1. Post Resuscitation. Fluids or Inotropes? David Rowney Anaesthesia & Intensive Care Royal Hospital for Sick Children Edinburgh Scottish Paediatric Anaesthesia Network Biennial Educational Meeting, November 2013 Teachers Building, Glasgow

2. Resuscitation- Aetiology? Sepsis / SIRS World-widePneumoniaMalariaMeasles Bacterial sepsis Diarrhoea Trauma ‘Western’ world TBI Blunt trauma Penetrating trauma Bacterial sepsis

3. What is ‘Post Resuscitation’ ? n Sepsis / SIRS response u Can remain for 48 hours or more. u Ongoing requirement for fluid resuscitation and titration of appropriate vasoactive drug infusions.

4. Post Resuscitation. Fluids or Inotropes? n Highlight what evidence is available to guide ‘post-resuscitation’ management. n Extrapolate available evidence / expert opinion / guidelines from the ‘resuscitation’ phase to help guide the use of fluids and inotropes in ‘post- resuscitation’ care.

5. Physiology revision n MAP = CO x SVR n CO = HR x SV n SV depends on: u Preload (Venous Return) u Contractility (inotropy) u Afterload (SVR) n Dao 2 = CO x Cao 2 n Cao 2  Hb x Sao 2 n Preload depends on: u CVP (end-diastolic volume) u HR u Diastolic function (compliance) ….see abstract

6. Paediatric Septic Shock - Pathophysiology n In children with septic shock ‘cold’ shock (low CO and high SVR) is more common than ‘warm’ shock (high CO and low SVR)

7. Presentation6 hours48 hours28 day survival Group 1 29 patients Cold Shockinotropes21880% Low COinotropes & vasodilator819 High SVRinotropes & vasopressor1 vasopressor1 Group 2 10 patients Warm Shockvasopressor10572% High COinotropes & vasopressor2 Low SVRinotropes2 inotropes & vasodilator1 Group 3 11 patients Warm Shockinotropes & vasopressor11690% Low COinotropes5 low SVR

9. Warm shock Cold shock

10. Take home message - 1 n In children with community acquired septic shock ‘cold’ shock (low CO and high SVR) Is more common than ‘warm’ shock (high CO and low SVR) u Mortality is associated with severe hypovolaemia and low cardiac output.

11. First hour: Normal heart rate & blood pressureNormal heart rate & blood pressure Capillary refill of  2sCapillary refill of  2s Normal pulses with no differentialNormal pulses with no differential between peripheral and central pulses Warm extremitiesWarm extremities Urine output> 1 ml/kg/hUrine output> 1 ml/kg/h Normal mental status.Normal mental status. Post-resuscitation optimisation: Superior vena cava oxygen saturationSuperior vena cava oxygen saturation (ScvO 2 ) ≥ 70% Cardiac index> 3.3 and 3.3 and < 6.0 l/min/m 2 The American College of Critical Care Medicine – Paediatric Advanced Life Support (ACCM-PALS) guidelines 2002 (rev. 2007) ‘Goals’ / ‘Targets’ of resuscitation

12. First hour: Normal heart rate & blood pressureNormal heart rate & blood pressure Capillary refill of  2sCapillary refill of  2s Normal pulses with no differentialNormal pulses with no differential between peripheral and central pulses Warm extremitiesWarm extremities Urine output> 1 ml/kg/hUrine output> 1 ml/kg/h Normal mental status.Normal mental status. Post-resuscitation optimisation: Superior vena cava oxygen saturationSuperior vena cava oxygen saturation (ScvO 2 ) ≥ 70% Cardiac index> 3.3 and 3.3 and < 6.0 l/min/m 2 The Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock 2004 (rev. 2008 & 2012) Decreased lactateDecreased lactate Improved base deficitImproved base deficit ‘Goals’ / ‘Targets’ of resuscitation

13. A caution about Capillary Refill Time.. Best predictive value for a reduced SVI

14. Superior vena cava oxygen saturation (ScvO 2 ) n ACCM-PALS 2007 Guideline goal: ScvO 2 ≥ 70% Because children with shock, die of low cardiac output and oxygen delivery, the ScvO 2 has become the “fifth vital sign” of paediatric intensive care. Joseph Carcillo Crit Care Med 2006 Vol. 34, No. 9 (suppl.)

15. n Addition of a treatment target of ScvO 2 ≥ 70% to the 2002 ACCM-PALS guidelines.

16. NNT- 3.6

18. Take home message - 2 Continuum of ‘high-quality’ / ‘aggressive’ care from the first hour of resuscitation from the first hour of resuscitation through Interhospital transport and the early period of intensive care admission saves lives.

19. Fluid Therapy n Aggressive early fluid resuscitation is the cornerstone of shock management. n 20 ml/kg bolus of isotonic intravenous fluid over 5-10 minutes repeated up to 3 times in the first hour until: u haemodynamic targets are reached or u signs of fluid overload: new onset crepitations increased work of breathing hepatomegaly worsening hypoxaemia How fast is too fast?

20. n Comparing two EGDT regimens u both using fluid and dopamine to achieve haemodynamic targets u fluid administration over 15 minutes vs. 60 minutes n No difference in:mortality rapidity of shock resolution requirement for intubation incidence of complications

21. Fluid Therapy n Aggressive early fluid resuscitation is the cornerstone of shock management. n 20 ml/kg bolus of isotonic intravenous fluid over 5-10 minutes repeated up to 3 times in the first hour until: u haemodynamic targets are reached or u signs of fluid overload: new onset crepitations increased work of breathing hepatomegaly worsening hypoxaemia Crystalloid or Colloid?

24. Exclusive use of 4.5% Albumin Albumin Saline

25. A caution about ‘Normal’ saline…

26. A caution about ‘Normal’ (0.9%) saline 81 children with meningococcal septic shock BE appeared to change by approximately -0.4 for every mmol/kg of chloride administered

27. Fluid Therapy n Aggressive early fluid resuscitation is the cornerstone of shock management. n 20 ml/kg bolus of isotonic intravenous fluid over 5-10 minutes repeated up to 3 times in the first hour until: u haemodynamic targets are reached or u signs of fluid overload: new onset crepitations increased work of breathing hepatomegaly worsening hypoxaemia Crystalloid or Colloid? There is broad agreement that crystalloids are preferable in the treatment of paediatric burns, trauma, surgical pathologies and gastroenteritis.

28. Fluid Therapy n Aggressive early fluid resuscitation is the cornerstone of shock management. n 20 ml/kg bolus of isotonic intravenous fluid over 5-10 minutes repeated up to 3 times in the first hour until: u haemodynamic targets are reached or u signs of fluid overload: new onset crepitations increased work of breathing hepatomegaly worsening hypoxaemia Blood?

29. n Addition of a treatment target of ScvO 2 ≥ 70% to the 2002 ACCM-PALS guidelines n Transfusion to a target Hb >10 g/dL to achieve ScvO 2 ≥ 70%

31. Fluid Therapy n Patients with fluid refractory shock (after 40-60 ml/kg) u Should be considered for CVP and Scv0 2 monitoring. u CVP / MAP-CVP response to a fluid bolus will help determine the need for further fluid. n Profound capillary leak as part of the sepsis/SIRS response can remain for 48 hours or more requiring ongoing fluid resuscitation (up to 200 ml/kg) over this period.

32. “Give Fluid Often. Remove Fluid Often” Joseph Carcillo Crit Care Med 2006 Vol. 34, No. 9 (suppl.)

33. Institution of a Dengue fever shock protocol that included diuretics and peritoneal dialysis, if not diuresing, was associated with improved survival. Early administration of CVVH (before 10% fluid overload) to control fluid overload was associated with improved survival in septic shock

34. Take home message - 3 Aggressive early fluid resuscitation with 20 ml/kg bolus of isotonic intravenous fluid over 5-10 minutes repeated up to 3 times in the first hour until haemodynamic targets are reached / signs of fluid overload FOLLOWED BY Further Fluid boluses (up to 200 ml/kg in first 48 hours) to maintain haemodynamic stability.

35. The American College of Critical Care Medicine – Paediatric Advanced Life Support (ACCM-PALS) guidelines 2007 First hour: n Fundamental requirement for early inotrope administration in fluid refractory shock. (after 40-60 ml/kg of fluid) n New recommendation: Administer peripheral / intraosseous inotropes pending placement of a central venous line. Vasoactive drugs– what, when, how much?

36. n Case-control study of deaths from meningococcal sepsis n Failure to administer inotropes was independently associated with increased risk of death u OR 23.7 (95% CI 2.6 to 213, p=0.005).

37. Vasoactive drugs– what, when, how much? ‘Cold’ shock n Community acquired septic shock. n Low CO and high SVR. n Immediate inotrope treatment if fluid refractory (40-60 ml/kg) u Dopamine (up to 10 mcq/kg/min) u Adrenaline (up to 0.3 mcq/kg/min) n There is no evidence to support a recommendation for a particular ‘first choice agent’ and practice varies widely.

38. Vasoactive drugs– what, when, how much? ‘Cold’ shock- refractory to fluid and first–line inotropes n If low MAP – u High-dose dopamine (> 10 mcq/kg/min) u High-dose adrenaline (>0.3 mcq/kg/min) u (NB: more fluid, acid-base, ionised calcium, blood sugar, steroids etc) n If normal MAP –Add a vasodilator to reduce afterload resulting in improved CO and global oxygen delivery. u Dobutamine u Milrinone

39. Vasoactive drugs– what, when, how much? ‘Warm’ shock n Hospital acquired septic shock (CVL infection). n High / normal / low CO and low SVR. n Immediate inotrope treatment if fluid refractory (40-60 ml/kg) u Dopamine (up to 10 mcq/kg/min) u Adrenaline (up to 0.3 mcq/kg/min) n There is no evidence to support a recommendation for a particular ‘first choice agent’ and practice varies widely.

40. Vasoactive drugs– what, when, how much? ‘ Warm’ shock- refractory to fluid and first–line inotropes n Add vasoconstrictor u Noradrenaline u High-dose dopamine (> 10 mcq/kg/min) u High-dose adrenaline (>0.3 mcq/kg/min) u Vasopressin (up to 0.008 U/kg/min)

41. Vasoactive drugs– what, when, how much?

42. Intubation & ventilation – the ideal time? Shock R x Vasoactive drugs Intubation & ventilation Fluid

43. Intubation & ventilation – the ideal time? n n All cases refractory to 40 ml/kg of fluid n n Signs of fluid overload / pulmonary oedema n n Facilitate central vascular access n n ACCM-PALS u u sedation to facilitate central vascular access u u intubate & ventilate for fluid overload Shock R x Vasoactive drugs Intubation & ventilation Fluid

44. Intubation & ventilation – the ideal time? Take home message - 4 1. 1.Administer 40-60 ml/kg of fluid rapidly 2. 2.Start an inotrope: dopamine / adrenaline via a peripheral or intraosseous line Prior to administering drugs for intubation. Shock R x Vasoactive drugs Intubation & ventilation Fluid

45. Put it all together and what have we got?

47. There is no clear evidence of benefit for any particular regimen or any recommendations for fluid therapy and cardiovascular support beyond the initial resuscitation phase. There is widespread agreement that there should be a continuum of ‘high-quality’ / ‘aggressive’ care from the first hour of resuscitation through Interhospital transport and the early period of intensive care admission, until the child improves. There is unequivocal evidence that specific treatment interventions for paediatric septic shock ‘bundled’ together in an ‘Early Goal Directed Therapy’ regimen saves lives. Caveat….

48. EGDT Critics n Rivers study is yet to be confirmed in other centres. n ProMISe (Protocolised Management in Sepsis, UK) n ARISE (Australian Resuscitation in Sepsis Evaluation) n ProCESS (Protocolised Care for Early Septic Shock, USA) n PERSPECTIVE (Pediatric Reversal of Shock with Fluids)

49. ACCM-PALS guidelines followed In only 38% If shock present at PICU admission- OR death 3.8 (95% CI 1.4 to10.2, p=0.008)

50. Summary n “Post Resuscitation. Fluids or Inotropes?” u Heterogeneous nature of the ‘collapsed’ child aetiology / age-range. u Not discussed Severe trauma / traumatic brain injury. Severe trauma / traumatic brain injury. Congenital heart disease or inborn errors of metabolism. Congenital heart disease or inborn errors of metabolism. Diabetic Ketoacidosis. Diabetic Ketoacidosis. n Focused on the child with septic shock u Clinical teams can extrapolate good published evidence and validated treatment guidelines from the resuscitation to post resuscitation stages of management.

51. Post Resuscitation. Fluids or Inotropes? Thank you. Scottish Paediatric Anaesthesia Network Biennial Educational Meeting, November 2013 Teachers Building, Glasgow