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.
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