Download necrotising enterocolitis

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
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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.
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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
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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
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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)
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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.
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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
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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.
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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.
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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
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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
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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
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NOTES
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