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14 February 2014 No: 05 NECROTISING ENTEROCOLITIS L Solomon Moderator: A Torborg School of Clinical Medicine Discipline of Anaesthesiology and Critical Care CONTENTS INTRODUCTION ................................................................................................... 3 INCIDENCE .......................................................................................................... 4 PATHOPHYSIOLOGY .......................................................................................... 5 Intestinal maturity............................................................................................. 5 Microbial colonisation ...................................................................................... 5 Hypoxia-ischaemia ........................................................................................... 5 Other contributors ............................................................................................ 6 PATHOLOGY ....................................................................................................... 6 RISKS FACTORS ................................................................................................. 6 CLINICAL ............................................................................................................. 7 DIFFERENTIAL DIAGNOSIS OF SUSPECTED NEC .......................................... 9 LABORATORY TESTS ........................................................................................ 9 RADIOGRAPHIC FINDINGS .............................................................................. 10 MANAGEMENT OF NEC .................................................................................... 12 Medical ............................................................................................................ 12 Surgical ........................................................................................................... 12 South African Context .................................................................................... 14 ANAESTHETIC MANAGEMENT OF NEC.......................................................... 15 Anaesthetic Considerations .......................................................................... 15 Near-infrared spectroscopy (NIRS) ............................................................... 17 COMPLICATIONS .............................................................................................. 18 Early Complications ....................................................................................... 18 Late Complications ........................................................................................ 18 PREVENTION STRATEGIES ............................................................................. 19 Oral Antibiotics ............................................................................................... 19 Corticosteroids ............................................................................................... 19 Breast Milk ...................................................................................................... 19 Neonatal Hypoxia ........................................................................................... 20 CONCLUSION .................................................................................................... 20 REFERENCES.................................................................................................... 21 Page 2 of 24 NECROTISING ENTEROCOLITIS INTRODUCTION There were more than 14 million babies born preterm in 2010 making up 11% of all the live births worldwide. 1 Very low birth weight (VLBW) infants make up 1.5% of live births, but account for 50% of infant deaths in the United States. 2 The number of preterm infants born are even higher in Africa and Asia than elsewhere, and 31% of all premature infants are born in Africa where only about 7.4% occur in Europe and North America combined. This is due to numerous factors including lower levels of education, poor access to antenatal facilities as well as a larger total number of deliveries in these regions. 3 Definitions Category Weight Low birth weight (LBW) <2500g Very low birth weight (VLBW) <1500g Extremely low birth weight (ELBW) <1000g ELBW infants in South Africa also have a poor rate of survival as demonstrated in the data collected in a study published in 2013 of infant survival. Infant survival in under 1000g in a single centre in South Africa 2012 120 100 80 Number of infants who died 60 Number of infants that survived 40 20 0 <500g <600g <700g <800g <900g 4 ELBW and VLBW infants are predisposed to several morbidities during their hospitalisation including infections, necrotising enterocolitis (NEC), chronic lung disease, intraventricular haemorrhage, periventricular leukomalacia, and retinopathy of prematurity. 5 Over time there has been improved survival of these infants. This is mostly due to improved Neonatal Intensive Care Units (NICUs) but with this increasing survival of ELBW and LBW infants the incidence of NEC remains on the rise. Although NEC does not only occur in premature infants, nearly 90% of patients who develop NEC are premature. Page 3 of 24 INCIDENCE NEC is the most common and most deadly disease affecting the gastrointestinal system of premature infants. Prematurity is the most constant risk factor for developing NEC, with incidence and mortality from NEC both inversely related to birth weight and gestational age. 6 The incidence worldwide is estimated to be between one to three cases per 1000 live births. It is seen in 1–8% of NICU admissions. 7 Approximately 7-10% of VLBW infants suffer from NEC, and almost 20% of these will be suspected of having NEC at some point during their postnatal care. NEC has an incidence of 5-6% of infants from 501g to 1500g.5 The disease appears to display neither gender nor ethnic predilection.6 While the survival of premature infants has improved and most of the major morbidities during hospitalisation (infections, chronic lung disease, periventricular leukomalacia and retinopathy of prematurity) have decreased, only intraventricular haemorrhages and NEC have not declined. 5 Causes of death according to the PPIP classification4 Cause of death n % Extreme multi-organ immaturity 179 63.9 RDS 71 25.9 Sepsis 12 4.29 NEC 5 1.79 Asphyxia 4 1.43 IVH 2 0.71 Others 7 2.52 Total 280 100 NEC is associated with a high mortality (reported between 19–50%), even in developed countries, with little improvement over the last two decades.8 With these advances in neonatal care there has been a substantial rise in the cost of treating patients with NEC. 9 Page 4 of 24 PATHOPHYSIOLOGY The pathophysiology of this condition is unclear. It is suggested there is a multifactorial cause with a combination of a genetic predisposition, intestinal immaturity, and an imbalance in micro vascular tone, abnormal microbial colonization in the intestine and immunoreactive intestinal mucosa. Intestinal maturity The chance of intestinal injury is increased in the premature infant by numerous factors including immaturity of digestion, motility, absorption, barrier function, immunity as well as circulatory regulation. 10 There is decreased gastric acid secretion in the preterm infant which has been linked to NEC; this may be particularly relevant in infants receiving H2 blockers in the NICU.11 There is an increased inflammatory response to luminal microbial stimuli in the preterm infant which change the protective barriers in the intestine. There is increased expression of toll-like receptor 4 (TLR4) compared with an adults. There is also decreased nuclear factor κB (NF-κB), which regulates inflammation. 12 The enterocytes in the preterm infant may not be equipped for the excessive stimulation of initial postnatal colonisation. The serum levels of several cytokines and chemokines that recruit inflammatory cells are increased in those with NEC compared with unaffected preterm infants. Interleukin-8, 13 mediates the migration of neutrophils to the site of inflammation and their activation, can cause necrosis and increased production of acute-phase proteins in the gut.14 Microbial colonisation The theory that inappropriate microbial colonisation is implicated in the development of NEC is supported by the fact this condition does not occur until at least 8 to 10 days after birth which coincides with the colonisation of the gastrointestinal system with anaerobic bacteria. Infants with NEC often have associated bacteremia.15 Unfortunately, no organism has consistently been implicated and studies suggest that the disorder is associated with both unusual intestinal microbial species and an overall decrease in the usual intestinal flora especially after prolonged antibiotic therapy. The immature enterocytes cause an excessive immature inflammatory response to these organisms and it is this reaction that is currently considered to be the most likely basis for the pathogenesis of NEC. Hypoxia-ischaemia The role of hypoxia–ischaemia is being questioned. However, hypoxia and ischemia do influence the microvascular tone due to production of vascular regulators such as nitric oxide and endothelin, which probably do play a role.16 Mucosal ischaemia arises from a neonatal insult resulting from factors such as a decrease in end diastolic blood flow, foetal distress, cold exposure, asphyxia, hypotension, congenital heart disease, or sepsis. Intestinal ischaemia results in local production of free radicals and initiates a cytokine cascade discussed above.7 Page 5 of 24 Other contributors Previously umbilical catheters we suggested as causative in NEC pathogenesis as well as parenteral nutrition. Both have been proven not to cause an increase in NEC. 17 The transfusion of red cell concentrate has also been implicated but whether or not this is contributory is unclear. 18 PATHOLOGY NEC is characterised by bowel wall necrosis of variable thickness, which leads to perforation in up to one-third of cases 20 NEC usually begins in the mucosal layer of the bowel. Bacterial hydrogen gas in the intestinal wall is often seen as intramural progression occurs (pneumatosis intestinalis). This gas may extend into the vessels and into the portal vein seen radiographically as portal venous gas. Macroscopically, there is considerable variation in the degree of bowel involvement from a minor inflammatory response of the bowel to full thickness necrosis. This may involve varying lengths of the intestine. The terminal ileum and caecum are most commonly affected, and it may affect the entire bowel and parts of the stomach. The affected bowel frequently extends beyond the macroscopic disease seen at surgery. 21 At surgery, the serosal surface is characterised by patches of full thickness necrosis, oedema, and subserosal haemorrhages in affected portions of bowel. Pneumatosis intestinalis may be seen and felt in the bowel wall and may extend into the mesentery. Perforation of transmural necrotic patches is common, with subsequent gross contamination and peritonitis. 21 RISKS FACTORS The most important risk factors for developing NEC are prematurity and formula feeding (including the timing of feeding). 22 Other risk factors associated with the pathogenesis of NEC are many in number and their relevance and extent to which they contribute is unclear. Factors which are may be more relevant in developing countries include antenatal factors, such as impaired umbilical artery flow, multiple pregnancy, and maternal infections, including HIV. 23 In the term neonates, the disease usually occurs in the first week after birth and is associated with other problems, such as maternal illicit drug use, intestinal anomalies (e.g., aganglionosis or atresias), congenital heart disease, and perinatal stress that may affect mesenteric blood flow.24 The suggested risk factors: Prematurity Enteral feeding (although about 10% of cases occur in infants never fed) Formula feeding (6 times more common than if only breast milk fed) Page 6 of 24 Hypertonic feeds Rapid introduction of enteral feeds Bowel ischaemia in term infants Cardiac surgery Patent ductus arteriosus Cyanotic congenital heart disease Polycythaemia Exchange transfusion Thrombocytosis Anaemia Abdominal surgery (esp. gastroschisis, intestinal atresia) Endocrine abnormalities Intrauterine growth restriction Placental abruption Premature rupture of membranes Perinatal asphyxia Low Apgar score Umbilical catheterisation (conflicting results) Hypoxia and shock Fluid overload Pathogenic bacteria Drugs (indomethacin, theophylline) 25 CLINICAL There are three forms of neonatal intestinal injury that occur in neonates. These are gastrointestinal abnormalities, spontaneous intestinal perforations, and classic NEC. Spontaneous intestinal perforations are often incorrectly labelled as NEC but seem to represent a different disease entity with different pathogenesis. Spontaneous intestinal perforation usually occurs earlier than NEC (in the first several days after birth) and is not associated with enteral feeding. There is little intestinal inflammation and necrosis in this condition with low levels of serum inflammatory cytokines. 27 Many of the signs of NEC are non-specific and can be part of numerous pathologies which makes this condition easy to miss. Infants with acute NEC usually present with both specific gastrointestinal signs as well as nonspecific physiologic signs often indicative of generalised infection. The classic history for a patient with NEC is a premature infant within 2 weeks of delivery who begins to develop feeding intolerance, distension, and blood per rectum after the initiation of formula feeds. The most common gastrointestinal signs reported are abdominal distension and blood per rectum. 26 Page 7 of 24 Gastrointestinal signs: Feeding intolerance Abdominal distension Blood per rectum Bilious emesis Haematemesis Nonspecific physiologic signs: Hypotension Temperature instability Apnoeic spells (with bradycardia) Lethargy Glucose instability Physical findings (can be subtle): Mild distension Tenderness Palpable bowel loops Inflammatory mass Erythema or oedema of the abdominal wall Numerous classification systems exist all with varying limitations. The most widely used is the ‘Modified Bell’s staging criteria’ 19 Table showing the Modified Bell’s Criteria and the Relevant Management Page 8 of 24 19 DIFFERENTIAL DIAGNOSIS OF SUSPECTED NEC Dysmotility of prematurity Septic ileus Bowel obstruction Gastroenteritis Anal fissure Cow’s milk protein sensitive enterocolitis Malrotation of the intestines with midgut volvulus Hirschsprung’s disease Intestinal atresia Intussusception Gastro-oesophageal reflux disease 19 LABORATORY TESTS The most commonly seen abnormalities seen in NEC are: Increased C-reactive protein Thrombocytopenia (80–90%) o platelet count of less than 100×109/L or a sudden fall in platelets was a poor prognostic indicator 28 Increased blood lactate Metabolic acidosis Hyponatraemia Low absolute granulocyte count, Leucopenia, high ratios of immature to total leukocyte counts (I/T ratios) Clotting abnormalities 29 Page 9 of 24 RADIOGRAPHIC FINDINGS Abdominal x-ray where the upper arrow points to portal air and the lower arrow points to a ring of intramural gas (pneumatosis intestinalis). Plain radiography remains the imaging modality of choice in the diagnosis of NEC. In 70% of cases, the diagnosis is established by the presence of pneumatosis intestinalis on plain abdominal radiograph. Abdominal x ray showing pneumatosis intestinalis in the right colon (arrow). Page 10 of 24 Contrast studies, such as computed tomography (CT) and magnetic resonance imaging (MRI) scans, have not been proven to be clinically useful in the evaluation of patients with NEC. A recent study has suggested a possible role for ultrasound due to its increased ability to detect intra-abdominal fluid, bowel wall thickness, and bowel wall perfusion. The resources available in developing countries may limit the applicability of ultrasound in such regions. 19 Nonspecific signs diffuse gaseous distension asymmetric, disorganised bowel pattern ‘featureless’ loops dilated bowel loops bowel wall thickening increased peritoneal fluid ascites (ground-glass appearance) thickening of the abdominal wall due to cellulitis 19 Diagnostic signs persistent loop or constant (“fixed”) small bowel loop present on serial x-rays remain unchanged in position over 24 to 36 hours (indicates necrotic loop of non peristalsing bowel) pneumatosis intestinalis (pathognomonic) submucosal air - bubbly or cystic appearance (may be confused with stool but stool usually moves on serial x-rays) subserosa air -linear or curvilinear appearance portal venous gas pneumoperitoneum (although may not be due to NEC indicates perforation) outline of falciform ligament highlighted by intraperitoneal air (“football sign”) outlining of the intestinal wall between two gas lucencies (“Rigler’s sign”) 30 Decubitis abdominal x-ray demonstrating pneumoperitoneum (arrow) and Rigler’s sign. Page 11 of 24 MANAGEMENT OF NEC Medical Initial management of acute NEC consists primarily of supportive care. Feeding should be stopped and decompression of the stomach achieved with an orogastric tube. Aggressive intravenous fluid resuscitation is critical in the early phase of NEC to prevent exacerbation of intestinal hypoperfusion. A urinary catheter should be placed to help monitor urine output and adequacy of resuscitation. Blood and urine cultures should be taken, and broad-spectrum antibiotics should be started. Currently, the recommended antibiotic therapy regimen includes ampicillin (gram positives), gentamycin (gram negatives), and clindamycin or metronidazole (anaerobes). In some of the literature several gram-negative bacteria resistant to ampicillin or gentamycin were isolated.31 Antibiotic strategies should be tailored to the local resistance patterns. 32 In addition to clinical exams and haemodynamic monitoring, disease progression should be monitored by using serial abdominal radiographs, ideally obtained every 6 to 8 hours. Daily x-rays may be adequate if there are cost restraints. Many institutions use supine abdominal images along with cross table lateral images, which allow the infants to remain supine, thereby minimising repositioning of the unstable patients. Alternatively, decubitus films often more clearly demonstrate pneumoperitoneum. If repeat radiographs display an unchanged or improving pattern of pneumatosis intestinalis, then expectant management may be continued, provided that the infant remains haemodynamically stable. 21 In the absence of surgical indications, acute medical management of patients with suspected NEC includes the following: 1. Resuscitation: intravenous fluids, orogastric decompression, careful control of acid-base balance, correction of electrolyte abnormalities, inotropes and ventilator support as required and analgesia. 2. Omit oral feeds and medications: use total parenteral nutrition (TPN) 3. Broad-spectrum antibiotics: guided by cultures and local microbiological profile. 4. Management of thrombocytopenia and abnormal clotting profile; important due to the potential for cerebral bleeds. 5. High index of suspicion for complications: frequent monitoring and reassessment as well as x-ray monitoring in the acute patient to look for pneumoperitoneum (6 to 8 hourly or as clinically indicated). 6. Early surgical consultation. 19, 21 Surgical Approximately 27-63% cases with NEC will require surgical intervention. Indications for surgical intervention focus on signs of perforation or impending perforation. Development of pneumoperitoneum on abdominal radiograph is considered an absolute indication for surgical intervention. Page 12 of 24 Other signs, such as a fixed loop on abdominal radiographs, an abdominal mass or erythema of the abdominal wall on physical exam, positive paracentesis, or little to no clinical improvement despite optimal medical management, are relative indications. Some suggest that portal venous air on radiography require surgical intervention due to its associated poor prognosis (up to 70% mortality), although this is not a universally accepted view. With the exception of evidence of pneumoperitoneum, the timing and method of surgical intervention must be made based on individual cases. 7, 33 The objectives of surgical management are to remove the necrotic bowel, preserve bowel length, divert faeces if required and control sepsis. There are generally accepted principles in the operative management of perforated NEC which have become standard. These guidelines include: 1. aggressive perioperative resuscitation including inotropic support as required 2. expedient and minimally invasive surgical intervention to attempt to limit the physiologic insult 3. evaluation of the entire intestine with resection of only necrotic or perforated bowel 4. diverting enterostomy proximal to intestine of questionable viability 5. preservation of the ileocecal valve if possible 7 There are several surgical options in the management of a critically ill infant with perforated NEC. The choice of operative intervention depends of numerous factors including the gestational age and physiologic status of the infant, institutional resources, and surgeon preference based on experience. This is in the form of either a peritoneal drain (PPD) or a laparotomy. Surgical procedures may involve exploratory laparotomy with resection of diseased bowel, and enterostomy with creation of a stoma or primary repair depending on the severity of the illness. An intermediate option is laparotomy with intestinal resection and delayed anastomosis 48 to 72 hours later. Finally, primary peritoneal drainage for perforated NEC may help to resuscitate and treat a critically ill infant initially, and in some instances, may be definitive operative intervention. 34 As to which of these options is superior and in what circumstances, there is much debate. Two large multicentre studies have attempted to clarify the situation. The first concluded that the type of procedure does not influence survival or other clinically important early outcomes. 35 The second study also showed no significant differences in outcomes between the groups, but it showed that infants treated with peritoneal drainage very often required a subsequent laparotomy.36 Further analysis of data from the latter study examined whether peritoneal drainage improved the patient’s immediate clinical status, and it showed no improvement when peritoneal drainage was used for this purpose.37 In addition, a systematic review of several studies suggested mortality was increased by more than 50% with peritoneal drainage as compared with laparotomy.38 Page 13 of 24 It is difficult to compare findings of different studies done on this subject. Many of the studies are small while others have wide ranging and vague criteria for selecting the various options. PPD are usually used in the smaller infants and those with the most deranged physiology making comparison of mortality and morbidity difficult. Many of the studies also included spontaneous intestinal perforations in the laparotomy group which are known to have better outcomes than NEC patients. The mortality of those treated with PPD is between 37 and 65%. 39 Primary peritoneal drainage is performed by using a 0.5-1cm incision to evacuate the peritoneum of all faecal and purulent material followed by aggressive irrigation and placement of a drain. Advocates of primary laparotomy argue that many patients with NEC treated initially with peritoneal drainage require subsequent laparotomy and therefore primary laparotomy would minimise the number of surgical interventions in these patients. It has also been suggested that peritoneal drainage may be particularly suited to the treatment of infants less than 26 weeks gestational age or who weigh less than 1,000 g because isolated intestinal perforations are more frequently encountered in this patient population. 40 In regions with scarce resources and a shortage of skilled personnel, primary peritoneal drainage may be the best initial option for all NEC patients who meet the criteria for surgical intervention. 41 Most authors agree that the extent of surgical intervention should be determined by the degree of bowel involvement encountered at laparotomy. Approximately 50% of infants with acute NEC present with focal disease, and the other 50% present with multiple areas of involvement. Nearly 20% of infants treated surgically for NEC are found to have involvement encompassing greater than 75% of the total intestine. 35 South African Context The success seen in the treatment of NEC has mostly been attributed to advanced neonatal intensive care. This is suggested as the most important reason why NEC treatment rates are much poorer in less developed countries. It has been suggested that those institutions without advanced neonatal care may need more aggressive surgical intervention which may lead to improved survival. In the study, conducted in Johannesburg, 450 neonates with NEC were treated with a more aggressive surgical protocol, and results were compared to prior data collected using previous protocols. The aggressive surgical protocol consisted of: 1. Laparotomy in all patients with radiological perforation within 8 hours. 2. Any neonate with peritonitis on clinical exam is actively resuscitated and reexamined in 4–6 hours. Continuing peritonitis leads to laparotomy within 4 hours. 3. If the main area of disease is found to be in the ileocolic region, extended colonic resection for all macroscopic disease is performed with ileostomy. Page 14 of 24 4. In the cases of multiple areas of perforation or necrosis, only the most obvious necrotic or perforated bowel is excised with anastomosis or enterostomy, and a second-look laparotomy is performed in 3-4 days. The authors reported an overall decrease in mortality rate from 82% to 48%, with the institution of the more aggressive surgical protocol. Infants with active disease involving a limited length of the terminal ileum and colon received the greatest benefit from the more aggressive protocol. Each individual hospital use the protocol suitable for the local resources available.42 ANAESTHETIC MANAGEMENT OF NEC Anaesthetic Considerations Resuscitation The infant should be resuscitated before surgery however in the life threatening situation the resuscitation can continue while the surgical intervention continues. While many suggest vague guidelines, the following have been proposed as appropriate endpoints for resuscitation: Sodium >135mmol/l Chloride >100mmol/l Serum bicarbonate <28-30mmol/l Potassium >3mmol/l Urinary Chloride >20mmol/l 64 One method to obtain these goals is to bolus 20ml/kg to correct dehydration and to run 0,45% Saline with 5% glucose at 6-8ml/kg/hr. Potassium is added to this regime once urine output has been established and depends on the serum potassium of the patient. 64 A very unstable infant with NEC will require the surgical intervention to be performed on the NICU in extreme circumstances. After an initial urgent intervention such as the insertion of an abdominal drain, subsequent operative procedures can be carried out in the operating theatre once haemodynamic stability has been obtained. 43 NEC babies often require large volumes of intravenous fluid (Ringer’s lactate is most commonly used) along with appropriate maintenance fluids to maintain normoglycaemia.44 Frequently, severely ill infants with NEC require inotropic support to maintain adequate perfusion. The assessment of intravascular volume and blood loss may be challenging. High infusion rates of 20 ml/kg together with boluses may be required as replacement fluid to maintain adequate circulating volume. 45 A good urine output may reflect an adequate perfusion pressure and hence correlate with an increased survival from an episode of severe NEC. Page 15 of 24 Coagulation defects Neonates with severe sepsis commonly have coagulation defects. Thrombocytopenia is present in many and platelet counts <100 000/mm3 predict a poor outcome. In patients with NEC, however, prophylactic platelet transfusions in the absence of bleeding have not been shown to be beneficial. There are no clear guidelines for septic neonates presenting for surgery, but it is suggested that platelets are transfused in neonates with low platelet counts prior to surgery, aiming for at least 50 000/ mm3. If there is active bleeding, higher platelet counts may be appropriate. Fibrinogen level is commonly low in these patients. Fibrinogen concentration should probably be >0.5 g/dl prior to surgery and higher if there is active bleeding. Plasma is often transfused, although there are concerns that the volume required to be efficacious in this group is prohibitive. Use of agents, such as antifibrinolytic drugs and rVIIa, are likely to carry a high risk of thrombosis and should generally be avoided. 66 Red cell transfusions The evidence for the appropriate transfusion trigger for these neonates is limited. The degree of prematurity however, is important and most neonates <1000g will require a transfusion at some point in there NICU stay. The degree of illness also plays a significant role in predicting the need for transfusion and the infants with more severe NEC are more likely to require blood. The Suggested Haemoglobin Targets for Neonates65 Haemoglobin Target 12-13.0 g/dl 10.0-11.0 g/dl 8.0-10.0 g/dl 7-8 g/dl 10.0g /dl Condition severe cardiopulmonary disease moderate cardiopulmonary disease symptomatic anaemia late anaemia, stable patient major surgery There is also little evidence guiding the optimal Haemoglobin (Hb) for neonates undergoing major surgery. An Hb of 10.0g/dl is suggested because of limited ability of the neonate’s heart, lungs and vasculature to compensate for anaemia. Additional factors include the decreased offloading of oxygen by foetal Hb and the developmental impairment of neonatal renal, hepatic and neurological function. These transfusion guidelines have to be individualised depending on the situation.65 General considerations Standard routine monitoring is used, while central venous pressure and invasive arterial pressure monitoring are useful. This may be difficult in the infant in severe shock. Infants are intubated and ventilated. The patients presenting with NEC for surgery are usually very sick and body temperature monitoring and active warming measures, including a warm theatre, a forced-air blanket, warmed fluids and a humidifier in the circuit are imperative. 44 Page 16 of 24 Anaesthetic technique Preterm babies undergoing surgery show an increased neuroendocrine response. Induction with a high dose of opioid (e.g. fentanyl 10 mcg/kg) 45 helps to avoid the complications caused by the systemic stress response. The neonates have been in the NICU for a while before developing NEC and might require higher doses of intraoperative opioids due to opioid tolerance. Nitrous oxide is contraindicated as it worsens bowel distension. The use of volatile anaesthetic agents, although not contraindicated, should be used cautiously due to the risk of haemodynamic instability. 26 Near-infrared spectroscopy (NIRS) Cardiac arrest is the most common cause of death in the perioperative period and ischaemic injuries to brain, gut, and kidneys are important causes of morbidity. The major causes of cardiac arrest in anesthetised neonates are cardiovascular usually as a consequence of underestimation of hypovolemia and haemorrhage. 67 Standard hemodynamic monitors provide little data and only approximate the circulatory status of the neonate. Small probes and blood pressure cuffs can also be unreliable. Standard vital sign parameters are not highly predictive of the degree of circulatory failure and often underestimate the oxygen supply: demand mismatch. 68 Biochemical indicators of organ hypoperfusion (blood lactate, unmeasured anions and base deficit) correlate with the severity of oxygen debt and mortality and are one option for monitoring but cannot be continuously measured so lag behind circulatory changes. Systemic venous oxygen (SvO2) saturation monitoring also provides an estimate of global oxygenation. SvO2-guided resuscitation is associated with improved outcomes in shock. Central lines are invasive, however, and repeated sampling will deplete the infant’s blood volume. 68 Near-infrared spectroscopy provides non-invasive continuous monitoring of the venous part of regional circulations. It can approximate organ-specific and global measures to enable the detection of circulatory abnormalities and to guide goaldirected interventions to reduce ischaemic injury. It is commonly used to measure regional tissue oxygenation and perfusion.The regional oxygen saturation (rSO2) approximates regional venous saturation. This in combination with the arterial oxygen saturation allows for the estimation of regional oxygen use. In normal newborns in the first week of life, the average resting cerebral rSO2 (rSO2C) was 77%, resting somatic-renal rSO2 (rSO2S) 86 %, and somatic-renal to cerebral difference (DrSO2SC) was 9%.69 The ability to decrease oxygen debt in sepsis is associated with improved survival. Physiologic measures associated with survival include the ability to increase cardiac index and oxygen delivery. Outcomes in septic shock are improved when goal-directed treatments include optimisation driven by SvO2 measurement. Paediatric multisite NIRS monitoring approximates SvO2 measurements and allows goal-directed treatments to begin earlier. 70 Regional oximetry in premature infants aids in the recognition of Page 17 of 24 potentially devastating complications such as NEC. Mesenteric/splanchnic somatic oximetry has shown potential as a continuous non-invasive monitor in the detection of mesenteric perfusion. 71 In preterm infants, reduced splanchnic NIRS correlates with feeding intolerance and NEC. 72 COMPLICATIONS NEC has a high mortality which is reported as up to 50%. Smaller infants, those with large amounts of intestine involved and infants requiring surgery have the highest mortality rates. With improvements in critical care the survival of patients with NEC has been improving. With this comes an increasing awareness of the post-operative complications and long term outcomes of these patients. Infants <28 weeks gestation have up to 47% complication rate while those that are older have a 29% complication rate. 46 Early Complications Approximately 39% of NEC patients who have surgery develop a complication related to the wound. 46 Laparotomy had a 7.9% incidence of wound dehiscence while PPD 1.3%. The overall incidence of postoperative intestinal stricture has been reported at 10.3% and intra-abdominal abscesses occur in 5.8%, both in the laparotomy and the peritoneal drain group. The overall rate of prolonged parental nutrition (>85 days) was 11% in both group. 47 Late Complications Late complications often become chronic conditions. Infants with NEC stage II or worse have a higher risk of long-term neurodevelopmental impairment compared to those VLBW without NEC. 48 The reason for this is not clear. One study reported up to 20% of NEC survivors had severe neurological deficits and 49% had significant neurodevelopmental delay. Neurological deficits included auditory and visual impairment. 49Late surgical complications include late colonic strictures, incisional hernias, adhesive bowel obstruction and short bowel syndrome. Short bowel syndrome has been reported to have a 33% mortality. Recurrent infections and gastrointestinal tract complaints requiring hospital admission are frequent. 49 . Page 18 of 24 PREVENTION STRATEGIES Preventative measures try to target the proposed mechanisms of NEC. Some approaches include: 1. administration of prophylactic oral antibiotics to decontaminate the GIT 2. administration of glucocorticoids to accelerate epithelial cell maturation 3. administration of breast milk, which is immunologically active and trophic for the intestinal mucosa Oral Antibiotics The theory behind the use of antibiotic treatment is that decontamination of the GIT may prevent pathogens from entering the bowel wall after mucosal breakdown. The results of trials on this topic have been mixed. One trial showed early introduction of gentamycin and amoxicillin in cases of suspected NEC to have a protective effect. 50 However, subsequent trials failed to demonstrate a reduced incidence of NEC in patients receiving prophylactic antibiotics.51 The use of prophylactic antibiotics in the prevention of NEC remains controversial and is not commonly practiced due to the potential for antibiotic resistance and pseudomembraneous colitis. Probiotic bacteria administration is also being investigated in NEC prevention but further studies are required. 52 Corticosteroids A large multicentre trial showed that there was a decreased number of infants who developed NEC if the mothers received prenatal steroids. 53 The Cochrane database, however, demonstrated no benefit to prenatal steroids in NEC from 15 randomised trials. The question of whether steroids should be used in the prevention of NEC remains unresolved. 54 Breast Milk It has been shown that neonates fed with human breast milk are 6-10 times less likely to develop NEC. In the same study, delayed enteral feeding was also associatedwith a decreased incidence of NEC. The precise reason of this protective affect is not clear. 55 Possible protective substances in breast milk include macrophages, neutrophils, lymphocytes, lactoferrin, oligosaccharides, growth factors, and immunoglobulins. 56 There are also many other issues involved around breast feeding. One is the speed at which feeds are introduced. Some have suggested the rate of the advancement of feeds are an important risk factors for NEC. 57 Others have not shown that slow advancement increases the risk of NEC. 58An option in those infants where feeding has been stopped is that of trophic feeds to try obtain the benefits of breast milk. Trophic feeding is defined as the use of minimal enteral feeds (continuous drip of less than 1 ml/hour) with parenteral nutrition. This has been shown to decrease feeding intolerance, shorten the duration of time to regain birth weight, and decrease the incidence of NEC. 59, 60 Page 19 of 24 There has also been a lot of work done on changing the chemical composition of formula milk, by reducing protein content, adding prebiotics, growth factors, or secretory IgA to modify intestinal development. There have been a number of reports of infants developing NEC following the addition of commercial fortifiers. 61 A key component of feeds that may be a modifiable risk factor for NEC is osmolarity. 62 Osmolarity is also altered but incorrect dilution of formula feeds and mixing formula with breast milk. For those unable to breast feed, donor milk is a viable alternative in NEC prevention. Table demonstrating some of the investigated prevention strategies and their efficacy.19 Neonatal Hypoxia Recurrent apnoea, respiratory distress, ventilation and umbilical artery catheterisation all may cause hypoxia and have all been implicated in the development of NEC. The proposed reason is that of diversion of cardiac output away from the gut. The use of hyperbaric oxygen therapy was attempted in rat models was shown to significantly reduce the severity of NEC but human trials are lacking. 63 Prevention of hypoxia in the premature infant is a very important prevention strategy. CONCLUSION NEC is a disease with a high morbidity and mortality which occurs predominantly in premature infants. The pathophysiology of this disease is unclear making it difficult for clinicians to know what to avoid. Only prematurity, which can be prevented by better antenatal care, and formula feeding have been well proven causes of NEC. As neonatal care improves, more premature infants survive leading to higher rates of NEC. Once the infant has developed symptoms and radiological evidence of the disease, the disease must be graded and then either medical or surgical management commenced. Medical management only being appropriate for the less severe forms. As this disease may be difficult to diagnose, clinicians must be vigilant especially in high risk groups. As anaesthesiologists, one may be involved in the resuscitation or the anaesthetic and on-going resuscitation in theatre. Page 20 of 24 REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. Blencowe H, Cousens S, Oestergaard MZ, Chou D, Moller AB, Narwal R, Adler A, Vera Garcia C, Rohde S, Say L, Lawn JE. National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications. 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