Four-year-old Ed is being resuscitated for presumed Invasive Group A Streptococcal Sepsis from tonsilitis. He presented tachycardic and hypotensive with a capillary refill time of 5 seconds. After 40ml/kg of IV 0.9% NaCl, his HR came down a little, but the effect was short-lived.
He has an HR of 190/min, and his BP is 85/35 mmHg. The CRT is unchanged.
You consider whether to start vasoactive medications.
What is Shock?
Shock is defined as a type of circulatory failure where lack of oxygen leads to dysfunction of vital organs. There are many types of shock which may affect children, and management is specific to the type of shock. Obviously, one also needs to address the cause of the shock, or any efforts in resuscitation will only bring a temporary improvement. This is beyond the scope of this blog post. The overall goal in managing any cause of shock is to restore oxygen delivery to the organs.
A quick physiology recap will help us better understand our treatment goals and how to achieve them.
For the organs to get enough oxygen, the heart needs to be able to pump enough oxygenated blood through the system and for it to be sent to where it is needed. This control requires an adequate blood pressure (BP). Without this control being possible, the body can’t ensure that all areas get sufficient blood. So, blood pressure is important, if only to allow the appropriate distribution of blood.
It’s worth a quick aside on why we can get so focussed on the BP, even if it only facilitates oxygen delivery, rather than being a good thing in itself. Firstly, oxygen delivery is very important, so anything compromising this is an issue. Beyond this, the body conserves BP at all costs – it is most of the reason we have a sympathetic nervous system – so a breakdown in this is very bad. And lastly, it’s actually quite hard to see how well the cardiovascular system is working, and this is one of its measurable features.
It’s only a piece of the puzzle, though. As Blood Pressure [is proportional to] Cardiac Output x Systemic Vascular Resistance (SVR), children with a low cardiac output could maintain their blood pressure by increasing resistance of the systemic vessels. Similarly, children with a high cardiac output could have low blood pressure if the resistance of the systemic vessels is decreased.
It’s worth considering the elements that make up the cardiac output a little. Heart rate is at least easy to count. However, it goes up with many benign things, so it cannot be used alone. In the context of developing cardiovascular compromise, the body will increase the HR as part of a package of compensation measures to maintain BP. This works well for a while, but eventually, the heart beats too fast to fill adequately. In practice, this starts to happen with HR over 200 in infants and 180 in older children. The amount of blood that comes from the heart with each contraction is the stroke volume (SV). The stroke volume is the difference between how full it is at the start and how full it is after a contraction. Almost all of the causes of shock lie in this difference, so it is worth understanding your patient’s heart as you manage the shock.
The volume at the start of a contraction relates to the pressure pushing blood into the ventricles and the health of the ventricular wall, which actively relaxes, sucking blood in. The pressure is referred to as preload. Unfortunately, this cannot really be measured in practice, as it’s the preload on the left side that would be needed. The central venous pressure is close to the preload for the right and often good enough to identify a low preload state, where fluid is good, or a high preload state, where fluid is bad. Other things that might help distinguish these states are chest X-rays, looking for an enlarged heart, or an echocardiogram, showing an empty or distended heart.
The next element of stroke volume is the emptying. How well this happens is down to the force the muscles of the heart generate (contractility) and how much resistance the heart is pumping against (sort of related to a physiological term called afterload). The way the heart is set up, it contracts more powerfully the more it is distended at the start of a contraction, up to a point (Frank-Maestrini-Starling law)
By distance, the most common cause of low cardiac output in children is insufficient preload, but contractility issues can occur. In the latter situation, the body’s response to the resulting low BP, by increasing SVR, leads to further trouble for the already challenged ventricular muscle and further worsens cardiac output. The BP might be okay, but oxygen delivery is not. Low BP in a child can be caused by low cardiac output but is also commonly caused by inappropriate cytokine-mediated vasodilation.
So, with these thoughts, we have identified three simple states for a decompensated child. Regrettably, some children have more than one at once. This can be confusing!
In the intervening time you have been thinking about the physiology, Ed’s HR has worsened. This is now 200, with a BP of 85/30 mmHg.
However, you will have noted that the response to the fluid given will have suggested at least some element of a preload problem. The wide pulse pressure and transient response would suggest an afterload problem.
So, fluid has been tried but has not got close to fixing the problem.
What are vasoactive drugs?
In middle-to-high-income countries, after 40-60ml/kg of fluid resuscitation, the Surviving Sepsis Campaign International Guidelines recommend using vasoactive drugs. This recommendation is based upon the availability of PICU support, with lower fluid volumes and earlier vasoactive use being recommended, particularly if there are signs of fluid overload. These would include developing respiratory distress.
Vasoactive drugs are either constrictors or dilators. Inotropes are drugs that increase the force of contraction, and chronotropes increase the heart rate. Many agents do more than one of these things. Inotropes and vasopressors can be used to optimise cardiac output and systemic vascular resistance.
Inotropes which act upon Alpha-1 receptors cause blood vessel constriction, whilst inotropes acting upon Beta (β1 & β2) cause increased heart rate and contractility and blood vessel dilation. Inotropes tend to work on multiple receptors but will affect one more than the other.
What different vasoactive drugs are available?
The Surviving Sepsis Campaign International Guidelines recommend either adrenaline or noradrenaline as the first-line inotrope. Either is reasonable as first-line, and there are not currently any studies which directly compare outcomes against each other for children with septic shock. Adrenaline and noradrenaline both work at α and β receptors. At lower doses, adrenaline can have more of a β effect with increased heart rate and contractility, whilst at higher doses, the α-effects are predominant. Noradrenaline similarly has both α and β, but the α (blood vessel constriction) effects are more predominant.
Although historically used quite frequently, dopamine is no longer recommended by advanced life support guidelines for septic shock unless adrenaline/noradrenaline are unavailable. Dopamine acts upon dopamine receptors and also has some β effects. The effect is variable and depends on the dose administered, but overall, it is an inotrope, chronotrope and vasoconstrictor. There are better agents, and it seems to basically function as weak adrenaline.
Dobutamine acts more on β receptors than α receptors and has a slight vasodilatory effect. This increases contractility without leading to increases in systemic vascular resistance. This makes it a popular choice for children with underlying heart disease (and those with cardiogenic shock), where an increase in systemic vascular resistance could be harmful for the above reasons.
Vasopressin can be added as a ‘second line’ agent for children with shock that are not responding to adrenaline and noradrenaline. Vasopressin acts on multiple receptors to cause constriction of the renal vessels and secondary increases to the systemic vascular resistance and, therefore, blood pressure.
Milrinone is an inodilator, causing increased cardiac contractility and vasodilation. There is also a lusitropic effect of ventricular relaxation, which improves cardiac perfusion and cardiac output. Its vasodilatory effects can cause a blood pressure drop and may worsen the situation, so it is usually used with a vasoconstrictor.
Steroids can have an anti-inflammatory action, which improves vascular tone in children with septic shock and may also improve the effect of adrenaline and noradrenaline. Steroids are used in refractory shock when a child is not responding to two or more inotropes. Dexamethasone, hydrocortisone, or methylprednisolone are all appropriate options.
Calcium can be used in some situations and should be given if ionised levels are low. Calcium is needed for cardiac contraction and for maintaining vascular tone. Its value when levels are normal is marginal. Shock and sepsis itself can cause low calcium levels due to intracellular shifts and lactate-binding calcium. The citrate in blood products can also bind to calcium and cause a drop in calcium levels, so do anticipate this for any children requiring blood transfusion. Check and replace the calcium if the ionised calcium levels are low.
Regardless of the choice of inotropes, we should always remember that inotropes may also lead to side effects.
After all these considerations and thinking about receptors, you feel that Ed is most likely to have a problem with low vascular tone. You want to start Noradrenaline. However, you have no central access.
While you are thinking about this, you give another 20 ml/kg of 0.9% NaCl, which again brings down the HR but doesn’t really change the BP.
Myth busting: Is peripheral administration safe?
A common belief is that inotropes can only be administered through central venous access. This is due to concerns about delivery and extravasation injury. There can also be difficulties and risks associated with obtaining central access, which may result in harm, with clinicians becoming task-focused due to delays in administering inotropes.
A recent systematic review and meta-analysis of 23 studies (seven involving children) explored the incidence of adverse effects from peripheral inotrope use. The seven studies in children included a meta-analysis of four studies, which included 388 children and demonstrated a pooled incidence of adverse events of 3.3%. This suggests that the incidence of adverse effects is low, and we should challenge the dogma of not using vasoactive drugs peripherally in an emergency.
In emergency situations, inotropes can, therefore, be delivered peripherally by intravenous or intraosseous access by diluting 10-fold in 0.9% normal saline and with careful monitoring for signs of extravasation. However, expert PICU support should be sought immediately for any child requiring inotropic support.
Peripheral Noradrenaline is now running at 0.1 mcg/kg/min through a line in the antecubital fossa.
The HR falls to 180/min, and BP improves to 95/45 mmHg.
Ed has been fairly drowsy, enough to allow an arterial line to be sited. An ABG comes back, showing a lactate of 5.3 mmol/L. What should you do now?
When should we use different vasoactive drugs?
Treatment for shock depends on the response to initial treatment. The concept of warm shock or cold shock is not that useful in children. For instance, a large observational study involving children with sepsis showed that some clinical signs (such as extremity temperature, pulse strength, and capillary refill) are more reliable than others (such as pulse pressure). That mismatched inotropes (e.g. noradrenaline rather than adrenaline) were not associated with increased complications. One should remain aware that the three causes of shock (table above) can all exist simultaneously in a child, and during the course of their illness, the predominant one may change. So, a constant review of HR, BP, lactate, and features of excessive preload, such as pulmonary oedema, is needed.
A repeat ABG shows a fall in lactate to 3.8 mmol/l. The CXR shows some cardiomegaly and mild pulmonary oedema.
You conclude there is an element of poor contractility now. On the other hand, Ed is more interactive now, although his breathing has deteriorated, with a respiratory rate of 35 and mild recession.
You are considering what to do, when the retrieval team arrives.
Of the available options, some can make the situation worse. That is why care for children like Ed is best carried out where there is sufficient monitoring and experience in managing these conditions.
Ed likely has a very mixed picture, with some redistribution and vasodilation managed by fluid and vasoconstrictors, but now the management of these has exposed a contractility problem.
The retrieval team decided to intubate and ventilate him to control the pulmonary oedema and then give him a little more fluid. Then, they decided to move him to the regional PICU. A few hours later, the lactate is unchanged and still abnormal. He is started on milrinone.
After two days of ventilation, he is extubated, and the following day, the milrinone and noradrenaline are stopped. Ed makes a full recovery.
Take home points
Consider inotropes if children with sepsis remain shocked after 40-60ml/kg of fluid resuscitation.
If there is evidence of cardiac dysfunction, consider starting an inotrope earlier.
The first line inotropes for septic shock are either adrenaline or noradrenaline.
Inotropes can be diluted and given peripherally in an emergency, though the central route is preferred.
Delicce AV, Makaryus AN. Physiology, Frank Starling Law. In: StatPearls. Treasure Island (FL): StatPearls Publishing; January 30, 2023.
Kanaris C, Wahida R. Inotrope use in children with septic shock: a guide for general paediatricians. Archives of Disease in Childhood – Education and Practice. Published Online First: 02 August 2023. https://doi.org/10.1136/archdischild-2021-322339
Owen VS, Rosgen BK, Cherak SJ, et al. Adverse events associated with administration of vasopressor medications through a peripheral intravenous catheter: a systematic review and meta-analysis. Crit Care. 2021;25(1):146. Published 2021 Apr 16. https://doi.org/10.1186/s13054-021-03553-1
Roland D. Surviving Sepsis Campaign International Guidelines. Don’t Forget The Bubbles. 2020. Available at https://doi.org/10.31440/DFTB.23460
Round J. Inotropes made simple. Paediatric FOAMed. 2017. Available at https://www.paediatricfoam.com/2017/05/inotropes/
Walker SB, Conlon TW, Zhang B, et al. Clinical Signs to Categorize Shock and Target Vasoactive Medications in Warm Versus Cold Pediatric Septic Shock. Pediatr Crit Care Med. 2020;21(12):1051-1058. https://doi.org/10.1097/PCC.0000000000002481
Weiss SL, Peters MJ, Alhazzani W, et al. Surviving Sepsis Campaign International Guidelines for the Management of Septic Shock and Sepsis-Associated Organ Dysfunction in Children. Pediatr Crit Care Med. 2020;21(2):e52-e106. https://doi.org/10.1097/PCC.0000000000002198