Post Resuscitation. Fluids or Inotropes? Sepsis is the most common cause of death in children worldwide (WHO 2005 estimate is 80%, due to: pneumonia, malaria, measles, bacterial sepsis and diarrhoea). Trauma is the most common cause of childhood death in the ‘Western’ world1. 1. Paediatric pathologies Aetiology of the ‘collapsed’ child requiring resuscitation is varied. Many children, in the developed / developing world, survive the initial insult and require post-resuscitation care. Below is a non-exhaustive table of causes of the ‘collapsed’ child. Sepsis / SIRS Trauma Multi-trauma +/- Traumatic Brain Injury (TBI) Isolated TBI Burns +/-toxic shock syndrome Cardiac Cardiomyopathy Myocarditis Cardiac arrest Congenital heart disease Metabolic DKA Inborn error of metabolism Anaphylaxis Gastroenteritis Hypovolaemic dehydration 2. What is ‘Post Resuscitation’ ? Almost 30 years ago Pollack produced a classification of the stages of paediatric septic shock in which he defined ‘Resuscitation’ as 2 or more therapeutic interventions (eg. fluid bolus, change in vasoactive drug administration) to reverse hypotension per 6-hour period and ‘Post resuscitation’ as 6 or more hours after the resuscitation stage when 1 or less therapeutic efforts are required per 6-hour period2. By design this is a retrospective staging of little use to the clinician in the acute setting. Experience tells us that in children, the sepsis/SIRS response can remain for 48 hours or more, requiring ongoing fluid resuscitation and titration of appropriate vasoactive drug infusion over this period. 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 unequivocal evidence that specific treatment interventions for paediatric septic shock ‘bundled’ together in to an ‘Early Goal Directed Therapy’ regimen saves lives3. There is widespread agreement that there should be a continuum of ‘high-quality’ / ‘aggressive’ care from the first hour of resuscitation through hour-six, Interhospital transport if required, and the early (48 hours) of paediatric intensive care admission, until the child improves. In this presentation I will endeavour to highlight what evidence is available to guide ‘post-resuscitation’ management. Where there is no evidence, I will extrapolate available evidence / expert opinion / guidelines from the ‘acute resuscitation’ phase to help guide the use of fluids and inotropes in ‘postresuscitation’ care. It is worth emphasising that the therapeutic goals that will be described are consistent throughout this continuum of care. However the complexity of care and hence the degree of clinical information attainable from the patient, to guide decision-making, will change as resources become available eg. transfer from a referring hospital (eg District general hospital) to a Paediatric Intensive care Unit. 3. Cardiovascular physiology and the ‘goals’ / ‘targets’ of resuscitation The fundamental aim of resuscitation / post-resuscitation stabilisation management in children is to achieve and maintain oxygen and nutrient delivery to the tissues. Unlike adults, in the majority of cases of paediatric shock, mortality is associated with severe hypovolaemia and low cardiac output and tissue oxygen delivery in children, not oxygen extraction, is the major determinant of oxygen consumption4. Useful Physiology revision (grossly simplified) Dao2 = CO x Cao2 Cao2 Hb x Sao2 + (dissolved O2) MAP = CO x SVR CO = HR x SV SV depends on: Preload (Venous Return) Contractility (inotropy) Afterload (SVR) Preload depends on: CVP (surrogate measure of end-diastolic volume) HR (excessive- reduces ventricular filling time) Ventricular diastolic function (compliance) Dao2 = Tissue o2 delivery Cao2 = blood oxygen content Hb = haemoglobin MAP = Mean arterial blood pressure CO = Cardiac output SVR = Systemic vascular resistance (degree of vasoconstriction) (afterload) SV = Stroke Volume VR = Venous return Contractility = myocardial muscle contractility at a given preload and afterload Afterload = Resistance to left ventricular out flow of blood (SVR) CVP = Central venous pressure HR = Heart rate In response to a significant insult sympathetic nervous system driven compensation in children will increase HR and SVR to maintain MAP in the presence of normal or reduced CO. This is seen in ‘early’ / ‘compensated’ shock. Loss of compensation is a relatively late occurrence (compared with adults) and is manifest by a falling MAP. Sepsis induced vasodilatation may overlay this picture. Otto Frank and Ernest starling law of the heart states ‘the energy of contraction is a function of the length of the muscle fibre’. Rapid high-volume (up to 60 ml/kg) fluid administration will optimise ventricular preload and place the patient at the optimum point on their specific Frank-Starling curve and maximising CO. Inotropy, chronotropy, vasoconstriction, vasodilatation and receptors. Positive inotropy results from receptor activation by an agonist (eg endogenous/exogenous adrenaline) leading to a second messenger / amplification cascade resulting in calcium mediated myocardial muscle contraction. A simplified list of receptors includes: Alpha () peripheral alpha (predominately 1) receptor activation results in vasoconstriction and increased SVR. Myocardial 1 receptor activation results in increased myocardial contractility Beta () 1 positive inotropy and chronotropy 2 vasodilatation eg in skeletal muscle Vasopressin V1 intense vasoconstriction Dopaminergic renal / splanchnic vasodilatation Adrenergic receptors undergo a process of significant receptor downregulation when exposed to continuous stimulation leading to ’tachyphylaxis’. Acidosis & hypoxia can result in receptor desensitization. The inotropic effect of, eg adrenaline, is a result of a ‘chain of contraction’ which is vulnerable to breakage at several points including sub-normal ionized calcium levels (calcium mediates muscle contraction). In severe paediatric septic shock all links in the chain need to be addressed. Examples of Vaso-active Drugs Inotropes/chronotropes Inoconstrictors - Adrenaline, Dopamine Inodilators -Dobutamine, Milrinone Vasoconstrictors Noradrenaline (also inotrope), Vasopressin Vasodilators GTN The specific observed effect depends on the drug, dose, patient (age), disease, metabolic/electrolyte milieu, direct drug action, patient compensatory response (eg baroreceptor) and a host of other factors. ‘Goals’ and ‘Targets’ The American College of Critical Care Medicine – Paediatric Advanced Life Support (ACCM-PALS) guidelines recommend rapid, stepwise interventions with the following therapeutic endpoints in the first hour: capillary refill of < 2s, normal pulses with no differential between peripheral and central pulses, warm extremities, urine output> 1 ml/kg/h and normal mental status. Further haemodynamic optimisation using metabolic endpoints to treat global tissue hypoxia include a superior vena cava oxygen saturation (ScvO2) ≥ 70% and cardiac index> 3.3 and < 6.0 l/min/m2 with normal perfusion pressure for age3. The Surviving Sepsis Campaign guidelines (2004, revised 2008 and 2012) also included: decreased lactate and increased base deficit5. Other ‘goals’ can include: age-appropriate HR and BP. A caution about CRT in the post-resuscitation care Tibby and colleagues demonstrated that in ventilated, general intensive care patients, capillary refill time was related weakly to blood lactate (0.47 (0.21 to 0.66) p< 0.001) and stroke volume index (SVI) (−0.46 (−0.67 to −0.18) p=0.001). The predictive value of capillary refill time to pick up a low SVI was assessed by a ROC curve. The best predictive ability was shown with a capillary refill time of > 6 seconds. They concluded that a normal value for capillary refill time of < 2 seconds has little predictive value and might be too conservative in post-resus ventilated septic shock patients6. Superior vena cava oxygen saturation (ScvO2) The ACCM-PALS guideline addresses early correction of paediatric septic shock using conventional measures. It includes an indirect measure of the balance between systemic oxygen delivery and demands using superior vena cava oxygen saturation (ScvO2 ≥ 70%) in a goal directed approach. De Oliveira compared the ACCM guideline with and without the inclusion of the ScvO2 ≥ 70% goal. Inclusion of ScvO2 goal-directed therapy resulted in administration of more fluid, red blood cells and inotropic support after the initial resuscitation, with a resulting 3.3-fold reduction in mortality7. Carcillo commented that because children with shock, die of low cardiac output and hence oxygen delivery, the ScvO2 has become the “fifth vital sign” of paediatric intensive care1. 4. Paediatric Septic Shock - Pathophysiology Unlike in adults, experience has shown that in children with septic shock, ‘warm’ shock (normal/high CO and low SVR) is less commonly seen than ‘cold’ shock (normal/low CO and high SVR). Ceneviva and colleagues studied fifty consecutive children with fluid-refractory septic shock who had a pulmonary artery catheter placed within 6 hours of resuscitation. After fluid resuscitation, 58% of the children had a low CI (‘cold’ shock) and responded to inotropic therapy, half needed addition of a vasodilator (80% 28-day survival), 20% had a high CI and low systemic vascular resistance (‘warm shock’) and responded to vasopressor therapy, half also needed the addition of an inotrope for evolving myocardial dysfunction (72% 28-day survival), and 22% had both vascular and cardiac dysfunction and responded to combined vasopressor and inotropic therapy (90% 28-day survival). They concluded that children with fluid-refractory shock are frequently hypodynamic and respond to inotrope and vasodilator therapy. The observed haemodynamic states were heterogeneous and changed with time requiring changes in the vaso-active drug administration regimen8. Brierley reported that in children fluid-resistant septic shock secondary to central venous catheter-associated infection was typically “warm shock” (15 of 16 patients; 94%), with high cardiac index and low systemic vascular resistance index. In contrast, this pattern was rarely seen in children with community-acquired sepsis (2 of 14 patients; 14%), where a normal or low cardiac index and ‘cold’ shock was predominant9. 5. Fluid Therapy Aggressive early fluid resuscitation (20 ml/kg bolus of isotonic intravenous fluid over 5-10 minutes repeated up to 3 times in the first hour, is the cornerstone of shock management3. There are few trials looking solely at fluid therapy or types of fluid in paediatric shock. A recent systematic review identified just nine studies, total of 1198 children, all in resource-poor settings, four studies in children with dengue shock, four malaria and one sepsis. Eight of the studies compared crystalloids with colloids and none had mortality as a primary outcome. The authors concluded that compared to crystalloids, volume expansion with albumin was more effective in reversing severe shock from dengue and malaria infections. Due to the considerable limitations in the existing studies, there was insufficient evidence to inform the preferential use of either colloids or crystalloids for treating paediatric shock10. Booy and colleagues reported a reduction in mortality to 5% with the exclusive use of albumin as part of a ‘bundle’ for treatment of meningococcal septic shock11. However, the Paediatric Intensive Care Society – Study Group (PICS-SG) recently reported that albumin was used only one sixth of the time in the UK for the early treatment paediatric septic shock12. Upadhyay reported no difference in outcome for paediatric septic shock between colloid and crystalloid treatment13. The various ‘EGDT’ treatment recommendations, stipulate 20 ml/kg boluses repeated up to 3 times until specific haemodynamic targets are reached or until signs of fluid overload: new onset crepitations, increased work of breathing, hepatomegaly, worsening hypoxaemia, develop. However, there is inconsistency with regard to the recommended time frame for the boluses varying from the first 15 minutes up to the first hour of resuscitation. Concern over causing acute fluid overload, in particular pulmonary oedema, is one of the barriers to achieving compliance with these recommendations. Santhanam and colleagues reported no difference in mortality, rapidity of shock resolution, requirement for intubation or incidence of complications comparing two EGDT regimens (both using fluid and dopamine to achieve recognised haemodynamic targets) one with faster fluid administration over 15 minutes and the other with a 60-minute fluid target14. Sub-group analysis in the adult ‘SAFE’ study suggested a trend toward improved outcome using albumin in adult septic shock15. There is no evidence to direct the use of blood for volume expansion in paediatric sepsis. Oliveira reported improved survival with the addition of a treatment target of ScvO2 ≥ 70% to the 2002 ACCM-PALS guidelines7. The achievement of the additional target required more blood administration. While conservative goals for blood administration are widely used in paediatric intensive care, the various recommendations for treatment of septic shock include transfusion to a target haemoglobin of 10 g/dl (to achieve Scvo2 ≥ 70%) in the acute resuscitation and ongoing post-resuscitation phase of septic shock3. Patients with fluid refractory shock (after 40-60 ml/kg) should be considered for invasive haemodynamic monitoring, particularly CVP and Scv0 2 monitoring. Changes in CVP and MAP-CVP immediately following a fluid bolus will help determine the need for further fluid. 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. There is broad agreement that crystalloids are preferable in the treatment of paediatric burns, trauma, surgical pathologies and gastroenteritis. A caution about ‘Normal’ (0.9%) saline for volume resuscitation Bolus fluid resuscitation with fluid containing supra-physiological concentrations of chloride, eg normal saline, will rapidly result in hyperchloraemic metabolic acidosis. The importance of this to the child with septic shock is unclear but the current accepted approach is that it doesn’t require specific treatment to reverse it during the post-resuscitation phase. O’Dell reported in 81 children with meningococcal sepsis that metabolic acidosis (BE -10) was common at presentation and persisted for up to 48 hours. However the nature of the acidosis defined using the ‘Stewart’ approach changed from one of ‘unmeasured anions’ (including lactate) to a hyperchloraemic acidosis by 8-12 hours after the start of resuscitation, during which time approximately 80% of the total fluid resuscitation had been administered, two-thirds of which was normal saline. BE appeared to change by approximately -0.4 for every mmol/kg of chloride administered (equivalent to BE -1.2 for every 20 ml/kg of normal saline). They concluded that recognition of hyperchloraemic acidosis may prevent unnecessary and potentially harmful prolonged resuscitation16. “Give Fluid Often. Remove Fluid Often1” High volume, rapid fluid administration is the cornerstone of hypovolaemic and septic shock reversal. 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 leading to the development of clinically significant tissue oedema and secondary organ dysfunction. This fluid should be removed/excreted timeously in the post resuscitation phase following shock reversal and stabilisation of the patient. Institution of a Dengue fever shock protocol that included diuretics and peritoneal dialysis, if not diuresing, was reported to be associated with improved survival17. An association with improved survival was reported with early implementation of renal replacement therapy to control fluid overload in septic shock18. 6. Cardiovascular agents – what, when, how much? Ninis and colleagues examined the factors leading to death in 143 children presenting with meningococcal disease. Failure of staff to administer adequate inotropes was found to be independently associated with increased risk of death (odds ratio 23.7, 955 CI 2.6 to 213, p=0.005)19. The fundamental requirement for early inotrope administration in fluid refractory shock (after 40-60 ml/kg) was emphasised in the 2007 revision of the ACCM-PALS guidelines with a new recommendation to administer peripheral / intraosseous inotropes pending subsequent placement of a central venous line3. The haemodynamic response of children with septic shock is variable and often different from that seen in adults. It is also dynamic, with changing patterns of shock seen as it progresses. The degree of observed effect (inotropy, chronotropy, systemic and pulmonary vasoconstriction and vasodilatation) of any given drug, combination of drugs vary considerably between patients and over time in an individual patient reflecting the variable and complex pharmacokinetics and pharmacodynamics in paediatric septic shock. Paediatric septic shock is even more heterogeneous than that seen in adults, affecting a wide age-range of children with developing organ structure/function. Heart, liver and kidney function are often altered, to a variable degree, during paediatric septic shock. Children exhibit an agespecific insensitivity to dopamine and dobutamine and adrenaline is more commonly required than in adults1. Recommendations for choice of agent(s) and quoted infusion rates are starting points only and treatment should be tailored and doses titrated to response throughout the resuscitation and post resuscitation phases. ‘Cold shock’ is a common presenting feature in children with community acquired septic shock presenting to hospital8,9. It is characterised by low CO and high SVR. Fluid refractory (40-60 ml/kg) Cold Shock should be immediately treated with an inotrope via peripheral, intraosseous or central venous vascular access3. Suitable ‘first-line’ inotropes are Dopamine (up to 10 mcq/kg/min), adrenaline (up to 0.3 mcq/kg/min) or dobutamine. There is no evidence to support a recommendation for a particular ‘first choice agent’ and practice varies widely. ACCM –PALS and others suggest dopamine as first choice progressing to adrenaline for fluid & dopamine refractory shock while others (including some ACCM-PALS committee members) recommend adrenaline first-line1,3. Normotensive ‘Cold Shock’ that is refractory to fluid and first-line inotrope therapy will require addition of a vasodilator agent to reduce left ventricular afterload, resulting in improved CO and global oxygen delivery. The choice of vasodilator includes: dobutamine (mild-moderate vasodilatation of blood vessels with 2 receptors, eg skeletal muscle), sodium nitroprusside, GTN, or a popular choice, is a type 3 phosphodiesterase inhibiter (PDEI) such as milrinone. Milrinone has a synergistic effect with -adrenergic agonists by inhibiting the breakdown of cAMP (cAMP is the second messenger produced by receptor activation) and a direct vasodilator action on the peripheral vasculature. Furthermore, PDEIs are unaffected by receptor downregulation and desensitisation. Caution, milrinone has a renal function dependent long elimination half-life of several hours. Hypotension caused by excessive milrinone activity can be treated with bolus fluid administration +/noradrenaline ( receptor activation will counteract the cAMP mediated peripheral vasodilatation of milrinone). ‘Warm Shock’ has been reported as more common in (hospital acquired) paediatric septic shock caused by central venous line infection9. This is similar to the prevalent form of adult septic shock, with high/normal CO and reduced SVR. In children this can quickly progress towards ‘Cold Shock’ as myocardial function and CO worsen. Management of warm shock centres around the use of vasoconstrictor agents typically noradrenaline, in many cases with additional inotropic agents in view of the propensity of paediatric sepsis to develop myocardial dysfunction8,9. Other agents include high-dose dopamine (> 10 mcq/kg/min) or adrenaline (>0.3 mcq/kg/min) or vasopressin / terlipressin (longer acting)3. Vasopressin activates V1 receptors (therefore is independent of adrenergic receptors) leading to signal amplification via the phospholipsae C system resulting in calcium mediated intense vasoconstriction. The VIP (Vasopressin in Paediatric Vasodilatory Shock) multi-center trial undertaken by the Canadian Critical Care Trials Group reported in 2009 that low-dose vasopressin (max dose 0.002 U/kg/min) did not result in any beneficial effects in their study of 65 children with vasodilatory shock, furthermore they witnessed a concerning trend toward increased mortality. Vasopressin (at similar and higher doses, up to 0.008 U/kg/min) is still widely used for noradrenaline refractory vasodilatory shock20. Levosimenden is a calcium sensitiser (binds to troponin C increasing actin/myosin interaction and contractility for given Ca mobilisation). It directly reverses the endotoxin-induced reduction in myocardial function seen in septic shock. It also appears to have some PDEI 3 activity and ATP-sensitive K+ channel activity. It is therefore an inodilator and chronotrope. 7. Put it all together and what have we got? The land mark study published by Rivers in 2001, to-date, is the only RCT in sepsis demonstrating that Early Goal-Directed Therapy (EGDT), to address fluid replacement and tissue perfusion in the first 6 hours of care in the emergency department, reduced hospital mortality (30% vs. 46%)21. This led to the widespread development of ‘bundle’ driven guidelines for the management of adult and paediatric sepsis, including the ACCM-PALS 2002 (revised 2007) Clinical Practice Parameters for Haemodynamic Support of Paediatric and Neonatal Septic Shock3, Surviving Sepsis Campaign (includes a section on paediatric considerations, 2004 & 2008 & 2012 revisions)5 and the World Federation of Paediatric Intensive Care and Critical Care Societies: (web-based) Global Sepsis Initiative (www.pediatricsepsis.org)22. Around the same time the Meningococcal Research Group based in St Mary’s, London started publishing practice guidelines for the management of meningococcal disease in children which led to a significant improvement in survival11. The group has continued to publish refinements to their guideline which can be found at www.meningitis.org. The most recent guideline incorporates the NICE Bacterial Meningitis and Meningococcal Septicaemia Guideline CG102. The Scottish Intercollegiate Guidelines Network has also published Management of Invasive Meningococcal Disease in Children and Young People, SIGN 102 www.sign.ac.uk. All of these ‘bundles’ share almost identical ‘goals’ and treatment recommendations. An ever-increasing number of studies have reported earlier resolution of shock and improved survival with the use of these goal-directed bundle guidelines. Notably, despite all but one (level B recommendation against the use of activated protein C in children) of the Surviving Sepsis Campaign 2008 recommendations being at level C or D (GRADE methodology), together as a ‘bundle’ of care they significantly improve survival11,12,19,23. Despite unequivocal evidence that ‘bundle’/guideline driven care saves lives in paediatric septic shock they are variably well implemented. The Paediatric Intensive Care Society Study group (PICS-SG) undertook an observational study on 200 children with septic shock accepted for PICU admission within 12 hours of admission to hospital (from 17 UK PICUs and 2 Regional Retrieval Services). 34 (17%) of children died following referral (7 before PICU admission and 27 following PICU admission). Those who had shock reversed prior to PICU admission had better outcomes than those in whom shock was not reversed (mortality rate 6% vs. 25%). In only 38% of children were ACCM-PALS 2002 guidelines followed for fluid and inotrope therapy prior to PICU admission (In the remainder shock was under appreciated / under treated). The odds ratio for death, if shock was still present at PICU admission was 3.8 (95% CI 1.4 to10.2, p=0.008)12. However EGDT has it’s critics and the study by Rivers study is yet to be confirmed in other centres. Three large ongoing multicentre RCTs: ProMISe (Protocolised Management in Sepsis, UK), ARISE (Australian Resuscitation in Sepsis Evaluation) and ProCESS (Protocolised Care for Early Septic Shock, USA) are studying resuscitation provided by teams comparing ‘usual care’ with ‘Rivers EGDT protocol’. The US study will also consider the utility of the ScvO2 target. Mechanical ventilation – the ideal time? Intubation and ventilation completes the triad (with bolus fluid and vasoactive agents) of essential therapies for the reversal of severe septic shock in children. All of the ‘EGDT’ type bundles acknowledge the importance of this but they vary in the rigidity of the recommendation offered from recommending it in all cases refractory to 40 ml/kg of fluid to recommending close vigilance be paid to signs of fluid overload and pulmonary oedema triggering cessation of fluid administration pending intubation and ventilation. It is accepted that achieving central venous access in children with septic shock is challenging and often the pragmatic approach is to intubate and ventilate to facilitate vascular access. The ACCM-PALS guidelines attempt to distinguish between sedation to facilitate central vascular access and the need to intubate and ventilate3. While this may be achievable in some cases in the PICU, it is not realistic for the majority of cases being managed in the emergency room. It is now common practice to have administered 40-60 ml/kg of fluid resuscitation rapidly, and started an inotrope (eg dopamine or adrenaline) through a peripheral or intraosseous line, prior to administering drugs for intubation. Other benefits of intubation and ventilation (with ongoing sedation +/- neuromuscular blockade) are reduction in the work of breathing (can account for 40% of CO and oxygen consumption) diverting oxygen delivery to other vital organs, reduction in left ventricular afterload (may be beneficial in ‘cold’ shock) and facilitation of temperature control measures (reduce global oxygen consumption). Excessive ventilation, impairing VR and hence CO, must be avoided. 8. Summary The subject title “Post Resuscitation. Fluids or Inotropes?” is challenging in many regards, not least the heterogeneous nature of the ‘collapsed’ child both aetiology and age-range. I have focused almost exclusively on the child with septic shock to the exclusion of severe trauma and notably traumatic brain injury. For septic shock clinical teams can extrapolate good published evidence and validated treatment guidelines from the resuscitation to post resuscitation stages of management. Other conditions, not considered, are often highly specialised eg congenital heart disease or inborn errors of metabolism or universally and rigidly protocolised eg Diabetic Ketoacidosis. References 1. Carcillo JA: What’s new in pediatric intensive care. Crit Care Med 2006; 34:S183–S190 2. Pollack MM, Fields AI, Ruttimann UE: Sequential cardiopulmonary variables of infants and children in septic shock. Crit Care Med 1984; 12:554-559 3. Brierley J, Carcillo JA, Choong K: Clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock: 2007 update from the American College of Critical Care Medicine. Crit Care Med 2009; 37:666–688 4. Carcillo JA, Fields AI: American College of Critical Care Medicine Task Force Committee Members: Clinical practice parameters for hemodynamic support of pediatric and neonatal patients in septic shock. Crit Care Med 2002; 30:1365–1378 5. Dellinger RP, Levy MM, Rhodes A, et al: Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock:2012. Crit Care Med 2013; 41:580-637 6. Tibby SM, Hatherill M, Murdoch IA: Capillary refill and core–peripheral temperature gap as indicators of haemodynamic status in paediatric intensive care patients. Arch Dis Child 1999;80:163–166 7. de Oliveira CF, de Oliveira DS, Gottschald AF, et al: ACCM/PALS haemodynamic support guidelines for paediatric septic shock: An outcomes comparison with and without monitoring central venous oxygen saturation. Intensive Care Med 2008; 34: 1065–1075 8. Ceneviva G, Paschall JA, Maffei F, et al: Hemodynamic support in fluid refractory pediatric septic shock. Pediatrics 1998; 102:e19 9. Brierley J, Peters MJ: Distinct hemodynamic patterns of septic shock at presentation to pediatric intensive care. Pediatrics 2008; 122:752759 10. Akech S, Ledermann H, Maitland K: Choice of fluids for resuscitation in children with severe infection and shock: systematic review. BMJ 2010; 341:c4416 11. Booy R, Habibi P, Nadel S, et al: Meningococcal Research Group: Reduction in case fatality rate from meningococcal disease associated with improved healthcare delivery. Arch Dis Child 2001; 85:386–390 12. Inwald DP, Tasker RC, Peters MJ, et al: Emergency management of children with severe sepsis in the United Kingdom: the results of the Paediatric Intensive Care Society sepsis audit on behalf of the Paediatric Intensive Care Society Study Group (PICS-SG). Arch Dis Child 2009; 94:348–353 13. Upadhyay M, Singhi S, Murlidharan J, et al: Randomized evaluation of fluid resuscitation with crystalloid (saline) and colloid (polymer from degraded gelatin in saline) in pediatric septic shock. Indian Pediatr 2005; 42:223–231 14. Santhanam I, Sangareddi S, Venkataraman S, et al: A Prospective Randomized Controlled Study of Two Fluid Regimens in the Initial Management of Septic Shock in the Emergency Department. Pediatric Emergency Care 2008; 24:647-655 15. Finfer S, Bellomo R, Boyce N, et al; SAFE Study Investigators: A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med 2004; 350:2247–2256 16. O’Dell E, Tibby SM, Durward A, et al: Hyperchloremia is the dominant cause of metabolic acidosis in the postresuscitation phase of pediatric meningococcal sepsis. Crit Care Med 2007; 35:2390–2394 17. Ranjit S, Kissoon N, Jayakumar I: Aggressive management of dengue shock syndrome may decrease mortality rate: A suggested protocol. Pediatr Crit Care Med 2005; 6:412–419 18. Foland FA, Fortenberry JD, Warshaw BL, et al: Fluid overload before continuous hemofiltration and survival in critically ill children; a retrospective analysis. Crit Care Med 2004; 32:1771–1776 19. Ninis N, Phillips C, Bailey L, et al: The role of healthcare delivery on outcome of meningococcal disease in children: Case control study of fatal and non-fatal cases. BMJ 2005; 330:1475 20. Choong K, Bohn D, Fraser DD, et al: Vasopressin in Pediatric Vasodilatory Shock. A Multicenter Randomized Controlled Trial. Am J Respir Crit Care Med 2009; 180:632–639 21. Rivers E, Nguyen B, Havstad S, et al: Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001; 346:1368–1377 22. Kissoon N, Carcillo JA, Espinosa V, et al: World Federation of Pediatric Intensive Care and Critical Care Global Sepsis Initiative. Pediatr Crit Care Med 2011; 12:494-503 23. Han YY, Carcillo JA, Dragotta MA, et al: Early reversal of pediatricneonatal septic shock by community physicians is associated with improved outcome. Pediatrics 2003; 112:793–799