Transitional changes after birth
At birth, the circulation through the placenta ceases and the
infant’s lungs inflate. The three shunts that permitted blood
to bypass the liver and lungs are no longer necessary and
cease to function. Some of these changes occur with the first
breath, whereas others may take place over hours and days.
Initially, there are functional changes, which are followed by
definitive anatomical changes.
Features of the changes from fetal to extrauterine life are:
• Removal of the placenta increases systemic vascular
resistance, and cessation of blood flow in the umbilical vein
results in closure of the ductus venosus. All blood entering the
liver now passes through the hepatic sinusoids. The ductus
venosus becomes the ligamentum venosum, which passes
through the liver from the left branch of the portal vein to the
IVC to which it is attached.
• Lung expansion and aeration causes an increase in alveolar
oxygen tension, which causes a rapid fall in the pulmonary
vascular resistance due to the vasodilatory effect of oxygen on
the pulmonary vasculature. Because of the increased
pulmonary blood flow, together with removal of the placenta
decreasing right atrial return and increasing systemic vascular
resistance, the pressure in the left atrium is now higher than
that in the right and the foramen ovale unctionally closes.
Anatomical closure occurs by 3 months of age, when the valve
fuses with the septum primum and the interatrial septum
becomes a complete partition between the atria. An oval
depression remains in the lower part of the interatrial septum
of the right atrium, the fossa ovale.
• Between 6 and 8 weeks after birth there is a second, slower
fall in the pulmonary vascular resistance and pulmonary
artery pressure, associated with the thinning of the
pulmonary arterioles.
• The ductus arteriosus closes due to increase in prostaglandin
E2 (PGE2) metabolism, arterial oxygen concentration (PaO2),
bradykinin and other vasoactive substances secondary to
ncreased oxygen content of aortic blood. Functional closure in
term newborns occurs in 50% by 24 hours, 75% by 48 hours
and close to 100% by 96 hours. Anatomical closure normally
occurs by 3 months of age.
• Delay in closure of the arterial duct can occur in preterm
infants (persistent ductus arteriosus, PDA; see Chapter 11,
Neonatal medicine) or can be induced in duct-dependent
congenital heart disease by infusing prostaglandin E2.
• If there is either perinatal asphyxia or neonatal
hypothermia, sepsis or meconium aspiration, the pulmonary
vascular resistance may not fall as usual with the infant’s first
breaths. This ‘persistent pulmonary hypertension of the
newborn’ (PPHN) means that the fetal pattern of right to left
shunting across the foramen ovale and ductus arteriosus
persists, which in turn leads to intrapulmonary shunting and
further hypoxia and acidosis.
Cerebrospinal Fluid
Distinct from the BBB, the CSF–brain barrier relates to the
extracerebral fluid that is found within the ventricles and around
the brain. It has two main categories of function: physical and
biochemical. From a physical standpoint, it acts to cushion and
protect the brain from shear forces and impact, and plays a role in
regulating intracerebral blood pressure and thus prevents
ischaemia. Biochemically it serves to remove waste and toxins from
the CNS, and helps regulate levels of
hormones and neurologically active substances.
Production
CSF is produced by a type of glial cell called an
ependymal cell. It is chiefly produced in the choroid plexi in the
lateral ventricles of the brain, and exits through the intraventricular
foramen of Munro, into the third ventricle, through the aqueduct of
Sylvius into the fourth ventricle, then down the spinal cord and over
the cerebral hemispheres. It is reabsorbed into the circulation via
arachnoid villi. CSF is produced at a rate of around 30 mL/hour. The
volume after the age of 2 years is around 150 mL, with about 35 mL
in the ventricular system. Abnormalities of the CSF circulation may
result in hydrocephalus:
• Communicating hydrocephalus – no obstruction
between ventricles and subarachnoid space caused by:
– Excessive CSF production (rare, e.g. choroid
plexus tumour)
– Impaired CSF resorption (e.g. blockage of
arachnoid granulations by debris after meningitis or haemorrhage)
• Non-communicating hydrocephalus – physical
obstruction between ventricles and subarachnoid
space. Caused by:
– Congenital malformation (e.g. aqueduct
stenosis, Arnold–Chiari malformation)
– Acquired obstruction (e.g. brain tumour)
Idiopathic intracranial hypertension is a special
case where the CSF is elevated in the absence of hydrocephalus or
intracranial mass lesion, and is described later in this chapter.
Treatment of hydrocephalus depends on the
cause. It may be via resection of an intracranial obstruction, placing
of a stent in a stenosed aqueduct, or by removal of excess CSF. In
many children this requires insertion of a one-way valved
ventriculoperitoneal shunt, which forms a direct drainage route for
CSF from the cranial vault to the low pressure of the peritoneal
cavity.
Clinical features of hydrocephalus depend on the
site of the obstruction and also on the capacity of the cranial vault
to expand if the sutures are not yet fused.
Symptoms of hydrocephalus may be acute (vomiting, irritability,
headache, change in consciousness) or chronic (visual disturbance,
‘sunsetting eyes’, early morning vomiting, pressure headache,
deterioration in school performance). Untreated, acute
hydrocephalus (for example, in a child with a blocked
ventriculoperitoneal shunt) can lead to brainstem herniation and
death. It is a neurosurgical emergency.
CSF analysis is of value in many disorders, the most common of
which is meningitis (Table 28.2). It is also of value in diagnosis and
management of metabolic disorders, leukaemias,
neurodegenerative conditions and autoimmune disorders.
The visual pathway
The anterior visual pathway
Isolated damage to the optic nerves, optic chiasm and optic tract produce
characteristic visual field defects (Fig. 30.6): bitemporal hemianopia caused by
chiasmal lesions, homonymous hemianopia caused by lesions of the optic tract,
optic radiation and occipital cortex. In practice, however, the visual field deficit
is rarely so clear cut. For instance, a child with an optic chiasmal glioma may
have a bitemporal hemianopia due to chiasmal involvement, but anterior
extension into the optic nerve may leave the child with functional vision in the
contralateral nasal hemifield only.
The posterior visual pathway
The optic radiations originate in the neurons of the
lateral geniculate nucleus (LGN); neurons from the
lateral portion of the LGN, conveying the homonymous superior visual field, fan
out laterally and inferiorly around the tip of the inferior horn of the lateral
ventricle and swing posteriorly, terminating in the inferior lip of the calcarine
fissure of the occipital cortex. Neurons from the medial portion of the LGN,
conveying the homonymous inferior visual field, pass almost directly
posteriorly, in the retrolentiform part
of the internal capsule before terminating in the superior lip of the calcarine
fissure of the occipital cortex. The visual cortex consists of the primary and
secondary visual area situated, for the most part, on the deep calcarine sulcus
on the posteromedial surface of the hemisphere. The macular area is
represented in the most posterior third of the visual cortex.
Circle of Willis
Neurology
Medications acting at voltage dependent
sodium channels
Carbamazepine
binds to voltage-dependent sodium channels extending the
inactivated phase and thus
preventing the generation of rapid action
potentials. It is usually well tolerated but may
cause systemic upset in the form of nausea,
vomiting and diarrhoea. Central side effects
include drowsiness, headache and dizziness. A
Stevens–Johnson type adverse reaction is possible
and more likely in certain ethnic groups.
Phenytoin – has been widely used for a great many
years. It acts on both voltage-dependent sodium
channels and on sodium–potassium ATPase and
thereby reduces synaptic transmission. Phenytoin
is an integral step in the management of status
epilepticus in Advanced Paediatric Life Support
(APLS) guidelines. Drug interactions are common.
Very few children will be maintained on long term
phenytoin due to the side-effect profile, which includes gum
hypertrophy, rash and excess hair growth.
Lamotrigine
also acts at voltage-dependent sodium channels, but is believed to
have other modes of actions. The major side effect of this drug is
development of a rash, which can progress to a Stevens–Johnson
syndrome. The risk can be reduced by very gradual titration of dose.
This slow introduction does, however, limit its usefulness in the
acute setting. Plasma levels are significantly elevated by sodium
valproate, so doses must be reduced appropriately.
Oxcarbazepine
a compound with a similar chemical structure to carbamazepine
and likely a similar mechanism of action.
Zonisamide
derived from the sulfonamide group of drugs and is unrelated to
other anticonvulsants. The main mechanism of action seems to be
at voltage-dependent sodium channels as well as calcium channels.
Side effects include behavioural change, drowsiness and dizziness.
Renal stones have also been reported.
Lacosamide
a newer drug that enhances slow inactivation of voltage-dependent
sodium channels resulting in the inhibition of repetitive neuronal
firing. This medication is usually well tolerated but experience is
more limited at present.
Rufinamide
structurally unrelated to other epilepsy drugs and modulates the
activity of sodium channels, prolonging their inactivation phase.
The most common side effects are sleepiness and vomiting.
Medications acting on calcium currents
Ethosuximide
reduces calcium channel currents in thalamic neurons, which are
thought to have a role to play in absence type seizures. The major
side effects include nausea, vomiting, sleep disturbance,
drowsiness, and hyperactivity. Because of its distinctive taste,
compliance can be an issue.
Medications affecting GABA systems
Gamma-aminobutyric acid (GABA) is a neurotransmitter that is
widely distributed throughout the central nervous system and
exerts postsynaptic inhibition.
Phenobarbitone
among the oldest AEDs still in current use. It is effective for the
management of both generalized and partial seizures. The main side
effect, which limits its use, is sedation.
Tiagabine
a second generation AED that is indicated as adjunctive treatment
for partial seizures. Its use in the paediatric setting is limited to date.
Vigabatrin
an irreversible inhibitor of GABAtransaminase,
which increases the concentration of GABA in the central nervous
system. It is particularly effective for infantile spasms in children
with tuberous sclerosis. The major and significant side effect is an
irreversible visual field loss on prolonged use. Therefore, it is rarely
used for more than 6 months. Assessing visual fields is very difficult
in younger children.
Benzodiazepines
enhance GABA inhibition by increasing the frequency of GABAmediated chloride channel openings. This group of medicines is
often associated with the development of tolerance, which
significantly limits their use in the longer term. Sudden
discontinuation may lead to withdrawal seizures and significant
behavioural change in children.
Diazepam and lorazepam
often used in the acute setting. Clobazam, clonazepam and
nitrazepam are sometimes used in the longer term, or for repeated
short courses, either when seizures are troublesome or when
background medications are being altered. Common side effects
include sedation, as well as drooling, insomnia, and behavioural
change.
Medications acting at glutamate receptors
Glutamate is the most prevalent excitatory
neurotransmitter.
Perampanel
a relative newcomer, which targets post-synaptic AMPA receptors,
and is only licensed in children over 12 years. Experience is limited.
Mood change, fatigue and headache have been reported as side
effects.
Medications with other mechanisms of action
A number of AEDs have multiple mechanisms by
which they prevent seizures.
Sodium valproate
a broad-spectrum AED used alone and in combination for the
treatment of generalized and partial seizures. It has been in
mainstream use for many years. It is known to act at voltagedependent sodium channels, as well as increasing gammaaminobutyric acid (GABA). It is also thought to act against certain
calcium channels.
Side effects include nausea, vomiting, hair loss and weight gain.
Use of this medication is teratogenic. This must therefore be taken
into account in teenage girls.
Topiramate
blocks voltage-dependent sodium channels, promotes activity of
GABA receptors, and antagonizes an NMDA–glutamate receptor. It
also weakly inhibits carbonic anhydrase in the central nervous
system.
Weight loss is a common side effect.
Levetiracetam
a broad-spectrum drug. The mechanism of action for this
medication is unknown. It is generally well tolerated. Oral and
intravenous administration is possible, with relatively fast
escalation. Side effects include behavioural change and sleepiness.
Non-pharmacological treatment of epilepsy
Vagus nerve stimulation
Vagus nerve stimulation (VNS) is an alternative management
strategy for patients with refractory epilepsy. Initial animal studies
indicated that stimulation of the vagus nerve could be used to
terminate seizures. Although the exact mechanism of vagus nerve
stimulation is not well understood, it probably relates to the
complex connections between the vagus nerve and various regions
of the brainstem, midbrain and cortex.The device is implanted on
the chest wall with electrodes attached to the left vagus nerve in the
neck.
Onset of benefit can take many months to emerge. MRI scanning is
not possible with VNS in situ.
Ketogenic diet
The ketogenic diet is a high-fat, low-carbohydrate, adequate
protein diet that has been used in the treatment of difficult epilepsy
for many years. This diet regime causes production of ketone bodies
(β-hydroxybutyrate, acetone and acetoacetate) – from fatty acid
oxidation by the liver – and reduced blood glucose levels. The
ketogenic diet is also the treatment of choice for a small number of
other neurometabolic conditions, including GLUT1 deficiency, and
PDH deficiency.
Elevated free fatty acids lead to chronic ketosis and
increased concentrations of polyunsaturated fatty
acids in the brain. Chronic ketosis is predicted to lead to increased
levels of acetone; this may activate potassium channels to
hyperpolarize neurons and limit neuronal excitability.
Chronic ketosis is also felt to alter brain biochemistry to promote
inhibitory neurotransmitter levels. This actual scientific basis is not fully
understood but is likely to involve many pathways, including free
radical generation, interleukin and cytokine balance, and various
mitochondrial pathways, ultimately leading to reduced membrane
hyperexcitability, and thus improved seizure control.
Careful dietetic planning and monitoring is required, and all children
need an individualized care plan in case of illness or hospital
admission.
Heart Anatomy
Diuretics Reduce preload – increased
excretion of sodium and water.
ACE inhibitors –enalapril, captopril, lisinopril
Prevent conversion of angiotensin I to
angiotensin II – increasing plasma renin levels
and reducing aldosterone secretion. Reduce
preload via venous dilatation and afterload
by decreasing peripheral vascular resistance
(angiotensin II is a potent vasoconstrictor).
Aldosterone antagonists
Spironolactone Competes with aldosterone for
receptor sites in distal renal tubule, increasing
water excretion whilst retaining potassium and
hydrogen ions.
Beta-blockers –atenolol
Increase stroke volume and decrease
contractility and left ventricular size. Long
term administration blocks the damaging
effects of overactive sympathetic activity.
Phosphodiesterase III inhibitor – milrinone
Positive inotrope and vasodilator with
little chronotropic (increasing heart rate)
activity. Also has lusitropic (myocardial
relaxation) activity to help myocardium
relax.
Digoxin
Cardiac glycoside inhibits Na/K ATPase that
increases intracellular Na+ and secondary
increase in intracellular Ca++ increasing force
of contraction.
Dopamine Catecholamine that stimulates β1,
α1 and dopaminergic receptors in adose
dependent fashion. Lower doses cause
vasodilation via dopaminergic receptors
in renal and splanchnic vascular beds.
Mid-range doses act on β-receptors to
increase heart rate and contractility. High
doses act on α-receptors to increase
systemic vascular resistance and increase
blood pressure.
Dobutamine
Sympathomimetic with stronger beta than
alpha action. Increases contractility via β1
stimulation and produces systemic
vasodilation via β2 receptors.
Adrenaline α-agonist – increases peripheral
vascular resistance. β2-agonist – positive
chronotrope and inotrope.
Nitroprusside
Vasodilation by relaxing vascular smooth
muscle and increases the inotropic activity of
the heart.
Cardiac Catheterization
Oxygenation of blood
Whilst some oxygen is dissolved in the plasma (3 ml/L of
arterial blood) the vast majority is transported bound to
haemoglobin. Oxygen saturation describes the percentage of
haemoglobin molecules that are bound to oxygen. When all
the possible sites for oxygen binding within haemoglobin are
Oxygen saturation and .%100occupied, oxygen saturation is
oxygen content of blood do not share a linear relationship.
The relationship is shown by the oxygen dissociation curve
(Fig. 17.5). The sigmoidal shape demonstrates how
haemoglobin is an effective carrier of oxygen.
Diuretics
Diuretics are agents which promote water and electrolyte
excretion and are predominantly used in conditions of fluid
overload, electrolyte imbalance and renal failure. They are
classified according to their mechanism of action and it 1$
this which determines their specific clinical indications and
their impact on plasma biochemistry,
Loop diuretics - e.g. furosemide. As suggested by their
name, loop diuretics act in the loop of Henle where they block
the t\la+'K+'2CI~ co-transporter.' In doing so, there is
increased excretion of sodium, chloride and potassium as
well as water (due to a reduced concentration gradient in the
medullary interstitium at the tip of the loop of Henle). Use of
loop diuretics can lead to hypovolaemia, hyponatraemia,
hypokalaemia and hypochloraemia. In response to low
potassium there is reabsorption of potassjum with secretion
of hydrogen, resulting in a metabolic alkalosis (5). This
reabsorption of potassium is not enough to prevent
hypokalaemia. Increased excretion of calcium (leading to
hypercalciuria) and magnesium (causing hypomagnesaemia)
also occurs.
Thiazide diuretics - e.g. chlorthiazide. Thiazide diuretics act
in the DCT by inhibiting sodium chloride reabsorption. Only
5% of sodium is reabsorbed in the DCT and thus there is only
a small increase in the overall amount of sodium chloride
excreted and their diuretic effect is relatively weak. Side
effects include hyponatraemia, hypokalaemia and a metabolic
alkalosis. Thiazide diuretics also increase the reabsorption of
calcium in the DCT and can therefore cause hypercalcaemia
(1). Chronic diuretic therapy (both loop and thiazide diuretics)
also causes hyperuricaemia by increasing reabsorption of
uric acid in the proximal tubule, secondary to volume
depletion, and as the diuretic itself competes for secretion in
the proximal tubule with uric acid, thereby reducing the
amount of uric acid secreted (6).
Aldosterone-antagonists - e.g. spironolactone. By blocking
the action of aldosterone in the DCT and collecting ducts,
sodium and water excretion is increased. However, in
contrast to other diuretics, potassium and hydrogen are
'spared' as they are no longer secreted in exchange for
sodium. Thus side effects include hyperkalaemia and a
metabolic acidosis,
Osmotic diuretics - e.g. mannitol. Osmotic diuretics act by
altering the osmotic pressure in the renal tubule. They are
freely filtered at Bowman's capsule and increase the
osmolality of the filtrate within the tubule which reduces water
(and subsequently sodium chloride) reabsorption. Excretion
of all electrolytes is increased (1). For further details
concerning the mechanisms of action of mannitol see chapter
34.
Bacterial Classification
Side Effects of Chemotherapeutic
Agents.
Vitamin D and Parathyroid Hormone
Actions
Haematouria and proteinuria
Diaphragmatic Hernia
Genetic Testing
Pedigre