HYPOTENSION © 2009 SNL All rights reserved

Inotropes in term neonates

Systemic is common in infants requiring intensive care. This article covers the pathophysiology of this condition and the importance of treating it. The article outlines management plans for the rational use of in these hypotensive newborns and suggests which further options are available in refractory cases.

Kiran Patwardhan etween one third to a half of all babies preloading of the left ventricle thereby MBBS, DCH, DNB, MRCP, FRCPCH Badmitted for neonatal intensive care increasing left ventricular output. If Paediatric Intensive Care Unit, Royal become hypotensive within 24 hours of complications occur during this transition, Hospital for Sick Children, Edinburgh admission. This systemic hypotension is a may be affected. [email protected] relatively common complication of preterm birth but also affect full term sick Blood pressure measurement neonates with a range of medical and Direct, invasive measurement obtained surgical conditions. Increasingly, more from a well-positioned, unobstructed intra- neonates are admitted to the paediatric arterial catheter is the gold standard. Mean intensive care unit peri-operatively needing blood pressure is minimally affected by the circulatory support. This article is written mechanical properties of the intra-arterial from the perspective of a paediatric catheter and the transducer system, micro intensivist, who often faces the challenge of air bubbles and site (central versus treating low blood pressure in the face of peripheral)2. If direct measurements are not poor evidence to support any treatment available, a Doppler probe with an approp- options. It will review the use of vasoactive riate sized cuff gives a similar degree of drugs in hypotensive newborn infants and accuracy, although it tends to overestimate suggest what further options may be the blood pressure in the hypotensive available in refractory cases. ranges. It would appear that oscillometric Circulatory adaptation at birth systems are inaccurate when the systolic blood pressure is less than 40mmHg. The time immediately after birth is a critical period for the newborn, as Definition of hypotension transition is made from fetal to neonatal A number of studies have looked at the life. This transition is a complex multi- blood pressure ranges in the newborns.2-5 organ system process1. The ability to make Perhaps the best data on normal values can Keywords these adjustments may be more difficult be found in a study done in the northern for a premature infant. Fetal circulation is newborn; blood pressure; inotropes; region in the UK. After four hours and characterised by a low systemic vascular hypotension before 24 hours of age, the systolic blood resistance due to the presence of a low pressure should not be lower than the Key points resistance placental vascular bed. In gestational age in weeks. The commonly contrast, the pulmonary vascular resistance Patwardhan K. Inotropes in neonates. cited ‘rule of thumb’ defines hypotension is high, allowing only 6-12% of the cardiac Infant 2009; 5(1): 12-17. as mean blood pressure below an infants’ 1. Systemic hypotension is a common output to travel to the lungs. After birth, gestational age in weeks6. However it must complication in infants on the with contraction of the umbilical arteries be stressed that blood pressure alone paediatric intensive care unit and and separation from the placenta, systemic remains an unreliable measure of either requires an individualised approach. vascular resistance rises rapidly. Pulmonary 2. Treatment is unnecessary for those who vascular resistance falls progressively as cardiac output or of systemic oxygen have adequate and no signs lungs expand. The ductus arteriosus shunts delivery (see below) and should not be of . blood predominantly from right to left in treated in isolation. 3. Although most term newborns will utero, but changes to shunt predominantly Physiology of blood pressure respond to standard treatment, several from left to right after birth, as a result of other options are available to treat the the changes in systemic and pulmonary regulation refractory cases. vascular resistance. Pulmonary blood flow Blood pressure is the product of cardiac 4. Clinical assessment and supportive increases resulting in increased pulmonary output and systemic vascular resistance. measures are equally important. venous return. This increases the Cardiac output is the product of heart rate

12 VOLUME 5 ISSUE 1 2009 infant HYPOTENSION

primary cause of neonatal hypotension in I. HYPOVOLAEMIA Preload Contractility Afterload a full term neonate with a medical or • Massive pulmonary haemorrhage surgical problem13. If there is an • Acute surgical emergencies identifiable volume loss, ideally the same Heart rate Stroke • Intracranial/subgaleal haemorrhage kind of fluid should be replaced. For volume • Disseminated intravascular example, in cases of blood loss, blood coagulation transfusion should be given. If Cardiac Systemic vascular • Dehydration: insensible water occurs secondary to disseminated output resistance losses/polyuria intravascular coagulation, fresh frozen • Third space losses, e.g. sepsis due to plasma, cryoprecipitate or platelet rich necrotising enterocolitis Blood pressure plasma should be used. This serves a dual • Decreased venous return purpose of treatment of the underlying TABLE 1 Physiology of blood pressure7. – Air leak syndromes problem and as volume replacement. In – High positive end expiratory cases of greater transepidermal water losses and . Stroke volume is pressure (PEEP)/high frequency or polyuria, administration of with dependent on the amount of blood oscillation more free water is indicated. returning to the heart (preload), strength II. CARDIOGENIC SHOCK If the cause of hypovolaemia or of hypo- of myocardial contractility (the pump) and • Birth asphyxia tension is unclear, isotonic saline should be the resistance against which the heart must used. A bolus of 10mL/kg (5mL/kg in case • Congenital heart disease pump (after load). Newborns have a of perioperative cardiac newborn) over 20- – Duct dependant lesions with limited ability to increase the stroke 30 minutes may bring about a sustained closure of the duct volume. Hence, neonatal cardiac output is increase in blood pressure. In such a case a more dependent on heart rate. – Total anomalous pulmonary venous connection further bolus can be repeated, if necessary. The strength of myocardial contractility However, if the central venous pressure • Postoperative cardiac surgery depends on the filling volume and pressure, (CVP) increases without appreciable • Cardiomyopathy as well as on the maturity and integrity of increase in blood pressure, hypovolaemia is the myocardium. Thus hypovolaemia, • Myocarditis unlikely. In such a situation treatment with arrhythmias, extreme prematurity, , • Arrhythmias an is indicated. The rationale for acidosis, electrolyte imbalances (especially III. SEPTIC SHOCK administration of an inotrope to a hypocalcaemia) and infections will affect hypotensive newborn unresponsive to the myocardial contractility, which may IV. ENDOCRINE volume therapy is to increase systemic lead to a fall in cardiac output. If systemic • Adrenal haemorrhage perfusion pressure, and thereby systemic vascular resistance (after load) is too high, • Congenital adrenal hyperplasia blood flow and oxygen delivery. the ability of the myocardium to pump against the increased resistance may V. DRUGS: Sedation on the ICU Inotropes become compromised and the cardiac TABLE 2 Causes of neonatal hypotension8. Drugs that improve myocardial output will fall. contractility are called inotropes. They In the clinical settings, it is difficult to increase the peak force of contraction Significance of hypotension in sick assess the adequacy of blood flow to the under isometric conditions. Drugs that neonates organs as it depends (among other things) increase the heart rate are called Systemic hypotension may reduce the on cardiac output and end organ vascular chronotropes. Generally, they accelerate blood flow to the vital organs and make resistance. Therefore, blood pressure is the heart and may also have inotropic them vulnerable to ischaemic injury. used as an indirect measure of perfusion. properties. The action of these drugs on Hypotension is independently associated When the oxygen delivery to the tissues is the myocardium can be due to an effect on with adverse neurodevelopmental compromised, shock ensues. Shock the calcium transit (up-stream outcome9. In addition, the duration and remains a major cause of neonatal regulation)14 or on the sensitivity of the severity of hypotension may be morbidity and mortality. contractile proteins to calcium (down- important10,11. In a recent article, stream regulation). No inotrope currently Barrington12 has emphasised the concept of Treatment of hypotension used in clinical practice increases the force ‘permissive hypotension’. Treatment of The most common pathological factors for of contraction by a direct effect on the systemic hypotension in infants with good neonatal hypotension are: myofibrils. A group of drugs known as perfusion and no signs of shock is probably 1. Inappropriate peripheral vasoregulation calcium sensitizers is currently under unnecessary and could be potentially resulting in vasoconstriction (usually investigation. Certain drugs (calcium harmful. Assessment of adequate perfusion first 24 hours after birth) or vasodilata- antagonists) have the property of can be very difficult and the intensivist tion (usually day 2 onwards). inhibiting calcium transit and thus cause a must use clinical judgement to decide 2. Dysfunction of the immature fall in contractility, relaxation of muscles when to treat. However, in sick neonates myocardium. and reduced conduction in sinoatrial and with systemic hypotension and signs of atrioventricular nodes. These are negative shock, it is important to treat the low Volume replacement inotropes. This article will concentrate on blood pressure. Absolute hypovolaemia may be the positive inotropes. infant VOLUME 5 ISSUE 1 2009 13 HYPOTENSION

15 Classification of inotropes I Does not increase myocardial oxygen I Ensure adequacy of ventricular filling Inotropes can be classified into three major demand I Administer inotropes through accurate groups depending on their mode of action. I Does not change heart rate infusion devices Class I drugs increase intracellular calcium; I Does not cause vasoconstriction I Use a dedicated lumen of a central line class II drugs increase sensitivity of I Redistributes blood flow to vital organs or PICC line. Single strength actomyosin to calcium ions, whereas class dobutamine can be infused peripherally. I Direct acting (does not rely on release of III drugs act through metabolic or I endogenous amines) Never flush the infusion line. endocrine pathways. Some drugs will have I Infusions should be written as per the I Demonstrates lusitropy (see text) multiple modes of action and belong to unit protocols and should be changed I Predictable and easily titrable more than one class. Characteristics of an regularly (at least every 24 hours). ideal inotrope (TABLE 3), commonly used I Lacks tolerance Changeover of the new syringe should inotropes in neonates (TABLE 4) and I Compatible with other vasoactive be according to the unit policy. general rules and precautions during ino- substances I Check compatibilities with other drugs tropes administration are listed (TABLE 5). I Energy neutral, energy sparing or being given simultaneously. inoprotective I Use inotropes for short term circulatory Inotropes support, but weaning should be a slow TABLE 3 Characteristics of an ideal inotrope. Adrenergic receptors fall into three process. categories: α-adrenergic, β-adrenergic and Dopamine I Extravasations may produce extensive dopaminergic (DA) receptors (TABLE 6). Dopamine is a naturally occurring catecho- tissue necrosis. Follow unit policy for Nearly all inotropes in clinical use are lamine precursor of noradrenaline. It was management. cleared by first order kinetics. Therefore, first synthesised in 1910 and shown to be a I When infusion rates of stronger agents changes in infusion rate linearly correlate neuro hormone in 1959. As it possesses fall below 0.5mL/hr, tiny boluses can to plasma concentrations, making them inotropic and vasopressor properties, it is cause massive pressure changes. Consider half strength solutions. practical to titrate to clinical effect. Due to often referred to as an inovasopressor16. Its I their rapid metabolism (liver), these actions are dose-dependent (see TABLE 4) on If the inotrope appears to be ineffective, check delivery apparatus. Make up new inotropes have short half lives (in dopaminergic, α and β adrenergic recep- infusion. minutes). Hence, these agents should be tors. It also exerts independent renal and administered as continuous infusions. endocrine effects17. Dopamine affects all TABLE 5 Administration of inotropes. However, the phosphodiesterase inhibitors three major determinants of cardiovascular citance, it augments preload. It increases are cleared by the kidney and have longer function (preload, myocardial contractility myocardial contractility and systemic half-lives. and after load). By decreasing venous capa- vascular resistance by direct stimulation of

Drug Site of action (predominant Dose range Haemodynamic effects receptors) (micrograms/kg/min) Dopamine Dopaminergic (1 & 2) 1-4 Renal and mesenteric vasodilatation α adrenergic 4-10 Inotrope β adrenergic 11-20 Vasopressor, ↑SVR, ↑PVR β β ↓ ↑ Dobutamine 1 & 2 adrenergic 5-20 Inotrope, SVR, CO minor α adrenergic effect α ↓ Adrenaline 1 adrenergic 0.03-0.1 Inotrope, some SVR β β ↑ (Epinephrine) 1 & 2 adrenergic 0.1-1.0 Vasopressor, SVR α α ↑↑ Noradrenaline 1 & 2 adrenergic 0.1-1.0 Vasopressor, SVR (Norepinephrine) Dopexamine β adrenergic 1-6 Inotrope ↓SVR ↑splanchnic blood flow? ↑↑ Vasopressin V1 0.0003-0.002 units/kg/min SVR (No inotropic effect) or 0.018-0.12 units/kg/hr Milrinone Phosphodiesterase Inodilator, lusitropy Inhibitor Bolus 50-75 µg/kg β ↑ ↓ Produces effects at 1 Infusion 0.35-0.75 contractility and SVR β & 2 receptors Methylene blue Inhibition of cGMP/nitric IV infusion of 1mg/kg Vasopressor, ↑SVR oxide pathway over one hour Hydrocortisone Enhanced sensitivity to Surgical stress 10mg/kg/day Uncertain – effects of circulating catecholamines Acute profound shock 50mg/kg/day circulating catecholamines KEY: SVR – Systemic Vascular Resistance; PVR – Pulmonary Vascular Resistance; CO – cardiac output TABLE 4 Drugs used in the management of neonatal hypotension.

14 VOLUME 5 ISSUE 1 2009 infant HYPOTENSION α β and receptors. Approximately 50% of Receptor Action on circulation these effects are secondary to peripheral α Vasoconstriction (increase in contractility) conversion to noradrenaline. 1 α In dopaminergic doses, it increases renal 2 Vasoconstriction (presynaptic sympathetic inhibition) β blood flow and glomerular filtration rate, 1 Increase in heart rate (sinus node) increases sodium, phosphorous and free Increase in contractility (atrium and ventricle) water excretion. It may increase bicarb- onate losses. By reversibly inhibiting renal Increase in conduction (atrioventricular node) + + β Na , K -ATPase activity, dopamine may 2 Vasodilatation (bronchodilatation) increase the hypoxic threshold of renal Dopaminergic 1 Renal and mesenteric vasodilatation tubular cells during episodes of Dopaminergic 2 Vasodilatation hypoperfusion and hypoxaemia. Its endocrine actions include decrease in TABLE 6 Adrenergic receptor subtypes 14. plasma prolactin and thyrotropin levels. There can be a significant inter-and intra- belief, if dopamine is being ineffective in of the ventricles (‘lusitropy’). It increases individual variability in the dose of maintaining blood pressure at higher doses pulmonary artery blood flow. Milrinone dopamine required to elicit the above (≥15µg/kg/min), adrenaline should be has an inotropy:vasodilatation ratio of effects. Lack of response may suggest added and dopamine slowly withdrawn. A 1:20. When used in combination with β vasopressin exhaustion18. In severe illness, ‘rule of thumb’ is if systolic pressure is low, agonists, milrinone has an additive effect. the response to dopamine may be use adrenaline; if diastolic pressure is low, Thus it is often administered as part of diminished due to adrenergic receptor use noradrenaline. combination therapy with adrenaline and down regulation, adrenal insufficiency and noradrenaline. effects of locally produced vasodilators. Side effects Milrinone is primarily bound to plasma Clinically important side effects include proteins (~75%) and excreted through the Dobutamine tachycardia, arrhythmias, worsening of kidneys. It has a long half-life. Due to the Dobutamine hydrochloride is a cardio V/Q mismatch, increased systemic and large volume of distribution, a loading selective synthetic analogue of pulmonary vascular resistance (except dose should be used. In a recent random- isoprenaline, developed in 1973. It dobutamine) and hyperglycaemia ised controlled trial, milrinone did not β possesses both inotropic ( 1 adrenergic (adrenaline). prevent low systemic blood flow during the β 21 stimulation) and chronotropic ( 2 first 24 hours in very preterm infants . adrenergic stimulation) properties. It has Dopexamine no dopaminergic activity. It increases Dopexamine is a synthetic catecholamine Steroids β cardiac output by increasing myocardial with strong 2 activity and less pronounced The sick neonate may suffer from relative β α 22 contractility and the stroke volume and 1, and dopaminergic activity. It is a or absolute adrenocortical insufficiency . causes peripheral vasodilatation. Thus, it is positive inotrope increasing cardiac output Glucocorticoids are involved in regulating a preferred agent for infants with poor by decreasing systemic and pulmonary the expression of cardiovascular adrenergic cardiac output, myocardial dysfunction vascular resistance. There may be some gut receptors. Sick neonates may be unable to and increased systemic vascular resistance protective effect either by increased splan- produce adequate amounts of endogenous as seen in perinatal asphyxia. chnic blood flow or redistribution of gut glucocorticoids to maintain cardiovascular flow to the mucosa (the main site of functional integrity. As a consequence Adrenaline and noradrenaline oxygen use in the gut). It may have a role in there is a down regulation of adrenergic Adrenaline is an endogenous catecholamine acute surgical conditions in the neonate19, 20. receptors and cardiovascular desensiti- with direct α and β adrenergic actions, and sation to sympathomimetics. This results is released from the adrenal medulla in Phosphodiesterase inhibitors/milrinone in vasopressor resistance. Steroids help response to stress. At low doses, it increases The phosphodiesterase (PDE) inhibitors maintain cardiovascular homeostasis by myocardial contractility and peripheral are a class of drugs called bibyridines that several other mechanisms23. β β vasodilatation ( 1 and 2 effects). At higher mediate both inotropy and vasodilatation Interestingly, adrenal insufficiency can doses, stimulation of α receptors causes and hence are often referred to as inodil- present with low cardiac output and high peripheral vasoconstriction and increased ators. These agents mediate their effect by systemic vascular resistance or high cardiac systemic vascular resistance. preventing hydrolysis of cAMP (type III output and low systemic vascular Noradrenaline is a catecholamine PDE inhibitors e.g. milrinone, enoximone, resistance. As hydrocortisone has both neurotransmitter released from peripheral amrinone) or cGMP (type V PDE glucocorticoid and mineralocorticoid adrenergic nerve endings. It is a potent inhibitors, e.g. sildenafil, dipyridamole). effects, it is recommended to treat adrenal vasopressor increasing heart rate, Milrinone was first developed in 1981. It insufficiency. myocardial contractility and systemic increases the cAMP concentrations that β vascular resistance. Lack of 2 effects improve myocardial contractility and also Calcium distinguishes it from adrenaline. decreases systemic and pulmonary vascular The pathophysiology of myocardial Dopamine and adrenaline have similar α resistance resulting in decreased ventricular dysfunction includes decreased and β agonist activities, adrenaline being afterload. Unique to this class of agents, intracellular calcium. Ionised more potent. Hence contrary to popular milrinone also aids in diastolic relaxation hypocalcaemia occurs due to parathyroid infant VOLUME 5 ISSUE 1 2009 15 HYPOTENSION ischaemia. Calcium is a vasoconstrictor oxide occurs through the activation of monitoring parameters are available to and increases systemic vascular resistance soluble guanylate cyclase and production help achieve this. and ventricular contraction even when the of cyclic guanosine monophosphate. ionised calcium level is normal. Calcium Methylene blue inhibits this activation27. Respiratory support does not increase myocardial oxygen A dose of 1mg/kg over an hour has been Optimise the respiratory support to reduce demand. However, calcium is the final used. the work of breathing. Avoid hypoxia and pathway to cell death and is important in hypocarbia. High mean airway pressure reperfusion injury. Therefore in PICU Tri-iodothyronine and PEEP will increase intra-thoracic and calcium is only used as an inotrope if Tri-iodothyronine is an effective inotrope, intra-alveolar pressure and so hinder hypocalcaemia is present, to counteract the which has been used to preserve cardiac cardiac filling, resist pulmonary and effects of raised potassium (following function. A recent randomised controlled capillary blood flow and reduce cardiac cardio-pulmonary bypass) or in emergency trial in neonates showed that use of tri- output. Treat air leaks (e.g. pneumothorax) as a temporary measure. iodothyronine, as a post cardiac surgery promptly. Optimise the use of analgesics The disadvantages of using calcium are inotrope, improved outcomes28,29. and sedatives (e.g. fentanyl and that the effect is short lived (20-30 minutes) midazolam), which improve patient and continuous infusion cannot be used. Naloxone synchrony but can drop blood pressure. Naloxone has been reported anecdotally to Procedures like suctioning of the airway, Vasopressin lead to haemodynamic recovery in installation of surfactant and routine Vasopressin is a naturally occurring neonates30. Naloxone is a potent pure nursing care can affect blood pressure. hormone produced by the posterior opioid antagonist. In severe septic shock Inadvertent movement of head/neck over pituitary. There are three types of there is release of the body’s own the body can increase systemic vascular 32 vasopressin receptors: the V1 receptors are endogenous opioids (β endorphins), which resistance and drop cardiac output . expressed in vascular smooth muscles, with can reduce blood pressure and cardiac Therefore the policy ‘minimum handling’

V1a being present in all vessels, while V1b output. Naloxone counteracts this effect. A should be adopted. are confined to the pituitary gland. The V2 bolus dose at 0.1 to 0.3mg/kg has been receptors mediate renal effects. tried31. However; the effect on concurrent Cardiac shunts The proposed mechanism(s) of action are: opiod administration (e.g. morphine/ Intra-cardiac (persistent foramina ovale) I release of calcium from sarcoplasmic fentanyl for analgesia) and precipitation of and extra cardiac (patent ductus arteriosus reticulum ‘withdrawal symptoms’ should be borne in [PDA]) shunts can significantly affect I potentiation of vasoconstrictive effects of mind. ventricular output. A significant PDA noradrenaline should be treated after consultation with a I inactivation of ATP-gated potassium Levosimendan paediatric cardiologist. channels This class II drug has multiple actions. It I inhibition of nitric oxide and atrial increases myofilament calcium sensitivity, Intensive care monitoring natriuretic peptide-induced cGMP improves diastolic relaxation, causes parameters production. vasodilatation, and does not increase When looking at the monitoring In shock, after initial elevation, serum myocardial oxygen consumption. At higher parameters, it is vital to look at the trends. vasopressin levels drop due to depletion of doses, it has a phosphodiesterase inhibitor stores24. In this situation, a modest dose of effect. It is unaffected by the down Heart rate vasopressin can usually resensitise the regulation of β adrenergic receptors. It has Tachycardia may have a number of causes vessels to catecholamine (noradrenaline) a short half life (approximately one hour) but can be a sign of hypovolaemia. raising blood pressure25. and is completely metabolised. Infusions of Tachycardia may give insufficient time for 0.1-0.4 µg/kg/minute with a preceding effective diastolic ventricular filling. Terlipressin bolus (6-24 µg/kg) have been used. Clearly Similarly, sinus bradycardia will reduce Terlipressin is a synthetic analogue of this drug has a huge potential but there are cardiac output, as the immature heart has vasopressin with a long half-life. It has a no studies in neonates to confirm this. only a limited ability to increase stroke higher V1a/V2 receptor ratio and hence is volume. Non-sinus arrhythmias may more efficient than vasopressin for Supporting measures impair ventricular filling reducing cardiac vasoconstriction26. Despite the availability of sophisticated output. A 12-lead ECG will help determine cardiovascular monitoring an intensivist the rhythm. Other agents obtains much information helpful for the Several other agents have been used as assessment of cardiovascular status from CVP rescue therapy. These are not inotropes, careful and frequent observation and A reliable CVP <3 indicates hypovolaemia but by their actions, have an effect on examination of the patient. Therefore, the and is likely to respond to fluid bolus33. myocardial contractility and systemic most important principle should be Serial measurements of mixed venous vascular resistance. Controlled trials are reassess, reassess, reassess. This is especially saturations (normally >70%) can give an needed to evaluate their usefulness. true if escalation of treatment is required. idea of tissue oxygen delivery, severity of This should, ideally be, supported by 2D shock and response to treatment34. Methylene blue echocardiography. A number of clinical, Measurements of the arterial to venous

In septic shock, excess synthesis of nitric haematological, biochemical and oxygen content difference (AVDO2) can

16 VOLUME 5 ISSUE 1 2009 infant HYPOTENSION further help in assessing the adequacy of Conclusion 17. Seri I. Circulatory support of the sick preterm infant. Semin Neonatol 2001; 6: 85-95. cardiac output. Normal values are less than In summary, sustained stabilisation of the 5mL O /100mL blood; values more than 18. Neonatal Formulary 4. BMJ. 2003. 2 neonatal blood pressure is a difficult task 19. Booker P.D., Pozzi M. A placebo-controlled study of 25 suggest reduced cardiac output. that requires an individualised approach. the effects of dopexamine on gastric mucosal perfusion in infants undergoing hypothermic Urine output In a normovolaemic newborn resistant to catecholamine, several other options are cardiopulmonary bypass. Br J Anaesth 2000; 84: 23- 27. Normally more than 20% of cardiac available to treat hypotension. Prospective, output goes to the kidneys. Hence oliguria 20. Kawczynski P., Piotrowski A. Circulatory and diuretic randomised controlled trials are urgently effects of dopexamine infusion in low birthweight (urine output <1mL/kg/hour) is an early required to assess whether any of these infants with respiratory failure. Interns Care Med sign of low cardiac output, reflecting interventions improve clinical outcomes. 1996; 22: 65-70. impaired renal perfusion. 21. Paradisis M., Evans N., Kluckow M., Osborn D. Acknowledgements Randomised trial of milrinone versus placebo for Perfusion prevention of low systemic blood flow in very The author would like to thank Dr Sam A prolonged capillary refill time (>3-5 preterm infants. J Pediatrics 2008. Richmond for his useful comments. 22. Ng P.C., Lam C.W., Fok T.F. et al. Refractory seconds) or a widened central-peripheral hypotension in preterm infants with adrenocortical temperature gap suggests hypoperfusion. References insufficiency. Arch Dis Child Fetal Neonatal Ed. 2001; However, ultrasound and near infrared 84: F122-24. 1. Leone T.A., Finer N.N. Fetal adaptation at birth. 23. Seri I, Tan R, Evans J. Cardiovascular effects of spectroscopy data have shown that many Current Paediatrics 2006; 16(6): 373-78. hydrocortisone in preterm infants with pressor- of these parameters are relatively poor 2. Nuntnarumit P., Yang W., Bada-Ellezey H.S. Blood resistant hypotension. Pediatrics 2001; 107: indicators of acute changes in organ blood pressure measurements in the newborn. Clin 1070-74. 35 Perinatol 1999; 26:981-96. flow in the sick neonate . 24. Landry D.W., Oliver J.A. The pathogenesis of 3. Watkins A.M., West C.R., Cooke R.W. Blood pressure vasodilatory shock (Review). New Engl J Med 2001; and cerebral haemorrhage and in very low Haematology 345: 588-95. birth weight infants. Early Hum Dev 1989; 19: 103- 25. Meyer S., Gortner L., McGuire W. et al. Vasopressin Anaemia commonly compounds the 10. in catecholamine-refractory shock in children. problem of hypotension. Transfusion with 4. Zubrow A.B., Hulman S., Kushner H., Falkner B. Anaesthesia 2008; 63 (3): 228-34. Determinants of blood pressure in infants admitted adult haemoglobin shifts the oxygen 26. Leone M, Martin C. Role of terlipressin in the to neonatal intensive care unit: a prospective dissociation curve to the right, makes more treatment of infants and neonates with multicenter study. J Perinatol 1995; 15: 470-79. oxygen available to the tissue mitochondria catecholamine-resistant septic shock. Clinical 5. Northern Neonatal Nursing Initiative. Systolic blood due to higher haemoglobin content and Anaesth 2008; 22(2): 323-33. pressure in babies of less than 32 weeks’ gestation also acts as a fluid bolus. 27. Driscoll W, Thurin S, Carrion V et al. Effect of in the first year of life. Arch Dis Child Fetal Neonatal methylene blue on refractory neonatal hypotension. Ed 1999; 80: F38-F42. J Pediatr 1996; 129: 904-08. Biochemical markers 6. Report of the Second Working Group of the British 28. Bettendorf M, Schmidt K G., Grulich-Henn J. et al. Persistent and a rising Association of Perinatal Medicine. Guidelines for Tri-iodothyronine treatment in children after cardiac lactate (>2.5 mmol/L) on an arterial blood good practice in the management of neonatal surgery: a double-blind, randomised, placebo- respiratory distress syndrome. British Association of gas suggest hypoperfusion and anaerobic controlled study. Lancet 2000; 356(9229): 529-34. Perinatal Medicine. 1998. 29. Dimmick S., Badawi N., Randell T. Thyroid hormone metabolism. Unfortunately, again, the 7. Oski’s Pediatrics: Principles and Practice. 3rd Ed. supplementation for prevention of morbidity and 36 correlation is poor . Arterial pH less than Lippincott Williams & Wilkins. 1999; 453: 2192-95. mortality in infants undergoing cardiac surgery. 7.25 compromises myocardial function 8. Fanaroff J.M., Fanaroff A.A. Blood pressure disorders Cochrane Database Syst Rev 2004; (3): CD 004220. and causes catecholamine unrespon- in the neonate: Hypotension and . 30. Furman W.L., Menke J.A., Barson W.J. et al. siveness. Administration of small doses of Semin Fetal Neonatal Med 2006; 11(3): 174-81. Continuous naloxone infusion in two neonates with 9. Low J.A., Froese A.B., Galbrath R.S. et al. The sodium bicarbonate to raise arterial pH septic shock. J Pediatr 1984; 105: 649-51. association between preterm newborn hypotension 31. Boeuf B., Poirier V., Gauvin F. et al. Naloxone for above 7.25 and anion gap less than 16 and hypoxemia and outcome during the first year. shock. Cochrane Database Systematic Rev 2003; should be carried out. Among others, an Acta Paediatr 1993; 82: 433-37. Issue 3. Art. No: CD004443. important side effect is hypercarbia which 10. Goldstein R.F., Thompson R.J., Oehler et al. 32. Andrásyová D., Kellerová E. Blood pressure and will need adjustment in minute ventilation. Influence of acidosis, hypoxemia and hypotension heart rate response to head-up position in full-term on neurodevelopmental outcome in very low birth Hypocalcaemia (see above) and newborns. Early Human Dev 1996; 44(3): 169-78. weight infants. Paediatrics 1995; 95: 238-43. 33. Skinner J.R., Milligan D.W.A., Hunter S. et al. Central hypophosphataemia (shifts oxygen 11. Mattia F.R., deRegnier R.A. Chronic physiologic venous pressure in ventilated neonates. Arch Dis dissociation curve to left) must be corrected. instability is associated with neurodevelopmental Child 1992; 67; 374-77. Hyperglycaemia can occur secondary to morbidity at one and two years in extremely 34. O’Connor T.A., Hart R.T. Mixed venous oxygenation stress, sepsis, TPN, steroids and inotropes premature infants. Paediatrics 1998; 102: e35. in critically ill neonates. Crit Care Med 1994; 22: (especially adrenaline therapy). It may 12. Barrington K.J. Hypotension and shock in preterm 343-46. infant. Semin Fetal Neonatal Med 2008; 13(1): 16- induce osmotic diuresis and deplete 35. Osborn D A, Evans N, Kluckow M. Clinical detection 23. of low upper body flow in very premature infants intravascular volume. This should be 13. Evans N. Volume expansion during neonatal using blood pressure, capillary refill time, and treated with insulin. A combination of intensive care: do we know what we are doing? central- peripheral temperature difference. Arch Dis glucose and insulin has a further advantage Semin Neonatol 2003; 8(4): 315-23. Child Fetal Neonatal Ed 2004; 89: F168-73. of acting like an inotrope37. Addressing 14. Oxford Textbook of Medicine. 3rd Ed. Oxford 36. Deshpande SA, Platt MP. Association between blood these small issues helps to further stabilise University Press 1996; Volume II: pp 2150 & 2253. lactate and acid-base status and mortality in 15. Elliott P. Rationale use of inotropes. Anaesth ventilated babies. Arch Dis Child 1997; 76: F15-20. the blood pressure. However, the most Intensive Care Med (e) 2006; 7(9): 326-30. 37. Hamdulay SS, Al-Khafaji A, Montgomery H. important principle still remains to 16. Pediatric Critical Care Medicine – Basic Science and Glucose-insulin and potassium infusions in septic reassess at every step. Clinical Evidence. 2007; 26: 289-94. shock. Chest 2006; 129: 800-04. infant VOLUME 5 ISSUE 1 2009 17