Special considerations in the premature and ex-premature infant

NEONATAL ANAESTHESIA

Special considerations in the premature and ex-premature infant

Learning objectives After reading this article, you should be able to: C define the terms prematurity, extreme prematurity and postmenstrual age C list the consequences of prematurity C describe factors associated with increased perioperative risk C explain the basic principles of anaesthetizing a premature infant

Geoff Frawley

Abstract Advances in neonatal medicine have progressively increased the survival of premature infants. Increased survival has, however, come at the cost of increased number of infants with prematurity related complications. This is represented by high rates of respiratory distress syndrome, bronchopulmonary dysplasia, necrotising enterocolitis, sepsis, periventricular leukomalacia, intraventricular haemorrhage, cerebral palsy, hypoxic ischaemic encephalopathy and visual and hearing problems in survivors. In addition to prolonged hospital stay after birth, readmission to hospital in the first year of life is common if chronic lung disease exists. Individual congenital conditions requiring surgical intervention in the neonatal period are uncommon. Neonates have a higher perioperative mortality risk largely due to the degree of prior illness, the complexity of their surgeries and infant physiology. It is important to consider contributing anaesthetic factors during the perioperative period that may affect cerebral perfusion and neurocognitive outcome, such as alterations in haemodynamics and ventilation. Outside of the neonatal period, the most common surgical procedures performed in ex-premature infants are inguinal hernia repair and ophthalmologic procedures due to retinopathy of prematurity. After even minor surgical procedures, ex-premature infants are at higher risk for postoperative complications than infants born at term.

Asia and sub-Saharan Africa.1 Preterm infants are also classified by birthweight as low birth weight (LBW <2500 g), very low birth weight (VLBW <1500 g) or extremely low birth weight (ELBW <1000 g). The limits of viability, considered to be between 22- and 26-weeks GA, vary widely among neonatal centres. The persistent decline in mortality in the ELBW infants with a concomitant decrease in severe neonatal morbidity has gradually lowered these limits. However, the increased risk of neurodevelopmental and behavioural disabilities remains high in children born at 24e25 weeks GA, so the viability limits remain broadly defined.

Consequences of prematurity Mortality and morbidity Perinatal mortality is inversely proportional to gestational age with the highest rates near the limit of viability (Figure 1). In a population-based British study (EPICure-2 study), the survival and morbidity of 3378 extremely preterm infants (22e26 weeks) born in 2006 were reported. The live birth rate was 60% with 83% requiring admission to an intensive care unit (ICU) and active resuscitation was withheld in 9%. The survival to discharge for all live births was 51%, and the survival for infants admitted to ICU was 62 percent. Among the infants who survived to discharge major morbidities occurred in 59% including bronchopulmonary dysplasia (68%), abnormal cerebral ultrasound (13%), laser treatment for ROP (16%) and laparotomy for necrotising enterocolitis (NEC; 8%). No major morbidity was reported in 41% of survivors to discharge. Although the risks of morbidity and mortality are much higher in early gestation (<34 weeks), late preterm birth (34e37 weeks) occurs more often and newborns born late preterm have a higher risk of adverse outcomes than babies born at term.2

Keywords Apnoea; bronchopulmonary dysplasia; premature infant; spinal anaesthesia Royal College of Anaesthetists CPD Matrix: 1A01,1C02, 2A03,2A05,2D02, 2G01,3D00

Definitions Neonates are defined according to both their gestational age (GA), their chronological age (CA or time elapsed from birth postnatal age) and their postmenstrual age (PMA, which is GA plus CA). These definitions replace older definitions such as postconception age (PCA). The World Health Organization (WHO) further defines preterm birth (birth <37 weeks), extremely preterm (<28 weeks); very preterm (28 to <32 weeks); and moderate to late preterm (32e37 weeks). The estimated global preterm birth rate is 10.6% which equates to 15 million live births in 2014 with 81% of these births occurring in

Chronic lung disease Bronchopulmonary dysplasia (BPD) is a chronic lung disease that remains one of the most prevalent long-term sequelae of premature birth. BPD in infants born less 32 weeks who require oxygen at 28 days of age is defined as severe if an FiO2 > 0.3 is required at 36 weeks PMA. Most infants currently developing BPD are born between 24 and 28 weeks’ gestational age, during the time of canalicular and saccular development. BPD in the post surfactant use era (‘new’ BPD) is characterized by uniform arrest of lung development, with simplified alveolar structures and dysmorphic capillaries. The severity of BPD is related to ventilator-induced barotrauma or volutrauma, oxygen toxicity, persistent patent ductus arteriosus and other unknown variables.

Geoff Frawley MBBS FANZCA is a Consultant Paediatric Anaesthetist at Royal Children’s Hospital, Melbourne and a Clinical Associate Professor, Department of Paediatrics, Melbourne University, Melbourne, Australia. Conflicts of interest: none declared.

ANAESTHESIA AND INTENSIVE CARE MEDICINE xxx:xxx

1

Ó 2019 Published by Elsevier Ltd.

Please cite this article as: Frawley G, Special considerations in the premature and ex-premature infant, Anaesthesia and intensive care medicine, https://doi.org/10.1016/j.mpaic.2019.12.002

NEONATAL ANAESTHESIA

Morbidity and mortality of premature infants. 100

Survival

IVH

23

24

PVL

NEC

BPD

ROP

Sepsis

90 80 Percentage

70 60 50 40 30 20 10 0 22

25 26 Gestation (weeks)

27

28

Low birth weight infants are not necessarily low gestation and may have suffered intrauterine growth retardation. IVH, intraventricular haemorrhage; BPD, bronchopulmonary dysplasia, NEC, necrotising enterocolitis; ROP, retinopathy of prematurity ; PVL, periventricular leukomalacia. For infants less than 1500 grams the incidences of mild, moderate and severe BPD were 13.5, 4.8 and 2.6% respectively

Figure 1

New neonatal ventilator strategies such as high frequency ventilation (HFV) and nasal CPAP may reduce the incidence. Essentially BPD patients have a lifelong susceptibility to respiratory complications after anaesthesia. BPD is associated with bronchial hyper-reactivity and these infants have an increased risk of perioperative bronchospasm and oxygen desaturation. BPD also renders the pulmonary capillary network vulnerable to pulmonary vasoconstriction in response to perioperative stimuli such as hypothermia and pain.

Neurological injury Ex-premature infants, especially those with severe neonatal brain injury, are more likely than term infants to have neurodevelopmental disabilities, including impaired cognitive skills, motor deficits and cerebral palsy, vision and hearing loss, and behavioural and psychological problems. The risk of these impairments increases with decreasing GA. Cardiac abnormalities There is a higher prevalence of cardiovascular malformations among infants born prematurely (12.5 cases per 1000 preterm infants versus 5.1 cases per 1000 full-term infants). The most common defects are pulmonary atresia with ventricular septal defect (23%); complete atrioventricular septal defect (22%); and coarctation of the aorta, tetralogy of Fallot, and pulmonary valve stenosis (each 20%).

Apnoea of prematurity Apnoea of prematurity is defined as cessation of breathing for >20 seconds or a shorter pause with bradycardia cyanosis or pallor. Recurrent prolonged apnoea and bradycardia occurs in most infants under 30 weeks’ gestation, in about 50% of infants at 30e32 weeks’ gestation and about 10% of those at 34e36 weeks’ gestation. Apnoea is primarily related to immaturity of the respiratory centre and control of upper airway with most apnoeas being a combination of central and obstructive apnoeas. Other contributing factors include sepsis, intraventricular haemorrhages, seizures, anaemia, hypoglycaemia, hypothermia, opioids and sedatives and general anaesthetics. The proportion of infants with apnoeas persisting beyond 38 weeks PMA is higher in infants born 24e26 weeks’ GA. Infants with BPD may have delayed maturation of respiratory control for as long as 2e4 weeks post term PMA. Treatment of frequent apnoeas is initially methylxanthines especially caffeine. Nasal continuous positive airway pressure (NCPAP) in conjunction with caffeine is effective in reducing the frequency and severity of apnoea.3

ANAESTHESIA AND INTENSIVE CARE MEDICINE xxx:xxx

Retinopathy of prematurity Retinopathy of prematurity (ROP) is a developmental vascular proliferative disorder that occurs in the retina of preterm infants with incomplete retinal vascularization. The most important risk factor for developing ROP is prematurity but more than 50 separate risk factors have been identified including elevated arterial oxygen tension, birth weight, supplemental oxygen, prolonged mechanical ventilation, Apgar score, anaemia, intraventricular haemorrhage (IVH), necrotising enterocolitis and sepsis. ROP typically begins about 34 weeks PMA but may be seen as early as 30e32 weeks.

2

Ó 2019 Published by Elsevier Ltd.

Please cite this article as: Frawley G, Special considerations in the premature and ex-premature infant, Anaesthesia and intensive care medicine, https://doi.org/10.1016/j.mpaic.2019.12.002

NEONATAL ANAESTHESIA

Transpupillary diode laser therapy is recommended as the first line treatment for ROP. Bevacizumab (avastin) is a vascular endothelial growth factor inhibitor used when laser surgery is contraindicated. The most common anaesthetic techniques involve sedation with analgesia, paralysis and ventilation in the neonatal unit or general anaesthesia in an operating theatre.

the child’s postconception age in weeks. The incidence of moderate hypotension in infants undergoing inguinal hernia repair was 3e4 times more common in those receiving general anaesthesia as compared to regional anaesthesia.6 A study using near infra-red spectroscopy (NIRS) in infants suggests hypotension is common but does not correlate well to cerebral desaturation events. A mean arterial pressure of >35 mmHg in anaesthetized neonates and infants <6 months preserves cerebral oxygenation (NIRS).

Laryngotracheal abnormalities Infants who require prolonged intubation can develop subglottic stenosis or tracheomalacia. In a study of 5000 paediatric intensive care admissions where low pressure high volume cuffed endotracheal tubes were used there was endoscopic evidence of tracheal pathology in 0.7% with acquired subglottic stenosis occurring in 0.15%.4 As a result, uncuffed ETTs are the airway of choice in ex-premature infants.

Perioperative morbidity and mortality: The incidence of perioperative morbidity is increased in ex-premature infants with the most frequent events being upper airway obstruction, laryngospasm, apnoea and post intubation stridor. In a retrospective analysis of premature infants who underwent emergency abdominal surgery the 30-day mortality ranged from 31% for infants born <24 weeks to 4.9% for those born at 35e36 weeks. Female sex, inotrope support, ventilator use, ASA class > 3 at time of operation were all significantly associated with increased mortality.7

Anaesthesia General principles It is well established that perioperative complications occur more frequently and are more severe in the neonatal population. As such all neonatal anaesthesia should occur in centres appropriate for ongoing management (NHS directive E02/S/c 2013/14 Paediatric Surgery: Neonates). The general principles include appropriate airway management, reliable intravascular access, maintenance of temperature and metabolic homeostasis and adequate analgesia. In a large prospective multicentre cohort study to determine the incidence and nature of severe critical. Events in children undergoing anaesthesia in Europe (APRICOT) the overall rate of complications was 5.2%. The incidence of cardiovascular and respiratory critical events was significantly higher in neonates (0e1 month) and infants (1 monthe1 year), with neonates having the highest rate of cardiovascular complications (12.1%). There was a significant effect of physical condition (ASA 3 or 4) and a protective role of an experienced anaesthetist (2% decrease in risk of cardiac severe critical events per year of experience.5 A prospective study to determine anaesthetic management of neonates and infants (NECTARINE) is yet to publish their findings. Perioperative cardiopulmonary assessment is essential in neonates presenting for surgery especially in those conditions associated with congenital cardiac conditions. Neonates with anorectal malformations or oesophageal atresia should have cardiac renal and cerebral ultrasound evaluation because of the high rates of VACTERL (vertebral anomalies, anal atresia, and cardiac, tracheoesophageal, renal/radial, and limb anomalies) syndrome. There is evidence that echocardiography in infants with congenital diaphragmatic hernia not only evaluates the underlying cardiac function and anatomy but may influence timing of surgical intervention. The 10-N quality paediatric anaesthetic model includes avoidance of fear and pain, maintenance of homeostasis, normotension, normal heart rate, normovolaemia, normoxaemia, normocarbia, normal electrolytes, normoglycaemia and normothermia. There is, however, a lack of normative data describing optimal intraoperative anaesthetized blood pressure. In premature infants a common rule that the MAP should not be less than

ANAESTHESIA AND INTENSIVE CARE MEDICINE xxx:xxx

Neonatal surgical emergencies Neonatal conditions requiring anaesthesia and surgery are uncommon but not rare. The most common conditions occur in the order of 1:10,000 live births (Table 1). In addition to the cardiac and chromosomal abnormalities there is a high proportion of neonates born prematurely electively or as a result of polyhydramnios. Many of the conditions are not detected antenatally. Congenital diaphragmatic hernia (CDH) is a malformation of the diaphragm that allows bowel to enter the thoracic cavity, resulting in pulmonary hypoplasia and pulmonary hypertension. The severity of pulmonary hypoplasia and hypertension are the major determinants of overall survival. The use of surfactant, nitric oxide and in rare cases extracorporeal membrane oxygenation has improved survival. Exomphalos is a midline defect where abdominal contents are covered by a thin peritoneal sac and gastroschisis is a herniation of bowel and other abdominal contents through an abdominal wall defect, just to the right of the umbilicus. Both are associated with chromosomal abnormalities (trisomy 13, 14, 15, 18 and 21) and syndromes, especially VACTERL. A tracheo-oesophageal fistula (TOF) is a congenital or acquired communication between the trachea and oesophagus occurring in 1:2000e4000 live births. The five main categories of congenital TOF include oesophageal atresia (OA) with distal fistula (87%), OA without fistula (8%), isolated TOF (4%), OA with proximal fistula (1%) and OA with proximal and distal fistula (1%). The H-type fistula occurs with an intact oesophagus. Necrotising enterocolitis occurs largely in premature infants with nearly 12% of infants <1500 g developing NEC and mortality exceeding 30%. Multiple factors, including hypoxia, feeding, sepsis, abnormal colonization of the bowel, and the release of inflammatory mediators stimulated by an ischaemicreperfusion injury in an immature gut, are thought to lead to NEC. Infants present for surgery with sepsis and intestinal perforation following failure of medical therapy. Symptomatic patent ductus arteriosus (PDA) is common in preterm neonates, occurring in about 30% of VLBW infants.

3

Ó 2019 Published by Elsevier Ltd.

Please cite this article as: Frawley G, Special considerations in the premature and ex-premature infant, Anaesthesia and intensive care medicine, https://doi.org/10.1016/j.mpaic.2019.12.002

ANAESTHESIA AND INTENSIVE CARE MEDICINE xxx:xxx

Neonatal surgery

Incidence

Comorbidities

Anaesthetic issues

Other

Intestinal atresia Anorectal malformations Oesophageal atresia

1:6,000 1:2000e5000 1: 3000

Bilious vomiting Sacral anomalies Tracheo-oesophageal fistula

Hyperchloraemic alkalosis Definitive repair at 3e6 months Mortality 4%

Congenital diaphragmatic hernia Necrotising enterocolitis

1e5:10,000

20% Trisomy 21 25% cardiac anomalies VACTERL syndrome VACTERL syndrome 30% cardiac anomalies Cardiac 30% Pulm HT

Complex ventilation nitric oxide ECMO Vascular access coagulopathy

Mortality 30%

Neurosurgical procedures Ex Premature infant surgery

Inguinal hernia repair Patent ductus arteriosus closure Laser for ROP

1.5/100,000 1e7% of NICU admissions 4:10,000

90% VLBW septic shock Meningo-myelocoele 0.2e0.4:1000

1e5% 6:10,000

Chronic lung disease Congenital heart disease

4% infants <1500 g

VLBW chronic lung disease

IVH 30% of infants <29 weeks 18% require shunt Apnoea Thoracotomy lung haemorrhage Prolonged surgery intubation required

Mortality 10e30% <1500 g

Significant spinal failure rate 7.9% vocal cord palsy post ligation TIVA peribulbar block possible

VLBW, very low birth weight (<1500 g); VACTERL, vertebral defects, anal atresia, cardiac defects, tracheo-oesophageal fistula, renal anomalies and limb abnormalities; IVH, intraventricular haemorrhage; ECMO, extracorporeal membrane oxygenation; PDA, patent ductus arteriosus; TIVA, total intravenous anaesthesia.

Table 1

NEONATAL ANAESTHESIA

4 Ó 2019 Published by Elsevier Ltd.

Please cite this article as: Frawley G, Special considerations in the premature and ex-premature infant, Anaesthesia and intensive care medicine, https://doi.org/10.1016/j.mpaic.2019.12.002

Common surgical procedures in neonates and ex-premature infants

ANAESTHESIA AND INTENSIVE CARE MEDICINE xxx:xxx

Technique

Agent

Pharmacokinetics

Dose modifications

General anaesthesia

Volatiles

MAC prems and newborns half MAC 1 e6months old low clearance at birth (0.03 L.min
1) PNA related increase

MAC Sevo 3.1% neonates

Propofol

Regional anaesthesia

Spinal Awake caudal Wound catheter

Multimodal analgesia

Paracetamol

Tramadol

lower plasma clearance and T1/2 elimination (7.6 vs 3.2 h) Median unbound and total levobupivacaine 0.02 and 0.3mg. L
1 Median unbound and total levobupivacaine 0.02 and 1.3 mg. mL
1 Clearance 51% lower preterm Elimination T 1/2 38% lower Clearance 84% of the mature value by 44 weeks PMA

0.1 mg kg
1 min
1 Bolus 0.5 mg kg
1

10-8-6 mg kg
1 h
1 model over predicts clearance by 216% 43% apnoea at 0.25 mg kg
1 min
1 Infusion 0.2e0.4 mg kg h
1

1 mg kg
1 3 mg kg
1 Bupivacaine 0.25% þ Adrenaline 0.125% at 0.2 mg kg
1 h
1

potential for local anaesthetic toxicity Described for PDA thoracotomy analgesia

28e32 weeks 10 mg kg
1 32e36 weeks 12.5 mg kg
1; 36 weeks 15 mg kg
1 1 mg kg
1

PMA adjusted 6 hourly dosing

MAC, minimum alveolar concentration; T½, half time; PNA, postnatal age; PMA, post menstrual age; PDA, patent ductus arteriosus.

Table 2

Comments

NEONATAL ANAESTHESIA

Remifentanil Dexmedetomidine

5 Ó 2019 Published by Elsevier Ltd.

Please cite this article as: Frawley G, Special considerations in the premature and ex-premature infant, Anaesthesia and intensive care medicine, https://doi.org/10.1016/j.mpaic.2019.12.002

Anaesthetic agents used for anaesthesia and analgesia and the dose modifications proposed from available pharmacokinetic studies in neonates

NEONATAL ANAESTHESIA

The PDA shunts blood flow from left-to-right resulting in increased flow through the pulmonary circulation and decreased perfusion of the systemic circulation. Persistent PDA shunting is associated with necrotising enterocolitis, periventricular haemorrhage, chronic lung disease and death. Significant respiratory or cardiac failure may prompt medical (indomethacin) or surgical closure.

Total intravenous anaesthesia (TIVA) Neonatal propofol clearance is only 10% that of the mature value at 28 weeks’ gestation, 38% at term and 90% of adult clearance by 70 weeks PMA. Postnatal age (PNA) may also have an additional effect on maturation of propofol clearance above that predicted by PMA. Predicted TIVA infusion rates (e.g. 24 mg kg
1 h
1 for the first 10 minutes in neonates) may cause delayed awakening, hypotension and an increased incidence of bradycardia in neonates and infants. Smaller infusion regimens targeting an effect site concentration of 3 mg L
1 are reported, but common effect measures used to assess depth of anaesthesia (spectral edge frequency, bispectral index, entropy, cerebral state index) are only validated in children older than 1 year.11 Propofol remifentanil anaesthesia has been reported as a useful technique for screening and laser photocoagulation of retinal vessels in infants with retinopathy of prematurity.

Operating in NICU Critically ill neonates in the neonatal intensive care unit (NICU) often require surgical procedures and the risks and benefits of surgical location need discussion. Transferring critically ill neonates to the operating theatre offers the best operating conditions but may increase perioperative risk. In a study of PDA ligation there was an increased risk of haemodynamic instability on transport postoperatively Surgery in NICU is recommended for neonates who require high-frequency oscillatory ventilation, inhaled nitric oxide therapy or extracorporeal membrane oxygenation (ECMO).

Pain management A multimodal approach to postoperative pain control, which may include local anaesthetic infiltration, peripheral nerve blocks, neuraxial techniques, and paracetamol is appropriate. When opioids are required, intensive monitoring or extended respiratory support may be required in the postoperative period.

Induction of anaesthesia Volatile induction is the preferred neonatal induction technique when difficult intubation is expected. The APRICOT study demonstrates that uncuffed tracheal tubes were more frequently used in neonates (69%) and in children younger than one year (56%). Positive pressure ventilation was recorded in 90% of children with an ETT. Almost all neonates were mechanically ventilated with pressure control ventilation (PCV) rather than volume control ventilation. The incidence of difficult intubation was higher in neonates (1%) and children under 1 year (1.1%) than any other age group (0.1e0.2%).8

Opioids and sedatives Limited data exist about long-term neurodevelopmental outcomes associated with sedatives and opioid analgesics in preterm neonates. Large randomized controlled trials in the Netherlands and the USA (NEOPAIN), and cohort studies (EPIPAGE in France) have advocated against the routine use of morphine infusions in mechanically ventilated preterm infants. Concerns about the effects of NMDA and GABA agonist has also curtailed the use of benzodiazepines. The use of clonidine or dexmedetomidine is increasing despite limited studies in neonates.

Maintenance of anaesthesia Traditionally, neonatal intravenous fluid replacement has been with 10% dextrose solution. Current recommendations are to use intraoperative and postoperative intravenous (IV) solution containing close to physiological concentrations of sodium.9 In a study of 34 neonates (0e7 days old) undergoing a variety of neonatal surgical procedures, a 12% overall incidence of postoperative hyponatraemia was reported with either 5 or 10% solutions. The reduction in plasma sodium correlated only to the amount of free water that is administered intraoperatively and not to the amount of free water administered before operation. Secondly, intraoperative free water administration in excess of 6.5 ml kg
1 h
1 was found to be associated with a postoperative reduction in plasma sodium (4 mmol L
1).10

Regional anaesthesia Both single shot and continuous central neuraxial analgesia are commonly used in neonatal anaesthesia. Awake spinal and awake caudal anaesthesia have an established role in reducing apnoea risk in ex-premature infants undergoing lower abdominal surgery, whereas local anaesthetic infusions through wound catheters have been described for management of thoracotomy pain in neonates. An increasing emphasis on the use of ultrasound guided central neuraxial anaesthesia has the potential to increase safety and effectiveness of regional anaesthesia. In all cases the potential for local anaesthetic toxicity is increased as a result of reduced protein binding and reduced metabolic capacity. Continuous epidural infusion of bupivacaine in neonates has demonstrated total drug accumulation after 48 hours and it is recommended that infusions are limited to no more than 72 hours. Unbound concentrations, however, remain constant.

Volatile anaesthesia All inhalation agents have been used in neonates. Neonates have a higher rate of uptake of inhalational anaesthetics due to their high cardiac output and increased minute ventilation. MAC is lower in neonates than in older infants and similar to older children. Sevoflurane is the preferred volatile and the perioperative cardiac arrest data suggests that the decreased use of halothane reduced the incidence of cardiac arrest in infants. Time to emergence is faster with desflurane than any of the other volatile anaesthetic agents; this may be particularly beneficial in the neonate in whom extubation is planned (Table 2).

ANAESTHESIA AND INTENSIVE CARE MEDICINE xxx:xxx

Anaesthetic-induced neuroapoptosis In 2016 the US Food and Drug Administration issued a warning that repeated or lengthy use of general anaesthetic and sedation drugs during surgeries or procedures in children younger than 3 years or in pregnant women during their third trimester may affect the development of children’s brains. Three prospective studies examining the influence of early anaesthetic exposure on

6

Ó 2019 Published by Elsevier Ltd.

Please cite this article as: Frawley G, Special considerations in the premature and ex-premature infant, Anaesthesia and intensive care medicine, https://doi.org/10.1016/j.mpaic.2019.12.002

NEONATAL ANAESTHESIA

neurodevelopment all refute this statement. The GAS study compared awake regional anaesthesia to sevoflurane and reported no differences in 2- and 5-year neurodevelopmental scores. The Pediatric Anesthesia & Neurodevelopment Assessment (PANDA) project compared children with a single anaesthesia exposure before age 36 months to siblings with no anaesthesia exposure reported no statistically significant differences in IQ scores in later childhood. The Mayo Safety in Kids (MASK) study also compared sibling’s neurodevelopment and cognitive functions between ages 8e15 years. Anaesthesia exposure before age 3 years was not associated with deficits in the primary outcome of general intelligence. The parents of multiply exposed children reported increased problems related to executive function, behaviour, and reading.

REFERENCES 1 Chawanpaiboon S, Vogel JP, Moller AB, et al. Global, regional, and national estimates of levels of preterm birth in 2014: a systematic review and modelling analysis. Lancet Glob Health 2019; 7: e37e46. 2 Pierrat V, Marchand-Martin L, Arnaud C, et al. Neurodevelopmental outcome at 2 years for preterm children born at 22 to 34 weeks’ gestation in France in 2011: EPIPAGE-2 cohort study. BMJ 2017; 358: j3448. 3 Eichenwald EC, Committee on F, Newborn AAoP. Apnea of prematurity. Pediatrics 2016; 137. 4 Greaney D, Russell J, Dawkins I, Healy M. A retrospective observational study of acquired subglottic stenosis using lowpressure, high-volume cuffed endotracheal tubes. Paediatr Anaesth 2018; 28: 1136e41. 5 Habre W, Disma N, Virag K, et al. Incidence of severe critical events in paediatric anaesthesia (APRICOT): a prospective multicentre observational study in 261 hospitals in Europe. Lancet Respir Med 2017; 5: 412e25. 6 McCann ME, Withington DE, Arnup SJ, et al. Differences in blood pressure in infants after general Anesthesia compared to awake regional Anesthesia (GAS study-A prospective randomized trial). Anesth Analg 2017; 125: 837e45. 7 Cairo SB, Tabak BD, Berman L, Berkelhamer SK, Yu G, Rothstein DH. Mortality after emergency abdominal operations in premature infants. J Pediatr Surg 2018; 53: 2105e11. 8 Engelhardt T, Virag K, Veyckemans F, Habre W, Network AGotESoACT. Airway management in paediatric anaesthesia in Europe-insights from APRICOT (Anaesthesia Practice in Children Observational Trial): a prospective multicentre observational study in 261 hospitals in Europe. Br J Anaesth 2018; 121: 66e75. 9 Sumpelmann R, Becke K, Brenner S, et al. Perioperative intravenous fluid therapy in children: guidelines from the Association of the Scientific Medical Societies in Germany. Paediatr Anaesth 2017; 27: 10e8. 10 Edjo Nkilly G, Michelet D, Hilly J, et al. Postoperative decrease in plasma sodium concentration after infusion of hypotonic intravenous solutions in neonatal surgery. Br J Anaesth 2014; 112: 540e5. 11 Morse J, Hannam JA, Cortinez LI, Allegaert K, Anderson BJ. A manual propofol infusion regimen for neonates and infants. Pediatr Anesth 2019; 29.

Surgery in ex-premature infants Inguinal hernia repair The incidence of inguinal hernias is approximately 3%e5% in term infants and 13% in infants born at less than 33 weeks’ gestation. Inguinal hernias in both term and preterm infants are commonly repaired shortly after diagnosis to avoid incarceration of the hernia. The most common postoperative event in expremature infants undergoing lower abdominal surgery is apnoea. In a meta-analysis of infants having hernia repair with halothane or enflurane, the reported average apnoea rates was 25%. Gestational age was inversely proportional to the risk of postoperative apnoea in expremature infants and anaemia was an independent risk factor. The GAS study has demonstrated a much lower rate of apnoea with sevoflurane anaesthesia and awake regional techniques. Overall noteworthy postoperative apnoea occurred in 4% of ex-premature infants. Early apnoeic episodes in the first 60 minutes in the recovery room were higher with general anaesthesia (3.4% versus 0.9%). While late apnoea rates were similar (regional 2.2% and general anaesthesia 2%), the general anaesthesia group was more likely to require bagmask ventilation or cardiopulmonary resuscitation to terminate the event. The postmenstrual age (PMA) below which expremature infants should have extended cardiorespiratory monitoring is debated, as are the optimal duration and type of postoperative monitoring. The most common are 50 weeks PMA and 12 hours apnoea free. A

ANAESTHESIA AND INTENSIVE CARE MEDICINE xxx:xxx

7

Ó 2019 Published by Elsevier Ltd.

Please cite this article as: Frawley G, Special considerations in the premature and ex-premature infant, Anaesthesia and intensive care medicine, https://doi.org/10.1016/j.mpaic.2019.12.002