resuscitation NICE recommends that the initial total volume in patients with evidence of poor perfusion should be at least 500ml , delivered as quickly as possible and certainly within 15 minutes. followed by further challenges up to a total of 20ml/kg as an initial bolus over less 10 min. In summary , the current recommendation is 30 mL/kg of lactated ringers within the first three hours of resuscitation, with the caveat of   utilizing clinical judgment to prevent fluid overload . Fluid challenge as 4ml/kg (250 – 500ml) bolus over 15 - 20 minutes.

63.  S e ym o ur 20 1 7 : M or e rapi d co m pl e tio n o f a 3- h o ur b u n d l e o f se p s is car e and rapi d a d minis tratio n o f an t ibio t ics, but n o t rapid c o m p l e ti on o f an i n iti a l b o l u s o f in trav e n o u s fluid s, were as sociat e d with l o w e r ri s k -a d juste d i n - h o s p ita l m ortality.  SSS P 2 (2 01 7 ) : Amo n g a d ults w ith s ep s is an d hyp o te n s ion , most o f w h o m w e re p o sitiv e for H I V , in a re s o urc e - limit e d s e tt ing, a pr oto co l for e arl y re s u scitati o n with a d m i n i s t r at i o n o f i n tr a ven o us f l u i d s an d vas o p re s so r s i n c rease d i n - h o s pi t a l m o r t al i ty co m p a re d w ith u s ual care.  C l a s s i c 20 1 6 : A p rot o co l aim e d a t re s trictin g re s u scitati o n fluid is fe a si b l e and r e s u l t ed in r ed u ced vo l u m e s of r e s us ci tat ion f l uid co m p a re d to a pr oto co l aim e d a t st an d ar d car e o f I C U p atie n t s who had u nd e rgo n e init ia l r e s u scitat ion .  F EA ST 20 1 1 : Inc r ease mo r tality as a bolus in malaria.  F A CTT 20 6 : Amo n g p atie n t s w ith ALI/ARDS, a conse r v a t i v e f l u id ma n age m e nt st rat e gy targe tin g a CVP < 4 m m Hg imp rov e s l u n g func t ion , d e crea s e s v e n tilator d a ys , an d r e d uces I C U d a y s c o m p a re d t o a l i b e r a l s tr a tegy.

64. Improved BP: M ean arterial pressure ( MAP ) ≥ 65 mmHg. SBP > 100 mmHg . Skin examination: Capillary refill < 2–3 sec if < 65 years; < 4.5 if > 65 years. Absence of skin mottling. Well felt peripheral pulses. Warm dry extremities. Improved sensorium. Normalized lactate levels (if initial level high ). MAP = [SBP + (2 *DBP)] ÷ 3 MAP is driving the driving pressure of perfusion. Invasive haemodynamic parameters (i.e. CVP and ScvO 2 ) are not superior to clinical targets of perfusion. However, can be used as adjuncts to guide patient care understanding their limitations and meaning. Resuscitation targets

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67. R ESUSCI TA TION ( 1 st 3 hours ) early go a l di re cte d fluid t h era p y achieving adequate int ra v as c ular v o lume status and tissues perfusi on fo r patient res cu e ; with p o sitive fluid b al a nce O PTIM IZ A TION ( o v er 1 st da y ) maintai ning stable adequate int ra v as c ular v o lume/per f u s ion status fo r o rgan re s cu e ; with an app r o priate degree o f mild p o sitive o r ne t - zero fluid b al a nce S T A B I L IZ A TION ( o v er d ays ) nor m al repla c ement/ maintenance therapy of v o lume and m etab o lic pr o fi l e f o r o r g an s u pp o r t ; with n e t- zero o r mild nega t ive fluid b al a nce E V ACU A TION ( o v er week s ) la te go a l di re cte d fluid remo v a l (with diu retic s- Alb umin o r R R T - U F ) o v erco ming fluid o v erl oad/interst itial edema f o r o rgan re c o v er y ; achieving an app r o priate nega t ive cum u l a ti v e fl u id bal an ce P ositiv e cu mulativ e fluid balance is as s ociated with high m o rtalit y and m o rbid i ty 76

68. I s o t o n i c S o l ut i o n s a n d M aj o r A d v e r s e R e n a l E v e n t s T ria l ( S M A R T trial ) M u lt i ce n tr i c 15, 8 02 adults r and om i z ed t o N S o r BC (L R o r Pla s m a - L y t e A) Prima r y: Major A d v e r s e Ki dn e y E v e n t a t d a y 30 ( M AK E 3 )

69. C ONC L US I ONS Among crit ic al l y i l l adult s , the u s e of ba lan c ed cr y s t al l o i d s f o r i n t ra v enous f l u id admi n i s t r a ti o n r esu l t ed in a l o w er r at e o f the c o m pos i t e ou t c o m e o f de a th f r o m a n y c ause, n e w r ena l- r ep l acem e n t the r a p y , o r pe r s i s t e n t r enal d y s fu ncti on than the u s e o f sa l i ne . S M A R T Co n c l us i o n s

70. Resuscitation: fluid type Crystalloid fluid is preferred: Lactate Ringers ( LR *), Ringer’s Acetate ( RA ), PlasmaLyte ( PL ) or normal saline. NS is associated with hyperchloremic acidosis. Albumin as effective as crystalloids in septic shock: Use in addition to crystalloid , when substantial crystalloids are needed for intravascular volume repletion. Do NOT give hypotonic fluid. Do NOT give semisynthetic colloids. i.e. starch-based colloids ( HES , dextrans ) have been associated with increased AKI, renal replacement therapy and mortality. Gelatine safety unknown . Use balanced crystalloids R.L or PL instead of normal saline for resuscitation ( SCC 2021).

71. albumin potentially resulted in a lower 28-day mortality (30.7% versus 35.3%) in patients with severe sepsis without causing impairment in renal or other organ function. V asopressor-free days were higher in albumin group but 90-day mortality was not statistically different between the two groups (24.1% versus 26.3%) The post hoc analysis of the septic shock subgroup in 1,121 patients of the same study supported a survival benefit to albumin. The 90-day mortality was 43.6% in the albumin group compared to 49.9% in the crystalloid group (p= 0.03). adding albumin to early standard resuscitation with lactated Ringer's was not associated with improved 7-day or 28-day mortality and it did not affect the renal replacement therapy needs. Cochrane review which included 10 RCTs with 12,492 patients comparing albumin versus crystalloids found no difference in 30-day or 90-day mortality or the need for RRT between groups. investigates whether the replacement with albumin and the maintenance of its serum levels of at least 30 g/l for 28 days improve survival in patients with septic shock compared to resuscitation and volume maintenance without albumin. For adults with sepsis or septic shock, it is suggested to use albumin in patients who received large volumes of crystalloids over using crystalloids alone. Weak recommendation, moderate quality of evidence. (SSC guideline 2021). Albumin

72. Initial Resuscitation & Fluid therapy Type Crystalloid: Isotonic -Balance salt isotonic solution Dose 30 ml/kg Rapid Bolus Re-Evaluation Hypotension 500-1000ml in 30 min 500-1000 ml/ hr Improved Yes No Sepsis induced hypotension Septic Shock

73. Don’t set it and Forget it! Data Source: A Users Guide to the 2016 Surviving Sepsis Guidelines. Society of Critical care Medicine. March 2017 Volume 45 Number 3. Remember Septic Shock is a Clinical Diagnosis! Newest Evidence-Based Guidelines Published in 2017 History of heart failure and liver failure are not contraindications to fluid resuscitation. For patients at risk for poor tolerance of fluids (e.g., reduced cardiac function, aortic stenosis, end-stage renal disease), however, we suggest frequent reassessment of intravascular volume status, with total volume of fluid-resuscitation based on response to therapy (II-E)

74. CIRRHOSIS Recommendations : There should be a high level of suspicion for infection/sepsis in cirrhotic patients admitted to the hospital. It is reasonable to consider albumin administration in addition to balanced crystalloids in patients who meet criteria for fluid resuscitation and have a low serum albumin (e.g. ≤3.2) (II-C) Severe liver disease can be considered an immunocompromised or hemodynamically at-risk state, and therefore represent a vulnerable population with regards to the development of sepsis or septic shock.

75. R ESUSCI TA TION ( 1 st 3 hours ) early go a l di re cte d fluid t h era p y achieving adequate int ra v as c ular v o lume status and tissues perfusi on fo r patient res cu e ; with p o sitive fluid b al a nce O PTIM IZ A TION ( o v er 1 st da y ) maintai ning stable adequate int ra v as c ular v o lume/per f u s ion status fo r o rgan re s cu e ; with an app r o priate degree o f mild p o sitive o r ne t - zero fluid b al a nce S T A B I L IZ A TION ( o v er d ays ) nor m al repla c ement/ maintenance therapy of v o lume and m etab o lic pr o fi l e f o r o r g an s u pp o r t ; with n e t- zero o r mild nega t ive fluid b al a nce E V ACU A TION ( o v er week s ) la te go a l di re cte d fluid remo v a l (with diu retic s- Alb umin o r R R T - U F ) o v erco ming fluid o v erl oad/interst itial edema f o r o rgan re c o v er y ; achieving an app r o priate nega t ive cum u l a ti v e fl u id bal an ce P ositiv e cu mulativ e fluid balance is as s ociated with high m o rtalit y and m o rbid i ty 85

76. OPTIMIZATION PHASE

77. WHO Health Emergencies program (WHE) Resuscitation: fluid challenge Give fluid for resuscitation as a fluid challenge (also termed bolus or loading ). For patients with sepsis induced hypoperfusion or septic shock Fluid resuscitation of 30 mL/kg of IV crystalloid should be started be given within the first 3 hr of resuscitation . If shock persists , continue to give additional fluid challenges (i.e., 250–500 mL) over 30 minutes as long a s t her e i s a c li n i cal response. R epe a t f ocuse d ex am ( af t er i n i t i al f l u i d r esusc i t a ti o n ) i n cl u d i n g v i t al s ig n s , c a r diopul monar y , c apil l ary r e f i l l , pulse, and ski n f i n ding ). Use dynamic measures to guide fluid resuscitation, over physical examination, or static parameters alone . DONT : Give fluid slowly (not more than 30minutes). Use the CVP to guide fluid challenge. Depend on BP to decide whether the pt needs more fluid or not. Give fluids without looking to the status of the lungs.

78. Administering fluid challenges when patient is no longer fluid responsive can be harmful: i.e. organ oedema, prolonged days of MV . However , predicting fluid responsiveness is a challenge: P er f or m bed s i d e c a r d io v as c ul ar ul t r asound t o d e t erm i n e ty p e o f sho ck. Single , static parameters , such as CVP or inferior vena cava (IVC) size do not reliably predict volume responsiveness in isolation. Dynamic variables may more reliably predict responsiveness, however cut-off points , sensitivity and specificity remain in question . Predicting fluid responsiveness Dynamic fluid resuscitation. Induce change in preload to observe the resulting effect on SV or CO. (Change in pulse pressure with preload > 15 %). Passive leg raising test. Fluid Tolerance : can be expressed as the degree to which a patient can tolerate the administration of fluids without the onset of organ dysfunction . Fluid Responsiveness : is commonly defined as a stroke volume (SV ) increase of at least 10% following a fluid bolus of 200–500 mL in 10–15 min

79. Fluid Responsive Test Static CVP PCWP RV/LV EDV RV/LV EDA LVEDV , LVEDA Dynamic -Fluid Challenge test -Passive leg rising Heart lung interaction -PPV, SVV-IVCDI Limitation Cardiac arrhythmia Tidal volume < 8 ml/kg Open Chest condition RV failure

80. Pulse Pressure Variation (PPV) Indications Ventilator with PEEP V T > 8 ml/kg No Cardiac arrhythmia PPV > 13% Fluid Responsive Inspire Expire (PPV Max-PPV Min)x 100 ( PPV Max+PPV Min )/2

81. Passive Leg Rising Test (PLR) Head elevated 45 ° Increase Venous Return CO Leg elevated 45 ° 60-90 sec CO (ABF) Increase > 10% = Fluid Responsive NO Positive Pressure = 300 ml

82. Dynamic parameters: cardiac ultrasound Left ventricular outflow tract velocity time integral ( VTI ) change of >18 % with PLR manoeuvre suggests fluid responsive . Δ IVC max-min/mean, during respiratory cycle, when ≥ 12% suggests fluid responsiveness. Validated only patients on controlled mechanical ventilation (set TV 8 mL/kg). Requires advanced ultrasound expertise.

83. Inferior vena cava distensibility index (IVCD) IVCD index = (IVC Max – IVC Min) x 100 IVC Min IVCD ≥ 18% = Fluid Responsive IVC Max IVC Min Indications Ventilator with PEEP (Positive Pressure)

84. Static parameters: CVP CVP response to fluids: If cardiac output and BP do not improve, and CVP remains unchanged, OK to try more fluids. But if CVP did increase then unlikely to respond to more fluid . Ongoing fluid resuscitation should be guided on individual basis, based on reassessment of clinical signs of perfusion, fluid responsiveness and risks of fluid overload. Capillary refill time can be used to guide resuscitation as an adjunct to other measures of perfusion. Fluid recusation can be assessed by decrease serum lactate in patients with elevated lactate level.

85. ADROMEDA- SHOCK Target goal Lactate level decrease by 20% every 2 hours verse normalization of capillary refill time All patients had initial resuscitation and norepinephrine to maintain a MAP 65mmHg or higher. Step 1 . Fluid responsiveness. Fluid challenges with 500mL of crystalloids every 30 minutes in fluid responders until the goal was achieved. Step 2 . If not meeting goal, patients with chronic hypertension transiently increased norepinephrine to reach MAP 80- 85mmHg. If goals met, then the higher MAP was maintained. Mortality decreased from 43.4 % in peripheral percussion group to 34.9 % in the lactate group, not statistically significant. JAMA 2019. 321(7): 654 SSC 2021: For adults with septic shock, we suggest using capillary refill time to guide resuscitation as an adjunct to other measures of perfusion . Weak recommendation, low-quality evidence In summary, there is no good “endpoint” guiding resuscitation in septic shock, but CRT or lactate clearance can be considered.

86. Less mortality Less SOFA score 5.6 vs 6.6 ANDROMEDA-SHOCK Trial SSC 2021: For adults with septic shock, we suggest using capillary refill time to guide resuscitation as an adjunct to other measures of perfusion. Weak recommendation, low-quality evidence

87. STABILIZATION PHASE

88. De-resuscitation • A positive fluid balance after resuscitation for sepsis is associated with worsened clinical outcomes. Extraneous or superfluous fluid administration (i.e., maintenance fluids or intravenous medications/carriers when enteral administration is acceptable) should be avoided . Achievement of a negative volume status (using diuresis or dialysis), once stable, should be achieved and guided by the utilization of physiologic parameters. (I-E)

89. Antibiotics and Early Fluid Resuscitation Are Key ↑ mortality with later fluid administration 13.3% (30 minutes) versus 16.0% (31 to 60 minutes) versus 16.9% (61 to 180 minutes) versus 19.7% (>180 minutes ). After adjusting for confounders, the higher proportion of total fluid received within the first 3 hours was associated with decreased hospital mortality. Increased Fluid Administration in the First Three Hours of Sepsis Resuscitation Is Associated With Reduced Mortality A Retrospective Cohort Study Sarah J. Lee , MD , MPH ; Kannan Ramar , MBBS , MD ; John G. Park , MD , FCCP ; Ognjen Gajic , MD , FCCP ; Guangxi Li , MD ; and Rahul Kashyap , MBBS CHEST, October 2014

90. Antibiotics and Early Fluid Resuscitation Are Key Decrease in hospital mortality was observed primarily in patients with heart and/or kidney failure (p<0.04) who received at least 2 Liters fluid resuscitation for severe sepsis with lactate between 2.1-3.9. Early fluid initiation ( 30-120 minutes ) was associated with significantly lower hospital mortality, mechanical ventilation, ICU admission, LOS and ICU days. No harm observed. CCM, October 2017, Volume 45, Number 10 A patient is deemed “fluid responsive” when SV increases by 10-15% after a fluid challenge (i.e., 250-500 mL); such patients should receive judicious fluids until the appropriate increase in SV/CO subsides. Administration of fluids to patients deemed not fluid responsive only serves to overload the patient with unnecessary fluid which subsequently impairs organ function.

91. WHO Health Emergencies program (WHE) If MAP remains < 65 mmHg, start vasopressors Vasopressors maintain a minimum perfusion pressure and adequate flow during life-threatening hypotension . Vasopressors are potent vasoconstrictors and increase myocardial contractility to lesser extent: Administer through a CVC. Give at a strictly controlled rate, titrate to desired effect. Discontinue when no longer needed to minimize risks. Start vasopressors after initial fluid bolus: But can be given early, during ongoing resuscitation when shock is severe and diastolic pressure is low. Do not delay administration .

92. 1 ) An n a n e D : 200 7 -- - N E + / - D ob ut amin e Vs Ep i . ( N o di f f ere n c e ) . 2 ) S O A P I I: N E Vs D op amin e ( M o re a rr h yt h mi a s ) . 3 V A S S T : A dd iti o n o f l o w do s e o f v as op re ss i n i s s af e a n d dec . N E D o s e. 4 V A NI S H : ( 2 01 6 ) : a mong ad ul ts w i th s e pt ic sh o c k , th e e a rly u s e o f v a s o p r ess i n di d n o t compa re w i th n o r e p i n e p h r i n e d id n o t i mp r o v e th e nu mb e r o f k i dne y fa i l u r e – f r e e day s. 5 E l A d awi (20 1 6 ) : I n s e p s i s - i n d u c ed re f r ac tory v as op le g ia m e t h y l en e b l ue ma y b e m o re e ff ect i v e tha n v a s o p re ssi n b ut fu r th er s tudi e s a re re q uire d . 6 A TH O S - 3 ( 2017 ) A n giote ns i n I I is go o d i n v as od il a tory sh o c k. 7 ) LE O -P A R DS 201 7 : T h e add iti o n o f le v o s i me n d an t o s t anda r d tre a t ment i n ad ul ts w i th s e p s i s wa s n o t as s o c i at e d w i t h l e ss s e v e r e or ga n dy s f u nc tio n o r l ow e r mort a lity . 8 ) L I U ( 20 1 8 ) :T e rl i p r e ss i n ve r s us no re pi n e phr i ne as i nfu s i o n i n p a tie nts w i th s e pt ic sh o c k , T h ere wa s n o s i g n i f i cant r e duc ti o n i n 2 8- d ay m o r tal i t y i n p a tie nts w i th s e pt ic sh o c k tre a ted w i th te r li pr e ss i n compa red to n o re pi n e p h r i n e .

93. Vasopressors Initiate norepinephrine early if MAP less than 65 mmHg after initial fluid bolus * If infusing norepinephrine greater or equal to 15 ug /min or 0.25 ug /kg/min , consider adding vasopressin 0.03 units/min (1.8 units/ hr ) * If cardiac dysfunction suspected, consider adding dobutamine or switching to epinephrine . (Echo, Scvo2 or physical exam). Repeat lactate every 2-4 hours if initial result greater than 2mmol/L, until normal In summary, the current recommendations   for vasopressor use in severe sepsis and septic shock follow an algorithmic approach, titrating a MAP >65 mmHg: intravenous fluid bolus , followed by norepinephrine , vasopressin , and then epinephrine if there is no underlying cardiac dysfunction.

94. Vasopressors Norepinephrine (first choice, titrate ): up to 0.5 mic /kg/min. potent vasoconstrictor with less increase in HR. Vasopressin (fixed dose 0.03 U/min): Can be used to reduce norepinephrine dose. Can add as additional agent to achieve effect . Caution if patient not yet euvolemic. Epinephrine (alternative, titrate): Potent vasoconstrictor, and also has inotropic effects . Can add as additional agent to achieve desired effect . Can use as an alternative to norepinephrine (if not available). Restrict dopamine use because it may be associated with increased mortality and increase in tachyarrhythmia. For adults with septic shock, we can start vasopressors peripherally to restore mean arterial pressure rather than delaying initiation until a central venous access is secured. ( weak recommendations SSC 2021 ). Peripheral access sites running vasopressors should be checked every hour. Up to 6 hours

95. Source: SARI Tool KIT 2nd edition Side-effects of vasopressors Tachyarrhythmias . Ischaemia to organs. Cool and cyanotic extremities.. Soft tissue necrosis ( with peripheral administration if the vasopressor is extravasated). Side-effects of inotropes. Tachyarrhythmias. Hypotension (due to peripheral vasodilation).

96. Peripheral administration of vasopressor Though preference is for central delivery , norepinephrine, dopamine or epinephrine can be given via peripheral IV . Caution : Risk of peripheral infusion is extravasation of medication and local tissue necrosis. Requires close nursing care to check infusion site: If necrosis, stop infusion and consider injection of 1 ml phentolamine solution subcutaneously. Phentolamine is a vasodilator. 5–10 mg in 10 mL of NS . Source: Permission C. Gomersall http:// www.aic.cuhk.edu.hk/web8/Dopamine_extra vasation_1.jpg

97. Source: SARI Tool KIT 2nd edition

98. Titrate vasopressors to desired effect Titrate to target MAP range ≥ 65–70 mmHg. Can individualize MAP target based on patient’s clinical characteristics: i.e. consider higher MAP (i.e. ≥ 80 mmHg ) in patients with chronic hypertension to reduce risk of AKI, if patient responds better to higher MAP. Titrate vasopressors to improve markers of perfusion : i.e. mental status, urine output, normalization of lactate* and skin examination. Titrate down vasopressors if blood pressure in above target range.

99. Inotropes for septic shock Add inotropes if patient shows continued signs of hypoperfusion despite achieving adequate fluid loading and use of vasopressors to reach target MAP. Measured or suspected low cardiac output (i.e. echocardiogram). Dobutamine is first choice inotrope. If not available, then E pinephrine alone : Start at 2.5 μ g/kg/min (max 20), titrate to improve clinical markers of perfusion and cardiac output. Do not aim to increase cardiac output to supranormal levels. Risks include tachyarrhythmias and hypotension. Don't use levosimendan.

100. Initial Recognition and Treatment of Sepsis

101. Sup p orti v e The r a p y

102. Mechani c al V e n til a tion of Se p si s - Induced ARDS T a r g e t a ti da l v o l um e o f 6 mL/kg p r ed i c t ed bod y w eig h t i n p a tie n ts with se p s i s -i nd u ced ARDS. In i tial uppe r lim i t g oa l f o r p l a t eau p r essu r es in a passi v ely i n f l a t ed lung be ≤30 c m H2 O . PEEP b e app l ied t o a v o id al v eo l ar c o lla p s e a t end e xp i r a ti on.

103.  AP R O C C H S 2 01 8 : I n criticall y il l p a tien t s w it h s e p t i c shock, the a d d itio n of h yd roc o r t i sone a n d f l u d r o co r t i sone co m p a re d to pla c e bo wa s a s s o ciated wit h a s i gn i fica n t i m p r o v e m en t i n m or t a lit y at 9 d a y s .  AD REN A L 2 01 8 : Among p a tien t s w it h s ep t i c shock un d ergoin g mech a nical v e n til a ti o n, a c on ti n u o u s in f u s io n o f hy d r o co r t i s o n e d i d no t re su l t i n lo w e r 90 - d ay m ort a l it y th a n p l a ce b o .  C O II T S S 2010 ( Cor t i c o s t er o i d T re a t me n t a n d I n ten s i v e I n s u l i n T he r a p y fo r S ept ic S ho ck i n A du lt s ): n o e vi denc e to s u pp o r t i n te n s i v e i n su l i n t h era p y ( b loo d gluc o s e t a rge t 80 t o 110 m g / d l [4. 4 4 t o 6. 1 m m ol / l] ) f o r p a tien t s w ith s e p t i c shock bei ng tre a ted wit h co rti co s te r oid s .  HY P R E S S: 2 1 6 Admini s tr a tion o f h y d ro c o r t i s o ne d i d n o t p r e v e n t the de v elo p ment o f sh o c k i n p a tien t s wit h s e v er e s e p s i s .  AN N A NE 2 00 2 : L o w d o s e h y d ro c o r t i s o ne a n d f l u d r o c o r t i s o ne re d uced the ri s k o f de a th i n p a tien t s wit h s ep t i c shock a n d rel a ti v e a d ren a l in s u f ficiency w it h o u t i n cre as in g adv er s e e v e n t s .  C O R T ICUS 2 8 : Th e u s e o f hy d rocorti s on e di d not decre a se mortal i ty i n a gener a l p o p u la t io n o f p a tien t s w it h s e p t i c s h oc k ( HY DR O C O R T IS ON Vs P lace b o).

104. Corticosteroids Indications - Vasopressor-unresponsive - Hypotension despite fluid resuscitation & vasopressors Timing > 60 minutes No ACTH stimulation test Dose 100 mg bolus, 200 mg iv in 24 hrs Taper off after vasopressors CIRCI Cortisol Hydrocortisone > 35 No 15-34 No & Yes < 15 Yes

105. WHO Health Emergencies program (WHE) Corticosteroids and shock Consider low dose IV hydrocortisone , if adequate fluid resuscitation and vasopressors fail to restore hemodynamic stability: 50 mg every 6 hours or continuous for adults for (i.e. 5 days). 50 mg/m2/24 hours (1–2 mcg/kg 6 hourly) in children. Taper when vasopressors no longer needed. i.e. 50 mg twice daily for days 6–8; 50 mg once daily days 9–11. R isks are hyperglycaemia and hypernatraemia . Precaution : Do not administer high doses steroids (i.e. > 300 mg daily). Do not use in sepsis without shock. Do not use to treat influenza pneumonitis alone, but can be used for other respiratory indications. For adults with septic shock and an ongoing requirement for vasopressor therapy we suggest using IV corticosteroids Weak recommendation; moderate quality of evidence Remark The typical corticosteroid used in adults with septic shock is IV hydrocortisone at a dose of 200 mg/day given as 50 mg intravenously every 6 h or as a continuous infusion. It is suggested that this is commenced at a dose of norepinephrine or epinephrine ≥ 0.25 mcg/kg/min at least 4 h after initiation. Administer hydrocortisone 50mg IV q6h if vasopressors expected/administered more than 4 hours

106. Blood Product Administration No Tissue hypoperfusion Tissue hypoperfusion Hct < 30% ScvO2 < 70% Blood Transfuse Myocardial ischemia Severe hypoxemia Acute hemorrhage - Hct < 30% Platelet Prophylactic < 10,000 High Risk bleeding < 20,000 3. Active bleed or Sx < 50,000 Hb < 7mg% Keep Hb 7-9

107. WHO Health Emergencies program (WHE) Hyperglycaemia and sepsis Initiate a protocolized approach to blood glucose management when two consecutive measurements > 10 mmol/l ( 180 mg/dl ): Target glucose of < 180 mg/dl. Avoid intensive insulin for tight glucose control (4.5–6 mmol/l, 80–110 mg/dl), this approach causes harm. Avoid wide swings in glucose levels. Frequently monitor blood glucose, every 1–2 hours until stable, then every 4 hours, to prevent hypoglycaemia. Major risk is severe hypoglycaemia: caution : point of care measurement can be falsely high in shock, interpret with caution.

108. Recommendations For adults with septic shock and hypoperfusion -induced lactic acidemia , we suggest against using sodium bicarbonate therapy to improve haemodynamics or to reduce vasopressor requirements. Weak recommendation, low quality of evidence For adults with septic shock, severe metabolic acidemia ( pH ≤ 7.1) and AKI (AKIN score 2 or 3), we suggest using sodium bicarbonate therapy. Weak recommendation, low quality of evidence Sodium Bicarbonate therapy

109. Sed a tion and Neu r omuscular Bloc k ade Co n ti n uou s o r i n t ermi t t e n t sed a ti o n be mi n i mi z ed in mech a n i c ally v e n ti l a t ed se p s is p a tie n ts, t a r g e t i n g spe c i f ic tit r a ti o n endpo i n ts. A shor t c ou r s e o f NM B A o f n o t g r e a t er than 48 hou r s f o r p a tie n ts with early se p s i s -i nd u ced ARDS and a P ao2/ F i o 2 < 150 mm Hg .

110. Stress Ulcer Prophylaxis Proton pump inhibitor (-- prazole ) Stress ulcer prophylaxis High risk -Coagulopathy -Head injury -On Ventilator -Liver cirrhosis - Hx . GIB H2 blocker (Ranitidine)

111. Nutrition Oral Or Enteral nutrition Start low dose feeding When should i start it ? Start - 24-48 hours -Parenteral + Enteral (Glucose IV + Oral feeding)

112. R ena l R epla c eme n t T h e r a p y (R R T ) : Co n ti n uou s R R T and i n t ermi t t e n t hemod i al y s is a r e equ i v ale n t in p a tie n ts with s e v e r e se p s is and acu t e r enal f ail u r e. Dee p V ei n Th r om b osis P r op h yl a xis : da il y subcu t ane o u s (LMWH ) a g ai n s t v enous th r o m b oemb o li s m (VT E ). St r es s Ulcer P r op h yl a xis : us i n g H 2 b l oc k er o r p r o t on pum p i nh i b i t o r . E arly e n t e r al n utrit i o n , a g ai n s t pa r e n t e r al nut r iti o n in the f i r s t 7 d. E l e v a t e hea d o f be d 30 – 45 deg r ee s in mechan i c al l y v e n til a t ed p a ti e n ts, sp o n t ane o u s b r e a thi n g t rial s , and a w ean i n g p r o t o c o l . Furthermore, various studies have proven that heparin can induce other significant effects (i.e., anti-inflammatory effects, anti- complemental activation , and the modulation of various proteases ) rather than solely prophylaxis ( via anti-coagulation ) in septic patients sepsis.

113. S S C r ec o mmend s A G A IN S T L o w d o s e Dopa m i n e f o r r enal p r o t ecti on . S t e r o i d s ( On l y if o n v as o p r esso r s – hy d r o c ort i sone 200 m g /d a y) . E ry th r o p o i e tin f o r seps is r el a t ed anem ia . IV Immunog l o bu li n s f o r se p s is o r se p tic shock . H igh f r equency o s cil l a t o r y v e n til a ti o n ( H F O V ) f o r seps is i nduce d ARDS . ß 2 a g o ni s ts f o r seps i s -i nduc e d AR D S without b r onch o spasm . P A C a th e t er f o r p a ti e n ts with se p s i s -i nduc e d AR D S .

114. Vitamin C PICO Question 2021 Recommendation Recommendation Strength and Quality Change from 2016 In adults with sepsis or septic shock, should we use intravenous vitamin C? For adults with sepsis or septic shock we suggest against using IV vitamin C. Weak recommendation, low quality of evidence New recommendation

115. VA-ECMO Helwani and colleagues demonstrated the use of VA-ECMO in patients with sepsis-induced cardiomyopathy. In the setting of persistent hypotension despite standard management of septic shock with evidence of severe cardiac systolic dysfunction and end-organ perfusion, VA-ECMO should be considered. 20 Current recommendations by the SSC are the   utilization of VV-ECMO in the setting of severe acute respiratory distress syndrome when conventional mechanical ventilation fails, without mention of VA-ECMO.

116. Sepsis and septic shock: current approaches to management Internal Medicine Journal, Volume: 49, Issue: 2, Pages: 160-170, First published: 12 February 2019, DOI: (10.1111/imj.14199)

117. Sepsis defination Sepsis , severe sepsis, and septic shock are on a continuum and are commonly referred to as " sepsis " Sepsis is a very heterogeneous disease: D ifficult to diagnose in its early stages. Difficult to treat in its later stages. H owever , routine screening may aid in early identification .

118. Early recognition with prompt disease stratification and rapid treatment initiation. Prevention and support of organ dysfunction , based on oxygen delivery ( DO2 ) optimisation, condition sine qua non for the maintenance of optimal oxygen consumption ( VO2 ) in tissues during sepsis. Rapid infection source control based on the immediate administration of adequate antimicrobial therapy and surgical/instrumental intervention when indicated . There are three priorities in the approach to the septic patient that have shown to reduce mortality

119. Early targeted resuscitation combined with early appropriate antimicrobial therapy saves lives in patients with sepsis and septic shock. Antimicrobial therapy should start within 1 hour. Early identification of patients with sepsis and implementation of early, evidence-based therapies improves outcomes and reduces mortality to treat patients with septic shock, it is crucial to deliver early, targeted resuscitation using crystalloid fluid, vasopressors and, in some cases, inotropes and/or blood transfusion . Fluid resuscitation with crystalloid fluids remains the most common intervention for septic shock; it should be given as a challenge to improve targets of perfusion, and promptly stopped when no longer responsive, to avoid harms of excess fluid . S ummary

120. Give supplemental oxygen, monitor response via SpO2. Start antibiotics early and pick appropriately. Do blood cultures, MSU, CXR and other swabs/tests as appropriate. 3. Give fluids, but usually no need to exceed 2 - 3 liters. If BP is still ‘soft’ after 3 liters, consider pressors , not more fluid. Consider vasopressors anytime you suspect pulmonary edema developing 4. Be prepared for hypotension, either have pressors ready or started ahead of time. Even ONE episode of transient hypotension can be a warning sign of impending hypotensive crisis.

121. 5. Choice of pressor ? Usually use norepinephrine infusion. If patient has tachycardia or arrhythmias then consider phenylephrine . 6. If still hypotensive after vasopressors, you can consider inotropic therapy with Dobutamine . 7. Try NOT to intubate. Patients are hypercapnic (helps venous return) and hyper-adrenergic ( maintains their blood pressure). If you sedate/intubate you take away this and they can crash. 8. If you need to intubate use ketamine and have a pressor ready.

122. 11. Remember, sepsis is a state of hypotension of the ‘distributive type’ ( ie not pump failure, hypovolemia etc ). The resulting vasodilation that occurs causes hypoperfusion . However with sepsis, you can have hypoperfusion without hypotension. 12. In early sepsis, the skin may be warm and flushed. As sepsis progresses the skin may become cool and pale.

123. 13. Use lactate as a marker of severity. Lactate > 2 mmol /L can be a sign of organ hypoperfusion in the absence of hypotension. Lactate > 4 mmol /L can be (but is NOT diagnostic of) a sign of severe sepsis. There is debate as to what constitutes ‘appropriate’ lactate clearance. Generally speaking if it doesn’t drop after 6 hours or if it has risen, then this should prompt a reevaluation of the patient’s perfusion status. Once perfusion is established, lactate is a poor marker of tissue perfusion.

124. [email protected]