Yorkshire and Humber Neonatal ODN (South) Clinical Guideline
Title: Hypotension
Author: Anna Calvert, Simon Clark, Elizabeth Pilling
Date written: October 2014 (review)
Review date: October 2017
This clinical guideline has been developed to ensure appropriate evidence based standards of care throughout the North Trent Neonatal
Network. The appropriate use and interpretation of this guideline in providing clinical care remains the responsibility of the individual clinician. If there is any doubt discuss with a senior colleague.
Best practice recommendations represent widely used evidence-based practice and high quality standards that all Neonatal Units across the
Network should implement. Subsequent suggested recommendations may be put into practice in local units. However, alternative appropriate local guidelines may also exist.
A. Summary page (s)
1. Aim of guideline
This guideline aims to provide a framework for the treatment of clinically significant hypotension in the neonatal period.
2 . Summary flow chart or quick reference guide
Confirm the baby is hypotensive

Fluid resuscitation: Give 10 to 20 mL/kg normal saline

If still hypotensive, inform the neonatal registrar, if not already aware.

Is there central venous access? If not, get it.


Complete fluid resuscitation of up to 20 mL/kg

If still hypotensive, confirm that we are not missing something

Start dopamine at 5 to 10 micrograms/kg/min increasing by 5 micrograms/kg/min every 15 minutes until a maximum of 20 micrograms/kg/min is reached.


If still hypotensive, investigate and confirm that we are not missing something


Consider referral for tertiary care

Start dobutamine at 5 to 10 micrograms/kg/min increasing by 5 micrograms/kg/min every 15 minutes until a maximum of 20 micrograms/kg/min is reached


If still hypotensive get an echocardiogram (where possible) if not already performed and consider further investigations and tertiary referral

The next sequence is at the discretion of the on call consultant.
At all times consider possible causes of hypotension, e.g. blood loss, cardiac performance etc.
The speed at which you progress through this protocol will be dictated by the baby’s clinical status and responses to the interventions. In otherwise stable preterm infants it may take several hours to get to maximal therapy.
In a profoundly septic term baby you could find yourself on adrenaline in less than an hour, even possibly skipping sections. However, that kind of
“short-cut” would require the active involvement of a consultant. Consider referral for tertiary intensive care, especially once more than 1 inotrope required.

B. Full guideline
1.
Background
Hypotension is a common problem in the neonatal period and is associated with multiple adverse outcomes including increased mortality, intraventricular haemorrhage, adverse neurodevelopmental outcomes and increased incidence of hearing loss 1-6 . Despite this there is no clear evidence that treating isolated hypotension in the first 24 hours of life improves outcome 7 .
Also t here is no universal definition of ‘normal’ blood pressure for neonates; a frequently used definition of hypotension is that of a mean blood pressure below the gestational age in weeks 8 , or alternatively a value below the 5 th or
10 th centile in a birth weight and gestational age reference range. Blood pressure itself is a poor marker for the more important consideration of systemic blood flow 9,10 , but it is the only measure available to us easily in the neonatal unit.
What is clinically significant hypotension?
In a well baby, i.e. one that is passing urine, has good perfusion, is easy to ventilate, is not acidotic, does not have a high lactate, or is not septic, taking the mean blood pressure as around the gestational age is appropriate.
11
Alternatively use the birth weight and the table below.
11
Birth Weight 10 th percentile for mean blood
500-750 grams pressure
26 mmHg
750-1000 grams
1000-1250 grams
1250-1500 grams
2000-2999 grams
3000-3999 grams
28 mmHg
29 mmHg
30 mmHg
32 mmHg
36 mmHg
4000 grams 42 mmHg
If the blood pressure is lower than these criteria treat it. In a baby with a borderline normal blood pressure, by either weight or gestational age criteria, take into account other factors and treat if any one of the following is present:
Appearance pale, clammy, poorly perfused
Toe - core temperature difference
>2°C
Capillary refill time Delayed
Acid base balance
Urine output
Oxygenation/ventilation index
Cardiac function metabolic acidosis or an elevated lactate
<1m/kg/hr high mean airway pressure/oxygenation echocardiographic evidence of poor contractility
In a critically sick baby with sepsis or persistent pulmonary hypertension allowing the blood pressure to fall to the 10 th percentile is probably too low.
The table below gives the average mean arterial blood pressure measured invasively and the upper confidence interval for that mean. In critically sick infants we should aim for at least the average mean, and potentially for the
95% upper confidence limit of the average.
11, 12, 13

Birth Weight
500-750 grams
750-1000 grams
1000-1250 grams
1250-1500 grams
2000-2999 grams
3000-3999 grams
4000 grams average mean arterial blood pressure
35 mmHg
38 mmHg
39 mmHg
40 mmHg
41 mmHg
47 mmHg
52 mmHg
95% upper confidence limit
44 mm Hg
47 mm Hg
48 mm Hg
49 mm Hg
50 mm Hg
55 mm Hg
62 mm Hg
Physiology
Low blood pressure is associated with worse outcomes 5,12,13 but there can be no normal values for mean arterial blood pressure in preterm infants, who by definition are not normal. Most centres use the gestation rule 11 i.e. the mean arterial blood pressure should be equivalent to the baby’s gestation. This is still not very helpful as many preterm babies are hypotensive by this definition.
What is important is the delivery of oxygenated blood to the tissues, but there is no easy way or measuring that. The actual blood pressure measurement is generated by the flow of blood through the vessels. Therefore, blood pressure depends on vasoconstriction/dilatation, the volume of the blood in the vessels and blood flow caused by myocardial performance. Vasoconstriction will decrease tissue oxygen delivery, especially with poor heart function whereas vasodilatation will improve tissue oxygen delivery, even from a poorly functioning heart. Reduced blood volume will also reduce tissue oxygen delivery. So is the low blood pressure you see on the monitor a product of vasodilatation, poor heart function, loss of blood volume or some combination of all three? Identification of which of these three is contributing to the hypotension will allow better tailored inotropic support.
Additionally critically sick babies may require higher blood pressures than just the 10 th percentile. This group includes those with persistent pulmonary hypertension, significant perinatal asphyxia and severe sepsis.
Technical Issues
Invasive monitoring is the most accurate.
14 Cuff blood pressures are usually higher 14 than arterial line readings, anywhere up to 15 mmHg 14 , and may be falsely reassuring. The first priority is to confirm the reading is accurate and that the transducer has been calibrated and positioned correctly. Next establish whether the hypotension is symptomatic of another problem.
Consider, patent ductus arteriosus, hypovolaemia, blood loss, pneumothorax, sepsis (particularly in persistent or late hypotension), adrenocortical insufficiency in extreme prematurity, high mean airway pressure on mechanical ventilation, intraventricular haemorrhage, necrotising enterocolitis, metabolic disorders, electrolyte problems and congenital heart disease. This list is not exhaustive, but if you find a specific cause treat that at the same time as treating the hypotension.

2. Guideline
2.1Investigate and confirm that we are not missing something e.g. blood loss, metabolic problems, electrolytes (especially low calcium or high potassium), cardiac disorders, pneumothorax, monitoring etc.
2.2 Give 10 to 20 mL/kg normal saline over 15 to 60 minutes depending on severity of hypotension. Consider packed cells for blood loss or if the baby is fluid loaded.
V OLUME AND F LUID T YPE
Resuscitation with up to 20mL/kg over up to an hour in some infants (probably about 50%) will be enough to bring up the blood pressure with no further intervention.
1, 15 If they do not respond to this then there are concerns that further fluid volumes are associated with worse outcome e.g. chronic lung disease, symptomatic arterial ducts and death.
16,17,18 Use of volumes over 20 mL/kg is reserved either for acute life saving resuscitation i.e. haemorrhage and then the use of packed cells are best, or at the discretion of the consultant on call.
18
Normal saline is the first fluid of choice. It is effective, cheap and there is no evidence of any advantages to colloid in neonates.
15, 16, 17, 19, 20 There are some suggestions that colloid is associated with worse clinical outcomes eg increased mortality, increased lung damage, increased neurodisability.
15, 16, 17,
19, 20 Many of the studies are small and the larger ones are not even paediatric let alone neonatal. Therefore, this does not ban the use of colloid, but it should be a carefully considered decision at consultant level.
2.3 Still hypotensive, inform the neonatal registrar, if not already aware.
2.4 Is there central venous access? If no central line is possible, attempt long line once volume resuscitation has been given, but do not let the baby get cold.
2.5 Complete fluid resuscitation of up to 20 mL/kg over 15 to 60 minutes.
Normal saline is still probably first choice, but in some scenarios human albumin solution may be preferential. Do not exceed 20 mL/kg of volume resuscitation unless there is blood loss (then use blood) or unless you are instructed to give more volume by the on call consultant. The type and volume is at their discretion. We should rarely exceed a total 40 mL/kg in acute resuscitation of any fluid type before starting inotropes, unless there is haemorrhage.
2.6 Still hypotensive, confirm that we are not missing something e.g. blood loss, metabolic problems, electrolytes (especially low calcium or high potassium), cardiac disorders, pneumothorax, monitoring etc. and consider informing consultant.

2.7 Start dopamine at 5 to 10 micrograms/kg/min (depending on the degree of hypotension, remembering to purge the giving sets if you want the baby to get any inotrope within an hour), increasing by 5 micrograms/kg/min every 15 minutes until a maximum of 20 micrograms/kg/min is reached. Consider starting dobutamine as well if little response to dopamine at 10 micrograms/kg/min. If no long line in situ consider using dilute dobutamine instead of dopamine and monitor infusion site. If you run dopamine peripherally monitor infusion site closely and preferably use dilute solution, looking for vasoconstriction/extravasations. Wean by reducing infusion rate by between 1 and 5 micrograms/kg/min depending on the blood pressure’s response.
2.8 Start dobutamine at 5 to 10 micrograms/kg/min (depending on the degree of hypotension, remembering to purge the giving sets again if you want the baby to get any within an hour), increasing by 5 micrograms/kg/min every 15 minutes until a maximum of 20 micrograms/kg/min is reached. Wean by reducing infusion rate by between 1 and 5 micrograms/kg/min depending on the blood pressure’s response. Consider referral for tertiary intensive care.
D OPAMINE AND D OBUTAMINE
Based on the Cochrane reviews of hypotension in neonates 21 dopamine is more effective than dobutamine for short term treatment of hypotension. This is mainly through vasoconstriction, with some degree of increased myocardial contractility and heart rate, which is different from improving cardiac output or tissue oxygenation. The use of dopamine as the first line agent does not necessarily mean it is better than other inotropes at improving survival, improving tissue oxygen delivery, or improving blood flow, but it is better at improving what we can easily measure, i.e. blood pressure. This, however, may be crucial in babies with low systemic vascular resistance and high pulmonary vascular resistance when the arterial duct is still open.
In some situations dopamine may be the not the first choice inotrope. When there is no central access the risk of extravasation injury is high. Also, as dopamine’s primary action is that of raising peripheral vascular resistance this can increase the workload of the heart and reduce tissue oxygenation. In situations where there are concerns about poor myocardial function, dobutamine may be the first choice agent. Dobutamine mainly works through increasing contractility. It also raises the heart rate and has mild vasodilating properties (so peripheral infusion is less of an issue). The combination of increased cardiac output and vasodilatation may improve systemic blood flow and tissue oxygenation. However, there is may be little alteration (up or down) in the blood pressure once dobutamine is commenced.
Regardless of whether dopamine or dobutamine is started first, if one does not work both are frequently used together. There is logical appeal in starting dopamine up to 10 micrograms /kg/minute and then adding in dobutamine, as you get vasoconstriction and increased contractility. However, there is no evidence of altered longer-term outcomes.
2.9 Still hypotensive? Get an echocardiogram if not already performed and consider further investigations to confirm that we are not missing something eg blood loss, metabolic problems, electrolytes (especially low calcium or high potassium), pneumothorax, monitoring etc. Consider referral to tertiary centre.

2.10 The next sequence is at the discretion of the on call consultant. a) If premature check to see if the baby had indomethacin/ibuprofen. If indomethacin/ibuprofen was used, discuss with consultant about whether hydrocortisone should be used and record the conversation on the notes. If premature and not had indomethacin/ibuprofen, or has had indomethacin/ibuprofen and the consultant chooses to use hydrocortisone:
Start hydrocortisone 1 mg/kg/dose 12 hourly.
Still hypotensive, discuss with consultant, who will probably add adrenaline.
H YDROCORTISONE
There is increasing evidence to support the use of steroids to acutely raise blood pressure in premature neonates.
16,17,18,19,20 It is thought to work through improving the immature neonatal stress response and by increasing the number of receptor sites for inotropes. As steroids work by increasing gene expression then it may take several hours for a response to be seen.
The Cochrane review on the use of steroids showed that there is insufficient evidence to support the routine use of hydrocortisone in the primary treatment of hypotension, but there is some evidence that corticosteroids can help in the treatment of refractory hypotension.
21 There is no evidence on whether steroids should be weaned before pressors or the other way round.
Concurrent use of Hydrocortisone with indomethacin or ibuprofen.
17,20 should be avoided due to concerns regarding intestinal perforation.
b) On triple inotrope therapy, or on double therapy and had indomethacin or a sick term infant:
Consider referral to tertiary centre
Start adrenaline starting at 0.05 to 0.1 micrograms/kg/min increasing by 0.05 micrograms/kg/min to a maximum of 1 micrograms/kg/min depending on response. Titrate other levels of inotropes depending on response to adrenaline. You should aim for 5 micrograms/kg/min dopamine (so called renal dose) and as low a dose of dobutamine as possible. Wean adrenaline by reducing infusion rate by between 0.05 to 0.1 micrograms/kg/min, depending on the blood pressure’s response.
A DRENALINE
On neonatal units adrenaline has never really gained the favour that it has in paediatric intensive care units. It is a highly effective inotrope and has been shown to be effective in neonates 28,29 , however the Cochrane review 30 on this found insufficient evidence to move to using adrenaline as a first or even second line therapy. It should only really be administered through a central line on consultant approval.

Medications not mentioned in this protocol:
M ILRINONE
The phosphodiesterase III inhibitor milrinone is used widely in adults and is gaining favour in some neonatal units. However, the randomised controlled trial published 31 showed no benefit in preventing systemic hypotension in neonates. In a study looking at its effect on oxygenation in neonates with severe persistent pulmonary hypotension there was a non significant trend shown towards improved blood pressure 32 , but there is no evidence to show efficacy in treating hypotension in neonates and its use would therefore be a consultant only decision.
Milrinone is an inotrope and vasodilator with little effect on heart rate. It works by reducing afterload and preload and increasing inotropy. There is a
Cochrane protocol registered to review its use in cardiac dysfunction 33 and we continue to await its publication.
V ASOPRESSIN AND ITS ANALOGUES
The neuropeptide hormone vasopressin and its analogues have been used to treat refractory hypotension in neonates 34 , however the recent Cochrane review shows there is insufficient evidence to recommend or refute the use of vasopressin or its analogues.
35
3.
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