Nottingham Neonatal Service Clinical Guidelines

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1 Title: MONITORING AND MANAGEMENT OF HYPOTENSION/ CARDIOVASCULAR SUPPORT IN NEONATES Version: 3 (Received and circulated July 2015) Date: Version 3: January 2015 Version 2: May 2006; Version 1: August 2003 Review Date: January 2018 Approval: Neonatal Guidelines Meeting May 2015 Author: Job Title: Reviewed by Consultation: Distribution: Risk Managed: Jane Gill, Stephen Wardle Neonatal ST 8 Trainee, Consultant Neonatologist Jane Gill Neonatal Policy Meetings Neonatal Unit Inadequate monitoring and treatment of low cardiac output increasing the risk of brain injury Clinical guidelines are guidelines only. The interpretation and application of clinical guidelines remain the responsibility of the individual clinician. If in doubt, contact a senior colleague. Caution is advised when using guidelines after a review date. This guideline has been registered with the Nottingham University Hospitals NHS Trust. This guideline will discuss management of preterm infants with a low systemic output during the first 72 hours after birth and the management of older infants with septic shock, surgical problems, persistent pulmonary hypertension and bleeding. Please ensure you are reviewing the section of the guideline for the correct patient group. For Summary of Treatment Regimens see Section 4.2 (preterm) and 5.7 plus appendix 2(term) Preterm Infants (less than 33+6 weeks gestation and less than 72 hours of age) 1. Background / Introduction A low mean arterial blood pressure (MABP) has been associated with mortality and morbidity in preterm infants including a 60% increased risk of IVH and a 40% increased risk of mortality [1]. However, there are no studies that have demonstrated that maintaining the blood pressure above certain limits has any effect on the long-term outcome [2,3,4]. This is partly because most studies that have looked at the effect of treatments for a low blood pressure have not reported longer-term outcomes. Some recent case control / cohort studies have suggested that tolerating a low mean arterial blood pressure in preterm babies without systemic disturbance 1

2 may avoid treatment and not have any disadvantages but there is no randomised data to support this [5]. Hypotension can be seen in the first 3 days after birth during the postnatal adaptation period, during which cardiovascular stability is established. Treatment has traditionally been aimed at improving the MABP to within reference ranges. The relative ease with which MABP can be monitored continuously has led to its widespread use as a measure of adequacy of the systemic circulation. The rationale for this is based on the assumption that MABP represents systemic blood flow and tissue oxygen delivery. Two main determinants of O 2 delivery are arterial O 2 concentration and systemic blood flow (SBF), which is difficult to measure. The Doppler measure of superior venacaval flow is low (to suggest low SBF to upper body and brain) in about 35% of babies born before 30 wks [6]. Direct measurements of flow may be better to direct treatment but at present these are not widely available. Thus, for example, SVC flow [7] may be a useful measurement of systemic output but it is not widely used and studies have demonstrated large intra- and inter observer variation with this measurement probably related to difficulties in assessing the diameter of the SVC [8]. Fractional shortening (FS), a measure of ventricular contractility, is affected by preload and afterload and is more accurate than ejection fraction, which tends to be used in adults. The reference range for FS in preterm babies measurement is 23-40% and 25-41% in term babies [9]. This gives information about left ventricular function but may not take into account the effects of a significant PDA causing a decrease in cardiac output or other reasons for poor tissue oxygen delivery. Nevertheless, measurements of cardiac output made by Doppler echocardiography have not only shown that MABP and cardiac output in ventilated preterm infants correlate poorly [10] but also that cerebral oxygenation may be independent of systemic BP [11]. However, blood pressure may be important to maintain adequate glomerular filtration. Causes of Hypotension: Hypotension in preterm babies may be due to cardiac dysfunction [9] but has several possible causes and it may not always be possible to define these in an individual. Causes / associations include: - Causes / Associations of Hypotension Sepsis Ductal and intra-atrial shunts [10,12,13] Cardiac dysfunction Poor venous return- high ventilator pressures Pneumothorax Adrenal insufficiency [14,15] Hypovolaemia (Rare) 2. Patient Group / Indications All ventilated infants should have routine monitoring of MABP and urine output. Nursing staff should record the blood pressure hourly and the urine output 8 hourly in this patient group. 2

3 3. Monitoring (See Neonatal Guideline G1 Insertion and Management of Umbilical and Peripheral Arterial Lines) In ventilated infants consideration should be given to the use of invasive blood pressure monitoring via a UAC or peripheral arterial line. Non-invasive measurements of blood pressure are unreliable, tend to be least accurate at low blood pressures and so should be interpreted with caution. [16] As invasive measurements are more accurate, particularly at low pressures, it is illogical to check an invasively measured low mean pressure using a non-invasive measurement. Always re-zero the arterial line before treating a low blood pressure It is important when using invasive blood pressure monitoring that the equipment is used correctly. Before intervening for a low pressure, therefore, always flush the line and re-zero it to ensure it has been correctly calibrated. If the value remains the same, and there is a good arterial waveform, then further assessment needs to be made. 3.1 Reference Ranges for Blood Pressure and Effects of Hypotension / Low Organ Perfusion A low blood pressure is often treated with the aim of maintaining / achieving adequate tissue oxygen delivery, however blood pressure does not correlate well with organ blood flow or tissue oxygenation. There is no doubt that low tissue oxygen delivery does occur in preterm infants and this may produce significant morbidity and mortality however identifying which infants will benefit from cardiovascular support is not always easy. Hypotension can be defined as the blood pressure value where vital organ function is affected. However this is difficult to define in preterm infants and is affected by factors such as gestation at birth, postnatal age, and pathogenesis of shock and illness severity. Cerebral Blood Flow and Auto regulation At normal blood pressures, when the blood pressure varies, there should not be any change in cerebral blood flow (CBF) i.e. there is no relationship between BP and CBF. [46] This is because of auto regulation, which occurs so that cerebral perfusion is maintained. Note CBF will vary with the ph (CO2) and with the haemoglobin concentration so these factors should also be taken into consideration. For example avoid high ph values (low CO2) when systemic blood flow may be compromised. [17] When the blood pressure is low then theoretically there will be a point at which auto regulation fails and the cerebral circulation becomes pressure passive i.e. CBF will vary with BP. At this point further falls in blood pressure may result in impaired tissue oxygenation and organ injury. The value of MABP at which this occurs is difficult to define but studies using near infra-red spectroscopy (NIRS) have shown that this may occur in some preterm infants at blood pressures above those normally treated [18] and it may improve with inotropes. [19] There are several published normal ranges for blood pressure in preterm infants and several definitions have been used. A blood pressure less than 30mmHg is known to be associated with cerebral injury. [2,20] Mean blood pressures less than the gestational age in weeks during the first three post-natal days roughly correlates with the 10 th centile for age in reference ranges. [21,22] This rule of thumb applies mainly in the first hours after birth after this time there is a gradual increases in the mean blood pressure so that most preterm infants have a mean 3

4 blood pressure above 30mmHg by day 3. [21] We acknowledge the ongoing research into treatment thresholds and await further results of these trials before changing this guidance. Importantly, these values are reference ranges and not normal values and there is no particular blood pressure below which treatment must be given. In addition, it is possible to have a blood pressure within the reference range but still have a low systemic output that requires treatment. As described below, the decision as to whether to treat or not should not be based on the blood pressure alone. A high blood pressure is usually due to pain / discomfort or other medications particularly dexamethasone treatment for chronic lung disease. If the MABP is persistently high despite adequate analgesia then see Hypertension Guideline E13 and discuss with the Consultant Neonatologist. 3.2 Assessment of Systemic Output In order to assess the need for support of a baby s cardiovascular system various parameters should be assessed in addition to the blood pressure. These are: - 1. Urine output Accurate recording of all urine output should be performed in all sick preterm babies, particularly when on inotropes. Urine output should generally be maintained above 1ml/kg/hour, although assessment of urine output using collection with cotton wool can sometimes be inaccurate. 2. Blood Lactate Concentration If there is significant tissue hypoxia, lactate will be produced. If the rate of production exceeds the rate of clearance then the blood lactate concentration will increase. The normal blood lactate concentration is below 2 mmol/l. Note that the base excess does not correlate with the blood lactate concentration and is generally unhelpful in this situation. Both blood lactate and urine output might reflect events that occurred over the previous few hours rather than the systemic output at any particular time point and must be interpreted in this context. 3. Peripheral perfusion This is very difficult to assess accurately however capillary refill time (CRT) may give a guide as to how well the skin is perfused. It should be assessed in the center of the chest not on a limb. [23] CRT is determined by applying minimal pressure (pressure needed to blanch skin) for 5 seconds, releasing and recording the number of seconds taken to restore perfusion. CRT may be affected by ambient temperature and there may be a large inter-observer variation. [23,24] 4. Cardiac Contractility Echocardiographic assessment, if possible, may be helpful in assessing cardiac contractility and in determining the cause of the low blood pressure and may help to direct treatment. 4

5 Summary Box 1: Is the baby clinically stable or unstable? Are other observations normal? Is there any acidosis? (What is the lactate?) Is skin perfusion normal? Is the urinary output normal? Consider the need for Echocardiography If lactate, perfusion and urine output are normal treatment is probably not needed 4. Theory of Management Treatment should be directed at the cause (see above). Volume and hypovolaemia Importantly, hypovolaemia is a rare cause of hypotension. To cause hypotension, in animal studies, a loss of 50% of circulating volume is required. Furthermore, when circulating blood volume is measured in preterm infants, there is no relationship between it and MABP. [25] A Cochrane review of use of early volume expansion versus inotropes has shown that dopamine is more successful in improving the low BP in hypotensive preterm infants. [26] There are many disadvantages to giving volume therapies and several of the causes of hypotension can be made worse by giving volume particularly in excess volumes. Therefore, volume therapies should only be given cautiously and sparingly in certain situations. Blood transfusion will improve systemic output and blood pressure in most circumstances. Not only does a transfusion increase venous return by increasing circulating volume, it also increases oxygen carrying capacity so that oxygen delivery should also be improved. If the haemoglobin concentration (Hb) is low a transfusion is, therefore, a very good way of treating a low systemic output to improve tissue oxygenation. Referencing the DO2 equation: Oxygen Delivery (DO2) = [(Oxygen bound to haemoglobin) + (Oxygen dissolved in plasma)] x cardiac output DO2 = [(1.39 x Hb x SaO 2 ) + (0.003 x PaO 2 )] x cardiac output Note that the amount of oxygen dissolved in plasma is small in comparison to that bound to haemoglobin so the haemoglobin concentration and the arterial oxygen saturation reflects blood oxygen content. However cardiac output may be difficult to assess in babies with an open ductus arteriosus. Of the possible inotropic drugs available traditionally dopamine and dobutamine have been used safely in preterm infants. Studies have compared the effects of dopamine and dobutamine on blood pressure. Studies up to 2003 are summarised in a Cochrane systematic review and meta-analysis. [27] More recent studies have also been published looking at morbidity and mortality with other agents. [28] Adrenaline has been less well studied however one study demonstrated an equivalent increase in heart rate and mean BP with adrenaline compared to Dopamine but the side effect profile of adrenaline needs to be considered. [29] There is 5

6 currently no evidence for the use of vasopressin in the preterm population. [30] Dopamine, a naturally occurring precursor of noradrenaline, may have specific dopaminergic actions in addition to well-recognized alpha and beta-adrenergic effects. [31] It is generally accepted that the inotropic and peripheral vasoconstrictor effects of dopamine predominate in the newborn period, although there is considerable controversy surrounding the existence of any vasodilator effects in renal, coronary and cerebral circulations. [32,33] There is some evidence that the vaso-constrictive effects may out-weigh the inotropic properties at higher doses and this increase in afterload may result in a decrease in cardiac output rather than an increase as the dose is increased. [34] Higher doses (above 10microgram /kg/hr) should therefore be avoided. Dobutamine is a synthetic catecholamine with principally beta-adrenergic actions. [31] It has been suggested that it may offer the same beneficial inotropic effects as dopamine without the tendency for peripheral vasoconstriction. The optimal dose of dopamine and dobutamine for the treatment of hypotensive preterm infants is uncertain. Pharmacokinetic studies have demonstrated wide variations in plasma concentrations between individuals for a given dose of dopamine or dobutamine. This is likely to be related to differences in plasma clearance rates that are independent of birthweight and gestational age. [31] In addition, there is a poor correlation between plasma dopamine or dobutamine concentration and blood pressure response. The Cochrane review of Dopamine vs. Dobutamine would suggest using dopamine as first line therapy based on the fact that it is more likely to result in an increase in blood pressure and if this fails the addition of Dobutamine The evidence that dopamine is more effective only extends as far as the short term effect on blood pressure and there is an argument that dobutamine may be more likely to increase systemic blood flow. [35] Therefore if there is a significant PDA present or if there is echo evidence of cardiac dysfunction the use of dobutamine before dopamine may be more logical. If inotropes fail to improve the systemic output / blood pressure, hydrocortisone can be considered as an additional treatment. There is some evidence that hypotensive infants may be relatively deficient in cortisol and hydrocortisone has been shown to be as effective at increasing blood pressure as dopamine. [36,37,38] However, the side effect profile of hydrocortisone means that it should always be used with caution. The risks of hyperglycemia, fungal infection and intestinal perforation are increased in hydrocortisone treated infants. Intestinal perforation is a particular risk in babies who are also being treated with Ibuprofen. 4.1 Treatment Regimen Before treatment for a low systemic output / low MABP is considered it is important to consider the cause and to adequately treat a pneumothorax / other obvious causes for low systemic output if these are present. If it is possible, an echocardiogram may be performed to assess cardiac contractility. In addition, consider treating a PDA, if present (see Neonatal Guideline E5 Ibuprofen). This intervention is unlikely to improve the systemic output rapidly, however, so other measures should also be used. 1. Give a blood transfusion if the haemoglobin is < 14g/dl (see Neonatal Guideline E1 Red Cell Transfusion in the Newborn). If a baby requires correction of a coagulation abnormality, then volume therapy in the form of FFP or cryoprecipitate may be indicated 6

7 but do not give volume or check clotting routinely. 2. Correct electrolyte imbalance (hypocalcaemia, hypomagnesaemia, hypophosphatemia, hypernatremia, hyperkalemia, hypoglycemia) if present as these may complicate cardiac function and inhibit the action of inotropic drugs. 3. If a central line is not already in situ, consider using dobutamine (up to 5 microgram/kg/min) peripherally whilst a central line is expediently sited. If a central line cannot be sited consider using Dobutamine /Dopamine through an umbilical arterial catheter following discussion with the Consultant Neonatologist on duty. 4. If inotropic drugs fail to improve the MABP /systemic output in certain preterm infants, then consider using hydrocortisone (36) following discussion with the Consultant Neonatologist on duty. If the blood pressure /systemic output improves, hydrocortisone should be discontinued at any stage. The combined use of hydrocortisone and ibuprofen may be associated with an increased risk of perforation, so their combination should be considered carefully before the addition of hydrocortisone. There is no evidence that anti-acid medications prevent this problem. It may useful to collect blood for a cortisol level (lithium heparin sample) before starting hydrocortisone, although circulating cortisol concentrations often fall within the normal range. Nevertheless, this may still reflect relative adrenal insufficiency in a stressed, sick preterm infant. [15] Given the current anxieties concerning the early postnatal use of steroid medication this should always be discussed with the Consultant Neonatologist on duty. When commencing inotropes start with the lowest dose (5 micrograms/kg/min) and gradually increase. There is often the temptation to start with a higher dose to try to get an immediate effect but this may result in rapid swings in blood pressure, which may be harmful. Advance the infusion as far along the IV line as possible so that there is not a long delay before the drug reaches the patient. 7

8 4.2 Algorithm for the treatment of Preterm Hypotension (<33+6 weeks, <72 hours of age) Try to identify cause of hypotension (exclude pneumothorax, excessive / high ventilator pressures). If possible perform echo to assess presence of PDA and cardiac contractility. If evidence of significant PDA or abnormal contractility consider using Dobutamine first followed by Dopamine. Start Dobutamine at 5mcg/kg/min and titrate dose according to response every minutes. Use Dobutamine up to a maximum dose of 20mcg/kg/min then add Dopamine. If no Echo images available or no clinical evidence of a significant PDA start Dopamine at 5 mcg/kg/min up to maximum 10 mcg/kg/min followed by Dobutamine initially at 5 mcg/kg/min up to a maximum of 20 mcg/kg/min When starting inotropes it is important to prime the line. See appendix 1 for line volumes. If remains hypotensive with evidence of impaired tissue perfusion (lactate, urine output, CRT) then consider hydrocortisone (discuss with consultant) If remains hypotensive with evidence of impaired tissue perfusion (lactate, urine output, CRT) then consider Adrenalin (discuss with consultant) Perform a cranial ultrasound scan as soon as is feasibly possible during the stabilisation process. Once blood pressure is stable for example >3 mmhg above the GA value for >30 minutes wean inotropes and monitor response of urine output, perfusion, lactate to any changes made. For weaning of hydrocortisone please see pharmacy information folder sheet for appropriate weaning regime. 5. Preterm infants after the first 72 hours of life and Term/ Late Preterm Infants (>33+6 weeks) 5.1 Background/ Introduction The aetiology of hypotension in this group is different to that of the preterm population and as such needs to manage according to the mechanism of the low mean blood pressure. The most 8

9 common causes of cardiovascular compromise are: Inappropriate vasoregulation resulting in vasodilatation or constriction for example septic shock or persistent pulmonary hypertension Dysfunction of the immature myocardium e.g. following a hypoxic insult Hypovolaemia e.g. secondary to fluid loss in a baby with gastroschisis preoperatively Treatment is being aimed at improving oxygen delivery to tissues by providing an adequate mean arterial blood pressure to do this. Echocardiographic assessment, as in the preterm population, can be used to guide targeted mean blood pressures and choice of inotrope Monitoring Blood Pressure Please see preterm recommendations for acceptable monitoring practice (section 3). 5.3 References ranges In the ex- premature group of babies it is reasonable to use a reference range of 30mmHg for the target of the mean blood pressure value. [2,20] For term babies (>33+6 weeks) a mean BP of 50mmHg [39] should be adequate to perfuse tissues but consider assessment of systemic perfusion and the estimate of pulmonary pressure findings from an echo if available. 5.4 Assessment of Systemic Output See Summary Box 1 It is good practice to document the commencement of inotropic support in the medical notes and to include the assessment of the baby s systemic perfusion as part of the rational behind the commencement of treatment. 5.5 Theory of management As with preterm babies there is little level A evidence available to guide treatment strategies for this group. There are case reports detailing the management of individual conditions and the use of specific therapies, for example the use of milrinone following cardiac surgery and in babies with persistent pulmonary hypertension. Management of septic term babies can be extrapolated from the PICU management strategies for example the widely recognized surviving sepsis document, 2012 [40], where the use of adrenaline and noradrenaline can be considered earlier than in the preterm population. 5.6 Treatment Regimen As with the preterm population immediately correctable causes of hypotension should be looked for and managed initially for example a tension pneumothorax or the use of high ventilator pressures causing cardiac compression. Transfusion with packed red cells in accordance with Red Cell transfusion guideline should be considered and correction of any coagulation abnormality with the appropriate blood product may also help improve mean blood pressure by providing additional intravascular volume but do not measure coagulation or give volume routinely. Correction of electrolyte abnormalities particularly ionized calcium of <1.0 measured on the blood gas may improve cardiac stability and enable inotropic drugs to function more effectively. [41] An echocardiographic assessment of cardiac function and pulmonary pressures may help guide 9

10 management strategy and define cause and should be performed if available. If central access is not available Dobutamine can be started peripherally at 5mcg/kg/min while central access is established. Hydrocrotisone has less of an evidence base in term infants than in the preterm. Term infants do not usually have an immature adrenal axis, nevertheless it may have some beneficial effects if inotropic treatment if not effective. If considering the use of hydrocortisone then checking the baseline serum cortisol is good practice. When following the treatment algorithm at the threshold point of consideration of addition of hydrocortisone the baby s care should be discussed with the on call Consultant Neonatologist. 5.7 Treatment Algorithms Identify the cause of hypotension in babies >33+6 weeks from birth or those preterm (<33+6) but now >72 hours of age Hypotension caused by sepsis See Table A Hypotension with suspected PPHN See Table B Hypotension caused by myocardial See Table C dysfunction e.g. in an hypoxic insult Hypotension caused by acute blood loss or hypovolaemia See Table D Hypotension post ductal surgery See Table E Tables in Appendix 2 At each stage of treatment reassess clinically as well as reviewing MABP. Only treat if there are clinical signs of impaired perfusion. Escalate treatment every 15-30minutes until response is seen. Once mean BP is > 33 mmhg in the ex premature population and >53 in the term population for a sustained period of 30 minutes consider weaning inotropic support as long as perfusion is maintained. Wean hydrocortisone as per the NUH pharmacopeia. 6. Audit Points Number of infants requiring inotropes Frequency and volume of volume expansion give to infants 7. Related Guidelines Neonatal Guideline G1 Insertion and Management of Umbilical and Peripheral Arterial Lines Neonatal Guideline E5 Management of PDA Neonatal Guideline B6 Management of PPHN this needs updating Neonatal Guideline E1 Red Cell Transfusion Neonatal Guideline E8 Neonatal Haemostasis and Thrombosis 10

11 Appendix 1 When starting inotropes the intravenous catheter needs to be primed with the inotrope of choice to avoid delay in the drug reaching the baby. This is of particular importance in the extremely low birth weight infants where infusion rates are low. The volume of lines commonly used on NICU is included for reference: Vygon Double lumen PUR Catheter Vygon 28G Premicath Vygon 24G ECC mm length Single lumen 2.7fr Broviac Line 0.26ml (Double lumen UVC) 0.07ml (Premi-cath longline) 0.12ml (Standard longline) 0.15ml (Surgically inserted) 11

12 Appendix 2 Treatment Algorithms for Term and Ex- preterm babies Table A Hypotension caused by sepsis Gestation at birth <33+6 weeks and >72 hours of age Assess presence of PDA (either clinically or with echo) Gestation at birth >33+6 weeks 0.9% Saline bolus 10ms/kg Duct present and clinically significant Dobutamine 5mcg/kg/min up to a maximum of 20mcg/kg/min Dopamine 5mcg/kg/min to a maximum of 10mcg/kg/min Hydrocortisone (see NICU pharmacopeia for dosing) Consider Adrenaline No evidence of PDA or not clinically significant Follow sepsis at >33+6 weeks gestation Reassess and consider further 10ml/kg Saline boluses Dopamine 5mcg/kg/min to a maximum of 10mcg/kg/min Hydrocortisone (see NICU pharmacopeia for dosing) Adrenaline mcg/kg/min and consider stopping/weaning dopamine Consider Noradrenaline 12

13 Table B Hypotension with Suspected PPHN Start Dobutamine 5mcg/kg/min to a maximum of 20mcg/kg/min Add Dopamine 5mcg/kg/min to a maximum of 10mcg/kg/min Add Hydrocortisone (see NICU pharmacopeia for dosing) Add Adrenaline mcg/kg/min Discuss with ECMO Centre Consider adding Milrinone and Vasopressin simultaneously Table C Hypotension caused by myocardial dysfunction e.g. in a hypoxic insult Start Dobutamine 5mcg/kg/min to a maximum of 20mcg/kg/min Add Dopamine 5mcg/kg/min up to a max of 10mcg/kg/min Add Hydrocortisone (see NICU Pharmacopeia for dosing) Adrenaline 0.1 to 0.5mcg/kg/min 13

14 Table D Hypotension caused by acute blood loss or hypovolaemia 0.9% Saline bolus 10mls/kg +/- 10mls/kg blood if/when available Consider further volume replacement and start Dobutamine 5mcg/kg/min to a maximum of 20mcg/kg/min If unresponsive consider other causes once fluid replaced 14

15 Table E Hypotension post ductal surgery Discuss with referring cardiac center e.g. Glenfield Consider Dopamine 5mcg/kg/min up to a max of 10mcg/kg/min Consider adding Milrinone 50-75mcg/kg IV administered over 15 minutes followed by a continuous infusion of 0.5mcg/kg/min Hydrocortisone (see NICU pharmacopeia for dosing) 15

16 Summary Box and Levels of Evidence Summary Always monitor ventilated babies with invasive arterial monitoring and measure urine output [42] Invasive monitoring is more accurate than non-invasive particularly at low a MABP [16] Do not use MABP alone to decide whether cardiovascular support is required [10] The MABP should be managed with the aim of maintaining it at or above the infant s gestational age in weeks [42] Dopamine is more effective than volume expansion at improving MABP [26,44] Dopamine is more effective than Dobutamine at increasing MABP [27] Hydrocortisone is as effective at increasing blood pressure as Dopamine [36, 37] Milrinone can be used to raise blood pressure following PDA ligation [43] Level of evidence C B C C A A A D 16

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19 33. Barrington KJ. Circulatory effects of dopamine in neonates. Journal of Pediatrics 1995; 127:843-4.Roze JC, Tohier C, Maingueneau C, et al. Response to dobutamine and dopamine in the hypotensive very preterm infant. Arch Dis Child. 1993;69: Osborn D, Evans N, Kluckow M: Random- ized trial of dobutamine versus dopamine in preterm infants with low systemic blood flow. J Pediatr 2002;140: Bourchier D, Weston PJ. Randomised trial of dopamine compared with hydrocotisone for the treatment of hypotensive very low birthweight infants. Arch Dis Child 1997; 76: Pak C Ng, C H Lee, Flora Liu bnur, Iris H S Chan. Double Blind Randomized Controlled study of a Stress Dose of Hydrocortisone for rescue treatment of refractory hypotension in preterm infants. Paediatrics 2006; 117: Istvan Seri, Rosemarie Tan, Jaquelyn Evans. Cardiovascular effects of hydrocortisone in preterm infants with pressor resistant hypotension. Paediatrics 2001; 107: Pejovic B, Peco-Antic A, Marinkovic-Eric J. Blood pressure in non-critically ill preterm and full-term neonates. Pediatr Nephrol 2007;22: Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: Crit Care Med. Feb 2013;41(2): Fink et al. Textbook of critical care th Ed Philidelphia Saunders Elsievier. Note 40 pg Report of a joint working group of the British Association of Perinatal Medicine and the Research Unit of the Royal College of Physicians. Development of audit measures for good practice in the management of neonatal respiratory distress syndrome. Arch dis Child 1992; 67: Sehgal A, et al. Use of milirinone in the management of haemodynamic instability following duct ligation. Eur J Pediatr (2011) 170: Gill AB, Weindling AM. Randomised controlled trial of plasma protein fraction vs dopamine in hypotensive very low birth weight infants. Arch dis child. 1993; 69: Paradisis M., Evans N., Kluckow M, Osborn D. Randomised trial of milrinone versus placebo for prevention of low systemic blood flow in very preterm infants. J Pediatrics Tyszczuk L, et al. Cerebral Blood Flow Is Independent of Mean Arterial Blood Pressure in Preterm Infants Undergoing Intensive Care. Pediatrics 1998; 102(2):