|Year : 2019 | Volume
| Issue : 2 | Page : 22-28
First line vasoactive therapy after fluid resuscitation in pediatric septic shock – Dopamine, Adrenaline or Noradrenaline?
Mehak Bansal1, Praveen Khilnani2
1 Pediatric intensive care fellow, Great Ormond street, London, UK
2 Praveen Khilnani Director PICU, Rainbow Children's hospital, New Delhi, India
|Date of Submission||15-Feb-2019|
|Date of Acceptance||30-Mar-2019|
|Date of Web Publication||20-Apr-2019|
Director, Madhukar Rainbow Children's hospital, New Delhi
Source of Support: None, Conflict of Interest: None
Severe sepsis and septic shock are the leading cause of morbidity and mortality in children all over the world, in both developed and developing nations. Surviving Sepsis Guidelines 2016 have recommended norepinephrine as the first choice of vasoactive agent in adult septic shock flowed by adrenaline or vasopressin in cases who do not respond to norepinephrine. In this article we have reviewed the literature and compared noradrenaline and adrenaline as first line vasoactive drug in children with fluid refractory septic shock. We have also discussed the change in the paradigm -use of dopamine as alternative instead of first line vasoactive agent
Keywords: Pediatric Sepsis, Dopamine, adrenaline, Noradrenaline, Septic shock
|How to cite this article:|
Bansal M, Khilnani P. First line vasoactive therapy after fluid resuscitation in pediatric septic shock – Dopamine, Adrenaline or Noradrenaline?. J Pediatr Crit Care 2019;6:22-8
|How to cite this URL:|
Bansal M, Khilnani P. First line vasoactive therapy after fluid resuscitation in pediatric septic shock – Dopamine, Adrenaline or Noradrenaline?. J Pediatr Crit Care [serial online] 2019 [cited 2023 Feb 3];6:22-8. Available from: http://www.jpcc.org.in/text.asp?2019/6/2/22/279913
| Introduction|| |
Severe sepsis and septic shock are the leading cause of morbidity and mortality in children all over the world, in both developed and developing nations. Septic shock accounts for about 2-3 % of the PICU admissions in the western world and nearly 40-67% of PICU admissions in India.,, Overall mortality due to sever sepsis and septic shock is around 25- 50%., Early recognition of septic shock and its timely management with judicious fluid resuscitation, vasoactive agents and antimicrobials is the key to reduce mortality and improve outcome. Guidelines have been formulated to guide the intensivists and pediatricians in the recognition and management of septic shock. Fluid refractory shock , which is defined as persistence of hypotension, signs of poor perfusion (decreased pulse volume, tachycardia, abnormal capillary refill time (CFT), temperature abnormality , altered mental status , decreased urine output), or signs of fluid overload (rales, hepatomegaly, worsening respiratory distress ), after administration of 20-60 ml/kg of fluid bolus within 60 min of presentation, requires commencement of vasoactive agents in order to maintain blood pressure and improve organ perfusion.
Surviving Sepsis Guidelines 2016 have recommended noradrenaline as the first choice of vasoactive agent in adult septic shock flowed by adrenaline or vasopressin in cases who do not respond to noradrenaline. Dopamine is reserved as an alternate vasopressor only in very selective patients who have a low risk of tachyarrhythmias and absolute/relative bradycardia. Although there is paucity of clinical research regarding the first line vasoactive agent in pediatric fluid refractory septic shock, in latest American College of Critical Care (ACCM) guidelines, adrenaline is recommended as initial drug with further tailoring of the drug according to the category of shock – warm shock (noradrenaline) or cold shock (adrenaline). In this article we have reviewed the literature and compared noradrenaline and adrenaline as first line vasoactive drug in children with fluid refractory septic shock. We have also discussed the change in the paradigm -use of dopamine as alternative instead of first line vasoactive agent and the current position of dobutamine in pediatric septic shock.
[TAG:2]Differences in the pathophysiology and hemodynamics in sepsis in children and adults,[/TAG:2]
About 90 % of the adults with septic shock exhibit hyperdynamic circulatory failure or warm shock with normal to high Cardiac Output (CO), low Systemic Vascular Resistance (SVR) and normal to decreased intravascular fluid status. Myocardial dysfunction is usually manifested as decreased ejection fraction, however, cardiac output is generally maintained due to crucial compensatory mechanisms – tachycardia, ventricular dilatation and decreased SVR. Patients who do not develop these compensatory mechanisms are at a high risk of death. Therefore, the adult septic shock generally requires a vasopressor agent,such as noradrenaline, which increases the SVR. On the contrary, children present with a completely different hemodynamic response to sepsis. Hypovolemia is a hallmark feature of pediatric septic shock and shock is responsive to volume resuscitation. Furthermore, nearly 50-60 % of the children with septic shock present with cold shock – low CO, high SVR and cold clammy peripheries.,,, Children have a limited cardiac reserve as compared to adults as they already have a high basal Heart Rate (HR). CO= HR x SV. In adults, fall in SV can be compensated by doubling the HR from 70-140/min, which is not possible in pediatric age group from 140-280/min as there will be insufficient time for diastolic filling which is essential for adequate coronary perfusion. Therefore, in children the predominant hemodynamic response to low CO is vasoconstriction to maintain Blood Pressure (BP). Due to this compensatory mechanism, hypotension is a late phenomenon in pediatric septic shock. Vasoconstriction and consequently increased afterload cause reduced SV and CO. Also, the left ventricle in infants and children is unable to significantly increase the contractility in response to stress owing to a reduced left; ventricle mass,, increased ratio of type 1 collagen (reduced elasticity) to type 3 collagen (increased elasticity) and less actin myosin content. Hence, management of septic shock in pediatric age group is focused on volume resuscitation to maintain preload to the heart, inotropes (low dose adrenaline or dopamine) to maintain CO and at times vasodilators (milrinone) to reduce SVR. Albeit hemodynamic variable and physical examination helps in judging category of shock (warm or cold), but they can be misleading to even experienced PICU clinicians.
| Vasoactive agents in pediatric septic shock Adrenaline as first line vasoactive drug|| |
Adrenaline has potent action on beta 1 adrenergic receptors in myocardium and moderate effect on beta 2 and alpha 1 adrenergic receptors in peripheral vasculature. At low doses (0.05-0.2 mcg/kg/min) it acts as a potent inotropic and chronotropic agent due to action on beta 1 receptors and modest vasodilator due to beta 2 adrenergic receptor stimulation resulting in increased CO and decrease in SVR. At higher doses it predominantly causes vasoconstriction owing to its action on alpha 1 receptors , which can result in decreased CO due to increase in after load As discussed earlier, since the pathophysiology of pediatric septic shock usually cold shock with low CO with increased CVR requiring an inotrope , the ACCM 2017 guidelines have recommended use of low dose adrenaline (0.05-0.3mcg/kg/min) as first choice vasoactive agent in pediatric septic shock to be administered via intravenous (iv) or intraosseous (IO) route in 10 times dilution as compared to central line dose. Although it is emphasized that adrenaline infusion must be shifted to central venous access as soon as it is inserted. Once the central venous line is placed in and other hemodynamic indices like CO, Scvo2 and perfusion pressure – Mean Arterial Pressure (MAP) – Central Venous pressure (CVP) have been obtained , vasoactive drug can be altered depending on the category of shock – adrenaline for cold shock and noradrenaline for warm shock.
There have been concerns regarding the local side effects of adrenaline after peripheral infiltration, but there is no data that demonstrates adrenaline can cause more local ischemia than dopamine or noradrenaline. Moreover, it is imperative to avoid delay in administration of vasoactive drugs as it has shown to increase the length of ICU stay., In a recent study done by Ventura et al did not observe any ischemic events related to peripheral administration of adrenaline at low doses. The local side effects depend on the concentration of adrenaline used and duration of infiltration into the skin. Other adverse effects of adrenaline aredecrease in splanchnic blood flow, gut injury due to increase in gastric pH and increased lactate levels in adults,, however no such adverse events have been reported in pediatric age group. Adrenaline causes hyperglycemia by stimulating gluconeogenesis and glycogenolysis and by inhibiting insulin.
| Issues around Dopamine in pediatric septic shock|| |
Dopamine is the drug of choice in neonatal septic shock. In pediatrics, dopamine can be used as an alternative to adrenaline if adrenaline is not available.
At doses of 5-10 mcg/kg/min it acts as an inotropic and chronotropic drug due to its action on beta 1 adrenergic receptors., At a dose of 10-20 mcg/kg/ min, dopamine predominantly acts as vasopressor due to its action on alpha 1 adrenergic receptors. At a dose of 1-2 mcg/kg/min, it can cause vasodilatation in renal, cerebral, coronary and mesenteric beds due to its action on dopaminergic receptors. Two recent Randomised Control Trials have supported the use of adrenaline over dopamine. In a double blinded study done by Ramaswamy et al on 60 children with fluid refractory hypotensive shock, resolution of shock was observed in greater proportion of children who received adrenaline than dopamine after 1 hour (41% vs 13%) and at 6 hours (48.3 % vs 29 %) of resuscitation. The patients who received adrenaline had lower Sequential Organ Function Assessment Scores (SOFA) and more organ failure free days. No difference in mortality was observed in both the groups. Lactate clearance was similar in both the groups. This RCT signifies the use of adrenaline as first line vasoactive agent in pediatric septic shock causes early resolution of cold shock than dopamine and is quite safe at low doses. 
The other RCT done by Ventura et al observed greater mortality (20.6% vs 7 % p=0.033) and hospital acquired infections (29 % vs 2% OR 67.7; 95% CI, 5.0-910.8) in the children who received dopamine infusion as compared to adrenaline infusion. The frequency of adverse effects was similar in both the groups. This study was a single centre study and had certain other aberrations like dose titration was aggressive and significant difference in the time to achieve the desired dose range among the dopamine and adrenaline group Further multi centre trials are required to evaluate the mortality benefit of adrenaline as first line vasoactive drug in fluid refractory septic shock.
Dopamine is also known to cause immunosuppression, increased cytokine production and increased oxidative stress. It is also known to decrease secretion of prolactin and of growth hormone and thyroid secretion which can contribute to poor neurodevelopmental outcome., Furthermore, in young children and infants with decompensated shock, response to dopamine is unpredictable as they have been known to develop insensitivity to dopamine and depletion of catecholamine in body in case of hypotensive shock. , Hence, higher dose infusion of dopamine (10- 15mcg/kg/min) for inotropic action and >15mcg/kg/ min for vasoconstriction may be required to attain similar effects. On the contrary, adrenaline has a predictable response in increasing CO and MAP with no side effects of immunosuppression and endocrine disturbance.
Considering these facts, so far, it can be suggested that adrenaline is replacing dopamine as a first line vasoactive drug in children with septic shock.
| Noradrenaline in warm shock|| |
Noradrenaline has a potent effect on alpha 1 and beta 1 adrenergic receptors. Mainly it increases MAP by vasoconstriction with minimal effect on HR and SV. It is not a good inotrope as the effect is counteracted by increase in afterload due to vasoconstriction. Therefore,noradrenaline is not advised in shock due to low CO. If child’s clinical state and hemodynamic parameters are suggestive of warm shock – warm peripheries, flash CFT, wide pulse pressure (DBP <1/2 of SBP) and bounding pulses, low SVR, additional use of noradrenaline can also be suggested at doses of adrenaline >0.3mcg/kg/min or dopamine >10 mcg/kg/min to add a vasopressor effect to the inotropic action of adrenaline or dopamine. In case of hyperdynamic circulation with low SVR, noradrenaline alone is recommended. In a single centre study demonstrating the use of noradrenaline in children with septic shock over a period of a decade showed that noradrenaline was used in 22% of the patients as first line agent and in rest as 2nd and 3rd line agent.
|Figure 1 : Algorithm of management of shock in infants and children by American College of Critical Care Medicine.|
Click here to view
In adults, noradrenaline is the first line vasoactive agent in septic shock as they present with hyperdynamic circulation and noradrenaline elevates MAP by its vasoconstrictive action with minimal effects on HR. Adrenaline is the 2nd line drug if the MAP is not achieved by noradrenaline alone. No data is available in pediatrics comparing noradrenaline with adrenaline. In adults, one RCT done by CAT study investigators shows no difference in mortality between the patients receiving adrenaline and noradrenaline, however, the earlier group had increased adverse effects due to administration of adrenaline. A meta-analysis done in 2015 comparing 4 RCTS also observed no mortality difference between adrenaline and noradrenaline groups. The same study also does not support the use of dopamine in adult septic shock and showed absolute risk reduction of 11 % in 28-day mortality in patients who were treated with noradrenaline as compared to dopamine with number needed to treat of.  Noradrenaline also was shown to have a better safety profile with half the risk of cardiac dysrhythmias and lesser side effects as opposed to dopamine. Hence, these results can be extrapolated to pediatrics and noradrenaline is a preferred vasopressor in warm shock in children, dopamine to be used as an alternative if noradrenaline is not available.
| Role of Dobutamine in pediatric septic shock|| |
Dobutamine mainly acts as an inotropic and chronotropic drug as it stimulates beta 1 adrenergic receptors. It also causes vasodilatation by acting on beta2 receptors with minimal action on alpha1 receptors. Overall, it causes increase in CO, decrease in SVR with no effect or mild reduction in BP. It is the drug of choice in cardiogenic shock in children with low CO and high SVR and should not be used as initial treatment in sepsis because of increased risk of hypotension. In children with cold shock with low CO, high SVR, normal BP and poor peripheral perfusion a vasodilator dobutamine or milrinone can be added to adrenaline, if adrenaline alone is not able to maintain adequate perfusion and increase CO. In patients with warm shock, dobutamine can be added to patients on noradrenaline infusion with Cardiac Index (CI) <3.3L/min/m2 to augment CO and counteract the vasoconstrictive effects of noradrenaline and improve microcirculatory function.,,
Vasodilator milrinone is the first line vasodilator in children with adrenaline resistant cold shock with normal BP. It is a phosphodiesterase inhibitor with inotropic and vasodilatory properties, but has long half life and is associated with adverse effects like hypotension, tachyarrhythmias . Therefore, it should be used judiciously.
Low dose Vasopressin can be added to noradrenaline in catecholamine refractory warm shock when noradrenaline and fluid cannot resolve hypotension in order to increase MAP. It is antiduretic hormone and is a pure vasopressor. At higher doses (>0.03 units/ kg/min ) it is associated with skin necrosis and gut ischemia.,
| Conclusion|| |
Current evidence suggests that hemodynamic response to sepsis is different in children and adults. Most of the adults present with hyperdynamic circulation, whereas infants and children more commonly exhibit cold shock. Adrenaline is vasoactive agent of choice in cold shock and the latest guidelines recommend adrenaline as the first-choice vasoactive drug in pediatric fluid refractory septic shock. Studies have demonstrated that adrenaline has better safety profile and better efficacy in reversing the shock during first hours of resuscitation than dopamine, making it a preferred vasoactive agent over dopamine in cold shock. However, further hemodynamic monitoring and bedside echocardiography is essential to assess the hemodynamic status of the child and to calculate ScVO2, CI and perfusion pressure (MAP-CVP). It is imperative to further guide the use of vasoactive agent according to the type of shock in children as vasodilatory shock in children is also not very uncommon and hemodynamics may change very rapidly in case of septic shock., Considering these arguments universal application of a single vasoactive drug as a first choice may be harmful, and vasoactive drugs must be optimised according to the hemodynamic requirements of a child. Further RCTS are required to evaluate the mortality benefit of adrenaline as first line agent in pediatric septic shock.
Source of funding: Nil
Conflict of interest: Nil
| References|| |
Schlapbach LJ, Straney L, Alexander J, et al. Mortality related to invasive infections, sepsis, and septic shock in critically ill children in Australia and New Zealand, 2002–13: a multicentre retrospective cohort study. Lancet Infect Dis 2015;15(1):46-54.
Wolfler A, Silvani P, Musicco M, Antonelli M.On behalf of the Italian Pediatric Sepsis Study (SISPe) group. Incidence of and mortality due to sepsis, severe sepsis and septic shock in Italian Pediatric Intensive Care Units: a prospective national survey. Intensive Care Med. 2008;34:1690-7.
Lodha R, Oleti TP, Kabra SK. Management of septic shock. The Indian Journal of Pediatrics. 2011;78(6):726.
Weiss SL, Fitzgerald JC, Pappachan J, Wheeler D, Jaramillo- Bustamante JC, Salloo A, et al. Global epidemiology of pediatric severe sepsis: the sepsis prevalence, outcomes, and therapies study. American journal of respiratory and critical caremedicine 2015;191(10):1147-57.
Kissoon N, Carcillo JA, Espinosa V, Argent A, Devictor D, Madden M. World Federation of Pediatric Intensive Care and Critical Care Societies: Global Sepsis Initiative. Pediatr Crit Care Med 2011;12:494-503.
Davis AL, Carcillo JA, Aneja RK, et al. American College of Critical Care Medicine Clinical Practice Parameters for Hemodynamic Support of Pediatric and Neonatal Septic Shock. Crit Care Med 2017;45(6):1061-93.
Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive care medicine 2017;43(3):304-77.
Aneja R, Carcillo J. Differences between adult and pediatric septic shock. Minerva Anestesiol 2011; 77:986-92.
Wynn J, Cornell TT, Wong HR, et al. The host response to sepsis and developmental impact. Pediatrics 2010; 125:1031-41.
Parker MM, Shelhamer JH, Natanson C. Serial cardiovascular variables in survivors and nonsurvivors of human septic shock: heart rate as an early predictor of prognosis. Crit Care Med 1987;15:923-9.
Ceneviva G, Paschall JA, Maffei F, et al. Hemodynamic support in fluid-refractory pediatric septic shock. Pediatrics 1998; 102:e19.
Brierly J, Thiruchelvan T, Peters MJ: Hemodynamics of early pediatric fluid resistant septic shock using non-invasive cardiac output (USCOM) distinct profiles of CVC infection and community acquired sepsis. Crit Care Med 2006; 33:171-1.
Deep A, Goonasekera CD, Wang Y, et al. Evolution of haemodynamics and outcome of fluid-refractory septic shock in children. Intensive Care Med 2013; 39:1602-9.
Joyce JJ, Dickson PI, Qi N, et al. Normal right and left ventricular mass development during early infancy. Am J Cardiol 2004; 93:797-801.
Ichihashi K, Ewert P, Welmitz G, Lange P. Changes in ventricular and muscle volumes of neonates. Pediatr Int 1999;41(1):8-12.
Marijianowski MM, van der Loos CM, Mohrschladt MF, Becker AE. The neonatal heart has a relatively high content of total collagen and type I collagen, a condition that may explain the less compliant state. J Am Coll Cardiol 1994;23(5):1204- 8.
Feltes TF, Pignatelli R, Kleinert S, et al. Quantitated left ventricular systolic mechanics in children with septic shock utilizing noninvasive wall-stress analysis. Crit Care Med 1994; 22:1647-58.
Wilson W, Lipman J, Scribante J, et al. Septic shock: Does adrenaline have a role as a first-line inotropic agent? Anaesth Intensive Care 1992; 20:470-4.
Paul R, Neuman MI, Monuteaux MC, et al. Adherence to PALS Sepsis Guidelines and Hospital Length of Stay. Pediatrics 2012; 130:e273- e280.
Paul R, Melendez E, Stack A, et al. Improving adherence to PALS septic shock guidelines. Pediatrics 2014; 133:e1358- e1366.
Ventura AM, Shieh HH, Bousso A, et al. Double-blind prospective randomized controlled trial of dopamine versus adrenaline as firstline vasoactive drugs in pediatric septic shock. Crit Care Med 2015;43:2292-2302.
Day NP, Phu NH, Bethell DP, et al. The effects of dopamine and adrenaline infusions on acid-base balance and systemic haemodynamics in severe infection. Lancet 1996; 348:219-223.
Levy B, Bollaert PE, Charpentier C, et al. Comparison of noradrenaline and dobutamine to adrenaline for hemodynamics, lactate metabolism, and gastric tonometric variables in septic shock: A prospective, randomized study. Intensive Care Med 1997; 23:282-7.
Olsen NV. Effects of dopamine on renal haemodynamics, tubular function and sodium excretion in normal humans. Dan Med Bull 1998;45(3):282-97.
Dasta JF, Kirby MG. Pharmacology and therapeutic use of low-dose dopamine. Pharmacotherapy 1986; 6:304.
Löllgen H, Drexler H. Use of inotropes in the critical care setting. Crit Care Med 1990; 18:S56.
Ramaswamy KN, Singhi S, Jayashree M, et al. Double-blind randomized clinical trial comparing dopamine and adrenaline in pediatric fluid-refractory hypotensive septic shock. Pediatr Crit Care Med. 2016;17(11):e502-12.
Ganesan L, Jayashree M. Dopamine in Pediatric Fluid- Refractory Septic Shock: Too Early to Sound the Death Knell? Crit Care Med 2016;44(2):e110-1.
Filippi L, Pezzati M, Poggi C, et al. Dopamine versus dobutamine in very low birthweight infants: Endocrine effects. Arch Dis Child Fetal Neonatal Ed 2007; 92:F367- F371
Van den Berghe G, de Zegher F, Lauwers P. Dopamine suppresses pituitary function in infants and children. Crit Care Med 1994;22:1747-53.
Bhatt-Mehta V, Nahata MC. Dopamine and dobutamine in pediatric therapy. Pharmacotherapy 1989; 9:303-14.
Eldadah MK, Schwartz PH, Harrison R, et al. Pharmacokinetics of dopamine in infants and children. Crit Care Med 1991; 19:1008-11.
Herget-Rosenthal S, Saner F, Chawla LS. Approach to hemodynamic shock and vasopressors. Clin J Am Soc Nephrol 2008;3(2):546-53.
Lampin ME, Rousseaux J, Botte A, et al. Noradrenaline use for septic shock in children: Doses, routes of administration and complications. Acta Paediatr 2012; 101:e426-e430.
Myburgh JA, Higgins A, Jovanovska A, et al. CAT Study investigators: A comparison of adrenaline and noradrenaline in critically ill patients. Intensive Care Med 2008; 34:2226-34.
Avni T, Lador A, Lev S, et al. Vasopressors for the Treatment of Septic Shock: Systematic Review and Meta-Analysis. PLoS One 2015; 10:e0129305
De Backer D, Creteur J, Dubois MJ, et al. The effects of dobutamine on microcirculatory alterations in patients with septic shock are independent of its systemic effects. Crit Care Med 2006;34:403-8.
Hernandez G, Bruhn A, Luengo C, et al. Effects of dobutamine on systemic, regional and microcirculatory perfusion parameters in septic shock: a randomized, placebo- controlled, double-blind, crossover study. Intensive Care Med 2013;39:1435-43.
Belletti A, Benedetto U, Biondi-Zoccai G, et al. The effect of vasoactive drugs on mortality in patients with severe sepsis and septic shock. A network meta-analysis of randomized trials. J Crit Care 2017;37:91-8.
Malay MB, Ashton JL, Dahl K, et al. Heterogeneity of the vasoconstrictor effect of vasopressin in septic shock. Crit Care Med 2004; 32:1327.
Dünser MW, Mayr AJ, Tür A, et al. Ischemic skin lesions as a complication of continuous vasopressin infusion in catecholamine-resistant vasodilatory shock: incidence and risk factors. Crit Care Med 2003; 31:1394.
Deep A, Goonasekera CD, Wang Y, et al. Evolution of haemodynamics and outcome of fluid-refractory septic shock in children. Intensive Care Med 2013; 39:1602-9.
Ranjit S, Aram G, Kissoon N, et al. Multimodal monitoring for hemodynamic categorization and management of pediatric septic shock: A pilot observational study. Pediatr Crit Care Med 2014; 15:e17-e26.