REVIEW URRENT C OPINION
Intraoperative hypotension in neonates: when and how should we intervene? Nigel McBeth Turner
Purpose of review Organ hypoperfusion remains an important cause of postoperative morbidity in neonates. Blood pressure (BP) is frequently mistakenly used as a surrogate of organ perfusion and the predictive value of BP for outcome is unclear. The current article will focus on the role of BP in the optimization of organ perfusion during anaesthesia in neonates. Recent findings Population studies show a range of normal values for BP in neonates and there is no consensus on the definition of hypotension in neonates undergoing anaesthesia. The relationship between BP and outcome is unclear. Unnecessary treatment of low BP in neonates can be harmful. A theoretical approach to the definition of hypotension and increasing knowledge of neonatal cardiovascular pathophysiology can give insights to improve anaesthetic management. Near-infrared spectroscopy as a measure of organ perfusion can help to determine the need for treatment. Summary Anaesthetic management should focus on optimizing organ perfusion and not merely on maintaining a particular BP. A collaborative approach is recommended. The carbon dioxide tension is crucial to perfusion in the presence of cardiovascular shunts. Keywords blood pressure, cardiac physiology, general anaesthesia, monitoring, neonate
INTRODUCTION Adverse outcomes of neonatal anaesthesia include ischaemic injury to the brain, gut and kidneys and perioperative cardiac arrest, and are associated with haemodynamic instability [1,2]. Hypoperfusion has been suggested as a putative mechanism of neurotoxic effects of anaesthesia [3], and it is clear that the avoidance of ischaemia to vital organs is an essential element of good anaesthesia. Blood pressure (BP) measurement is a mainstay of haemodynamic monitoring as it is quickly and easily performed. However, noninvasive BP measurement can be inaccurate and no agreement exists on normal values in neonates undergoing anaesthesia. BP is frequently mistakenly used as a surrogate of organ perfusion. BP is the product of cardiac output (CO) and systemic vascular resistance (SVR) and will only reflect global blood flow if SVR remains constant, which is unlikely during haemodynamic instability as both CO and SVR are influenced by autonomic responses, already present in utero. BP poorly reflects systemic blood flow, especially in sick neonates or when foetal shunts are open and serious www.co-anesthesiology.com
organ hypoperfusion can occur in the absence of hypotension [4]. The current article will focus on the role of BP in the optimization of organ perfusion during anaesthesia in neonates.
NORMATIVE STUDIES OF BLOOD PRESSURE IN NEONATES There is no consensus on the definition of hypotension in neonates undergoing anaesthesia. Normative data from population-based studies show some contradictions. Many factors affect neonatal
Department of Vital Functions, Wilhelmina Children’s Hospital at the University Medical Centre, Utrecht, The Netherlands Correspondence to Nigel McBeth Turner, Consultant Paediatric Cardiac Anaesthesiologist and Educationalist, Paediatric Intensive Care – Pelikaan, Huispost KG.02.307.0, Wilhelmina Children’s Hospital at the University Medical Centre, Postbus 85090, 3508AB Utrecht, The Netherlands. Tel: +31 887575199; fax: +31 887555347; e-mail: [email protected] Curr Opin Anesthesiol 2015, 28:308–313 DOI:10.1097/ACO.0000000000000196 Volume 28 Number 3 June 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Intraoperative hypotension in neonates Turner
KEY POINTS Blood pressure is not a surrogate of organ perfusion and the relationship between blood pressure, organ perfusion and outcomes is unclear. It is not clear whether treatment of low blood pressure with fluids or inotropes in neonates is helpful or harmful, but overtreatment in the premature infant increases the risk of intraventricular haemorrhage. In the absence of consensus on the definition of hypotension in neonates undergoing anaesthesia, it is useful to take a collaborative, individualized and combined normative and physiological approach to low blood pressure. Using near-infrared spectroscopy, the adequacy of cerebral blood flow can be assessed as a guide to treatment. Maintenance of haemodynamic stability using fluids, inotropes and manipulation of carbon dioxide tension requires a good understanding of neonatal cardiovascular physiology.
BP, including age, gestational age, maternal age and medication [5]. Neonatal BP increases on the first days of life. Typical values for the mean systolic BP (SBP) of term neonates are 62.6 mmHg at birth, 68.4 mmHg at 36 h after birth and 72.7 mmHg at 7 days [6]. Preterm neonates show a more protracted rise in BP with age after the first few days of life. Ex-premature neonates have a higher BP than term neonates of the same postconceptual age, so BP seems related to the duration of extrauterine life [7]. BP may differ by 10 mmHg between sleeping and awake neonates [8]. Population studies show a clinical significant spread in BP. Park and Lee [8] found an average mean arterial pressure (MAP) of 53.0 mmHg with a standard deviation of 7.3 mmHg in neonates older than 36 h. Although normative studies can be helpful in guiding BP management, population-derived values cannot be used unqualified to define the required BP to maintain organ perfusion in a particular infant.
EFFECTS OF ANAESTHESIA ON BLOOD PRESSURE Anaesthesia generally reduces BP in neonates and has complex effects on regional blood flow mediated by changes in vascular tone, myocardial performance, autonomic reflexes, tissue metabolism and fluid, electrolyte and blood gas homeostasis [9,10 ]. For example, hypercapnia has opposite effects on the vascular resistance in the lung and &
the brain and also leads to sympathetic activation with unpredictable effects on the splanchnic and renal circulation.
MEASUREMENT ISSUES Oscillometric measurement at the upper arm gives a clinically useful estimate of SBP and correlates with intra-arterial measurement in neonates, although there is a trend towards a slight overestimation with oscillometry [11 ,12]. Accuracy depends on the correct technique, including correct cuff size which does not always receive due attention in clinical practice. The BP difference between the arm and legs in awake, active neonates may be less important at rest or under anaesthesia [13]. Park and Lee [6] found a clinically insignificant difference in MAP of 0.9 6.9 mmHg at a mean MAP of 50 mmHg between the upper arm and the calf. The BP varies between anatomical sites under pathological conditions and the pressure at the site of measurement is not necessarily the same as that in the region of interest due to transitional shunts or pathological conditions such as coarctation of the aorta. &
VIEWS OF PAEDIATRIC ANAESTHESIOLOGISTS There is no consensus among paediatric anaesthesiologists on the definition of hypotension in neonates nor on the methods and targets for its treatment. Many different definitions are used and there is not even agreement about the most appropriate parameter to use, with paediatric anaesthesiologists usually targeting the SBP and neonatologists using the mean pressure. Less than half of paediatric anaesthesiologists use the diastolic BP (DBP) despite its importance for coronary perfusion [14,15 ]. Most paediatric anaesthesiologists take a SBP of 45–50 mmHg or a 20–30% decrease from baseline to be the threshold for intervention [16]. These values are significantly lower than the fifth percentile in many normative studies, implying that many anaesthesiologists accept a lower BP during anaesthesia than awake [17]. Hypotension is particularly common before surgical incision occurring in 27% paediatric cases [16]. &
DEFINITIONS OF HYPOTENSION With no universally accepted definition of hypotension, the concept of ‘normal’ BP during neonatal anaesthesia remains vague. It is then helpful to take
0952-7907 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.co-anesthesiology.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
309
Pediatric anesthesia
a theoretical view by considering the effect of BP on global and organ-specific flow and tissue oxygenation. This approach has led to three paradigms for the definition of hypotension, which are as follows: ‘normative’, according to population-derived data; ‘physiological’, based on the point at which low BP is detrimental to organ perfusion; and ‘operational’, the point at which the anaesthesiologist should intervene [18].
NORMATIVE DEFINITIONS OF HYPOTENSION The normative definition of hypotension under anaesthesia makes use of the statistical lower limits for BP for a given gestational age and is the easiest to define. As the 10th percentile of MAP roughly corresponds to the gestational age in weeks, it has been recommended to regard this as the minimum acceptable BP in preterm neonates [19]. This guideline has been widely adopted even though the authors acknowledge its scientific basis is weak. Many neonatologists regard 30 mmHg as the lowest absolute limit of MAP as there are data suggesting an association between cerebral injury and a persistently lower MAP.
PHYSIOLOGICAL DEFINITIONS OF HYPOTENSION Acceptance of BP as a poor surrogate for perfusion and problems of definition have led to a more physiological approach to hypotension [20]. Using this approach and focusing on the brain as the most vulnerable organ, the threshold of hypotension can be defined in three ways: the MAP associated with the onset of cerebral ischaemia leading to permanent injury; the MAP corresponding to the cerebral blood flow (CBF) at which normal function is lost; the MAP at which autoregulation is lost.
suggesting that a low early postnatal BP may itself not be important in the pathogenesis of brain injury [23,24]. Hypotension in low birth-weight is not associated with increased abnormalities on cerebral ultrasound and there is little indication that normotension is correlated with a better outcome. Treating hypotension may not improve long-term outcome either [25–27]. Early inotropic support has been associated with cerebral haemorrhage and leucomalacia, although it is not clear whether this is the result of treatment or whether hypotension is a marker of existing neurological damage [28,29]. Of course, one cannot assume from this evidence against an independent effect of BP on outcome that hypotension is well tolerated for older neonates, but it does imply that a definition of hypotension based on ischaemia is not useful as a practical guide to therapy.
Definition based on loss of function The loss-of-normal function is difficult to apply to define hypotension during anaesthesia when normal function is suppressed. Cerebral function can be measured with the amplitude-integrated electrocephalogram. This measurement is, however, influenced unpredictably by depth anaesthesia and may not detect haemodynamic changes, which complicates its interpretation [30–32].
Definition based on loss of autoregulation The most useful physiological definition of hypotension is the MAP at which autoregulation is lost, being in the region of 28–30 mmHg for term neonates, but which shows considerable interindividual variation and is disrupted by disease and anaesthesia [33]. This definition implies an approach to clinical monitoring of organ perfusion, including nearinfrared spectrometry (NIRS) and echocardiography [10 ,28]. &
Definition based on ischaemia The level of hypotension leading to ischaemia is difficult to define, the definition is only applicable retrospectively and is too late to be clinically useful. Although moderate hypotension, as defined by normative studies, is common in neonatal anaesthesia and is generally well tolerated [16], hypotension below a certain level will reduce CBF, which will cause brain injury [21,22]. In the preterm infant, low systemic blood flow is associated with adverse outcomes but this is not always reflected in the BP [12]. Hypotension on the first day of life is common in the premature infant and is not associated with outcome 310
www.co-anesthesiology.com
MONITORING The usual methods used to monitor the circulation during neonatal anaesthesia, including invasive or noninvasive BP, plethysmography, urine production, acid–base balance and lactate are all, in economic terms, ‘supply-side’ measures of organ well-being and are generally both nonspecific and insensitive [10 ]. Urine output provides a retrospective indication of the adequacy of renal perfusion and vascular filling over the collection period. Consideration of the preoperative urine output and the concurrent BP can give an idea of the BP necessary to maintain renal function in a particular infant. &
Volume 28 Number 3 June 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Intraoperative hypotension in neonates Turner
Near-infrared spectroscopy
Echocardiography
NIRS provides an estimate of organ oxygen use, if not oxygen demand, and is a useful and simple addition to intraoperative monitoring. NIRS relies on the translucency of tissues in the near-infrared range and provides a continuous measurement of the average haemoglobin oxygen saturation in the sampled area – the regional saturation (rSO2) [10 ]. The rSO2 provides an estimate of average saturation throughout the sampled area, but is closer to the cerebral venous saturation as 75–90% of the blood in the brain is venous. By comparing this with the arterial saturation, an estimate of cerebral oxygen extraction can be made, which is dependent on both oxygen demand and delivery. As oxygen demand is generally low and fairly constant during anaesthesia, oxygen extraction gives useful information about CBF. Studies showing a reduction in rSO2 during hypocapnia and a good correlation between changes in rSO2 and in concomitant transcranial Doppler give validity to use of rSO2 to estimate CBF [10 ,32]. The rSO2 shows a wide range of normal values consistent with the wide range of CBF values detected by PET scan. In healthy neonates, rSO2 values of 60–80% and an oxygen extraction of 20–40% are typical [10 ]. This wide range confounds interindividual comparisons of NIRS data, but within-patient trends are clinically useful. NIRS only provides information about the small part of the brain sampled, does not penetrate deeper into cerebral structures and consequently says little about the regional distribution of CBF, which may be of critical importance to the development of local ischaemia [28]. Nonetheless, rSO2 has been shown to correlate with outcome in neonate intensive care patients [34]. The rSO2 is useful for confirming the presence and limits of cerebral autoregulation. Although deliberate manipulating the BP to assess its effect on CBF would be unethical, review of trend information relating rSO2 to changes in BP can provide useful information to guide therapy. Following cardiopulmonary bypass, persistent low cerebral oxygen saturations have been associated with worse outcomes [35]. NIRS can also be used to measure rSO2 in the kidneys, abdominal contents and skeletal muscles. The normal somatic oxygen saturation is generally 10–15% lower than the concomitant cerebral value, and also shows large interindividual differences. Narrowing of the somatic–cerebral rSO2 difference may reflect increased sympathetic tone and can be a useful signal of early compensated shock [10 ].
Addition of perioperative echocardiography to standard monitoring can give a clinically useful estimate of cardiac output, but says little about the adequacy of organ perfusion [12]. It is the only commonly monitored parameter which gives useful information about pulmonary blood flow, which is an interdependent determinant of left-sided cardiac output. Functional echocardiography has not been shown to improve outcome in the operating theatre or intensive care, but does allow a more considered pathological diagnosis of the cause of hypotension [36].
&
&
&
&
OPERATIONAL DEFINITION OF HYPOTENSION The operational threshold of hypotension is the BP at which the anaesthesiologist should intervene and is best defined using a combined normative and physiological approach to determine the adequacy of the BP and the need for intervention on an individual basis. The target BP for each patient is estimated preoperatively using normative data, whereas all haemodynamic parameters of organ perfusion, including cerebral oximetry, are considered to check the adequacy of the BP during anaesthesia. This approach allows the anaesthesiologist to assess the impact of a low BP, make on assumptions about causes and decide on the most appropriate treatment.
PRACTICAL APPROACH TO LOW BLOOD PRESSURE As the relationship between inadequate tissue perfusion and BP in an individual neonate is difficult to predict, it is important to consider all haemodynamic parameters when considering intervention for a low BP. It is unclear whether treatment of a low BP with fluids or inotropes is helpful or harmful in neonates, but overtreatment in the premature is certainly not without risk, so each intervention should be carefully considered [37]. Optimizing haemodynamics in neonates under anaesthesia is challenging and requires a good understanding of cardiovascular pathophysiology, which has been recently reviewed by Wolf and Humphry [15 ]. Balancing the effect of anaesthesia against the degree of surgical stress requires skill and judgement and avoidance of too deep anaesthesia before skin incision is important. Improving the care of neonates involves setting therapeutic targets in collaboration with anaesthesiologists, surgeons and neonatologists as advised in a recent Dutch national recommendation.
0952-7907 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
&
www.co-anesthesiology.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
311
Pediatric anesthesia
Measuring the BP before induction is often considered standard practice but measurement issues in awake neonates make the interpretation of an unexpected value immediately before induction difficult. The approach to hypotension begins with consideration of the cause. As BP is the product of SVR and CO, the problem can be a reduction in resistance or in output or both. Adrenal insufficiency should also be considered as a cause of hypotension in the sick neonate [38]. The ventilation strategy requires special consideration in the presence of a patent ductus arteriosus or (potential) intracardiac shunts. Vascular resistance reacts markedly to carbon dioxide tension and hypocapnia causes cerebral vasoconstriction and pulmonary vasodilatation leading to increased steal, both of which can reduce CBF. Air embolism should be avoided as periods of hypercapnia and/or hypoxia can increase the right-to-left shunt. Due to these shunts global systemic perfusion is better conceived of as the total flow returning to the heart via the vena cavae, which can be estimated echographically, rather than the output of the systemic ventricle [39]. Little normative data on cardiac output in the sick neonate is available.
Effect of fluids, inotropes and vasoconstrictors The best way to treat low BP in neonates depends on the cause. There are relatively few interventions available to the anaesthesiologist, consisting mainly of fluid administration, inotropes, chronotropes, vasoactive agents and manipulation of the blood carbon dioxide tension. Hypovolemia is a common cause of hypotension during anaesthesia and can be corrected with fluid replacement. However, the neonatal heart has a limited ability to react to an increase in preload, and overcorrection can lead to heart failure, sometimes accompanied by hypertension [15 ]. Bradycardia may imply a primary cardiac problem due to the effect of anaesthesia or the result of myocardial ischaemia due to a low DBP. Distinguishing between these two situations, which require different therapies – chronotropes or vasoconstrictors respectively – can be difficult, and many anaesthesiologists would treat this with an agent with both properties such as adrenaline. The neonatal myocardium is sensitive to catecholamines, which can increase the BP and maintain coronary blood flow, but catecholamines deplete myocardial energy stores and overzealous use can lead to myocardial damage [15 ]. Downregulation of b-receptors can occur in sick neonates, leading to resistance to catecholamines and escalating doses.
Milrinon is a popular phosphodiesterase-3 blocker, which increases the availability of calcium in the myocardium during systole and calcium reuptake during diastole. Milrinon improves systolic and diastolic function and reduces systemic and pulmonary vascular resistance. Milrinon can prevent low CO syndrome after cardiac surgery in neonates, although other vasodilators may be equally effective in this regard [15 ,40]. In vitro, milrinon preserves myocardial energy stores and restores the effect of b-agonists and thus can be usefully combined with catecholamines. Low-dose vasopressin ameliorates catecholamine resistance, has an intrinsic inotropic effect with probable coronary and pulmonary vasodilatation and may also reduce the incidence of shock after cardiac surgery [41]. &
SUMMARY Hypotension in neonates requires a combined physiological and normative, considered and collaborative approach. It is important to take a wider view of the maintenance of organ perfusion during anaesthesia. There is a need for more population studies relating BP and the treatment of hypotension during neonatal anaesthesia to outcome. It would not be surprising if BP did not emerge as an independent determinant of outcome from such studies. Acknowledgements The author would like to thank Dr Ton Schouten for his help in preparing this article. Financial support and sponsorship None. Conflicts of interest There are no conflicts of interest.
&
&
312
www.co-anesthesiology.com
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Bhananker SM, Ramamoorthy C, Geiduschek JM, et al. Anesthesia-related cardiac arrest in children: update from the Pediatric Perioperative Cardiac Arrest Registry. Anesth Analg 2007; 105:344–350. 2. Hoffman GM. Outcomes of pediatric anesthesia. Semin Pediatr Surg 2008; 17:141–151. 3. Fritz KI, Delivoria-Papadopoulos M. Mechanisms of injury to the newborn brain. Clin Perinatol 2006; 33:573–591. 4. Pizov R, Eden A, Bystritski D, et al. Hypotension during gradual blood loss: waveform variables response and absence of tachycardia. Br J Anaesth 2012; 109:911–918. 5. Mattingly J, D’Alessio J, Ramanathan J. Effects of obstetric analgesics and anaesthetics on the neonate: a review. Pediatr Drugs 2003; 5:615– 627.
Volume 28 Number 3 June 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Intraoperative hypotension in neonates Turner 6. Park MK, Lee DH. Normative arm and calf blood pressure values in the newborn. Pediatrics 1989; 83:240–243. 7. Georgieff MK, Mills MM, Go´mez-Marı´n O, Sinaiko AR. Rate of change of blood pressure in premature and full term infants from birth to 4 months. Pediatr Nephrol 1996; 10:152–155. 8. Park MK. Normative arm and calf blood pressure values in the newborn. Pediatrics 1989; 83:240. 9. Murat I, Levron J, Berg A, Saint-Maurice C. Effects of fentanyl on baroreceptor reflex control of heart rate in newborn infants. Anesthesiology 1998; 68: 717–722. 10. Scott JP, Hoffman GM. Near-infrared spectroscopy: exposing the dark & (venous) side of the circulation. Pediatr Anesth 2014; 24:74–88. A balanced discussion of the benefits and limitations of NIRS monitoring in neonates, including a review of the evidence for the use of NIRS and a clear explanation of the physical measurement principles. 11. McCann ME, Schouten ANJ. Beyond survival; influences of blood pressure, & cerebral perfusion and anesthesia on neurodevelopment. Pediatr Anesth 2014; 24:68–73. An critical analysis of the concept of normal blood pressure and of hypotension in the neonate, specifically geared towards the anaesthesiologist. 12. Kluckow M. Low systemic blood flow and pathophysiology of the preterm transitional circulation. Early Human Dev 2005; 81:429–437. 13. Crossland DS, Furness JC, Abu-Harb M. Variability of four limb blood pressure in normal neonates. Arch Dis Child Fetal Neonatal 2004; 89: F325–F327. 14. Bijker JB, van Klei WA, Kappen TH, et al. The incidence of intraoperative hypotension as a function of the chosen definition: literature definitions applied to a retrospective cohort using automated data collection. Anesthesiology 2007; 107:213–220. 15. Wolf AR, Humphry AT. Limitations and vulnerabilities of the neonatal cardi& ovascular system: considerations for anesthetic management. Pediatr Anesth 2014; 24:5–9. An excellent review of the current understanding of cardiovascular physiology in the newborn. 16. Nafiu OO, Voepel-Lewis T, Morris M, et al. How do pediatric anesthesiologists define intraoperative hypotension? Pediatr Anesth 2009; 19:1048–1053. 17. Jones JE, Jose PA. Neonatal blood pressure regulation. Semin Perinatol 2004; 28:141–148. 18. Cayabyab R, McLean CW, Seri I. Definition of hypotension and assessment of hemodynamics in the preterm neonate. J Perinatol 2009; 29:S58–S62. 19. Joint Working Group of the British Association of Perinatal Medicine and the Research Unit of the Royal College of Physicians. Development of audit measures and guidelines for good practice in the management of neonatal respiratory distress syndrome. Arch Dis Child 1992; 67:1221– 1227. 20. Limperopoulos C, Bassan H, Kalish LA, et al. Current definitions of hypotension do not predict abnormal cranial ultrasound findings in preterm infants. Pediatrics 2007; 120:966–977. 21. Anand KJ, Hall RW, Desai N, et al. Effects of morphine analgesia in ventilated preterm neonates: primary outcomes from the NEOPAIN randomised trial. Lancet 2004; 363:1673–1682. 22. Bada HS, Korones SB, Perry EH, et al. Mean arterial blood pressure changes in premature infants and those at risk for intraventricular hemorrhage. J Pediatr 1990; 117:607–614.
23. Versmold HT, Kitterman JA, Phibbs RH, et al. Aortic blood pressure during the first 12 h of life in infants with birth weight 610 to 4,220 grams. Pediatrics 1981; 67:607–613. 24. Logan JW, O’Shea TM, Allred EN, et al. Early postnatal hypotension is not associated with indicators of white matter damage or cerebral palsy in extremely low gestational age newborns. J Perinatol 2011; 31:524–534. 25. Ahn SY, Kim ES, Kim JK, et al. Permissive hypotension in extremely low birth weight infants (1000 gm). Yonsei Med J 2012; 53:765–771. 26. Osborn DA1, Evans N. Early volume expansion for prevention of morbidity and mortality in very preterm infants. Cochrane Database Syst Rev 2004; CD002055. 27. Osborn DA, Paradisis M, Evans N. The effect of inotropes on morbidity and mortality in preterm infants with low systemic or organ blood flow. Cochrane Database Syst Rev 2007; CD005090. 28. Vutskits L. Cerebral blood flow in the neonate. Paediatr Anaesth 2014; 24:22–29. 29. Kuint J, Barak M, Morag I, Maayan-Metzger A. Early treated hypotension and outcome in very low birth weight infants. Neonatology 2009; 95:311–316. 30. McKeever S, Johnston L, Davidson AJ. Sevoflurane-induced changes in infants’ quantifiable electroencephalogram parameters. Paediatr Anaesth 2014; 24:766–773. 31. Kasdorf E, Engel M, Perlman JM. Amplitude electroencephalogram characterization in preterm infants undergoing patent ductus arteriosus ligation. Pediatr Neurol 2013; 49:102–106. 32. McLean CW, Cayabyab R, Noori S, Seri I. Cerebral circulation and hypotension in the premature infant – diagnosis and treatment. In: Perlman JM, editor. Neonatology questions and controversies: neurology. Philadelphia: Saunders/Elsevier Co; 2008. pp. 3–26. 33. Nagdyman N1, Ewert P, Peters B, et al. Comparison of different near-infrared spectroscopic cerebral oxygenation indices with central venous and jugular venous oxygenation saturation in children. Paediatr Anaesth 2008; 18:160– 166. 34. Lemmers PM, Zwanenburg RJ, Benders MJ, et al. Cerebral oxygenation and brain activity after perinatal asphyxia: does hypothermia change their prognostic value? Pediatr Res 2013; 74:180–185. 35. Hoffman GM, Brosig CL, Mussatto KA, et al. Perioperative cerebral oxygen saturation in neonates with hypoplastic left heart syndrome and childhood neurodevelopmental outcome. J Thorac Cardiovasc Surg 2013; 146:1153– 1164. 36. Kluckow M, Seri I, Evans N. Functional echocardiography – an emerging clinical tool for the neonatologist. J Pediatr 2007; 150:125–130. 37. Fanaroff JM, Wilson-Costello DE, Newman NS, et al. Treated hypotension is associated with neonatal morbidity and hearing loss in extremely low birth weight infants. Pediatrics 2006; 117:1131–1135. 38. Evans N. Management of hypotension and circulatory assessment on NICU. Early Human Dev 2005; 81:397–398. 39. Barrington KJ. Common hemodynamic problems in the neonate. Neonatology 2013; 103:335–340. 40. Hoffman TM, Wernovsky G, Atz AM, et al. Efficacy and safety of milrinon in preventing low cardiac output syndrome in infants and children after corrective surgery for congenital heart disease. Circulation 2003; 107:996–1002. 41. Alten JA, Borasino S, Toms R, et al. Early initiation of arginine vasopressin infusion in neonates after complex cardiac surgery. Pediatr Crit Care Med 2012; 13:300–304.
0952-7907 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.co-anesthesiology.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
313
Intraoperative hypotension in neonates: when and how should we intervene? Nigel McBeth Turner
Purpose of review Organ hypoperfusion remains an important cause of postoperative morbidity in neonates. Blood pressure (BP) is frequently mistakenly used as a surrogate of organ perfusion and the predictive value of BP for outcome is unclear. The current article will focus on the role of BP in the optimization of organ perfusion during anaesthesia in neonates. Recent findings Population studies show a range of normal values for BP in neonates and there is no consensus on the definition of hypotension in neonates undergoing anaesthesia. The relationship between BP and outcome is unclear. Unnecessary treatment of low BP in neonates can be harmful. A theoretical approach to the definition of hypotension and increasing knowledge of neonatal cardiovascular pathophysiology can give insights to improve anaesthetic management. Near-infrared spectroscopy as a measure of organ perfusion can help to determine the need for treatment. Summary Anaesthetic management should focus on optimizing organ perfusion and not merely on maintaining a particular BP. A collaborative approach is recommended. The carbon dioxide tension is crucial to perfusion in the presence of cardiovascular shunts. Keywords blood pressure, cardiac physiology, general anaesthesia, monitoring, neonate
INTRODUCTION Adverse outcomes of neonatal anaesthesia include ischaemic injury to the brain, gut and kidneys and perioperative cardiac arrest, and are associated with haemodynamic instability [1,2]. Hypoperfusion has been suggested as a putative mechanism of neurotoxic effects of anaesthesia [3], and it is clear that the avoidance of ischaemia to vital organs is an essential element of good anaesthesia. Blood pressure (BP) measurement is a mainstay of haemodynamic monitoring as it is quickly and easily performed. However, noninvasive BP measurement can be inaccurate and no agreement exists on normal values in neonates undergoing anaesthesia. BP is frequently mistakenly used as a surrogate of organ perfusion. BP is the product of cardiac output (CO) and systemic vascular resistance (SVR) and will only reflect global blood flow if SVR remains constant, which is unlikely during haemodynamic instability as both CO and SVR are influenced by autonomic responses, already present in utero. BP poorly reflects systemic blood flow, especially in sick neonates or when foetal shunts are open and serious www.co-anesthesiology.com
organ hypoperfusion can occur in the absence of hypotension [4]. The current article will focus on the role of BP in the optimization of organ perfusion during anaesthesia in neonates.
NORMATIVE STUDIES OF BLOOD PRESSURE IN NEONATES There is no consensus on the definition of hypotension in neonates undergoing anaesthesia. Normative data from population-based studies show some contradictions. Many factors affect neonatal
Department of Vital Functions, Wilhelmina Children’s Hospital at the University Medical Centre, Utrecht, The Netherlands Correspondence to Nigel McBeth Turner, Consultant Paediatric Cardiac Anaesthesiologist and Educationalist, Paediatric Intensive Care – Pelikaan, Huispost KG.02.307.0, Wilhelmina Children’s Hospital at the University Medical Centre, Postbus 85090, 3508AB Utrecht, The Netherlands. Tel: +31 887575199; fax: +31 887555347; e-mail: [email protected] Curr Opin Anesthesiol 2015, 28:308–313 DOI:10.1097/ACO.0000000000000196 Volume 28 Number 3 June 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Intraoperative hypotension in neonates Turner
KEY POINTS Blood pressure is not a surrogate of organ perfusion and the relationship between blood pressure, organ perfusion and outcomes is unclear. It is not clear whether treatment of low blood pressure with fluids or inotropes in neonates is helpful or harmful, but overtreatment in the premature infant increases the risk of intraventricular haemorrhage. In the absence of consensus on the definition of hypotension in neonates undergoing anaesthesia, it is useful to take a collaborative, individualized and combined normative and physiological approach to low blood pressure. Using near-infrared spectroscopy, the adequacy of cerebral blood flow can be assessed as a guide to treatment. Maintenance of haemodynamic stability using fluids, inotropes and manipulation of carbon dioxide tension requires a good understanding of neonatal cardiovascular physiology.
BP, including age, gestational age, maternal age and medication [5]. Neonatal BP increases on the first days of life. Typical values for the mean systolic BP (SBP) of term neonates are 62.6 mmHg at birth, 68.4 mmHg at 36 h after birth and 72.7 mmHg at 7 days [6]. Preterm neonates show a more protracted rise in BP with age after the first few days of life. Ex-premature neonates have a higher BP than term neonates of the same postconceptual age, so BP seems related to the duration of extrauterine life [7]. BP may differ by 10 mmHg between sleeping and awake neonates [8]. Population studies show a clinical significant spread in BP. Park and Lee [8] found an average mean arterial pressure (MAP) of 53.0 mmHg with a standard deviation of 7.3 mmHg in neonates older than 36 h. Although normative studies can be helpful in guiding BP management, population-derived values cannot be used unqualified to define the required BP to maintain organ perfusion in a particular infant.
EFFECTS OF ANAESTHESIA ON BLOOD PRESSURE Anaesthesia generally reduces BP in neonates and has complex effects on regional blood flow mediated by changes in vascular tone, myocardial performance, autonomic reflexes, tissue metabolism and fluid, electrolyte and blood gas homeostasis [9,10 ]. For example, hypercapnia has opposite effects on the vascular resistance in the lung and &
the brain and also leads to sympathetic activation with unpredictable effects on the splanchnic and renal circulation.
MEASUREMENT ISSUES Oscillometric measurement at the upper arm gives a clinically useful estimate of SBP and correlates with intra-arterial measurement in neonates, although there is a trend towards a slight overestimation with oscillometry [11 ,12]. Accuracy depends on the correct technique, including correct cuff size which does not always receive due attention in clinical practice. The BP difference between the arm and legs in awake, active neonates may be less important at rest or under anaesthesia [13]. Park and Lee [6] found a clinically insignificant difference in MAP of 0.9 6.9 mmHg at a mean MAP of 50 mmHg between the upper arm and the calf. The BP varies between anatomical sites under pathological conditions and the pressure at the site of measurement is not necessarily the same as that in the region of interest due to transitional shunts or pathological conditions such as coarctation of the aorta. &
VIEWS OF PAEDIATRIC ANAESTHESIOLOGISTS There is no consensus among paediatric anaesthesiologists on the definition of hypotension in neonates nor on the methods and targets for its treatment. Many different definitions are used and there is not even agreement about the most appropriate parameter to use, with paediatric anaesthesiologists usually targeting the SBP and neonatologists using the mean pressure. Less than half of paediatric anaesthesiologists use the diastolic BP (DBP) despite its importance for coronary perfusion [14,15 ]. Most paediatric anaesthesiologists take a SBP of 45–50 mmHg or a 20–30% decrease from baseline to be the threshold for intervention [16]. These values are significantly lower than the fifth percentile in many normative studies, implying that many anaesthesiologists accept a lower BP during anaesthesia than awake [17]. Hypotension is particularly common before surgical incision occurring in 27% paediatric cases [16]. &
DEFINITIONS OF HYPOTENSION With no universally accepted definition of hypotension, the concept of ‘normal’ BP during neonatal anaesthesia remains vague. It is then helpful to take
0952-7907 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.co-anesthesiology.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
309
Pediatric anesthesia
a theoretical view by considering the effect of BP on global and organ-specific flow and tissue oxygenation. This approach has led to three paradigms for the definition of hypotension, which are as follows: ‘normative’, according to population-derived data; ‘physiological’, based on the point at which low BP is detrimental to organ perfusion; and ‘operational’, the point at which the anaesthesiologist should intervene [18].
NORMATIVE DEFINITIONS OF HYPOTENSION The normative definition of hypotension under anaesthesia makes use of the statistical lower limits for BP for a given gestational age and is the easiest to define. As the 10th percentile of MAP roughly corresponds to the gestational age in weeks, it has been recommended to regard this as the minimum acceptable BP in preterm neonates [19]. This guideline has been widely adopted even though the authors acknowledge its scientific basis is weak. Many neonatologists regard 30 mmHg as the lowest absolute limit of MAP as there are data suggesting an association between cerebral injury and a persistently lower MAP.
PHYSIOLOGICAL DEFINITIONS OF HYPOTENSION Acceptance of BP as a poor surrogate for perfusion and problems of definition have led to a more physiological approach to hypotension [20]. Using this approach and focusing on the brain as the most vulnerable organ, the threshold of hypotension can be defined in three ways: the MAP associated with the onset of cerebral ischaemia leading to permanent injury; the MAP corresponding to the cerebral blood flow (CBF) at which normal function is lost; the MAP at which autoregulation is lost.
suggesting that a low early postnatal BP may itself not be important in the pathogenesis of brain injury [23,24]. Hypotension in low birth-weight is not associated with increased abnormalities on cerebral ultrasound and there is little indication that normotension is correlated with a better outcome. Treating hypotension may not improve long-term outcome either [25–27]. Early inotropic support has been associated with cerebral haemorrhage and leucomalacia, although it is not clear whether this is the result of treatment or whether hypotension is a marker of existing neurological damage [28,29]. Of course, one cannot assume from this evidence against an independent effect of BP on outcome that hypotension is well tolerated for older neonates, but it does imply that a definition of hypotension based on ischaemia is not useful as a practical guide to therapy.
Definition based on loss of function The loss-of-normal function is difficult to apply to define hypotension during anaesthesia when normal function is suppressed. Cerebral function can be measured with the amplitude-integrated electrocephalogram. This measurement is, however, influenced unpredictably by depth anaesthesia and may not detect haemodynamic changes, which complicates its interpretation [30–32].
Definition based on loss of autoregulation The most useful physiological definition of hypotension is the MAP at which autoregulation is lost, being in the region of 28–30 mmHg for term neonates, but which shows considerable interindividual variation and is disrupted by disease and anaesthesia [33]. This definition implies an approach to clinical monitoring of organ perfusion, including nearinfrared spectrometry (NIRS) and echocardiography [10 ,28]. &
Definition based on ischaemia The level of hypotension leading to ischaemia is difficult to define, the definition is only applicable retrospectively and is too late to be clinically useful. Although moderate hypotension, as defined by normative studies, is common in neonatal anaesthesia and is generally well tolerated [16], hypotension below a certain level will reduce CBF, which will cause brain injury [21,22]. In the preterm infant, low systemic blood flow is associated with adverse outcomes but this is not always reflected in the BP [12]. Hypotension on the first day of life is common in the premature infant and is not associated with outcome 310
www.co-anesthesiology.com
MONITORING The usual methods used to monitor the circulation during neonatal anaesthesia, including invasive or noninvasive BP, plethysmography, urine production, acid–base balance and lactate are all, in economic terms, ‘supply-side’ measures of organ well-being and are generally both nonspecific and insensitive [10 ]. Urine output provides a retrospective indication of the adequacy of renal perfusion and vascular filling over the collection period. Consideration of the preoperative urine output and the concurrent BP can give an idea of the BP necessary to maintain renal function in a particular infant. &
Volume 28 Number 3 June 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Intraoperative hypotension in neonates Turner
Near-infrared spectroscopy
Echocardiography
NIRS provides an estimate of organ oxygen use, if not oxygen demand, and is a useful and simple addition to intraoperative monitoring. NIRS relies on the translucency of tissues in the near-infrared range and provides a continuous measurement of the average haemoglobin oxygen saturation in the sampled area – the regional saturation (rSO2) [10 ]. The rSO2 provides an estimate of average saturation throughout the sampled area, but is closer to the cerebral venous saturation as 75–90% of the blood in the brain is venous. By comparing this with the arterial saturation, an estimate of cerebral oxygen extraction can be made, which is dependent on both oxygen demand and delivery. As oxygen demand is generally low and fairly constant during anaesthesia, oxygen extraction gives useful information about CBF. Studies showing a reduction in rSO2 during hypocapnia and a good correlation between changes in rSO2 and in concomitant transcranial Doppler give validity to use of rSO2 to estimate CBF [10 ,32]. The rSO2 shows a wide range of normal values consistent with the wide range of CBF values detected by PET scan. In healthy neonates, rSO2 values of 60–80% and an oxygen extraction of 20–40% are typical [10 ]. This wide range confounds interindividual comparisons of NIRS data, but within-patient trends are clinically useful. NIRS only provides information about the small part of the brain sampled, does not penetrate deeper into cerebral structures and consequently says little about the regional distribution of CBF, which may be of critical importance to the development of local ischaemia [28]. Nonetheless, rSO2 has been shown to correlate with outcome in neonate intensive care patients [34]. The rSO2 is useful for confirming the presence and limits of cerebral autoregulation. Although deliberate manipulating the BP to assess its effect on CBF would be unethical, review of trend information relating rSO2 to changes in BP can provide useful information to guide therapy. Following cardiopulmonary bypass, persistent low cerebral oxygen saturations have been associated with worse outcomes [35]. NIRS can also be used to measure rSO2 in the kidneys, abdominal contents and skeletal muscles. The normal somatic oxygen saturation is generally 10–15% lower than the concomitant cerebral value, and also shows large interindividual differences. Narrowing of the somatic–cerebral rSO2 difference may reflect increased sympathetic tone and can be a useful signal of early compensated shock [10 ].
Addition of perioperative echocardiography to standard monitoring can give a clinically useful estimate of cardiac output, but says little about the adequacy of organ perfusion [12]. It is the only commonly monitored parameter which gives useful information about pulmonary blood flow, which is an interdependent determinant of left-sided cardiac output. Functional echocardiography has not been shown to improve outcome in the operating theatre or intensive care, but does allow a more considered pathological diagnosis of the cause of hypotension [36].
&
&
&
&
OPERATIONAL DEFINITION OF HYPOTENSION The operational threshold of hypotension is the BP at which the anaesthesiologist should intervene and is best defined using a combined normative and physiological approach to determine the adequacy of the BP and the need for intervention on an individual basis. The target BP for each patient is estimated preoperatively using normative data, whereas all haemodynamic parameters of organ perfusion, including cerebral oximetry, are considered to check the adequacy of the BP during anaesthesia. This approach allows the anaesthesiologist to assess the impact of a low BP, make on assumptions about causes and decide on the most appropriate treatment.
PRACTICAL APPROACH TO LOW BLOOD PRESSURE As the relationship between inadequate tissue perfusion and BP in an individual neonate is difficult to predict, it is important to consider all haemodynamic parameters when considering intervention for a low BP. It is unclear whether treatment of a low BP with fluids or inotropes is helpful or harmful in neonates, but overtreatment in the premature is certainly not without risk, so each intervention should be carefully considered [37]. Optimizing haemodynamics in neonates under anaesthesia is challenging and requires a good understanding of cardiovascular pathophysiology, which has been recently reviewed by Wolf and Humphry [15 ]. Balancing the effect of anaesthesia against the degree of surgical stress requires skill and judgement and avoidance of too deep anaesthesia before skin incision is important. Improving the care of neonates involves setting therapeutic targets in collaboration with anaesthesiologists, surgeons and neonatologists as advised in a recent Dutch national recommendation.
0952-7907 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
&
www.co-anesthesiology.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
311
Pediatric anesthesia
Measuring the BP before induction is often considered standard practice but measurement issues in awake neonates make the interpretation of an unexpected value immediately before induction difficult. The approach to hypotension begins with consideration of the cause. As BP is the product of SVR and CO, the problem can be a reduction in resistance or in output or both. Adrenal insufficiency should also be considered as a cause of hypotension in the sick neonate [38]. The ventilation strategy requires special consideration in the presence of a patent ductus arteriosus or (potential) intracardiac shunts. Vascular resistance reacts markedly to carbon dioxide tension and hypocapnia causes cerebral vasoconstriction and pulmonary vasodilatation leading to increased steal, both of which can reduce CBF. Air embolism should be avoided as periods of hypercapnia and/or hypoxia can increase the right-to-left shunt. Due to these shunts global systemic perfusion is better conceived of as the total flow returning to the heart via the vena cavae, which can be estimated echographically, rather than the output of the systemic ventricle [39]. Little normative data on cardiac output in the sick neonate is available.
Effect of fluids, inotropes and vasoconstrictors The best way to treat low BP in neonates depends on the cause. There are relatively few interventions available to the anaesthesiologist, consisting mainly of fluid administration, inotropes, chronotropes, vasoactive agents and manipulation of the blood carbon dioxide tension. Hypovolemia is a common cause of hypotension during anaesthesia and can be corrected with fluid replacement. However, the neonatal heart has a limited ability to react to an increase in preload, and overcorrection can lead to heart failure, sometimes accompanied by hypertension [15 ]. Bradycardia may imply a primary cardiac problem due to the effect of anaesthesia or the result of myocardial ischaemia due to a low DBP. Distinguishing between these two situations, which require different therapies – chronotropes or vasoconstrictors respectively – can be difficult, and many anaesthesiologists would treat this with an agent with both properties such as adrenaline. The neonatal myocardium is sensitive to catecholamines, which can increase the BP and maintain coronary blood flow, but catecholamines deplete myocardial energy stores and overzealous use can lead to myocardial damage [15 ]. Downregulation of b-receptors can occur in sick neonates, leading to resistance to catecholamines and escalating doses.
Milrinon is a popular phosphodiesterase-3 blocker, which increases the availability of calcium in the myocardium during systole and calcium reuptake during diastole. Milrinon improves systolic and diastolic function and reduces systemic and pulmonary vascular resistance. Milrinon can prevent low CO syndrome after cardiac surgery in neonates, although other vasodilators may be equally effective in this regard [15 ,40]. In vitro, milrinon preserves myocardial energy stores and restores the effect of b-agonists and thus can be usefully combined with catecholamines. Low-dose vasopressin ameliorates catecholamine resistance, has an intrinsic inotropic effect with probable coronary and pulmonary vasodilatation and may also reduce the incidence of shock after cardiac surgery [41]. &
SUMMARY Hypotension in neonates requires a combined physiological and normative, considered and collaborative approach. It is important to take a wider view of the maintenance of organ perfusion during anaesthesia. There is a need for more population studies relating BP and the treatment of hypotension during neonatal anaesthesia to outcome. It would not be surprising if BP did not emerge as an independent determinant of outcome from such studies. Acknowledgements The author would like to thank Dr Ton Schouten for his help in preparing this article. Financial support and sponsorship None. Conflicts of interest There are no conflicts of interest.
&
&
312
www.co-anesthesiology.com
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Bhananker SM, Ramamoorthy C, Geiduschek JM, et al. Anesthesia-related cardiac arrest in children: update from the Pediatric Perioperative Cardiac Arrest Registry. Anesth Analg 2007; 105:344–350. 2. Hoffman GM. Outcomes of pediatric anesthesia. Semin Pediatr Surg 2008; 17:141–151. 3. Fritz KI, Delivoria-Papadopoulos M. Mechanisms of injury to the newborn brain. Clin Perinatol 2006; 33:573–591. 4. Pizov R, Eden A, Bystritski D, et al. Hypotension during gradual blood loss: waveform variables response and absence of tachycardia. Br J Anaesth 2012; 109:911–918. 5. Mattingly J, D’Alessio J, Ramanathan J. Effects of obstetric analgesics and anaesthetics on the neonate: a review. Pediatr Drugs 2003; 5:615– 627.
Volume 28 Number 3 June 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Intraoperative hypotension in neonates Turner 6. Park MK, Lee DH. Normative arm and calf blood pressure values in the newborn. Pediatrics 1989; 83:240–243. 7. Georgieff MK, Mills MM, Go´mez-Marı´n O, Sinaiko AR. Rate of change of blood pressure in premature and full term infants from birth to 4 months. Pediatr Nephrol 1996; 10:152–155. 8. Park MK. Normative arm and calf blood pressure values in the newborn. Pediatrics 1989; 83:240. 9. Murat I, Levron J, Berg A, Saint-Maurice C. Effects of fentanyl on baroreceptor reflex control of heart rate in newborn infants. Anesthesiology 1998; 68: 717–722. 10. Scott JP, Hoffman GM. Near-infrared spectroscopy: exposing the dark & (venous) side of the circulation. Pediatr Anesth 2014; 24:74–88. A balanced discussion of the benefits and limitations of NIRS monitoring in neonates, including a review of the evidence for the use of NIRS and a clear explanation of the physical measurement principles. 11. McCann ME, Schouten ANJ. Beyond survival; influences of blood pressure, & cerebral perfusion and anesthesia on neurodevelopment. Pediatr Anesth 2014; 24:68–73. An critical analysis of the concept of normal blood pressure and of hypotension in the neonate, specifically geared towards the anaesthesiologist. 12. Kluckow M. Low systemic blood flow and pathophysiology of the preterm transitional circulation. Early Human Dev 2005; 81:429–437. 13. Crossland DS, Furness JC, Abu-Harb M. Variability of four limb blood pressure in normal neonates. Arch Dis Child Fetal Neonatal 2004; 89: F325–F327. 14. Bijker JB, van Klei WA, Kappen TH, et al. The incidence of intraoperative hypotension as a function of the chosen definition: literature definitions applied to a retrospective cohort using automated data collection. Anesthesiology 2007; 107:213–220. 15. Wolf AR, Humphry AT. Limitations and vulnerabilities of the neonatal cardi& ovascular system: considerations for anesthetic management. Pediatr Anesth 2014; 24:5–9. An excellent review of the current understanding of cardiovascular physiology in the newborn. 16. Nafiu OO, Voepel-Lewis T, Morris M, et al. How do pediatric anesthesiologists define intraoperative hypotension? Pediatr Anesth 2009; 19:1048–1053. 17. Jones JE, Jose PA. Neonatal blood pressure regulation. Semin Perinatol 2004; 28:141–148. 18. Cayabyab R, McLean CW, Seri I. Definition of hypotension and assessment of hemodynamics in the preterm neonate. J Perinatol 2009; 29:S58–S62. 19. Joint Working Group of the British Association of Perinatal Medicine and the Research Unit of the Royal College of Physicians. Development of audit measures and guidelines for good practice in the management of neonatal respiratory distress syndrome. Arch Dis Child 1992; 67:1221– 1227. 20. Limperopoulos C, Bassan H, Kalish LA, et al. Current definitions of hypotension do not predict abnormal cranial ultrasound findings in preterm infants. Pediatrics 2007; 120:966–977. 21. Anand KJ, Hall RW, Desai N, et al. Effects of morphine analgesia in ventilated preterm neonates: primary outcomes from the NEOPAIN randomised trial. Lancet 2004; 363:1673–1682. 22. Bada HS, Korones SB, Perry EH, et al. Mean arterial blood pressure changes in premature infants and those at risk for intraventricular hemorrhage. J Pediatr 1990; 117:607–614.
23. Versmold HT, Kitterman JA, Phibbs RH, et al. Aortic blood pressure during the first 12 h of life in infants with birth weight 610 to 4,220 grams. Pediatrics 1981; 67:607–613. 24. Logan JW, O’Shea TM, Allred EN, et al. Early postnatal hypotension is not associated with indicators of white matter damage or cerebral palsy in extremely low gestational age newborns. J Perinatol 2011; 31:524–534. 25. Ahn SY, Kim ES, Kim JK, et al. Permissive hypotension in extremely low birth weight infants (1000 gm). Yonsei Med J 2012; 53:765–771. 26. Osborn DA1, Evans N. Early volume expansion for prevention of morbidity and mortality in very preterm infants. Cochrane Database Syst Rev 2004; CD002055. 27. Osborn DA, Paradisis M, Evans N. The effect of inotropes on morbidity and mortality in preterm infants with low systemic or organ blood flow. Cochrane Database Syst Rev 2007; CD005090. 28. Vutskits L. Cerebral blood flow in the neonate. Paediatr Anaesth 2014; 24:22–29. 29. Kuint J, Barak M, Morag I, Maayan-Metzger A. Early treated hypotension and outcome in very low birth weight infants. Neonatology 2009; 95:311–316. 30. McKeever S, Johnston L, Davidson AJ. Sevoflurane-induced changes in infants’ quantifiable electroencephalogram parameters. Paediatr Anaesth 2014; 24:766–773. 31. Kasdorf E, Engel M, Perlman JM. Amplitude electroencephalogram characterization in preterm infants undergoing patent ductus arteriosus ligation. Pediatr Neurol 2013; 49:102–106. 32. McLean CW, Cayabyab R, Noori S, Seri I. Cerebral circulation and hypotension in the premature infant – diagnosis and treatment. In: Perlman JM, editor. Neonatology questions and controversies: neurology. Philadelphia: Saunders/Elsevier Co; 2008. pp. 3–26. 33. Nagdyman N1, Ewert P, Peters B, et al. Comparison of different near-infrared spectroscopic cerebral oxygenation indices with central venous and jugular venous oxygenation saturation in children. Paediatr Anaesth 2008; 18:160– 166. 34. Lemmers PM, Zwanenburg RJ, Benders MJ, et al. Cerebral oxygenation and brain activity after perinatal asphyxia: does hypothermia change their prognostic value? Pediatr Res 2013; 74:180–185. 35. Hoffman GM, Brosig CL, Mussatto KA, et al. Perioperative cerebral oxygen saturation in neonates with hypoplastic left heart syndrome and childhood neurodevelopmental outcome. J Thorac Cardiovasc Surg 2013; 146:1153– 1164. 36. Kluckow M, Seri I, Evans N. Functional echocardiography – an emerging clinical tool for the neonatologist. J Pediatr 2007; 150:125–130. 37. Fanaroff JM, Wilson-Costello DE, Newman NS, et al. Treated hypotension is associated with neonatal morbidity and hearing loss in extremely low birth weight infants. Pediatrics 2006; 117:1131–1135. 38. Evans N. Management of hypotension and circulatory assessment on NICU. Early Human Dev 2005; 81:397–398. 39. Barrington KJ. Common hemodynamic problems in the neonate. Neonatology 2013; 103:335–340. 40. Hoffman TM, Wernovsky G, Atz AM, et al. Efficacy and safety of milrinon in preventing low cardiac output syndrome in infants and children after corrective surgery for congenital heart disease. Circulation 2003; 107:996–1002. 41. Alten JA, Borasino S, Toms R, et al. Early initiation of arginine vasopressin infusion in neonates after complex cardiac surgery. Pediatr Crit Care Med 2012; 13:300–304.
0952-7907 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.co-anesthesiology.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
313
