Ambiguous Genitalia
Individuals who have a genital appearance that does not permit gender declaration are said to have ambiguous genitalia (AG).
This includes infants with bilateral cryptorchidism, perineal hypospadias with bifid scrotum, clitoromegaly, posterior labial fusion, phenotypic female appearance with palpable gonad (with or without inguinal hernia), and infants with discordant genitalia and sex chromosomes.
This is a neonatal emergency. The commonest cause of AG is congenital adrenal hyperplasia (CAH)
Two major concerns are:- • Underlying medical issues - dehydration, salt loss (adrenal crisis) - urinary tract infection - bowel obstruction • Decision on sex of rearing or psychosocial issues - avoid wrong sex assignment - prevent gender confusion
EVALUATION Ideally, baby/child with parents should be brought to a competent team of experienced paediatric endocrinologist, surgeon, psychiatrist and geneticist.
1. HISTORY - exclude CAH in all neonates • Parental consanguinity. • Obstetric: previous abortions, stillbirths, neonatal deaths. • Pregnancy: drugs taken, exogenous androgens, endocrine disturbances. • Family History: Unexplained neonatal deaths in siblings and close relatives o Infertility, genital anomalies in the family o Abnormal pubertal development o Infertile aunts • Symptoms of salt wasting in the first few days to weeks of life. • Increasing pigmentation • Progressive virilisation
2. PHYSICAL EXAMINATION • Dysmorphism (Turner phenotype, congenital abnormalities) • Cloacal anomaly • Signs of systemic illness • Hyperpigmentation • BP • Appearance of external genitalia o size of phallus, erectile tissue o position of urethral opening (degree of virilisation) o labial fusion / appearance of scrotum
o presence / absence of palpable gonads o presence / absence of cervix (per rectal examination) o position & patency of anus
• Psychosocial behaviour (older children)
Algorithms Approach to Ambiguous Genitalia
Ambiguous Genitalia
Karyotype
Palpable Gonads
Absent Present
CAH Screen
Positive Negative
Endocrine profile, Ultrasound scan Ultrasound Scan Genitogram Genitogram Gonadal inspection and biopsy
3. INVESTIGATION • Chromosome karyotype • Ultrasound for uterus, vagina & urinary system • Genitogram • Exclude salt losing CAH o Serial BUSE in neonatal period o Urine Na, K at the time of presentation o Serum 17-hydroxyprogesterone (taken after the first day of life) o Cortisol, testosterone, renin o 24 - hour urine for pregnanetriol • Testosterone, LH, FSH • LHRH stimulation test (stimulated LH, FSH at 0’, 30’, 60’)
• hCG stimulation (testosterone, DHT at Day 1 & 4) • Androgen receptor study (may not be available) • DNA analysis for SRY gene (sex-determining region on the Y chromosome)
Trial of testosterone enanthate 25 mg IM monthly 3x doses This is done to demonstrate adequate growth of the phallus and is essential before a final decision is made to raise an ambiguous child as a male.
4. Differential Diagnosis Uterus present Uterus absent
46 XX, Virilising CAH 46 XY, Androgen insensitivity syndrome 46 XX, Foetal exposure to excessive androgen 46 XY, 5-alpha reductase deficiency 46 XY, 45XO/46XY 46 XY, Defect in testosterone synthesis Gonadal dysgenesis True hermaphroditism
Differential Diagnosis Hyperpigmentation + - - - Palpable gonad(s) - + + + Uterus present + + - - Dysmorphism - +/- - - Systemic illness + - - - Diagnosis 21-hydroxylase Gonadal Partial AIS Testosterone deficiency dysgenesis biosynthesis True defect hermaphroditism Karyotype 46 XX XO/XY 46 XY 46 XY 46 XY 46 XX
5. Management
Goals • Preserve fertility • Ensure normal sexual function • Phenotype and psychosocial outcome concordant with the assigned sex
General considerations • Admit to hospital. Salt losing CAH which is life threatening must be excluded. • Urgent diagnosis • Do not delay decision on sex assignment • Do not register the child until final decision is reached • Protect privacy of parents and child pending diagnosis • Counseling of parents that intersex condition is biologically explainable. • Encourage bonding
Gender Assignment : Gender assignment and sex of rearing should be based upon the most probable adult gender identity and potential for adult function. Factors to be considered in this decision include :- • Diagnosis • Fertility potential • Adequacy of the external genitalia for normal sexual function. A minimum phallic length of 2 cm when considering male sex of rearing. • Endocrine function of gonads. Capacity to respond to exogenous androgen. • Parents’ socio-cultural background, expectations and acceptance • Psychosocial development in older children.
Decision about sex of rearing should only be made by an informed family after careful evaluation, documentation, and consultation.
Gender Reinforcement • Appropriate name • Upbringing, dressing • Treatment and control of underlying disease e.g. CAH • Surgical correction of the external genitalia as soon as possible
• Assigned female - 46,XX, 46,XY, Gonadal dysgenesis, True hermaphroditism - Remove all testicular tissue - Vaginoplasty after puberty
• Assigned male - 46XY - Orchidopexy - Remove all Mullerian structures - Surgical repair of ‘hypospadias’ - KIV gonadectomy if dysgenetic
Notes :
1. In complete testicular feminisation, bringing up the child as a male is strictly contraindicated as the phallic size will not increase in size even with high dose of androgens. 2. In complete testicular feminisation the testis is not removed till after puberty . By doing so, the normal stimulus of pituitary gonadotrophins results in some gonadal function. A desired side effect, probably from oestrogen (a metabolite of testosterone) being breast development. (A less satisfactory breast development is achieved with oestrogen therapy following prepubertal oestrogen). Because of a risk of malignancy, the cryptorchid testis should be removed after puberty. Vaginoplasty may be needed (after puberty). 3. Bilateral inguinal hernia is rare in girls (femoral hernia is the rule). Always suspect the presence of gonads.
References : Evaluation of the infant with ambiguous genitalia. Christopher P Houk, Lynne L Levitsky. 2004 Uptodate online 12.1 (www.uptodate.com) Management of the infant with ambiguous genitalia. Christopher P Houk, Lynne L Levitsky. 2004 Uptodate online 12.1 (www.uptodate.com)
CONGENITAL ADRENAL HYPERPLASIA (CAH)
A. Presentation Management of CAH
1. Neonatal period 1. Correction of salt deficit • Ambiguous genitalia 2. Correction of cortisol deficiency. • Salt loss (75%) 3. Designation of correct sexual • F/H of previous unexplained identity neonatal death
2. Hyperpigmentation (90%) in both sexes 3. Boy with precocious puberty but small testis (volume <4 ml) 4. Virilisation of a girl 5. Hypertension
B. Management of salt losing crisis
1. Shock • Normal saline (0.9%) bolus or 5% dextrose in NS : 10 - 20 ml/kg • Correct hypoglycemia : 2 - 4 mg/kg of 10% glucose • Correct hyperkalaemia with administration of glucose and insulin if necessary. • Rehydrate using 1/2 NS 5% dextrose • Monitor hydration status, BP, HR, glucose
NB : Hypotonic saline or 5% dextrose should not be used because it can worsen hyponatraemia.
2. Steroid replacement • Hydrocortisone 4 - 6 mg/kg/dose 6 hourly Later when patient is in no stress, change to oral hydrocortisone at 15 - 20 mg/m 2/day. • Fludrocortisone 100 - 150 mcg daily when tolerating orally. Titrate dose till plasma electrolytes return to normal.
3. Supplemental oral salt 1 - 2 g daily
Tail off IV hydrocortisone & IV fluids Monitor symptoms, weight gain, BUSE.
C. Long Term Management of CAH
The various therapeutic rules outlined for simple virilizing form during medical and surgical stress apply to the salt-losing form as well.
• Tablet hydrocortisone 10 - 20 mg/m 2/day, divided into 2 - 3 daily doses using the least effective dose to normalize 17-OHP serum level. Duration of treatment : life long. • Fludrocortisone 100 – 200 mcg daily. Duration of treatment : life long. The dose of fludrocortisone may decrease due to salt intake in the normal diet. • Salt 1-2 g daily, about 8 mEq/kg/day for the first 2 years of life. The dose maybe decreased after early infancy. Salt tablet can often be discontinued as older children’s taste for salty food increases. • Treatment during stress as in fever, vomiting, diarrhoea and surgery (Refer to section E) • Medic alert : is life-saving in an emergency situation. • Surgical correction of the external genitalia before second year of life. • Vaginoplasty after puberty.
D. Long Term Monitoring of CAH
• Height, weight, BP - 3 monthly • Aim for normal height velocity • Bone age yearly if necessary • Investigations - Plasma 17-OHP - Plasma renin activity. If it is not available, do serum Na and K - Testosterone or androstenedione • Ensure normal growth, pubertal development & psychosocial development concordant with the sex of rearing • Signs of over-treatment : ↓↓↓ height velocity, hypertension, delayed bone age • Signs of under-treatment : ↑↑↑ height velocity, advanced bone age • Psychological & emotional support
E. Treatment of CAH During Stress
Patients on prolonged glucocorticoid therapy have an unresponsive hypothalamic-pituitary- adrenal axis and therefore unable to respond to stress with an increased cortisol secretion. For this reason additional glucocorticoid must be provided. Stress is often aggravated because patients are unable to retain oral therapy during acute illness.
1. Infection
Minor infection : Any increase in medication may not be required e.g. in URTI.
Moderate stress : It is necessary to double the maintenance dosage.
Major infection : It is necessary to triple or quadruple the baseline dose. Triple dose is 50 mg/m 2 of hydrocortisone given in 3 - 4 divided doses. This can be given by mouth if patient is able to tolerate orally or by IV or SC.
During treatment with stress doses of hydrocortisone, mineralocorticoid replacement is unnecessary.
Parents are advised to go the emergency room of the nearest hospital for further management of possible hypoglycaemia, sodium and fluid loss.
2. Treatment at the Time of Surgery :-
Prior to Surgery : Give hydrocortisone (Solu-Cortef) 25 mg/m 2 IV just prior to the start of anaesthesia. This is followed by a 2nd dose of hydrocortisone 50 mg/m 2 administered as a constant infusion throughout the surgical procedure. Then a 3 rd dose of hydrocortisone 50 mg/m 2 is given at constant rate for the rest of the 24-hour period. (Total of approximately 125 mg/m 2 during the surgical day)
Postsurgical Day : When the patient is unable to take oral treatment, give a constant infusion of hydrocortisone at 75 mg/m 2/day.
When the patient can resume oral feeding then oral therapy can be started using 1 - 4 times replacement glucocorticoid therapy, depending on the evaluation of the stress condition.
Mineralocorticoid : Commence administration of mineralocorticoid once patient can take orally. Dose : 100 -150 mcg/day orally
In both medical and surgical stress, the increased dose of glucocorticoids should be limited in time. Return to the maintenance level as soon as possible to avoid overtreatment.
PRENATAL DIAGNOSIS AND TREATMENT
Objectives: To prevent prenatal virilisation of female infants To anticipate the potential for salt wasting in the newborn
For pregnancies at risk :- Give dexamethasone 1.5 mg/day in divided doses by 5 weeks of gestation. At 10 weeks, chorionic villous biopsy is done and sent for DNA analysis / HLA typing. Continue treatment only if foetus is an affected female.
References
• Evaluation of the newborn with developmental anomalies of the external genitalia. Policy statement. American Academy of Paediatrics, July 2000. • Technical Report: Congenital Adrenal Hyperplasia (RE0027) .American Academy of Paediatrics, December 2000. • Endocrine update - Lecture on ambiguous genitalia by Prof. Wu Loo Ling, HUKM. • Nelson Textbook of Paediatrics. • Management of the infant with ambiguous genitalia. Christopher P Houk, Lynne L Levitsky. 2004 Uptodate online 12.1 (www.uptodate.com) • Treatment of congenital adrenal hyperplasia due to CYP21A2 (21-hydroxylase) deficiency in infants and children. Lynette K Nieman, David N Orth, John L Kirkland. 2004 Uptodate online 12.1 (www.uptodate.com) • Adrenal disorders page 717-856 of Wilkins, The Diagnosis and Treatment of Endocrine Disorders in Childhood and Adolescence 4th edition by Michael S. Kappy, Robert M. Blizzard, Claude J. Migeon.
POST-STREPTOCOCCAL ACUTE GLOMERULONEPHRITIS Acute glomerulonephritis (AGN) implies that it is of abrupt onset and associated with one or more features of what is known as acute nephritic syndrome.
Acute nephritic syndrome • Oedema e.g. facial puffiness • Hematuria – microscopic/macroscopic (urine – tea coloured or smoky) • Decreased urine output (oliguria) • Hypertension • Azotaemia In children, the commonest cause of acute nephritic syndrome is post infectious AGN. The majority of post infectious acute glomerulonephritis is due to post streptococcal infection of the pharynx or skin. Post streptococcal AGN is commonest in the 6 – 10 year age group.
Presenting features of Post streptococcal acute glomerulonephritis • Acute nephritic syndrome – most common • Nephrotic syndrome • Rapidly progressive glomerulonephritis • Hypertensive encephalopathy • Pulmonary oedema • Subclinical – detected as a result of screening or routine examination Investigation findings in Post streptococcal AGN 1. Urinalysis and culture • Hematuria ( RBC distorted and fragmented ) • Proteinuria (usually trace up to 2+ but if > 2+, need to consider nephrotic syndrome ) • RBC casts (pathognomonic for acute glomerulonephritis) • Other cellular cast • Pyuria may also be present 2. Bacteriological and serological test for evidence of an antecedent streptococcal infection • ASOT increased ( > 200 units ) • Increased anti DNAse B (if available) – better serological marker of preceding streptococcal skin infection • Throat swab or skin swab 3. Renal function test • Blood urea, electrolytes and serum creatinine 4. Full blood count • Anaemia ( mainly dilutional in nature ) • Leucocytosis may be present 5. Complement levels: • C3 level – low at onset of symptoms and normalise by 6 weeks. • C4 is usually within normal limits in Post streptococcal AGN.
Differential diagnosis of Acute Nephritis • Post streptococcal AGN • Post infectious acute glomerulonephritis (due to infectious agents other than group A β –haemolytic streptococci ) • Subacute bacterial endocarditis • Henoch Schoenlein purpura • IgA nephropathy • Hereditary nephritis • Systemic lupus erytematosus • Systemic vasculitidis Management 1. Strict monitoring – fluid intake, urine output, daily weight, BP (nephrotic chart). 2. Penicillin V for 10 days to eliminate beta haemolytic Streptococcal infection. 3. Fluid restriction to control edema and circulatory overload during oliguric phase until child diureses and blood pressure is controlled. • Day 1 – up to 400 mls / m2/ day. Omit if child has clear signs of fluid overload. • Day 2 till patients diureses – 400 mls / m2 / day • When child is in diuresis – free fluid 4. Diuretic e.g. frusemide may be useful for treatment of hypertension and if fluid retention has not improved with fluid restriction. 5. Diet – no added salt diet. Protein restriction is unnecessary 6. Look out hypertension and complications of post streptococcal AGN – hypertensive encephalopathy, pulmonary edema ( acute left ventricular failure ), acute renal failure. 6.1. Hypertension • Significant hypertension but asymptomatic Bed rest and recheck BP ½ hour later If BP still high, give oral nifedipine 0.25 – 0.5 mg/kg. Recheck BP ½ hour later. Monitor BP hourly x 4 hours then 4 hourly if stable. Oral nifedipine can be repeated if necessary on prn basis. May consider regular oral nifedipine ( 6 – 8 hourly ) if BP persistently high. Add frusemide 1 mg / kg / dose if BP still not well controlled. Other anti hypertensives – captopril (0.1 0.5 mg/kg q8 hourly); metoprolol 1 4 mg/kg 12 hourly • Symptomatic or severe hypertension or hypertensive emergency / hypertensive encephalopathy Symptom / sign: headache, vomiting, loss of vision, convulsions, papilloedema. Emergency management is indicated to reduce BP sufficiently to avoid hypertensive complications yet to maintain it at a level that permits autoregulatory mechanism of vital organs to function. Reduce mean BP (DBP + 1/3 (SBP – DBP) ) by 25% over 3 – 12 hours then the rest over 48 hours.
Antihypertensive drug used for hypertensive emergency in children Drug Dose Nifedipine 0.25 – 0.5 mg/kg/dose oral, may be repeated twice if no response. Caution with the sublingual route Sodium nitroprusside 0.5 – 1.0 mcg/kg/min, iv infusion, may increased stepwise to 8.0 mcg/kg/min maximum. Needs to be given in the ICU setting . Caution: in liver and renal failure Labetolol 0.2 – 1.0 mg/kg/dose by repeated iv boluses OR 0.25 – 2.0 mg/kg/hour by iv infusion. Hydralazine 0.2 – 0.4 mg/kg/dose by iv bolus, may be repeated twice if no response. 6.2. Pulmonary edema • Give oxygen. • Prop patient up. • Ventilatory support if necessary. • Intravenous frusemide 1 – 5 mg / kg / dose stat then double the previous dose 4 hours later if still poor response. • Fluid restriction – withhold fluids for 24 hours if possible • Consider dialysis if no response to diuretics. 6.3. Acute renal failure • mild renal impairment in Post streptococcal AGN is common but severe persistent oliguria or anuria with azotaemia is uncommon. • Management – refer section on acute renal failure. Indications for renal biopsy • Severe acute renal failure • Miscellaneous factors: o prior h/o renal disease o family history of nephritis • Delay resolution o oliguria > 2 weeks o Azotaemia > 3 weeks o Gross haematuria > 3 weeks o Persistent proteinuria > 6 months
Follow of patients with Post streptococcal AGN • Follow up for at least 1 year at 1 – 3 months interval. • Do urine FEME (and renal function if initially abnormal) to evaluate recovery. • Monitor BP at every visit. Outcome • Short term outcome – excellent, mortality <0.5%. • Long term outcome in children – 1.8% with chronic kidney disease following post streptococcal AGN.
Natural history of Acute Post-Streptococcal Glomerulonephritis weight, urea, hypertension Haematuria ASOT
2 wk. 0 2 wk. 4 wk. 6 wk. 1 yr
Streptococcal complement (C3) infection
REFERENCES 1. LB Travis, A Kalia. Acute nephritic syndrome. Clinical Peadiatric Nephrology. Second edition. RJ Postlethwaite. Butterworth Heinemann 1994. Pg 201 – 209. 2. Malaysian Hypertension Consensus Guidelines 1998. Ministry of Health & Academy of Medicine of Malaysia. 3. Simokes AM, Spitzer A. Post streptococcal acute glomerulonephritis. Paediatric Review. 16: 278 – 279. 1995. 4. Rodriguez Iturbe B. Epidemic post streptococcal glomerulonephritis. Kidney Int 1984; 25:129 136 ACUTE RENAL FAILURE (ARF)
Definition Abrupt rise in serum creatinine and decreased glomerular filtration rate resulting in inability of the kidneys to regulate fluid and electrolyte balance.
Clinical features • Of underlying cause. • Oliguria (< 300 ml/m 2/day in children; < 1 ml/kg/hour in neonates). • Non-oliguric. Common causes of ARF
Investigations Pre-renal : hypovolaemia (dehydration, Blood : Full blood count / blood film bleeding, 3 rd space loss e.g. nephrotic Urea*, electrolytes, creatinine syndrome); congestive heart failure Blood gas Renal Serum albumin, calcium, phosphate : glomerulonephritis (infectious, + Uric acid Systemic lupus erythematosus, chronic glomerulonephritis); acute tubular necrosis (drugs e.g. aminoglycosides, chemotherapy Urine : protein, microscopy agents; toxins e.g. myoglobin, haemoglobin; venom e.g. bee sting); tumour lysis & uric acid Imaging : renal ultrasound scan (urgent if nephropathy; vascular lesions (hemolytic cause unknown) uraemic syndrome, renal venous thrombosis); sepsis Other investigations as determined by cause. Post-renal : urethral obstruction e.g. posterior urethral valves; bilateral ureteric obstruction; obstruction in solitary kidney * blood urea is affected by state of hydration, gastro-intestinal bleeding, high protein intake and catabolic state.
Fractional excretion of Na (FE Na ) is useful to differentiate pre-renal from renal causes of ARF
FE Na = Urine Na x Plasma creatinine x 100% Plasma Na Urine creatinine
- in pre-renal ARF, FE Na < 1% ( < 2.5% in neonates) and in intrinsic ARF, FE Na > 2% in children. - some falsely low FE Na in intrinsic renal failure includes some glomerulonephritides, contrast-induced nephropathy and rhabdomyolysis. - beware of medications / conditions which alter sodium reabsorption e.g. diuretics, oliguria.
For post-renal causes of ARF, refer to the urologist / nephrologist / surgeon.
MANAGEMENT: ARF
1. Fluid balance 2. Hypertension 3. Metabolic acidosis 4. Electrolyte abnormalities 5. Nutrition 6. Medications
1. Fluid balance a) Hypovolaemia - fluid resuscitation regardless of oliguric/anuric state. - give *crystalloids e.g. isotonic (0.9%) saline / Ringer’s lactate 20 ml/kg fast (in < 20 mins) after obtaining vascular access. - transfuse blood if haemorrhage is the cause of shock. - hydrate to normal volume status. - if urine output increases, continue fluid replacement. - if there is no urine output after 4 hours (confirm with urinary catheterization), monitor central venous pressure to assess fluid status
*refer to section on shock for details of management. b) Hypervolaemia / Fluid overload - intravenous frusemide 2 mg/kg/dose (over 10-15 minutes) tds, maximum of 5 mg/kg/dose or - iv frusemide infusion 0.5 mg/kg/hour. - dialysis if no response.
Once normal volume status is achieved, give insensible loss (400 ml/m 2/day) plus obvious losses (urine / extrarenal). Monitor: weight, BP, clinical status, nutritional needs, intake / output.
2. Hypertension Commonly related to fluid overload and / or alteration in vascular tone. If related to volume overload, remove fluid appropriately by dialysis if patient does not respond to diuretics. Choice of anti-hypertensives depends on degree of BP elevation, presence of CNS symptoms of hypertension and cause of renal failure.
Definitions: Severe hypertension: BP exceeding 99 th percentile for age, height percentile and gender. Hypertensive emergency: rise in systolic and diastolic BP associated with end-organ injury to brain, heart + kidneys.
Clinical features of hypertensive emergency include congestive cardiac failure, pulmonary oedema, ARF, hypertensive encephalopathy, stroke, myocardial infarct.
Management Airway, Breathing, Circulation, Drugs Control seizures if present. Treat underlying cause. Hypertensive emergencies need monitoring in ICU or high-dependency unit. Use medications that you are familiar with and available in your unit.
Some drugs used in hypertensive emergencies: - labetalol 0.2 – 1.0 mg/kg/dose iv push over 2 minutes. If no response, may repeat every 5 – 10 minutes incrementally to maximum dose of 60mg OR - labetalol 0.25 – 2.0 mg/kg/hour iv continuous infusion OR - hydralazine 0.2 – 0.5 mg/kg/dose iv every 4 – 6 hourly (maximum 3.5 mg/kg/day)
Some oral drugs used in hypertension: Drugs Dosage Nifedipine 0.2- 0.3mg/kg 3 times/day OR 5 – 10mg 3 times/day Maximum: 3mg/kg/day Atenolol 1 – 2mg/kg once or twice /day Maximum: 100mg/day Metoprolol 1mg/kg twice /day Maximum: 8mg/kg/day Prazosin 0.01 – 0.015mg/kg 2 – 4 times/day Maximum: 0.5mg/kg/day Captopril* 0.1 – 0.5mg/kg 3 times/day Maximum: 2mg/kg 3 times/day *Avoid in neonates if possible, especially preterm ones – risk of renal failure, anuria, hypotension. Keep dose as low as possible in renal failure. If a diuretic is indicated, use a loop diuretic rather than thiazide. Observe BP every 15 minutes for the first hour after initial dose – look for hypotension.
Neonatal hypertension Hypertension occurs in ~ 2% of term and premature neonates. Risk factors: prematurity, ARF, respiratory distress or severe infection, those with family history of congenital renal or heart disease. Hypertension that may resolve once underlying cause is treated: obstructive uropathy, hypervolaemia associated with ARF, coarctation of aorta, thromboembolism from umbilical arterial catheter.
Medications that can be used: Drug group Medication doses (neonates) Beta-adrenergic Propranolol 0.5 – 5.0 mg/kg/day PO 6 – 12 hourly antagonists Labetalol 1 – 20 mg/kg/day PO 8 – 12 hourly or 0.2 – 1.0 mg/kg/dose iv bolus or 0.25 – 3.0 mg/kg/hour iv continuous infusion Ca-channel antagonists Nifedipine 0.125 – 0.5 mg/kg/dose PO 6 – 8 hourly (maximum 3 mg/kg/day) Diuretics Frusemide 0.5 – 4.0 mg/kg dose iv/ PO 6 – 8 hourly (maximum 4 mg/kg/day) Vasodilators Hydralazine 0.1 – 0.6 mg/kg/dose im/iv 4 – 6 hourly or 0.75 – 5.0 mcg/kg/min iv continuous infusion
3. Metabolic acidosis - treat if pH < 7.2 or symptomatic or contributing to hyperkalaemia. - deficit = 0.6 x body weight (kg) x base excess (BE) - replace half the deficit with iv NaHCO 3 4.2% if indicated. - monitor blood gases. Hyperkalaemia on ECG : 4. Electrolyte abnormalities
i. tall peaked T waves a) Hyperkalaemia Definition: serum K + concentration > 6.0mmol/l (neonates) ii. prolonged PR interval and > 5.5mmol/l (children). iii. widened QRS complex Cardiac toxicity generally develops when plasma K + > iv. flattened P wave 7mmol/l. v. sine wave (QRS Regardless of degree of hyperkalaemia, treatment should complex merges with be initiated in anyone with ECG abnormalities. peaked T waves) vi. VF or asystole - do 12-lead ECG and look for hyperkalaemic changes
- if ECG is abnormal or plasma K + > 6 – 7 mmol/l , connect patient to cardiac monitor and give the following in sequence:
Φsalbutamol dose based on nebulized salbutamol 2.5 – 5 mg (0.5 – 1 ml Φ:2 ml NaCl) 0.5% formulation. (onset of action 30 mins) * insulin may not be
necessary. # NaHCO not considered IV 10% Calcium gluconate 0.5 – 1.0 ml/kg (1:1 dilution) 3 useful unless metabolic over 5 – 15 mins acidosis is responsible for (immediate onset of action) hyperkalaemia.
Ψdiuretics useful in chronic IV dextrose 0.5 g/kg (2 ml/kg of 25%) over 15 – 30 mins hyperkalaemia due to heart then iv insulin* 0.1 unit/kg failure, hyperaldosteronism. (onset of action 30 mins)
IV 4.2% Na bicarbonate # 1 mmol/kg over 10 – 30 mins (onset of action 15 – 30 mins)
Calcium polystyrene sulphonate (Calcium Resonium) 0.25g/kg oral or rectally 4 times/day (maximum 10g/dose) [give rectally (NOT orally) in neonates 0.125 – 0.25g/kg 4 times/day] OR Sodium polystyrene sulphonate (Resonium) 1g/kg oral or rectally 4 times/day (maximum 15g/dose)
IV frusemide Ψ 1 – 2 mg/kg (onset of action 15 – 30 mins)
- asymptomatic hyperkalaemia (no ECG changes) – give calcium or sodium polystyrene sulphonate
Dialysis may be necessary to remove large amounts of potassium.
b) Hyponatraemia - usually dilutional from fluid overload. - treat if symptomatic or serum Na < 120 mmol/l (correct to 125). - aim to bring up serum Na level to 120 to alleviate symptoms, then correct over 24 – 36 hours. - Na deficit (mmol Na) = 0.6 x body weight (kg) x (125 – serum Na) - infuse deficit over several hours - dialyze if above measure fails. - if asymptomatic, fluid restrict.
c) Hypocalcaemia - treat if severe or symptomatic, and / or if NaHCO 3 is required for hyperkalaemia - give iv 10% Calcium gluconate 0.5 ml/kg over 30 – 60 minutes with continuous ECG monitoring.
d) Hyperphosphataemia Age CaCO 3 dose - low phosphorus diet - Phosphate binders e.g. calcium < 1 yr 125mg with feeds carbonate (CaCO 3) PO with main 1 – 6 yrs 250mg tds / qid meals 6 – 12 yrs 500mg tds / qid
> 12 yrs 1000mg tds / qid
5. Nutrition Optimal intake in ARF influenced by nature of disease causing it, extent of catabolism, modality and frequency of renal replacement therapy.
Goals in managing nutrition: i. maintaining adequate caloric intake ii. avoiding excessive protein intake iii. minimizing phosphorus and potassium intake iv. reducing fluid intake (if applicable) Energy requirements during critical illness depends on basal requirements and hypermetabolism, the prediction of which can be determined by the following:
Average hospital energy requirements Increases in energy with stress weight (kg ) kcal/kg/day Fever 12% per degree Celsius > 37C
0 – 10 100 Heart failure 15 – 25% 10 – 20 1000 + 50/kg Major surgery 20 – 30% > 20 1500 + 20/kg Burns up to 100% Severe sepsis 40 – 50%
- newborns and infants – if the gastro-intestinal tract is intact and functional, start enteral feeds as soon as possible. - start with dilute formula, then feedings increased and concentrated to achieve optimal caloric intake. - Total parenteral nutrition via central line if enteral feeding is not possible; use concentrated dextrose (25%), lipids (10 – 20%) and protein (1.0 – 2.0g/kg/day). - if oliguric and caloric intake insufficient because of fluid restriction, start dialysis earlier. 6. Medications - avoid nephrotoxic drugs if possible; if needed, monitor drug levels and potential adverse effects. - check dosage adjustment for all drugs used.
Dosage adjustment in renal failure for some common antibiotics
*Gentamicin : give 5mg/kg, check trough level before next dose, and peak, 1 hour post-dose. Await plasma level result before further dosing. " *Amikacin : give initial dose, take trough sample immediately before next dose and peak, 1 hour post-dose. *Vancomycin : give initial / loading dose, take trough sample immediately before next dose and peak sample, 1 hour after completion of infusion.
*Re-dose patient if trough level achieved, omit dose if trough level is toxic. If peak level is high, lower dosage, if within therapeutic range, maintain dosage.
Cefotaxime : if creatinine clearance < 5ml/min/1.73m 2 , give normal dose initially, then half the dose, keeping same frequency; otherwise no dose adjustment. Ceftriaxone : if creatinine clearance < 10ml/min/1.73m 2 , dose should not exceed 40mg/kg (2g)/day; otherwise no dose adjustment. Cloxacillin : if creatinine clearance < 10ml/min/1.73m 2 , increase dosage interval to 8- hourly; otherwise no dose adjustment. Drug Creatinine clearance Dose Dosage interval (ml/min/1.73m 2) (hours) Ceftazidime 30 – 50 50 - 100% 12 15 – 30 50 - 100% 24 5 – 15 25 – 50% 24 < 5 25 – 50% 48
Drug Creatinine clearance Dosage interval (ml/min/1.73m 2) (hours) Cefuroxime > 20 8 10 – 20 12 < 10 24 Crystalline / benzylpenicillin 10 – 50 8 – 12 < 10 12 Amoxicillin –clavulanic acid 10 – 30 normal dose initially, then (Augmentin) half dose 12-hourly. < 10 normal dose initially, then half dose 24-hourly Calculated creatinine clearance (ml/min/1.73m 2) = height (cm) x 40 # serum creatinine (umol/l)
# not reliable for infants, although it may be used. Use 30 instead of 40 in neonates. This formula is only applicable once the serum creatinine level reaches a steady state without dialysis.
References 1. Pediatric Nephrology 5 th edition, editors Ellis D Avner, William E Harmon, Patrick Niaudet, Lippincott Williams & Wilkins, 2004 2. Paediatric Formulary 6 th edition, Guy’s, St Thomas’ and Lewisham Hospitals, 2001 ACUTE PERITONEAL DIALYSIS
The purpose of dialysis is - to remove endogenous and exogenous toxins and - to maintain fluid, electrolyte and acid-base equilibrium until renal function returns. Peritoneal dialysis (PD) is usually the preferred method for dialysis therapy for infants and children
Indications for Acute Dialysis Fluid overload Pulmonary oedema Congestive cardiac failure Refractory hypertension Hindrance to adequate nutrition Oliguria following recent heart surgery Oliguria during ECMO Symptomatic electrolyte / acid-base imbalances Hyperkalaemia (K+ > 7.0) Hypo- or hypernatraemia Acidosis (pH<7.2; or <7.3 with hyperkalaemia) Toxins Ureamia (puritus, pleuritis, pericarditis, CNS symptoms) Hyperuricemia Exogenous toxins: lithium, salicylate, ethanol, methanol, bromide ethylene glycol, aminoglycosides Haemodialysis (HD) is the therapy of choice for rapid treatment of dialyzable poisonings Inborn errors of metabolism Encephalopathy Hyperammonemia
Contraindications To Acute PD 1. Abdominal wall defects or infection 2. Bowel distension, perforation, adhesion or resection 3. Communication between the chest and abdominal cavities
Types of Catheter Access 1. A straight rigid catheter. If dialysis treatment is expected to be short 2. A medical Tenckhoff (Seldinger method) or a surgically placed cuffed Tenckhoff. If prolonged dialysis therapy is anticipated
Site of insertion Commonest site: midline infraumbilical position one inch below the umbilicus Other site esp. in very small infants: Two-thirds of the distance from the umbilicus to the left last rib (just lateral to the border of rectus muscle)
Procedure of PD catheter insertion
1. The bladder must be emptied before catheter insertion 2. The procedure must be done under aseptic technique 3. Prepare the set of PD lines and spike the PD fluids 4. Clean the area with povidone iodine and drape the patient 5. Infiltrate the area with lignocaine for local anaesthesia. For young children additional IV sedation may be needed 6. For very small infants and patients with very scaphoid abdomen, one may need to infiltrate the abdominal cavity using a branula size 20G or larger with 10 – 15 ml/kg PD fluids before catheter insertion to prevent traumatic puncture of underlying viscus. 7. A small skin incision, slightly smaller than the diameter of the catheter is made using a sharp pointed blade. Do not cut the muscle layer 8. The catheter must be checked carefully by withdrawing the stilette from the catheter for any breakages before insertion. 9. The catheter with the stilette is introduced perpendicular to the abdominal wall while controlling the length with the dominant hand until the peritoneum is pierced. The stilette is then withdrawn and the catheter gently pushed in, directing towards either iliac fossa. 10. Connect the catheter to the PD lines. 11. Skin sutures are unnecessary if a retaining knob is present. Bleeding from the insertion site can be stopped by a purse-string suture. Dress with dry gauze or gauze impregnated with povidone iodine for the older children.
P.D Regime
Exchange volume 1. Start at 20 ml/kg and observe for discomfort, cardiorespiratory changes or leakage at the catheter site 2. The volume is increased by 5 ml/kg/run up to a maximum of 60 – 100 ml/kg in infants. Usually 40 ml/kg is sufficient. Cycle Duration 1. First 6 cycles are rapid cycles i.e. no dwell time. 2. Subsequent cycles usually last an hour - 5-10 minutes to instill (depending on exchange volume) - 40 minutes dwell - 10-15 minutes to drain (depending on exchange volume) As homeostasis improves, longer dwelling can be instituted 3. The cycles can be done manually or with automated cycler machine (can simplify the process and reduce infection))
Type of PD Fluids 1. Commercially available dialysis fluids – 1.5%, 2.5% and 4.25% dextrose 2. PD is usually initiated with 1.5% - if more rapid ultrafiltration is required higher glucose concentration can be used but watch for hyperglycaemia 3. Add potassium of 3 mls of potassium chloride [1 g (13 mmol) in 10 mls] in every litre dialysate if serum K+ < 4 mmol/l 4. The addition of heparin (500 units/litre dialysate) is usually recommended for the first 3 days and subsequently if blood or fibrin is in the effluent. 5. If lactic acidosis is a significant problem, a bicarbonate containing dialysis fluid can be used.
Duration of PD The duration of PD depends on the needs of the patient The usual practice is 60 cycles but at times more cycles may be needed based on biochemical markers or clinical needs. Peritonitis is frequent when dialysis is prolonged or when acute catheters are used for more than 3 to 4 days
Monitoring while on PD Serial measurements of fluid balance, weight, vital signs and serum chemistries and dialysate effluent for daily cell count and culture
Common complications to watch out for a. Poor drainage (omental obstruction, kinking) - For temporary PD cannulas Reposition Reinsert catheter if reposition unsuccessful - For surgically implanted catheters Irrigation Instillation of fibrinolytic agents Add heparin (500 units/ litre) into PD fluids b Peritonitis - Signs and symptoms - Abdominal pain, fever, cloudy PD effluent, PD effluent cell count > 100 WBC/mm 2 ) - Treatment: Intraperitoneal antibiotics (empirical Cloxacillin + Ceftazidime) for 7 to 14 days. Adjust antibiotics once culture results known (dosage as given in the table). c Exit site infection Topical mupirocin cream d Leaking dialysate - At exit site – resuture immediately - Leakage from tubings – change dialysis set. Empiric intraperitoneal antibiotics for one to two days may be needed.
Paediatric Antibiotic Dosing Recommendations Administration should be via intraperitoneal route unless specified otherwise. Continuous therapy Loading dose Maintenance dose Intermittent therapy Glycopeptides Vancomycin 500 mg/L 30 mg/L 30 mg/kg q 5-7 days
Cephalosporins Cepazolin/cephalothin 250 mg/L 125 mg/L 15 mg/kg q 24 hrs Cefuroxime 200 mg/L 125 mg/L 15 mg/kg q 24 hrs Cefotaxime 500 mg/L 250 mg/L 30 mg/kg q 24 hrs Ceftazidime 250 mg/L 125 mg/L 15 mg/kg q 24 hrs
Antifungals Amphotericin B 1 mg/kg IV 1 mg/kg/day IV --- Fluconazole ------3-6 mg/kg IP, IV, or PO q 24-48 hrs (max dose 200 mg) Aminoglycosides Amikacin 25 mg/L 12 mg/L Gentamicin 8 mg/L 4 mg/L Netilmycin 8 mg/L 4 mg/L
Penicillins Piperacillin --- 250 mg/L Ampicillin --- 125 mg/L Amoxicillin 250 -500 mg/L 50 mg/L
Combinations Ampicillin/Sulbactam 1000 mg/L 100 mg/L Imipenem/Cilastin 500 mg/L 200 mg/L TMP/Sulfamethoxazole 320/1600 mg/L 80/400 mg/L
References 1. Paediatric Nephrology 3rd Edition 2. National Renal Replacement Therapy Guidelines
NEPHROTIC SYNDROME
Diagnosis
Nephrotic syndrome is a clinical syndrome of massive proteinuria defined by 1. Oedema 2. Hypoalbuminaemia of < 25g/l 3. Proteinuria > 40 mg/m2/hour ( > 1g/m2/day ) OR an early morning urine protein creatinine index of > 200 mg/mmol ( > 3.5 mg/mg ) 4. Hypercholesterolaemia is not needed in definition
The main cause of nephrotic syndrome in children is primary or otherwise known as idiopathic nephrotic syndrome when the actual cause of the nephrotic syndrome is unknown. The treatment for nephrotic syndrome caused by other diseases example post streptococcal glomerulonephritis or systemic lupus erythematosus follows that for the treatment of the primary renal/systemic disorder.
Investigations at initial presentation
1. Full blood count 2. Renal profile - urea, electrolyte, creatinine 3. Serum albumin 4. Urinalysis and Culture 5. Quantification for urinary protein excretion (spot urine protein creatinine ratio or 24 hour urine protein)
Other investigations if the clinical features are atypical / presence of poor prognostic features 1. Antinuclear factor / anti ds DNA 2. Serum complement (C3, C4) level 3. ASOT 4. Others as indicated
Renal biopsy
Not indicated for idiopathic nephrotic syndrome in children prior to starting corticosteroid therapy. • Main indication is steroid resistant nephrotic syndrome defined as failure to achieve remission despite 4 weeks of adequate corticosteroid therapy. • Other indications would depend on presence of atypical features and features to suggest other renal diseases e.g. persistent hypertension, gross haematuria and shall be left to the discretion of the attending paediatrician in consultation with the paediatric nephrologist.
Management
A. Management of the oedematous state
• Bed rest This is not required and usually not practical unless the child has gross oedema. • Diet A normal protein diet with adequate calories is recommended. No added salt to the diet during the oedematous state. • Antibiotics. Penicillin V 125 mg BD (1-5 years old); 250 mg BD (6-12 years old) 500 mg BD (>12 years) is recommended during relapse particularly with gross oedema.
• Fluid status Carefully assess the haemodynamic status. Check for signs and symptoms which may indicate underfilling – abdominal pain, cold peripheries, tachycardia and poor pulse volume, low blood pressure or overfilling e.g. basal lung crepitations and rhonchi, hypertension. Fluid restriction - not usually recommended except in chronic oedematous states. o Diuretics. e.g. frusemide is not usually necessary in steroid responsive nephrotic syndrome but if required should be used with caution as it can precipitate hypovolaemia. o Human albumin (20-25%) at 0.5 – 1.0 g/kg can be used in symptomatic grossly oedematous states together with intravenous frusemide at 1-2 mg/kg to produce a diuresis. Caution: fluid overload and pulmonary oedema with salt poor albumin infusion. Urine output and blood pressure should be closely monitored. o Human albumin at 0.5 – 1.0 g/kg of 5%, 20% or 25% (whichever is available) over one hour in those suspected to have hypovolaemia/underfilled state. Do not give frusemide in this instant.
B. Management of the complications of nephrotic syndrome
• Hypovolaemia . Clinical features: abdominal pain, cold peripheries, poor pulse volume, hypotension, and haemoconcentration. Treatment: infuse salt poor albumin at 0.5 to 1.0 g/kg/dose over one hour. If salt poor albumin is not available, other volume expanders like 5% albumin, plasma protein derivatives or human plasma can be used.
• Primary Peritonitis Clinical features: fever, abdominal pain in children with frank nephrotic syndrome. Investigations: Blood culture, peritoneal fluid culture (not usually done) Treatment: parenteral penicillin and a third generation cephalosporin
• Thrombosis Thorough investigation and adequate treatment with anticoagulation is usually needed.
C. General advice • Inform regarding high probability (85-95%) of relapse. • Home urine albumin monitoring. Urine dipstix testing of the first urine specimen in the morning daily. Parents are advised to consult the doctor if albuminuria > 2+ for 3 consecutive days.
Immunocompromised status o The parents and children should be advised and cautioned about contact with chickenpox and measles, and if exposed should be treated like any immunocompromised child. Immunisation. While the child is on corticosteroid treatment and within 6 weeks after its cessation, only killed vaccines may safely be administered to the child. Live vaccines can be administered 6 weeks after cessation of corticosteroid therapy. • Acute Adrenal Crisis This may be seen in children who have been on long term corticosteroid therapy (equivalent to 18 mg/m 2 of cortisone daily) when they undergo situations of stress. Prevention and treatment: corticosteroids (hydrocortisone) given in 3 divided doses at 2-4 mg/kg/dose. .
D. Corticosteroids
Corticosteroids is effective in inducing remission of nephrotic syndrome but the most optimal dose and duration is yet to be resolved although it has been found that longer duration results in more prolonged remission.
Prednisolone dosage at: * 60 mg / m2 / day ( maximum 80 mg / day ) for 4 weeks * followed by 40 mg / m2 / EOD (maximum 60 mg) for 4 weeks. * then reduce prednisolone dose by 25% monthly over next 4 months.
90% of children will achieve remission defined as urine dipstix is trace or nil for 3 consecutive day within 28 days, many within 7 - 14 days. Steroid resistance is defined as failure to achieve response to an initial 4 weeks treatment with prednisolone 60 mg/m2/day and such case should be referred to a nephrologist for a renal biopsy.
Treatment of relapses The majority of children with nephrotic syndrome will relapse.
A relapse is defined by urine albumin excretion > 40 mg / m2 / hour or urine dipstix of 2+ or more for 3 consecutive days.
Treatment - Prednisolone 60 mg/m2 /day until remission then 40 mg / m2/EOD for 4 weeks and off.
Breakthrough proteinuria may occur with intercurrent infection and usually does not require prednisolone if the child has no edema, remains well and the proteinuria resolves with resolution of the infection. If proteinuria persists, treat as relapse.
Management of frequent relapses
Frequent relapses = 2 or more relapses within 6 months of initial response or 4 or more relapses within any 12 month period.
Treatment Prednisolone 60 mg / m2 / day till urine albumin nil/trace for 3 days, then 40 mg / m2 / alternate mornings for 4 weeks. Taper prednisolone dose every 2 weeks and keep on as low alternate day dose as possible for 6 months. Should a child relapse while on low dose alternate day prednisolone, the child should be re-induced as for a relapse.
Management of steroid dependent nephrotic syndrome Steroid dependence = 2 consecutive relapses occurring during the period of steroid `taper or within 14 days of its cessation.
Treatment If the child is not steroid toxic, re-induce with steroids and maintain on as low a dose of alternate day prednisolone as possible. If the child is steroid toxic (short stature, striae, cataracts, severe cushingoid features) consider cyclophosphamide therapy.
E. Cyclophosphamide therapy
This is indicated for the treatment of steroid dependent nephrotic syndrome with signs of steroid toxicity and should be started when the child is in remission following induction with corticosteroids. Dose: 2-3 mg/kg/day for 8-12 weeks Monitoring: FBC and Urine FEME two weekly.
Relapses post cyclophosphamide Relapses after a course of cyclophosphamide is treated as for relapses after the initial diagnosis of nephrotic syndrome if the child does not exhibit any further signs of steroid toxicity.
Should the relapse occur soon after a course of cyclophosphamide when the child is still steroid toxic, or the child again becomes steroid toxic after multiple relapses, then a paediatric nephrology opinion should be sought.
Steroid resistant nephrotic syndrome / chronically nephrotic child Refer for renal biopsy. Specific treatment will depend on the histopathology.
General management Control of edema - (a) Restriction of dietary sodium. (b) Diuretic e.g. Frusemide, Spironolactone. ACE inhibitor e.g. captopril to reduce proteinuria Control of hypertension. Penicillin prophylaxis. Monitor renal function. Summary of treatment of nephrotic syndrome
1. INITIAL EPISODE OF NEPHROTIC SYNDROME Prednisolone 60 mg/m2/day for 4 weeks
response no response prednisolone 40 mg/m2/alternate day for 4 weeks renal biopsy prednisolone taper at 25% monthly over 4 months
2. RELAPSE Prednisolone 60 mg/m2/day till remission Then 40 mg/ m2/alternate day for 4 weeks and discontinue
3. FREQUENT RELAPSES Reinduce as for ( 2 ), then taper and keep low dose Alternate day prednisolone at 0.1 – 0.5 mg/kg/dose for 6 months
4. RELAPSE ON PREDNISOLONE As for ( 3 ) if not steroid toxic Consider cyclophosphamide if steroid toxic
5. RELAPSES POST CYCLOPHOSPHAMIDE As for ( 2 ) and ( 3 ) if not steroid toxic. If steroid toxic, refer paediatric nephrologist to consider • second course cyclophosphamide or • cyclosporin therapy
REFERENCE 1. Consensus statement - Management of idiopathhic nephrotic syndrome in childhood. Ministry of Health, Academy of Medicine Malaysia. 1999. 2. Hodson EM, Knight JF, Willis NS, Craig JC. Corticosteroid therapy for nephrotic syndrome in children (Cochrane Review). In: The Cochrane Library , Issue 1, 2003. Oxford: Update Software. 3. P McIntyre & JC Craig. Review article. Prevention of serious bacterial infection in children with nephrotic syndrome. J Paediatr. Child Health ( 1998 ) 34, 314 - 317. 4. Special report. Consensus statement on management and audit potential for steroid responsive nephrotic syndrome. Arch Dis Child 1994; 70: 151 - 157. 5. Durkan A, Hodson E, Willis N, Craig J Non-corticosteroid treatment for nephrotic syndrome in children (Cochrane Review). In: The Cochrane Library , Issue 1, 2003. Oxford: Update Software.
URINARY TRACT INFECTION
EPIDEMIOLOGY Urinary tract infection (UTI) comprises 5% of febrile illnesses in early childhood. The commonest age for first infection is during first 2 years of life. Total morbidity risk by 11 years of age is 3% for girls and 1.1% in boys. UTI have been considered an important risk factor for the development of hypertension, renal failure and end stage renal disease.
DEFINITIONS • UTI is growth of bacteria in the urinary tract. • Significant bacteriuria is > 10 5 colony forming units of a single organism per ml of freshly voided urine (Kass). • Acute pyelonephritis is infections involving the renal parenchyma which carries a higher risk of renal scarring. • Acute cystitis is infections limited to the lower urinary tract presenting clinically with acute voiding symptoms, including dysuria, urgency, frequency, suprapubic pain, and incontinence. • Asymptomatic bacteriuria is presence of bacteriuria in repeated samples from a otherwise asymptomatic child, usually detected at routine investigations.
Clinical Presentation
Symptoms depend on the age of the child and the level of infection. In infants and toddlers; usually non-specific e.g. fever, irritability, jaundice and failure to thrive. The presence of UTI should be considered in children younger than 2 years with unexplained fever . High fever with loin tenderness usually accompanies acute pyelonephritis. Symptoms of lower UTI such as pain with micturition and frequency are often not recognized before the age of two.
Physical Examination • General examination, growth, blood pressure • Abdomen for distended bladder, ballotable kidneys, other masses, genitalia. • Back for any spina bifida • Lower limbs for deformities, wasting etc in neurogenic bladder
Diagnosis
Accurate diagnosis is extremely important as false diagnosis of UTI would lead to unnecessary interventions that are costly and potentially harmful. The quality of the urine sample is of crucial importance.
Collection of urine
• Bag urine specimen - high contamination rate of up to 70%. A positive culture should be confirmed with a clean catch or suprapubic aspiration specimen (SPS) • Clean catch specimen - in a child who is bladder trained. • Catheterisation - sensitivity of 95% & specificity of 99% compared to SPA. There is a low risk of introducing infection. • Suprapubic aspiration (SPA) - the best technique (“gold standard”) of obtaining an uncontaminated urine sample and any growth from SPA specimen is significant. With the child in supine position; a thin needle is attached to a syringe is inserted vertically in the midline, 1 to 2 cm above the symphysis pubis. Urine is usually obtained at a depth of 2 to 3 cm. Usually done in infants less than a year but procedure also applicable in children up to 4 or 5 years of age.
Good method • suprapubic aspirate • catheter specimen • mid stream specimen • clean catch • bag urine Poor method
Urine specimen transport After collection; urine should be sent to the lab as soon as possible as contaminating bacteria will continue to proliferate in the warm medium. Otherwise; the specimen should be refrigerated at 4 0C or a bacteriostatic agent e.g. boric acid (1.8%) added.
Urine analysis
Sensitivity and specificity of various tests for UTI AAP guidelines 1999 Test Sensitivity % Specificity % (range) (range)
Leucocyte esterase (LE) 83 (67-94) 78 (64-92) Nitrite 53(15-82) 98 (90-100) LE or nitrite positive 93 (90-100) 72 (58-91) Pyuria 73 (32-100) 81 (45-98) Bacteria 81(16-99) 83 (11-100) Any positive test 99.8 (99-100) 70 (60-90) ** the three most useful tests are the leucocyte esterase test, nitrite test and microscopy.
Treatment
Antibiotic should be started without delay after the collection of satisfactory urine specimen Oral antibiotic is satisfactory in non toxic child. The usual choices include trimethoprim or a cephalosporin. Agents that are excreted in the urine but do not achieve therapeutic concentrations in the blood stream ( e.g. nalidixic acid or nitrofurantoin ) should not be used to treat UTI in febrile infants and young children in whom renal involvement is likely. Patients who are toxic-appearing or unable to retain oral intake should receive parenteral antibiotic. Duration of treatment is 7-14 days. Always review antibiotic when urine C & S result available. Repeat urine culture after 2 days of treatment. Bacteriuria is almost always eradicated within 24 – 48 hours of introducing effective treatment. Change antibiotic if bacteriuria persist. Children treated for UTI should continue antibiotic at prophylactic dosage while awaiting hospital referral and imaging studies.
Antibiotics used in UTI Drug Therapy Prophylaxis Trimethoprim 4 mg/kg/dose bd 1 – 2 mg/kg nocte Nitrofurantoin * 1 mg/kg/dose qid 1 mg/kg nocte Amoxycillin 20 –40 mg/kg/dose tds Amikacin 15 mg/kg/dose od Gentamicin 5 mg/kg/dose od Cephalexin 50 – 100 mg/kg/day in 4 dose 5 mg/kg nocte * must check G6PD status
Investigations Aims - to identify those with abnormalities that predispose to renal damage - to detect renal scarring
Ultrasonography • Reveals dilatation of upper tracts, renal sizes and major bladder anomaly • Timing is not crucial except when response to treatment is slower than anticipated; it should then be done urgently to exclude obstruction or pus collection
Micturating Cystourethrogram (MCUG ) • Detects vesico-ureteric reflux and infravesical obstruction e.g. posterior urethral valves in boys • Done when child is free of infection; usually 6 weeks after an acute infection
99m Tc DMSA scan • In the early phase of infection; uptake defects represents areas of acute inflammation • 6 months after an infection; uptake defects represents area of permanent scars • Estimates the differential renal function of both kidneys
Recommendation for imaging studies:
0 – 2 years old Ultrasound, DMSA & MCUG 2 – 5 years old Ultrasound & DMSA. MCUG if ultrasound & DMSA abnormal or child has severe or recurrent infection or family history of reflux. Over 5 years Ultrasound. MCUG if recurrent infection or ultrasound abnormal *DMSA / MCU usually done 4 – 6 weeks after initial UTI.
Factors predisposing to renal scarring : • growing kidneys of a young child • delayed treatment of UTI, recurrent UTI • more severe grades of reflux • host susceptibility, bacterial virulence General supportive measures • Encourage child to drink plenty and empty bladder adequately. • Avoid constipation • Proper toilet habits - wipe from front to back. Encourage double micturation.
Further management This depends upon the results of investigation.
(A) Normal renal tracts investigation.
• Prophylaxis antibiotic not required except if there are frequent and troublesome symptomatic recurrences (> 3 per year). • Urine culture during any febrile illness or if the child is unwell. • Follow up for at least 1 year.
(B) Vesicoureteral reflux (VUR) – refer section on VUR.
(C) No VUR but renal scarring present.
• Repeat DMSA 6- 12 months later to ensure that the defect is real scar and not pyelonephritis. • Repeat urine culture only if symptomatic. • Annual BP surveillance for life. • Annual renal function test and urine FEME (for proteinuria) if bilateral or severe scarring. • Close follow up during pregnancy. • Uncertain role of prophylactic antibiotic.
(D) Posterior urethral valve – refer urologist/surgeon.
(E) Renal dysplasia, hypoplasia or evidence of obstruction
• May need further imaging to evaluate function and drainage. Refer surgeon as necessary. • Monitor renal function, BP and growth parameters.
References
1. RJM Coward, TL Chambers. An evidence-based appraisal of the investigation of childhood urinary tract infections. Current Paediatrics (1999) 9, 215 – 221. 2. JM Savage. The investigation and follow up of UTI. Current Paediatrics. ( 1994 ) 4, 240 –244. 3. HG Rushton. Urinary tract infections in children. Epidemiology, evaluation and management. The Paediatric Clinics of North America. October 1997. Pg 1130 –1169. 4. JM Smellie. Management and investigation of children with UTI. Clinical Paediatric Nephrology. Second edition. Butterworth-Heinemann Ltd 1994. Pg 160 – 174. 5. Pilling D, Postlethwaite R. Imaging in urinary tract infection. British paediatric Association Standing committee on paediatric practice guidelines 1996. 6. KB Robert, SM Downs, S Hellerstein, MJ Holmes, RL Lebowitz, JA Lohr, LD Shortliffe, RW Steele. Subcommittee on UTI. American Academy of Paediatrics. The diagnosis, treatment and evaluation of the initial UTI in febrile infants and young children. Paediatrics. Vol 103, No 4, April 1999. Pg 843 – 852.
VESICOURETERAL REFLUX
Definition
Vesicoureteral reflux (VUR) is defined as the retrograde flow of urine from the bladder into the ureter and collecting system. In most individuals VUR results from a congenital anomaly of ureterovesical junction (primary VUR), whereas in others it results from high pressure voiding secondary to posterior urethral valve, neuropathic bladder or voiding dysfunction (secondary VUR).
Significance of VUR
It is the commonest radiological abnormality in children with UTI (30 – 40%). Children with VUR are at risk for further episodes of pyelonephritis with potential for increasing renal scarring and renal impairment (reflux nephropathy).
ESRD (End Stage Recurrent Progressive VUR Renal Disease) UTI renal scarring
Hypertension
Classification of Severity
International Reflux Study Committee (Grade I – V). Grade 1 Ureter only Grade 2 Ureter and upper collecting system without dilatation Grade 3 Mild or moderate dilatation of ureter and mild or moderate dilatation of renal pelvis, but no or slight blunting of fornices Grade 4 Moderate dilatation and/or tortuosity of ureter with moderate dilatation of renal pelvis and calyces and complete obliteration of sharp angles of fornices, but maintenance of papillary impressions in the majority of calyces Grade 5 Gross dilatation and tortuosity of ureters, renal pelvis and calyces; papillary impressions are not visible in the majority of calyces
Management of The Child With VUR
Medical management is the treatment choice for • All infants (regardless of the reflux grade). • Older children with mild to moderate VUR (Grade I – III) who can be maintained infection free.
Rational: • Most reflux resolves spontaneously with time (Grade I to II – 80%; Grade III – 50%; Grade IV- 25%). • Studies have not shown any significant difference in outcome between both medical and surgical treatment.
Medical approaches include: • Continuous antibiotic prophylaxis to maintain sterile urine until o at least age 4 to 5 years ( based on the fact that new scars have only rarely been seen to develop after the age of 4 to 5 years but optimal duration is not yet well defined ) or o reflux has resolved spontaneously. • For mild reflux (Grade I and II), discontinuing prophylaxis after age 2 years. If DMSA scan shows scarring; repeat 1 year later. If DMSA normal; can discharge. • Advice on general measures to prevent recurrent UTI (refer to UTI section) • Periodic urine culture (approximately every 3 months) to detect asymptomatic bacteriuria as well as culture when a fever is present. • Immediate treatment for any breakthrough infection.
Surgical management (ureteral reimplantation) is considered if: • antibiotic prophylaxis fails to prevent breakthrough infection • new scar formation • non compliance to medical prophylaxis • persisting high grade (IV – V) VUR beyond age 2 years especially in girls.
Follow up of patients with renal scar – refer section on UTI
Sibling screening – There is now abundant evidence that primary VUR is inherited by an autosomal dominant mechanism. High risk group would be siblings younger than 5 years of age.
REFERENCES
1. Elder JS, Peters CA, Arant BS Jr, Ewalt DH, Hawtrey CE, Hurwitz RS, et al. Paediatric Vesicoureteral Reflux Clinical Guideline Panel summary report on the management of primary vesicoureteral reflux in children. J Urol 1997; 157 : 1846 – 51. 2. AB Belman. The Peadiatric Clinic of North America.1997. Vesicoureteral reflux. Pg 1171 –1190. 3. Mark H, Kenneth IG. Vesicoureteral reflux. Paediatric Urology. Third edition. Butterworth Heinemann 1997. Pg 440 – 465. 4. Weiss R, Duckett J, Spitzer A. Result of a randomized clinical trial of medical versus surgical management of infants and children with grade III and IV primary vesicoureteral reflux. J urol 1992; 148 : 1667 – 73. 5. KV Jones. Prognosis for VUR. Arch Dis Child 1999: 81 : 287 – 294.
Antenatal Hydronephrosis Definition: The most generally accepted definition is the maximum antero-posterior diameter of renal pelvis. No universally accepted value defining this abnormality.
Sensitivity and specificity An 8 mm pelvic diameter has a sensitivity of 91% and specificity of 72%. (1)
Timing of detection 90% after eighteen weeks of gestation. (2) 95% by 22 weeks.
Grading The Society of Fetal Urology (SFU) has developed the following classification system: (3) SFU Grade 0 Intact central renal complex (renal pelvis) SFU Grade I Mild splitting of central renal complex SFU Grade II Pelviectasis but no calyectasis* SFU Grade III A markedly split pelvis with uniformly dilated calyces, but normal renal parenchyma SFU Grade IV Characteristics of grade III with thinning of renal parenchyma. *Pelviectasis : Dilatation of pelvis Calyectasis: Dilatation of calyx
Another system of grading looked at the length of renal pelvis diameter (RPD). (4) 5-8 mm Mild hydronephrosis 8-12 mm Moderate hydronephrosis >12 mm Severe hydronephrosis
Marked hydronephrosis is frequently seen in pelvic ureteric junction obstruction whereas the mild hydronephrosis is associated with vesicoureteric reflux. (4)
Frequency 0.14 - 0.67% in unselected population. (5) Increased frequency of up to 8% with positive family history of renal agenesis, multicystic kidney, reflux nephropathy and polycystic kidneys. (6)
Epidemiology Male to female ratio is 2:1. Bilateral in 20 to 40 %. (7)
Review of causes of antenatal hydronephrosis (8) Abnormality Frequency (%) Transient 48 Physiologic 15 Pelvic ureteric junction (PUJ) obstruction 11 Vesicoureteric reflux (VUR) 4 Megaureter, obstructed or non-obstructed 4 Multicystic kidneys 2 Ureterocoeles 2 Posterior urethral valves (PUV) 1
Transient and physiologic hydronephrosis 60% of antenatal hydronephrosis is physiological. This will resolve before end of pregnancy or within first year of life. Fetal urine flow is four to six times greater than neonatal urine production. This is due to differences in renovascular resistances, GFR and concentrating ability before and after birth. (9) These differences may contribute to ureteric dilatation in-utero in the absence of functionally significant obstruction.
Postnatal management Physical examination • Abdominal mass: Enlarged kidney due to pelvicureteric junction obstruction OR Multicystic dysplastic kidneys. • Palpable bladder :Posterior urethral valves in a male infant. • Deficient abdominal wall with undescended testes: Prune Belly syndrome. • Poor stream and dribbling: Posterior urethral valves in a male infant • Abnormalities in spine and lower limb: Neurogenic bladder • Patulous anus: Neurogenic bladder
Examination for other anomalies should also be carried out.
Blood and urine investigations All patients with bilateral hydronephrosis should have the following done within 48 hours of life: • Renal profile (If the first creatinine is elevated serial monitoring is advised.) • Liver function test, calcium and phosphate • Full blood count • Blood gas For all patients with unilateral or bilateral hydronephrosis: • Urine FEME • Urine C&S
Ultrasound examination Perform after 48 hours of life. Hydronephrosis may not be detected because of physiologic volume depletion and relative oliguria. Do earlier in male infants suspected of having bilateral hydronephrosis OR those with hydronephrotic single kidneys. Repeat ultrasound three months later if initial ultrasound is normal or if there is only mild hydronephrosis.
Micturating Cystourethrogram (MCU) All patients with postnatal moderate and gross hydronephrosis should get an MCU done. Needs to be done on an urgent basis in boys with bilateral hydronephrosis to exclude posterior urethral valves. Non urgent appointments can be taken for other patients.
99m DTPA SCAN Appointments are taken for DTPA scans when: (i) The hydronephrotic kidney on postnatal ultrasound has features of pelviureteric junction obstruction (ii) MCU has excluded the diagnosis of vesicoureteric reflux. However due to the long waiting time for DTPA scans in MOH hospitals it would be advisable to arrange for appointments earlier rather than wait for MCU results. Best done after one month of life for clearer images. It will assess: • Total renal function • Individual renal function • Drainage time from renal pelvis (a) In a dilated system, washout occurs rapidly after intravenous frusemide. (b) The system is considered obstructed if washout is delayed beyond 20 minutes after intravenous frusemide.
Intravenous Urogram (IVU). It may not reveal additional information in asymptomatic infants and increases risk of radiation exposure. In the absence of DTPA services, IVU after one month of life with non-ionic contrast media may be considered to evaluate duplex systems and pelvic ureteric junction obstruction.
Antibiotics Antibiotic prophylaxis is started in infants with antenatal hydronephrosis until reflux has been excluded. Commonly used prophylactic antibiotics: (10) Trimethoprim 1-2 mg/kg at night
Nitrofurantoin 1 mg/kg at night. Recommended after 3 months old .May cause haemolytic anaemia in G6PD deficient babies.
Cephalexin 5 mg/kg at night
Posterior urethral valves • Insert urinary catheter for continuous bladder drainage, urgent micturating cystourethrogram to confirm diagnosis of posterior urethral valves. • Send urine FEME and cultures. • Empirical second-generation cephalosporin is recommended if urine is turbid • Assess hydration status • Monitor renal function, electrolytes and acid base status • Refer to nephrologists/urologist for primary valve ablation or vesicostomy as soon as possible.
Advantages of prenatal detection Has allowed identification of conditions that require immediate treatment and which otherwise would go unrecognized until symptoms arose postnatally.
Algorithm
Antenatal hydronephrosis
Ultrasound kidneys Male infants with & urinary tract bilateral
hydronephrosis
and/or palpable No or mild Confirmed hydronephrosis hydronephrosis bladder and poor urinary stream
MCU and *DTPA Appointment
VUR confirmed PUJ obstruction Repeat Ultrasound in continue three months confirmed, refer Urgent MCU to exclude prophylactic nephrologist/urologist PUV antibiotic
*It would be advisable to get dates for DTPA scans early due the long waiting time for DTPA appointments in MOH hospitals.
References 1.Ouzounian JG, Castro MA, Fresquez M et al Prognostic significance of antenatally detected fetal pyelactasis. Ultrasound Obstet Gynecol 1996; 7: 724. 2. Kramer SA. Current status of fetal intervention for congenital hydronephrosis. J Urol 1983; 130:641. 3. Fernbach SK, Maizels M, Conway JJ. Ultrasound grading of hydronephrosis: introduction to the system used by the Society of Fetal Urology. Pediatr Radiol 1993; 23:478. 4. Baskin L Postnatal evaluation of antenatally diagnosed fetal hydronephrosis www.uptodate.com 2004. 5.Madarikan BA, Hayward C, Roberts GM et al. Clinical outcome of fetal uropathy. Arch Dis Child 1988; 63:961. 6.ReussA, Wladimiroff JW, Niermeijer MF. Antenatal diagnosis of renal tract anomalies by ultrasound. Pediatr Nephrol 1987; 1:546. 7. Gonzales R, Schimke CM. Uteropelvic junction obstruction in infants and children. Pediatr Clin North Am 2001; 48:1505. 8.Woodward M, Frank D. Postnatal management of antenatal hydronephrosis. BJU Int 2002; 89:149. 9. Keating MA, Escala J, Snyder HM et al. Changing concepts in management of primary obstructive megaureter. J Urol 1989; 142:636 10.Paediatric Formulary Guy’s, St. Thomas’ and Lewisham Hospital 4 th edition.1998. THE ANAEMIC CHILD
APPROACH TO AN ANAEMIC CHILD
Suspected anaemia
• History • Physical Examination • Preliminary Investigations -Hb, Hct, red cell indices retic ulocyte count, blood film
Presence of generalized
lymphadenopathy and / or
hepatosplenomegaly?
Yes No
Differential diagnosis : Differential diagnosis : Acute / chronic leukaemias Acute blood loss Chronic haemolytic anaemia: Iron deficiency Thalassaemia Folate deficiency Hereditary spherocytosis B12 deficiency Hereditary elliptocytosis Acute haemolytic anaemia: G6PD deficiency G6PD deficiency with oxidant Malignancies e.g. lymphoma stress Chronic infection e.g. tuberculosis Autoimmune ABO incompatibility Infection e.g. malaria Drug induced Bone marrow failure Aplastic anaemia Fanconi’s anaemia Diamond-Blackfan Others Hypothyroidism Chronic renal failure
Variation in FBC indices with age i
Age Hb (g/dl) RBC ( ×××10 12 /l) MCV (fl) Birth 14.9 – 23.7 3.7-6.5 100-135 2 mon 9.4-13.0 3.1-4.3 84-105 12 mon 11.3-14.1 4.1-5.3 71-85 2-6 yr 11.5-13.5 3.9-5.3 75-87 6-12 yr 11.5-15.5 4.0-5.2 77-95 12-18 yr F 12.0-16.0 4.1-5.1 78-95 12-18 yr M 13.0-16.0 4.5-5.3 78-95
IRON DEFICIENCY ANAEMIA Causes : 1. Chronic blood loss Laboratory findings : 2. Increase demand Prematurity 1. Red cell indices Growth ↓ MCV 3. Malabsorbtion ↓ MCH Worm infestation 2. Low serum ferritin 4. Poor diet
Treatment :
Nutritional counseling: Maintain breastfeeding. Use iron fortified cereals.
Oral iron medication: 6 mg/kg/day of elemental iron in 3 divided dosages for 6-8 weeks after haemoglobin level is restored to normal. Syrup FAC (Ferrous ammonium citrate): 1 mg elemental iron per ml. Ferrous fumarate tablet: 200 mg elemental iron per tablet.
Consider the following for failure to response to oral iron: • Non – compliance • Inadequate iron dosage • Unrecognized blood loss • Incorrect diagnosis • Impaired GI absorption
Blood transfusion: In general no transfusion required in chronic anemia unless there are signs of decompensation (e.g. cardiac dysfunction) and the patient is otherwise debilitated. Give low volume packed cells (< 5mls/kg) if necessary over 4-6 hours with i.v. frusemide (1mg/kg) in severe anaemia (Hb < 4 g/dL).
THALASSAEMIA – refer to Thalassaemia protocol
HEREDITARY SPHEROCYTOSIS
Pathogenesis Due to a defect in the main structural protein (spectrin) of the RBC membrane producing spheroidal shaped and osmotically fragile RBCs that are trapped & destroyed in the spleen causing shortened RBC life span. The degree of clinical severity is proportional to the severity of RBC membrane defect.
Clinical features – mild, moderate & severe Anaemia Intermittent Jaundice Splenomegaly Pigmented gallstones – adolescents & young adults Haemolytic crises Aplastic crises – Parvovirus B19 Megaloblastic crises – all patients should receive folate supplement Inheritance Dominant in 2/3 Nondominant in 1/3, de novo or recessive Rare manifestations Leg ulcers Extramedullary haematopoietic tumours Spinocerebellar ataxia Myopathy
Investigation Reticulocytosis Microspherocytes in peripheral blood film Osmotic fragility is increased Elevated MCHC Normal direct antiglobulin test Autohaemolysis is increased and corrected by glucose
Treatment Splenectomy to be delayed as long as possible In mild cases – avoid splenectomy unless gallstones developed Folic acid supplement – 1 mg day
Note: Splenectomy is avoided for patients < 5 years because of the increased risk of postsplenectomy sepsis. Give pneumococcal, haemophilus & meningococcal vaccination 4-6 weeks prior to splenectomy & prophylactic oral penicillin to be given post splenectomy.
i Lieyman JS, Hann IM. Paediatric Haematology.London, Churchill Livingston, 1992. HAEMOPHILIA
Haemophilia describes a group of inherited blood disorders in which there is a life-long defect in the clotting mechanism. It is inherited as an X linked recessive: therefore males are affected and females are carriers. In 30% cases no family history is obtainable as it is a spontaneous new mutation. The most common haemophilias are:
1) Haemophilia A – Deficiency of factor VIII (85% cases) 2) Haemophilia B – Deficiency of factor IX (15% cases)
PRESENTATION :
Although the defect is present from birth, bleeding in the neonatal period is unusual. Children usually present with easy bruising when they start crawling /walking i.e.: 9 –12 months. Haemarthrosis (bleeding into a joint) is characteristic of haemophilia. Large joints are usually affected (knee, ankle, elbow) and the child presents with a swollen, painful joint. Bleeding can occur at other sites: epistaxis, gum bleeding, haematuria and life-threatening intracranial haemorrhages. Bleeding may occur spontaneously or after trauma or operation.
INVESTIGATIONS:
1. Full blood count 2. Coagulation screen: PT, APTT 3. Specific factor assay: FVIII level (low in Haemophilia A) 4. Specific factor assay: FIX level (low in Haemophilia B)
In haemophilia, the activated partial thromboplastin time (APTT) is prolonged, the platelet count and prothrombin time (PT) are normal. When the APTT is prolonged, then the lab will proceed to do the factor VIII antigen level. If this is normal, only then will they proceed to assay the Factor IX level. Once the level has been measured, then the haemophilia can be classified as below.
CLASSIFICATION OF HAEMOPHILIA :
Factor level Classification
< 1 % Severe 1-5 % Moderate 5-25 % Mild
In severe haemophilia, spontaneous bleeding occurs and there is a risk of intracranial haemorrhage. In mild – moderate haemophilia, bleeding may only occur after trauma or surgery.
FURTHER INVESTIGATIONS :
1. Hepatitis B surface antigen, anti HBS antibody 2. Hepatitis C antibody 3. HIV serology 4. Diagnosis of carrier status for genetic counseling. • Mother of a newly diagnosed son with haemophilia • Female siblings of boys with haemophilia • Daughter of a man with haemophilia
Once a child is diagnosed to have haemophilia, check the viral status at diagnosis and then yearly. This is because treatment carries the risk of acquiring viruses. All haemophiliacs should be immunized against Hepatitis B.
TREATMENT:
1. Treatment of haemophilia consists of replacing the missing factor: Factor VIII concentrates are used in haemophilia A, Factor IX concentrates in Haemophilia B. Fresh frozen plasma and cryoprecipitate ideally SHOULD NOT be used to minimize the high risk of viral transmission.
2. The dose of factor replacement depends on the type & severity of bleed.
TYPE OF BLEED DOSE OF FACTOR VIII DOSE OF FACTOR IX Haemarthrosis 20 U/kg 40 U/kg Soft tissue /muscle bleeds 30- 40 U /kg 60-80 U/kg Intracranial haemorrhage or surge ry 50 U/kg 120 U/kg
3. Alternative formula for calculating dose: a. Units of Factor VIII: (% rise required) x (weight in kg) x 0.5 b. Units of Factor IX: (% rise required) x (weight in kg) x 1.4
4. The percentage of factor aimed for depends on the type of bleed. a. For haemarthroses, 30-40 % is adequate. b. For a soft tissue or muscle bleed (which has the potential to track and cause compression/compartment syndrome), aim for 40- 50 % level. c. For intracranial bleeds or patients going for surgery, aim for 100%.
5. Factor VIII is normally given every 8 – 12 hours. Factor IX can be given every 12 – 24 hours. The duration of treatment also depends on the type of bleed: haemarthroses 2-3 days, soft tissue bleeds 4-5 days, intracranial bleeds or surgery 7-10 days.
SUPPORTIVE TREATMENT :
1. ANALGESIA: Usually there is rapid pain relief in haemarthroses as soon as the missing factor concentrate is infused. If analgesia needs to be given, avoid intramuscular injections. Also do not use aspirin or the non-steroidal anti- inflammatory drugs (NSAIDS) as they will also cause bleeding.
2. DENTAL CARE: It is important that children with haemophilia maintain good dental hygiene. Once dental caries has developed, it will be a regular source of bleeding causing multiple hospital admissions. Dental clearance with factor replacement will be required in severe cases.
3. IMMUNISATIONS: This is important and must be given: in this case intramuscular injections are allowed: use the smallest gauge needle to avoid trauma. If a baby has had haematoma formation after immunization, the solution is to administer the next injection under factor cover.
COMPLICATIONS:
1. Joint destruction: Recurrent haemarthroses into the same joint will eventually destroy the joint causing osteoarthritis and deformity. This can be prevented by prompt and adequate factor replacement.
2. Acquisition of viruses e.g.: Hepatitis B, C or HIV: immunisation and regular screening recommended
3. Inhibitors: in 15-25% cases of haemophilia A, patients may develop antibodies to the missing factors. This is suspected when factor replacement does not result in clinical improvement. If a patient is suspected to have inhibitors, the case should be discussed with a haematologist.
SPECIFIC GUIDELINES FOR MANAGEMENT
A) Intracranial haemorrhage (ICH)
1. Factor replacement should be given for any suspected ICH i.e. before it is confirmed by CT scan. Initial large bolus of factor concentrate should be given immediately to increase Factor VIII:C level to 100% and for haemophilia B if monoclonal FIX is used a level of 80% is adequate and if PCC is used 50% level is recommended. 2. Admission 3. Urgent CT scan 4. If CT scan confirms ICH : maintain factor level above 50% , factor concentrates to be given 6-8 hourly for a minimum of 3-5 days depending on the clinical response, then reduce the dose to maintain at 30% initially 12 hourly and then daily up to a total of 10 – 14 days replacement therapy 5. If CT scan show no evidence of ICH, admit 1 day for observation 6. Follow up for long term sequelae. 7. Lab investigation : • Full coagulation profile – PT,PTT • Pre-treatment factor assay level and inhibitor level – before starting treatment and to repeat after 3 days of treatment to ensure adequate levels have been achieved and no inhibitor has developed • Post treatment factor assay level ( ½ hour after infusion ) – to ensure the required factor level is achieved ( if the level is not achieved , consider development of inhibitors ) and should be repeated after 3 – 5 days • Follow up CT scan after 2 weeks
B) Surgery
A. Pre-op investigations • Full coagulation profile – PT, PTT • Pre-factor assay level and inhibitor level • Blood grouping and full antibody screening and if blood required full cross matching
B. Calculate Dose
• ½ hour before operation, infuse patient with appropriate factors. • Preferable level : i. 80-100% for factor VIII ii. 70% for monoclonal factor IX iii. 50% if prothrombin complex complex (PCC) is being used • Check post transfusion specific factor level ½ hour later if necessary or after surgery to ensure correct factor level is achieved • Clotting factor level should be maintained above 50% during the operation and 24 hours after surgery. • Repeat pre factor assay and check inhibitor level on day 3 to ensure adequate level and no inhibitor had develop • Day 3 till day 7 – maintain at 50% • Day 8 till day 14 – reduce the dose gradually • Post operatively a minimum of 10 to 14 days replacement therapy is recommended • Replacement therapy should be given as long as there is bleeding plus another 5 –10 days after the bleeding stops, till the wound heals
C) Ilio-psoas Bleed
Investigation
1. USS abdomen – to assess the size of haemorrhage 2. Full coagulation profile 3. Pre-factor specific assay and inhibitor screen 4. Full blood picture 5. Renal function test
Management
1. Complete bed rest 2. Factor replacement should be given early in adequate dosage to raise the factor level to more than 50% for haemophilia A & B; maintain above 50% with factor concentrates given 8 hourly for haemophilia A & 12 hourly for haemophilia B for a minimum of 3-5 days. Then reduce the dose accordingly. A minimum of 10 – 14 days replacement therapy is recommended 3. Physiotherapy – when pain subsides 4. Repeat USS 1 week later to assess progress
D) Haematuria
Management a. Rest in bed b. Drink plenty of water (1 ½ maintenance). c. Monitor for 1 st 24 hour: UFEME & Urine C&S d. If bleeding persists for > 24 hours, start factor concentrate infusion. e. Perform KUB & Ultrasound of the kidneys
DO NOT give anti-fibrinolytic drugs (tranexamic acid) because this may cause formation of clots in the tubules which may not recanalize.
E) Joint haemorrhages
• Episodic replacement therapy is the main stay of treatment • Most spontaneous haemarthroses respond to a single infusion of factor concentrate. Aim for a level of 30 % to 40%. • If swelling or spasm is present, treatment to level of 50% is required and infusion may have to be repeated at 12-24 hours interval – until pain subsides • Minor haemarthroses may not require immobilization, elastic bandage or slings and ice may help in pain relief • Severe haemarthroses o Splint in position of comfort o Rest o Factor replacement o Joint rehabilitation to be started as soon as possible o Analgesic
HAEMOPHILIA SOCIETY
All haemophiliacs should be registered with the Haemophilia Society. They should have a medic-alert bracelet/chain which identifies them as haemophiliacs. They usually carry a book in which the diagnosis, classification of severity, types of bleeds and admissions can be recorded.
Address: The Haemophilia Society of Malaysia C/O Pusat Perkhidmatan Darah Hospital Kuala Lumpur Jalan Pahang 50586 Kuala Lumpur Wilayah Persekutuan Malaysia
Reference:
1. Malaysian CPG for Management of Haemophilia.
IMMUNE THROMBOCYTOPENIC PURPURA
Definition
Isolated thrombocytopenia with otherwise normal blood count in a patient with no clinically apparent associated conditions that can cause thrombocytopenia (such as HIV infection, SLE, lymphoproliferative disorders, alloimmune thrombocytopenia, and congenital or hereditary thrombocytopenia).
Pathogenesis • disorder of increased platelet destruction • probably caused by the development of autoantibodies to platelet-membrane antigens • in children, ITP is usually an acute, self-limited disorder that resolves spontaneously; in adults, it is typically a chronic disorder with a more insidious onset
Clinical Manifestation • Onset is usually acute • Cutaneous bleeding – especially over the legs • Mucosal bleeding – palatal petechiae, epistaxis, haematuria, gastrointestinal bleeding, menorrhagia • Intracranial haemorrhage (ICH) • No hepatosplenomegaly, no lymphadenopathy • Full blood count – only thrombocytopenia, normal haemoglobin and total white cells count • Peripheral blood picture – normal except reduced amount and slightly larger size platelet • Bleeding time – prolonged
Diagnosis • The diagnosis of ITP is based principally on the history, physical examination, full blood count, and examination of the peripheral smear, which should exclude other causes of thrombocytopenia
• Other causes of thrombocytopenia to be excluded: 1. Neonatal alloimmune/ isoimmune thrombocytopenia if < 6 months old 2. Sepsis and infections including HIV infection 3. Drug-induced thrombocytopenia 4. Haematological malignancy e.g. acute leukaemias 5. Congenital marrow failure syndromes e.g. Fanconi anaemia, thrombocytopenia with absent radius 6. Autoimmune disorders e.g. SLE, Evan syndrome 7. Primary immunodeficiency syndromes e.g. Wiskott-Aldrich syndrome
• Threshold for performing a bone marrow aspiration must be low and is indicated if there is: 1. Presence of atypical features e.g. organomegaly, significant lymphadenopathy, abnormal blood counts or suspicious peripheral blood picture. 2. Before starting steroid therapy (to avoid partially inducing an undiagnosed acute leukaemia) 3. Not responding to IV Ig therapy 4. Persistent thrombocytopenia beyond 6 months 5. Thrombocytopenia recurs after initial respond to treatment
• Other tests may be indicated when there is atypical presentation from the history, physical examination, FBC or PBF: e.g. Antinuclear factor, Coomb's test, ultrasound of abdomen, HIV testing.
Treatment
Not all children with diagnosis of acute ITP need hospitalization.
Hospitalization is indicated if: • Severe life-threatening bleeding (e.g. ICH) regardless of platelet count • Platelet count < 20,000 with evidence of bleeding • Platelet count < 20,000 without bleeding but inaccessible to health care • Parents request for admission
Most of childhood ITP remit spontaneously with 70% achieves platelet count > 50,000 by the end of 3 rd week.
Careful observation and monitoring platelet count without specific treatment is appropriate for patients with: • Platelet count > 20,000 without bleeding • Platelet count > 30,000 with only cutaneous purpura
Treatment is indicated if there is: • Life threatening bleeding episode ( e.g. ICH) regardless of platelet count • Platelet count < 20,000 with mucosal bleeding • Platelet count < 10,000 with any bleeding
Choice of treatment include: 1. Oral prednisolone 4 mg/kg/day for 7 days, then taper and discontinue at 21 days 2. IV Methylprednisolone 30 mg/kg/day for 3 days 3. IV Immunoglobulin 0.8 g/kg/dose for 1 day or 250 mg/kg for 2 days. 4. IV Anti-Rh(D) immunoglobulin (50 – 75 microgram/kg) in Rhesus positive patients – may cause haemolytic anaemia.
All are effective in raising platelet count much quicker compared to no treatment with IVIg the quickest. However no direct evidence indicates that any of these treatments reduce bleeding complications or mortality from ITP. No influence on progression to chronic ITP.
Side effects of IVIG is common (15 – 75% incidence) and include fever, flushing, headache, nausea, aseptic meningitis and transmission of Hepatitis C (older preparation).
Steroids should not be continued, however, if there is no response or if there is a rapid relapse after withdrawal. The considerable risks of long-term side-effects in a growing child outweigh the benefits of either too-frequent high-dose pulses or any attempt to titrate the platelet count against a regular lower steroid dose.
Treatment should not be directed at increasing the platelet count above a preset level but rather on the clinical status of the patient.
Intracranial Haemorrhage • The most feared complication of ITP with 50% mortality rate • Cumulative risk of ICH in newly diagnosed ITP child within 1 st year is < 1% • Risk of ICH is highest in children with platelet count < 20,000, history of head trauma, aspirin use and presence of cerebral AV malformation. • 50% of all ICH occurs after 1 month of presentation, 30% after 6 months • Early treatment with steroid or IVIG may not prevent late onset ICH
Emergency treatment of ITP with ICH (alone or in combination): 1. IVIG 1 g/kg/dose/day for 2 days 2. IV anti-Rh(D) 50 – 75 microgram/kg 3. High dose IV Methylprednisolone 30 mg/kg/day for 3 days 4. Platelet transfusion 5. Neurosurgical intervention if indicated. 6. Splenectomy if other modalities fail & if craniotomy required.
Chronic ITP
• Persistent thrombocytopenia after 6 months of onset (20%) • Wide spectrum of manifestations varying from mild symptomless low platelet counts through intermittent relapsing symptomatic thrombocytopenia to the rare stubborn and persistent symptomatic and haemorrhagic disease
Management • Every opportunity should be given for disease to remit spontaneously as the majority will do so if given enough time • Revisit the diagnosis to exclude other causes of thrombocytopenia (Immunodeficiency, lymphoproliferative or collagen disorders or HIV infection). • Symptomless children can be left without therapy and kept under observation. • Symptomatic children may need short course of treatment to tide them over the relapse which include:
1. Intermittent pulses of IVIg 2. Intermittent anti-Rh(D) antibody treatment for those with Rhesus D positive 3. Intermittent pulses of steroid
• Care must be taken with any pulse steroid strategy to avoid treatment-related steroid side-effects. Aware of immunosuppression e.g. risk of severe varicella • No justification for long-term continuous steroids
Splenectomy is indicated when: 1. Persistence of disease after 12 months with 2. Bleeding symptoms and 3. Platelet count < 10,000/µL (ages 3 – 12 years) or < 10,000/ µL to 30,000/ µL (ages 8 – 12 years) 4. No response or only transient success with intermittent IVIg, anti-D or pulse steroids 5. No contra-indications to surgery. Operative mortality < 1%.
• Over 70% rate of complete remission post-splenectomy • Pre-splenectomy immunization against pneumococci, haemophilus influenzae type b and meningococci infection mandatory 2 weeks before surgery • Post-splenectomy penicillin prophylaxis
Post-splenectomy failure or relapse, consider: danazol, vincristine, azathioprine, cyclophosphamide, alpha-interferon, staphylococcal protein A immunoadsorption, cyclosporine, cholchicine or dapsone.
References:
George, J.N., Woolf, S.H., Raskob, G.E., Wasser, J.S., Aledorf, L.M., Ballem, P.J., Blanchette, V.S., Bussel, J.B., Cines, D.B., Kelton, J.G., Lichtin, A.E., McMillan, R., Okerbloom, J.A., Regan, D.H. & Warrier, I. (1996) Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology. Blood, 88, 3-40.
Lilleyman, John S. Management of Childhood Idiopathic Thrombocytopenic Purpura. British Journal of Haematology, 1997, 105, pp 871-875
James J Corrigon. Treatment Dilemma in Childhood Idiopathic Thrombocytopenic Purpura. Lancet, 305, p602
David G. Nathan, Stuart H. Orkin, David Ginsburg, A. Thomas Look. Nathan and Oski’s hematology of Infancy and Childhood. 6 th edition 2003. W.B. Saunders Company.
Oncologic Emergencies
I. Metabolic Emergencies
A. Tumour Lysis Syndrome Characterised by ↑ Uric acid Massive tumour cell death with ↑ K+ rapid release of intracellular ↑ PO4 with associated ↓ Ca ++ metabolites, which exceeds the excretory capacity of the kidneys leading to acute renal failure. Can occur before chemotherapy is started.
Risk factors for tumour Iysis syndrome More common in • Bulky disease Iymphoproliferative tumours • Rapid cellular turnover. • Tumour which is exquisitely sensitive to chemotherapy. with abdominal involvement • ↑↑ LDH / se uric acid (e.g. B cell/ T cell • Depleted volume Iymphoma, leukaemias and • Concentrated urine or acidic urine. Burkitt's Iymphoma) • Poor urine output
a. Hyperuricaemia: Release of intracellular purines increase uric acid b. Hyperkalaemia Occurs secondary to tumour cell Iysis itself or secondary to renal failure from uric acid nephropathy or ↑↑ PO4. c. Hyperphosphotaemia ( ↑PO4) with associated ↓Ca ++ ) Most commonly occurs in Iymphoproliferative disorders because Iymphoblast PO 4 contents is 4 times higher than normal lymphocytes. Causes: 1. Tissue damage secondary to CaPO4 precipitation. Occurs when Ca X PO4 > 60 mg/dl. Results in renal failure, pruritis with gangrene and inflammation of the eyes and joints. 2. Hypocalcaemia leading to altered sensorium, photophobia, neuromuscular irritability, seizures, carpopedal spasm and GIT symptoms d. Renal failure Multifactorial: • Uric acid, phosphorus and potassium are excreted by kidneys • The environ of the collecting ducts of the kidney is acidic coupled with lactic acidosis due to high leucocyte associated poor perfusion – uric acid crystallizes causing uric acid obstructive nephropathy. Usually occur when levels > 20 mg/dl. • Increased phosphorus excretion causing calcium phosphate precipitation(in vivo solubility dependant on Ca X P = 58) in microvasculature and tubules. • Risk increases if renal parenchymal is infiltrated by tumour eg lymphoma or ureteral/venous obstruction from tumour compression (lymph nodes)
Management (Prevention): To be instituted in every case of acute leukaemia or Iymphoma prior to induction chemotherapy.
1. Hydration: 3000 ml/m 2/day (i.e. double hydration) No potassium should be added. 2 2. Alkalization of urine: Adding NaHCO 3 at 150-200 mmol/m /day (3 mls/kg/day NaHCO 3 8.4%) into IV fluids to keep urine pH 7.0 - 7.5. Avoid over alkalinization. (Aggravate hypocalcemia and cause hypoxanthine and xanthine precipitation, also precipitation of calcium phosphate in pH >8) 3. Allopurinol 10mg/kg/day, max 300mg/day. 4. KIV delay chemotherapy until metabolic status stabilizes. 2+ 2- 5. Close electrolyte monitoring- BUSE, Ca , PO 4 , uric acid, creatinine, bicarbonate. 6. Strict I/O charting. Make sure urine is flow is adequate once hydrated. Use diuretics with caution.
Management (Treatment) 1. Treat hyperkalemia – resonium, dextrose-insulin-bicarb, dialyze if indicated. 2. Diuretics 3. Hypocalcaemia management depends on the PO 4 level: • If PO 4 is ↑, then management is directed to correct the ↑ PO 4 ++ • If PO 4 is normal OR if child is symptomatic, then IV Ca replacement is given. • And if hypocalcaemia is refractory to treatment, associated hypomagnesaemia (Mg 2++ ) is to be excluded 4. Dialysis if indicated. Haemodialysis most efficient at correcting electrolyte abnormalities, peritoneal dialysis ineffective in removing phosphates.
B. Other Metabolic Emergencies a. Hyponatraemia ( ↓↓↓ Na +) Usually occurs in AML. Treat as for hyponatraemia. b. Hypokalaemia ( ↓↓↓ K +) Common in AML. Rapid cellular generation leads to uptake of K + into cells. (Intracellular K+ is 30 - 40 X higher than extracellular K +). Therefore may develop ↑ K + after chemotherapy. c. Hypercalcaemia (Ca ++ ) Associated with Non Hodgkin and Hodgkin Lymphoma, alveolar rhabdo, rhabdoid tumours, etc. Management: 1. Hydration. 2. Oral PO4 3. IV Lasix (which increases Ca 2- excretion) 4. Mithramycin
II. Haematologic Emergencies a. Hyperleucocytosis Occurs in acute leukaemia. Defined as TWBC ≥ 100 000. Associated • in ALL with high risk of tumour Iysis • in AML with leucostasis (esp monocytic) • Affecting the lungs causing SOB, hypoxaemia and RV failure • Affecting the CNS causing headaches, papilloedema, seizures, haemorrhage or infarct. • Others: renal failure, priapism, dactylitis Mechanism: - Excessive leukocytes form aggregates and thrombi in small veins ⇒ obstruction; worsens when blood is viscous. - Excessive leukocytes compete for oxygen and damage vessel wall ⇒ bleeding Management 1. Hydration • to facilitate excretion of toxic metabolites • to reduce blood viscosity 2. Avoid ↑ blood viscosity. • Cautious use of blood transfusion and diuretics. 3. During induction in hyperleukocytosis, keep platelet >20 000 and coagulation profile near normal 4. Exchange transfusions and leukopheresis should not be used alone as rapid rebound usually occur. Concurrent drug treatment should therefore be initiated soonest possible
B. Coagulopathy AML especially M3 associated with an initial bleeding diathesis 2 0 to consumptive coagulopathy. Due to release of a tissue factor with procoagulant activity from cells. However the use of all-Trans retinoic acid (Atra) has circumvented this complication.
Management. Other Haematological Emergencies 2 1. Platelet transfusions – 6units/m should increase platelets by Thrombocytopenia 50,000/ml 3. Severe Anaemia 2. FFP or cryoprecipitate 3. Vitamin K Treat appropriately. 4. +/- heparin therapy (10u/kg/hr) - controversial
III. Infections
A. Febrile neutropaenia
Common organisms in febrile Febrile episodes in oncology patients MUST be neutropenic patients are treated with urgency especially if associated with • Staph. Aureus and epidermidis neutropenia. Nearly all episodes of bacteraemia or • Strep. Pneumonia disseminated fungal infections occur when the absolute • E. coli; Pseudomonas; Klebsiella neutorphil count (ANC) <500. Risk increases maximally • Candida. if ANC < 100 and greatly reduced if the ANC > 1000.
Approach to a Febrile Neutropenic Patient.
History and P/E to identify possible source(s) of infection
Septic Work-up (FBC, CRP, CXR, bacterial and fungal cultures- blood, urine, stool, wound)
. Site unknown Site identified
Broad Spectrum antibiotics (e.g. Proper specimen collected cephalosporin and aminoglycoside plus nystatin) Specific antibiotics
T° settles in 3 days Remains febrile after 2 days
Continue Treatment Reculture, Change antibiotics May add systemic antifungal
Still febrile after 4 days . Stop Treatment after
1/52. Observe Look for possible sites of infection, re-Xray reculture
, Echo, USS, if necessary add antifungals. May consider changing antibiotics. Consider removal of CVL if present
Other Management : 1. If central line present, culture from central line from both lumens, add anti Staph cover e.g. cloxacillin. 2. Repeated P/E to look for new clues and signs and symptoms of possible sources. 3. Close monitoring of patient’s well-being – vital signs, perfusion, BP, I/O. 4. Repeat cultures if indicated 5. Investigative parameters, FBC, CRP, BUSE as per necessary . 6. * In presence of oral thrush or other evidence of candidal infection, start antifungals.
7. Try to omit aminoglycoside and vancomycin if on Cisplatinum - nephrotoxic and ototoxic. If required, monitor renal function closely.
B. Typhilitis
Necrotizing colitis localised to the caecum occuring in neutropenic patients. Pathophysiology:
Bacterial invasion of mucosa causing inflammation. Can lead on to full thickness infarction and perforation. Organisms: Clostridium, Pseudomonas
X-ray shows non specific thickening. At the other end of the spectrum, there can be presence of pneumatosis intestinalis +/- evidence of free gas
Management Usually conservative (unless surgically indicated) with broad spectrum antibiotics covering Gram negative organisms and anaerobes (metronidazole), mortality 20-100% Criteria for surgical intervention: • Persistent GI bleed despite resolution of neutropenia and thrombocytopenia and correction of coagulation abnormalities. • Evidence of perforation • Clinical deterioration suggesting uncontrolled sepsis (controversial)
C. Shock Common causes of shock in child with cancer Distributive Hypovolemic Cardiogenic Sepsis Haemorrhage Myopathy – Anthracycline - haemorrhagic cystitis -- High dose cyclo Anaphylaxis - GI bleed- ulcers -- Radiation therapy -Etoposide - typhilitis -L-Asparaginase - massive haemoptysis Cardiac tamponade -ATG - Intracardiac tumour -Cytosine Pancreatitis - Intracardiac thrombus -Carboplatin - Pericardial effusion -Blood products Addisonian crisis - Constrictive pericarditis - Amphotericin B Intractable vomiting Metabolic Veno occlusive disease -Hyperkalaemia Diabetes mellitus -Hypokalaemia -Hypocalcaemia Diabetes insipidus Myocarditis –viral, bacterial, fungal Hypercalcemia
Management: Ascertain cause and treat accordingly.
IV. Neurological Emergencies
A. Spinal Cord Compression Prolonged compression leads to permanent neurologic sequelae. Epidural extension: Iymphoma, neuroblastoma and soft tissue sarcoma Intradural: Spinal cord tumour
Presentation: Back pain-localized or radicular, aggravated by movement, straight leg raising, neck flexion. Later – weakness, sensory loss, incontinence.
Diagnosed by CT myelogram/MRI
Management: 1. Laminectomy urgently (If deterioration within 72 hours). 2. Once paralysis have been there longer than 72hours, chemotherapy might be the better option if tumour is chemosensitive especially for lymphoma. This avoids vertebral damage. Other chemosensitve tumour include neuroblastoma and Ewing’s with an onset of action similar to radiotherapy. 3. Prior IV Dexamethasone 0.5mg/kg 6 hourly to reduce oedema 4. +/- Radiotherapy
B. Increased ICP and brain herniation Cause : brain tumours e.g. astrocytoma, PNET, usually infratentorial and block the 3 rd or 4 th ventricle.
Signs and symptoms vary according to age/site. Infant; vomiting, lethargy, regression of milestones, seizures, symptoms of obstructive hydrocephalus and increased OFC. Older: early morning recurrent headaches with or without vomiting. Cerebellar: ipsilateral hypotonia and ataxia Herniation of cerebellar tonsil – head tilt and neck stiffness Tumours near 3 rd ventricle – cranio, germinoma, optic glioma, hypothal and pit tumours - visual loss, increased ICP and hydrocephalus - obstruction of aqueduct of Sylvius due to pineal tumour – raised ICP and Parinaud’s synd (impaired upward gaze, convergence nystagmus and altered pupillary response)
Management: 1. Assessment of vital signs, look for focal neurological deficit, 2. Look for evidence of raised ICP (bradycardia, hypertension and apnea) and 3. Look for evidence of herniation (changes in respiratory pattern, pupil size and reactivity. 4. Dexamethasone 0.5 mg/kg QID 5. Urgent CT to determine cause 6. Prophylactic antiseizures 7. LP is contraindicated 8. Decompression- ie shunting +/- surgery.
C. Cerebrovascular accident Direct or metastatic spread of tumour, antineoplastic agent, haematologic abnormality L-Asparaginase associated with venous or lateral and sagittal sinus thrombosis caused by rebound hypercoagulable state AML especailly APML associated with DIVC and CVA. Due to release of procoagulant.
Management Suportive Use of anticoagulant potentially detrimental In L-Aspa induced, recommended BD FFP Miscellanous
V. Miscellaneous Emergencies
A. Superior Vena Cava Obstruction Common in NHL/Hodgkin Lymphoma/ALL . Rarely: malignant teratoma, thymoma, neuroblastoma, rhabdo or Ewing’s may present with anterior or middle mediastinal mass and obstruction. 50% associated with thrombosis. Presentation: shortness of breath, facial swelling, syncope.
Management: 1) Tissue diagnosis is important but should be established by the least invasive measure available. Circulatory collapse or respiratory failure may occur with GA or sedation. • BMA • Biopsy of superficial LN under local anaesthesia. • Measurement of serum markers eg α-FP
If tissue diagnosis is unobtainable, empiric treatment may be necessary based on the most likely diagnosis. Both chemo and DXT may render histology uninterpretable within 48 hours, therefore biopsy as soon as possible.
2) Avoid upper limp venepunctures • Bleeding due to ↑ intravascular pressure • Aggravate SVC obstruction. 3) 1° mode of treatment is with steroids. } if pathology due to NHL 4) Chemotherapy. } 5) +/- DXT.
On commencement of therapy, there may be initial tracheal and tumour swelling leading to increasing respiratory compromise.
B. Pancreatitis In patients on L-Aspa and steroids
C. ATRA (all-trans retinoic acid) syndrome Characterised by: fever, respiratory distress, respiratory failure, oedema, pleural/pericardial effusion, hypotension Pathophysiology: Respiratory distress due to leukocytosis associated with ATRA induced multiplication and differentiation of leukaemic promyelocytes. Treatment: Dexamethasone 0.5 – 1mg/kg/dose BD, maximum dose 20mg bd.
REF: Pizzo & Poplack: Principles and Practice of Paediatric Oncology. 4th Ed, 2002 Pinkerton & Plowman: Paediatric Oncology. 2 nd Ed. 1997 Paediatric clinic of North America, Aug 1997. THALASSAEMIA
β Thalassaemia major is an inherited blood disorder presenting with anaemia at 4 - 6 months of age in the majority of cases with lethargy, failure to thrive and hepatosplenomegaly. In Malaysia, the beta-thalassaemia carrier rate is estimated at 3- 5% and the vast majority of them are unaware of their carrier/thalassaemia minor status.
Baseline investigations to be done for all new patients: - • Full blood count and peripheral blood film (In typical cases, the Hb would be < 7g/dl) • Hb Electrophoresis • HbA decreased or absent • Hb F increased • HbA 2 variable • Serum Ferritin • Red Cell Phenotyping (ideal) before first transfusion. • DNA analysis (optional) – indicated for confirmation of difficult cases, used in prenatal diagnosis and detection of α carrier (available at IMR, HUKM, UMMC and USM) • Liver function test • Infective screen – HIV, Hepatitis B & C, VDRL screen (before first transfusion) • HLA typing (for any patient with an unaffected sibling) • All nuclear family members must be investigated by Hb Electrophoresis for genetic counseling
Management
Regular maintenance blood transfusion and iron chelation therapy are the mainstay of treatment in patients with transfusion dependent thalassaemia.
1. Maintenance Blood Transfusion
Beta thalassaemia major When to start blood transfusion? • After completing blood investigations for confirmation of diagnosis. • Hb < 7g/dl for more than 1 week (in the absence of other factors e.g. infection) • Hb > 7g/dl in the presence of impaired growth, bone changes & enlarging liver & spleen.
Transfusion targets? • Maintain pre transfusion Hb level between 9.5 -11.5 g/dl • Aim to keep a mean post-transfusion Hb between 13.5-15.5g/dl. • Not advisable to raise the post transfusion Hb above 15.5 g/dl . • Current recommendation is to keep mean Hb 12 - 12.5g/dl. This allows for normal physical activity and growth, abolish chronic hypoxaemia and reduce compensatory marrow hyperplasia.
Transfusion interval? • Usually on a 4 weekly interval. • Interval varies from individual patients (range: 2 - 6 weekly) • Volume of 20mls/kg (maximum) packed cells over 4 hours
In the presence of cardiac failure or Hb < 5g/dl, use low volume packed cells (< 5ml/kg) at slow infusion rate over >4 hours with frusemide 1 mg/kg (20 mg maximum dose).
It is recommended for patients to use leucodepleted packed cells < 1 week old & utilise bedside filters to prevent non-hemolytic febrile reactions by removing the white cells.
Aim for a pre transfusion Hb ≥≥≥ 9.5 g/dl
Beta thalassaemia intermedia Late onset and milder form of β thalassaemia, presenting later than 2 years with Hb 8g/dl or more. The severity of these patients is very heterogeneous from being symptomatic at presentation to being asymptomatic until later in adult life. If they require regular transfusion, follow β thalassaemia major transfusion regime
Alpha thalassaemia (Hb H disease) Transfuse only if Hb < 7g/dl or symptomatic
2. Iron Chelation Therapy
This is essential to prevent iron overload. Current effective medication available is Desferrioxamine (Desferral).
When to start? • Usually when the child is > 3 years old and when the serum ferritin reaches 1000ng/ml. This usually occurs after 15-20 blood transfusions.
Dosage & Route • Average daily dose is between 20 – 60mg/kg/day administered by subcutaneous continuous infusion over 8-10 hours daily for 5 (minimum) - 7 nights per week. • Aim to maintain serum ferritin level below 2000 ng/ml • Vitamin C augments iron excretion with desferral.
Complications of desferral: • Local skin reactions • Yersinia infection – present with fever, abdominal pain & diarrhoea. Stop desferral and treat with cotrimoxazole. • Severe allergy (rare) • Desferral toxicity (high doses > 50mg/kg/day); • ocular toxicity – reduced vision, visual field and night blindness; reversible when desferral discontinued • auditory toxicity – high tone deafness. Not usually reversible • growth retardation • skeletal lesions – pseudo rickets, metaphyseal changes, vertebral growth retardation, etc
Complications of chronic iron overload in thalassaemics over 10 years include;
• endocrine – growth retardation, pubertal delay, hypothyroidism, hypoparathyroidism & diabetes mellitus • cardiac – arrhythmias, pericarditis, cardiac failure • hepatic – liver cirrhosis
Oral iron chelator
Deferiprone (L1) is only indicated if iron chelation is ineffective or inadequate despite optimal desferral use or if desferral use is contra-indicated. There is a small risk of reversible agranulocytosis, arthritis & GI disturbance.
3. Monitoring of patients
During each admission for blood transfusion, the following should be done and noted: - • Clinical assessment – height, weight, liver & spleen size assessment • Pre transfusion Hb, Platelet count and Post transfusion Hb (half hour post transfusion) • Volume of blood transfused • Other medications
Every 6 months • Evaluate growth and development • Serum Ferritin • LFT
Every year or more frequent if indicated • Evaluate growth and development
• Endocrine assessment - RBS, T4/TSH, Ca, PO 4 (If Ca low- check PTH & Vit. D) • Sexual development from 10 years onwards • Tanner stage • FSH/LH • Oestradiol/testosterone • Infection screen – Hepatitis B & C, HIV, VDRL • Calculate transfusion indices • Evaluate iron balance • Bone – osteoporosis & skeletal abnormalities
Cardiac assessment at variable intervals
4. Splenectomy Indications • Blood consumption > 1.5X normal or >200-220 ml/kg/year in those > 5 years of age to maintain average haemoglobin levels. • Evidence of hypersplenism.
Pneumococcal and HIB vaccinations 4-6 weeks prior to splenectomy. Penicillin prophylaxis for life post splenectomy. Post splenectomy low dose aspirin may be required if there is thrombocytosis > 800,000/mm 3.
5. Diet and supplements • Oral Folate at minimum 1 mg daily may benefit most patients. • Low dose Vitamin C at 3 mg/kg augment iron excretion for those on Desferral. (Dose: <10 years, 50mg daily; >10yrs, 100mg daily given only on deferral days ). Only to be given for patients on Desferral • Avoid iron rich food such as red meat and iron fortified cereals • Tea may help decrease GI iron absorption • Dairy products are recommended as they are rich in calcium
6. Bone Marrow Transplantation
Potential cure option when there is a HLA -compatible sibling. Classification of patients into 3 risk groups based on the presence of hepatomegaly, iron chelation status and presence of liver fibrosis. The Pesaro group (Lucarelli et al) reported the following results.
Class No of risk factors Survival % Disease free survival ( >10 yrs) % 1 0 92 85 2 1-2 84 80 3 3 61 53
Clearly the best results are obtained if BMT is done at the earliest age possible in Class 1 patients.
Therefore in newly diagnosed cases, the family should be informed of this option and referred to a Paediatrician for counseling & HLA typing of patient and unaffected siblings to identify a potential donor.
Antenatal diagnosis This can be done by chorionic villous sampling at 9-11 weeks period of gestation.
Support Group Various State & local Thalassaemia Societies are available throughout the country providing support for families as well as organising fund raising activities to assist in subsidising the cost of desferral. It is also active in carrying out awareness campaigns and health professionals are welcomed to join. GENERAL GUIDELINES FOR CHILDREN WITH ALL ON MAINTENANCE CHEMOTHERAPY
1) Check height, weight and calculate surface area (m2) every 3 months and adjust drug dosages accordingly. In the absence of a Normogram to calculate the surface area, use the following formula i.e.
SURFACE AREA = SQUARE ROOT (Height (cm) x Weight (kg) / 3600)
2) Check full blood picture every 2 weeks for the next 1- 2 months after starting maintenance chemotherapy and monthly thereafter if stable.
3) Bone marrow aspiration should be considered if counts are repeatedly low or if there is clinical suspicion of relapse. The majority of relapse (>2/3) would occur within the first year of diagnosis.
4) CNS disease would present itself usually with headache, vomiting, abnormal sensorium or hypothalamic symptoms (e.g. Hyperphagia & abnormal weight gain).
5) Cotrimoxazole is routinely used as prophylaxis against pneumocystis pneumonia and continued on till end of therapy.
6) In the event of chronic cough or unexplained tachypnoea, CXR may be required. If there is evidence of interstitial pneumonitis, send off nasopharyngeal secretions for PCP IFT and treat empirically with high dose Bactrim/Septrim (20 mg/kg/day in divided doses) for a total of 2 weeks.
7) Adjust chemotherapy to maintain absolute neutrophil counts between 0.75- 2.5 X 10 9 /dL. If neutrophils level is between 0.5 – 0.75 x 109 /L (500 - 1000/mm3) or platelet level 50-75 x 109/L, reduce 6MP and methotrexate (MTX) dose by 50%. Keep at this dose until counts are above those levels. Then increase 6MP and MTX to 75% recommended dose and review in 1 week. If counts are OK continue at 100% dose, If neutrophil count < 0.5 x 109 /L or platelets < 50 x 109 /L, stop both drugs. Restart drugs at 50% dose once neutrophil count >1.0 x 109 /L and then increase to 75% and 100% as above.
8) Normally Hb would remain stable but repeated falls in haemoglobin alone may be due to 6MP intolerance; hence reduce dose as above and attempt to increase dose gradually again. MTX should stay at top dose. If counts take longer to recover, consider performing bone marrow aspiration after 2-3 weeks.
9) Anaemia occurring early in the course of continuing therapy should be treated with transfusion and the dose of 6MP and MTX maintained. If persistent anaemia occurs (i.e. Hb < 8 gm/dl) despite reducing the dose of 6MP, the MTX dose should be reduced appropriately.
10) If counts are persistently low and dose of 6MP/MTX are suboptimal, consider withholding Bactrim.
11) In severe diarrhoea and vomiting, stop both drugs. Restart at 50% protocol when better and return to full dose when tolerated.
12) Severe MTX mucositis; withhold MTX until improvement and restart at full dose. 13) Initiate supportive treatment with mouthwash, antifungal treatment (Nystatin / Daktarin oral gel / Gentian violet paint ± systemic antifungal drugs e.g. Ketoconazole / Fluconazole) and local anaesthetic e.g. viscous xylocaine.
14) Clinically significant liver dysfunction (e.g. Jaundice); oral MTX should be stopped until improvement occurs. Restart at reduced dose and increase as tolerated. Investigate for causes of liver dysfunction. Monitor LFT.
15) Infections. Febrile neutropaenia (ANC < 1 x 109/dL) o If there is significant fever (To ≥ 38.5o C x 1 or ≥ 38 o C x 2 one hour apart), stop all drugs and admit for IV antibiotics. o Take appropriate cultures and CXR if indicated and start IV antibiotics immediately without waiting for specific bacteriological confirmation. Use a combination of aminoglycoside and cephalosporins to cover both gram negative and gram positive organisms. o If nosocomial infection is suspected, use the appropriate antibiotics according to your hospital's cultures sensitivity pattern. Assume multiresistant bacterial sepsis when dealing with patients presenting with septic shock. o Early & aggressive therapy will save lives.
Antifungal therapy may be indicated in prolonged neutropenia or if there is no response to antibiotics or if fungal infection is suspected.
Vancomycin may be indicated if there is a long line in situ or if MRSA or coagulase negative Staphylococcus infections are suspected.
Chicken Pox/Measles o These are life-threatening infections in ill immunocompromised children. o Always reinforce this information on parents when they come for follow-up. o If a patient is significantly/directly exposed (in the same room > one hour), including the 3 days prior to clinical presentation, to sibling, classroom contact, enclosed playmate contact or other significant contact, they are at increased risk of developing these infections. GIVE:- Measles: Human broad-spectrum immune globulin IM 0.25 mg/kg as prophylaxis & 1-2 ml/kg if infected. Chickenpox: There is no Zoster immune globulin readily available locally. For exposed patients; oral acyclovir (Zovirax), 200mg 5 x/day for 5 days if < 6 years old and 400 mg 5 x/day if > 6 years for 5 days. These patients must be monitored for signs of infections. If a patient develops chickenpox, admit, isolate and treat immediately with IV acyclovir 500 mg/m2/dose every 8 hours. Chemotherapy must be stopped on suspicion of exposure and if infected and treated it should only be recommenced @ 2-3 weeks after the last vesicle had dried up.
16) Vaccinations. Children on chemotherapy should not receive any vaccinations until 12 months after cessation of chemotherapy. They may then recommence their immunisation programme continuing from where they left off.
Acute Gastroenteritis
This protocol is based on the WHO protocol for Management of Acute Gastroenteritis in Children. However modifications were made to the treatment plan C in keeping with the fluid resuscitation methods recommended in the Paediatric Advanced Life support course.
AGE is a leading cause of childhood morbidity and mortality and important cause of malnutrition. Many diarrhoeal deaths are cause by dehydration , which can be safely and effectively treated ( except when severe ) by using ORS solution.
If you have gone through the PALS course, first assess the state of perfusion of the child. Is the child in shock? If so go straight to treatment Plan C. OR you can also use the WHO chart below to assess the degree of dehydration and then choose the treatment plan as needed.
1. Look Well. Alert * Restless, irritable *Lethargic or unconscious At general condition or floppy of the child Eyes Normal *Sunken *Sunken Tears Present Absent Absent Mouth and Tongue Moist Dry Very Dry Thirst Drinks normally * Thirsty, drinks *Drinks poorly or unable to or not thirsty eagerly drink 2. Feel Goes back * Goes back slowly *Goes back very slowly Skin Pinch quickly 3. Decide The patient has If the patient has 2 If the patient has 2 or no signs of or more *signs , more *signs there is dehydration there is some severe dehydration ( < 5 % ) dehydration ( > 10% ) ( 5-10% ) 4. Treat Use treatment Weigh the patient Weigh the patient, and use Plan A if possible, and use treatment Plan C treatment Plan B
Note: Children in treatment Plan C would show signs of shock such as tachycardia, weak peripheral pulses, delayed capillary refill time > 2 secs, cold peripheries, depressed mental state with or without hypotension.
A. TREATMENT PLAN “A” TO TREAT DIARRHOEA
EXPLAIN THE THREE RULES FOR TREATING DIARRHOEA AT HOME:
1. GIVE EXTRA FLUIDS (as much as the child will take) • Breastfeed frequently and for longer at each feed • If child exclusively breastfed, give ORS in addition to breast milk • If child not exclusively breastfed, give one or more of the following: ORS, food- based fluids (soup and rice water)
It is especially important to give ORS at home when: • The child has been treated with Plan B or Plan C during visit • The child cannot return to a clinic if the diarrhoea gets worse
Teach mother how to use ORS and how much ORS to give in addition to usual fluid intake: • Up to 2 years : 50 to 100ml after each loose stool • 2 years or more : 100 to 200ml after each loose stool (If weight available, replace 10ml/kg of ORS after each loose stool) Give mother 8 packets of ORS to use at home
Tell mother to give frequent small sips from cup/spoon. If child vomits, wait 10 mins then continue but more slowly. Continue to give extra fluid until diarrhoea stops.
2. CONTINUE FEEDING • Breast fed infants should continue nursing on demand • Formula fed infants should continue their usual formula immediately on rehydration • Lactose-free or lactose-reduced formula usually are unnecessary • Children receiving semi-solid or solid foods should continue to receive their usual diet during episodes of diarrhoea • Foods high in simple sugar should be avoided as osmotic load might worsen diarrhoea
3. WHEN TO RETURN • Not able to drink or breastfeed or drinking poorly • Becomes sicker • Develops a fever • Blood in stool
B. TREATMENT PLAN “B” TO TREAT DEHYDRATION WITH ORS
1. AMOUNT OF ORS SOLUTION TO GIVE OVER 4-HOUR PERIOD Age Up to 4 4 months up 12 months up 2 years up to months to 12months to 2 years 5 years Weight <6kg 6- <10kg 10- <12kg 12- 19kg In ml 200-400 400-700 700-900 900-1400
* Use the patient's age only when you do not know the weight. The approximate amount of ORS required (in ml) can also be calculated by multiplying the child’s weight (in kg) times 75
NOTE: ENCOURAGE THE MOTHER TO CONTINUE BREAST-FEEDING. • If the patient wants more ORS, give more, • If the eyelids become puffy, stop ORS and give other fluids. If diarrhoea continues, use ORS again when the puffiness is gone • If the child vomits, wait 10 minutes and then continue giving ORS, but more slowly (i.e. 1 spoonful every 2 - 3 minutes). Some children may want to drink too quickly. This may make them vomit.
2. AFTER 4 HOURS, REASSESS THE CHILD • Reassess the child and classify the child for dehydration • Select the appropriate plan to continue treatment • Begin feeding the child in clinic
3. IF THE MOTHER MUST LEAVE ANY TIME BEFORE COMPLETING TREATMENT: • Show her how to prepare ORS solution at home. • Show her how much ORS to give to finish the 4 hour treatment at home. • Give her enough ORS packets to complete rehydration. Also give her 8 packets as recommended in Plan A. • Explain the 3 rules of Home treatment: 1. GIVE EXTRA FLUID 2. CONTINUE FEEDING 3. WHEN TO RETURN – see Plan A .
C. TREATMENT PLAN “C” - TO TREAT SEVERE DEHYDRATION QUICKLY
Follow the arrows, if answer is “YES” , go across. If “NO” go down
Can you give Start IV or IO fluids immediately. If intravenous or Yes patient can drink, give ORS by mouth intraosseous fluids while the drip is being set up. Give 100 immediately? ml/kg Ringers lactate or normal saline divided as follows:-
Age First give 20 ml/kg Then give as fast as the possible. Repeat remaining No fluid boluses as fluid over necessary < 12 months until perfusion has 5 hours old improved. > 12 months 2 1/2 hours old
• reassess the patient after every bolus and stop the boluses once perfusion improves or when fluid overload is suspected. Inotropic agents may then be necessary to maintain perfusion.
• If the patient does not respond to rapid bolus rehydration, should consider the possibility of an underlying disorder e.g. septic shock, toxic shock syndrome, myocarditis, myocardiopathy or pericarditis
• as soon as patient can drink, also give ORS (5 ml/kg/hour) . Usually after 3 to 4 hours for infants, and 1 to 2 hours for older child
• evaluate the patient using the assessment chart after 6 hours for infants, and 3 hours for older child Then choose the most appropriate Plan (A, B, or C) to continue treatment.
Is I/V or I/O Yes • Send the patient for I/V treatment treatment immediately. available nearby • If the patient can drink, provide the mother within 30 with ORS and show her how to feed the minutes? child on the journey.
Arrange and send the patient to the nearest hospital or clinic
(where IV or IO assess can be given) as you start to
No rehydrate the child via NG or oral feed at your centre.
Continue rehydration along the journey
• Start rehydration by tube with ORS Are you trained Yes solution, give 20 ml/kg/hour for 6 hours to use NG tube (total 120 m/kg) for rehydration? • Start re-hydration by mouth with ORS Yes solution, give 20 ml/kg/hour for 6 hours (total 120 m/kg) No
Then Can the patient drink? • Reassess the patient at 1 to 2 hours intervals
No • If there is repeated vomiting or increase of abdominal distension, give the fluid more slowly. URGENTLY send the patient for IV or • Reassess the patient after six hours, then NG treatment. select the most appropriate treatment plan.
• If possible, observe the patient at least 6 hours after re-hydration making sure that the mother maintains hydration by feeding ORS fluid • If there is an outbreak of cholera in your area, give an appropriate oral antibiotic after the patient is alert.
D. Criteria for admission to Hospital
Inpatient care is indicated for children if: • Caregivers cannot provide adequate care at home • Substantial difficulties exist in giving ORS including intractable vomiting, ORS refusal or inadequate ORS intake • Concern exist for other possible illness complicating the clinical course • ORS treatment fails including worsening diarrhoea or dehydration despite adequate volume • Severe dehydration (> 9% of body weight) • Social or logistical concerns that might prevent return evaluation if necessary • Factors especially young age, unusual irritability/drowsiness, progressive course of symptoms, or uncertainty of diagnosis that might need closer observation
E. When oral rehydration fails
In about 5% of children the signs of dehydration do not improve during ORT, or they worsen after initial improvement. The usual causes are : • Continuing rapid stool loss ( > 15-20ml/kg/hour ) • Insufficient intake of ORS solution owing to fatigue or lethargy • Frequent , severe vomiting
Treatment : Give ORS solution by nasogastric tube Or IV Hartmann solution (amount to be given depend on the degree of dehydration)
F. When oral rehydration should not be given • All children who are severely dehydrated and in state of shock or near shock require immediate iv therapy • Unconscious child • Abdominal distension with paralytic ileus , usually caused by opiate drugs ( e.g. codeine, loperamide ) and hypokalaemia • Glucose malabsorption – indicated by marked increase in stool output, failure of the signs of dehydration to improve and a large amount of glucose in the stool when ORS solution is given.
Treatment : • Rehydration should be given IV • NG therapy should not be used
G. Electrolytes disturbances
Knowing the levels of serum electrolytes rarely changes the management of children with diarrhoea. The disorders described below are all adequately treated by using ORS solution.
1. Hypernatraemic dehydration
Def : serum Na > 145mmol/l
Clinical features : Clinical presentation is notoriously deceptive Shock is late and ominous sign Skin having a characteristic doughy appearance Anterior fontanelle is typically not sunken
Treatment : a. Resuscitation If in shock , give normal saline/Ringer’s lactate 20ml/kg intravenously over ½ to 1 hour and repeat as necessary b. Rehydration
Aim : reduce sodium slowly , dramatic fall results in cerebral oedema and convulsions Rehydrate over 48 to 72 hours Reduction in plasma sodium should not exceed 10 mmol/L per 24 hours
Oral rehydration is the method of choice and the safest. Only if this fails is slow IV rehydration necessary
Calculate the fluid deficit and give together with maintenance fluids over at least 48 hours. If fluid was given to resuscitate, the amount given should be subtracted from the fluid deficit. This is particularly important in hypernatraemic dehydration to avoid giving too much fluid
* use ½ normal saline/5%dextrose for the duration of fluid replacement after this if the Na is still > 145mmol/l, continue using this fluid until the serum sodium is < 145mmol/l, after which 0.18%saline/5%dextrose may be used. Add KCL when child PU and review BUSE.
Monitor BUSE 6 HOURLY
2. Hyponatraemia • ORS solution is safe and effective therapy for nearly all children with hyponatraemia EXCEPT those with oedema
3. Hypokalaemia • can be prevented, and the potassium deficit corrected, by using ORS solution for rehydration therapy and by giving food rich in potassium during diarrhoea and after it has stopped.
If intravenous drip is required:- Notes: Fluid deficit (mls) = percentage dehydration X body weight in grams
• Correction of metabolic acidosis if pH < 7.1. Otherwise metabolic acidosis self corrects with rehydration • Administration of IV 8.4% NaHCO3 (mEq or ml)= 1/3 x base deficit x weight * usually only ½ correction is given. Review with a repeat blood gas • Maintenance fluid using 0.18% saline 5% dextrose solution (up to 2 years) , ½ normal saline 5% dextrose (children) +/- KCL in drip
Less than 6 months = 150 ml/kg/day: 6 months to 1 year = 120 ml/kg/day More than 1 year (according to weight): 1st 10 kg = 100 ml/kg; 10-20 kg = 1000 ml for first 10 kg + 50 ml/kg for any subsequent kg Over 20kg = 1500 ml for first 20kg and 20 ml/kg for any subsequent kg.
• Normal daily requirement of K+ = 3 mmol/kg/day x body weight (kg) • Normal daily requirement of Na+ = 3 mmol/kg/day x body weight (kg) • Sodium deficit (mmol) = (140 - patient’s serum Na level x 0.6 x wt (kg)
H. Management of acute bloody diarrhoea (Dysentery )
1. Assessment for amount of dehydration and treat accordingly 2. Treat for 5 days with an antimicrobial.
Trimethoprim (TMP) 5 mg/kg and sulfamethoxazole(SMX) 25 mg/kg twice a day for 5 days OR Ampicillin 25 mg/kg 4 times a day for 5 days
3. May consider discharging if • Disappearance of fever • Less blood in the stool • Passage of fewer stools • Improved appetite • Return to normal activity
*check for sensitivities of local strain *
I. Other problems associated with diarrhoea
1. Fever It may be due to • Another infection • Dehydration
Always search for the source of infection if there is fever, especially if it persists after the child is fully rehydrated
2. Convulsion Consider : Febrile convulsion ( evaluate for possible meningitis ) Hypoglycaemia Hyper – or hyponatraemia
3. Lactose intolerance
Usually formula-fed babies less than 6 months old with infectious diarrhoea
Clinical features: • Persistent loose stool • Abdominal distension • Increased flatus • Perianal excoriation
Diagnosis • History • Clinitest • Benedict’s test
Collect stool fluid in diapers lined with plastic. Dilute 5 drops of stool fluid with 10 drops of water in a test tube Clinitest – Add a Clinitest tablet into the resultant mixture. A colour reaction indicating over 0.5% reducing substances suggests the diagnosis Benedict’s test – 5 ml of Benedict solution is mixed with 0.5ml of liquid stool. The resultant solution is boiled for about 5 minutes. A colour reaction indicating over 0.5% reducing substances suggests the diagnosis
Treatment If diarrhoea is persistent and watery ( over 7-10 days ) and there is evidence of lactose intolerance, a lactose free formula may be given The usual formula can usually be reintroduced after 3 – 4 weeks
J. Pharmacological Agents
1. Anti microbial medication Not indicated as majority of diarrhoea are caused by viruses. Even when bacterial cause is suspected, antimicrobial therapy is not indicated among children because in majority of cases diarrhoea are self limited. Exceptions involve special needs of individual children (e.g.. Immune compromised host, premature infants or children with underlying disorder)
2. Antidiarrheal compound As a general rule, these pharmacologic agents should not be used to treat acute diarrhoea
3. Supplemental zinc Number of trials have supported zinc supplementation as an effective agent in treating and preventing diarrhoea, Further research is needed to identify mechanism of action and to determine optimal delivery.
4. Probiotic - Lactobacillus containing compounds currently are not recommended in the treatment of acute diarrhoea in children ( based on limited scientific evidence; efficacy has not been shown, although toxic effects are not a concern
Acute Gastroenteritis
This protocol is based on the WHO protocol for Management of Acute Gastroenteritis in Children. However modifications were made to the treatment plan C in keeping with the fluid resuscitation methods recommended in the Paediatric Advanced Life support course.
AGE is a leading cause of childhood morbidity and mortality and important cause of malnutrition. Many diarrhoeal deaths are cause by dehydration , which can be safely and effectively treated ( except when severe ) by using ORS solution.
If you have gone through the PALS course, first assess the state of perfusion of the child. Is the child in shock? If so go straight to treatment Plan C. OR you can also use the WHO chart below to assess the degree of dehydration and then choose the treatment plan as needed.
1. Look Well. Alert * Restless, irritable *Lethargic or unconscious At general condition or floppy of the child Eyes Normal *Sunken *Sunken Tears Present Absent Absent Mouth and Tongue Moist Dry Very Dry Thirst Drinks normally * Thirsty, drinks *Drinks poorly or unable to or not thirsty eagerly drink 2. Feel Goes back * Goes back slowly *Goes back very slowly Skin Pinch quickly 3. Decide The patient has If the patient has 2 If the patient has 2 or no signs of or more *signs , more *signs there is dehydration there is some severe dehydration ( < 5 % ) dehydration ( > 10% ) ( 5-10% ) 4. Treat Use treatment Weigh the patient Weigh the patient, and use Plan A if possible, and use treatment Plan C treatment Plan B
Note: Children in treatment Plan C would show signs of shock such as tachycardia, weak peripheral pulses, delayed capillary refill time > 2 secs, cold peripheries, depressed mental state with or without hypotension.
A. TREATMENT PLAN “A” TO TREAT DIARRHOEA
EXPLAIN THE THREE RULES FOR TREATING DIARRHOEA AT HOME:
1. GIVE EXTRA FLUIDS (as much as the child will take) • Breastfeed frequently and for longer at each feed • If child exclusively breastfed, give ORS in addition to breast milk • If child not exclusively breastfed, give one or more of the following: ORS, food- based fluids (soup and rice water)
It is especially important to give ORS at home when: • The child has been treated with Plan B or Plan C during visit • The child cannot return to a clinic if the diarrhoea gets worse
Teach mother how to use ORS and how much ORS to give in addition to usual fluid intake: • Up to 2 years : 50 to 100ml after each loose stool • 2 years or more : 100 to 200ml after each loose stool (If weight available, replace 10ml/kg of ORS after each loose stool) Give mother 8 packets of ORS to use at home
Tell mother to give frequent small sips from cup/spoon. If child vomits, wait 10 mins then continue but more slowly. Continue to give extra fluid until diarrhoea stops.
2. CONTINUE FEEDING • Breast fed infants should continue nursing on demand • Formula fed infants should continue their usual formula immediately on rehydration • Lactose-free or lactose-reduced formula usually are unnecessary • Children receiving semi-solid or solid foods should continue to receive their usual diet during episodes of diarrhoea • Foods high in simple sugar should be avoided as osmotic load might worsen diarrhoea
3. WHEN TO RETURN • Not able to drink or breastfeed or drinking poorly • Becomes sicker • Develops a fever • Blood in stool
B. TREATMENT PLAN “B” TO TREAT DEHYDRATION WITH ORS
1. AMOUNT OF ORS SOLUTION TO GIVE OVER 4-HOUR PERIOD Age Up to 4 4 months up 12 months up 2 years up to months to 12months to 2 years 5 years Weight <6kg 6- <10kg 10- <12kg 12- 19kg In ml 200-400 400-700 700-900 900-1400
* Use the patient's age only when you do not know the weight. The approximate amount of ORS required (in ml) can also be calculated by multiplying the child’s weight (in kg) times 75
NOTE: ENCOURAGE THE MOTHER TO CONTINUE BREAST-FEEDING. • If the patient wants more ORS, give more, • If the eyelids become puffy, stop ORS and give other fluids. If diarrhoea continues, use ORS again when the puffiness is gone • If the child vomits, wait 10 minutes and then continue giving ORS, but more slowly (i.e. 1 spoonful every 2 - 3 minutes). Some children may want to drink too quickly. This may make them vomit.
2. AFTER 4 HOURS, REASSESS THE CHILD • Reassess the child and classify the child for dehydration • Select the appropriate plan to continue treatment • Begin feeding the child in clinic
3. IF THE MOTHER MUST LEAVE ANY TIME BEFORE COMPLETING TREATMENT: • Show her how to prepare ORS solution at home. • Show her how much ORS to give to finish the 4 hour treatment at home. • Give her enough ORS packets to complete rehydration. Also give her 8 packets as recommended in Plan A. • Explain the 3 rules of Home treatment: 1. GIVE EXTRA FLUID 2. CONTINUE FEEDING 3. WHEN TO RETURN – see Plan A .
C. TREATMENT PLAN “C” - TO TREAT SEVERE DEHYDRATION QUICKLY
Follow the arrows, if answer is “YES” , go across. If “NO” go down
Can you give Start IV or IO fluids immediately. If intravenous or Yes patient can drink, give ORS by mouth intraosseous fluids while the drip is being set up. Give 100 immediately? ml/kg Ringers lactate or normal saline divided as follows:-
Age First give 20 ml/kg Then give as fast as the possible. Repeat remaining No fluid boluses as fluid over necessary < 12 months until perfusion has 5 hours old improved. > 12 months 2 1/2 hours old
• reassess the patient after every bolus and stop the boluses once perfusion improves or when fluid overload is suspected. Inotropic agents may then be necessary to maintain perfusion.
• If the patient does not respond to rapid bolus rehydration, should consider the possibility of an underlying disorder e.g. septic shock, toxic shock syndrome, myocarditis, myocardiopathy or pericarditis
• as soon as patient can drink, also give ORS (5 ml/kg/hour) . Usually after 3 to 4 hours for infants, and 1 to 2 hours for older child
• evaluate the patient using the assessment chart after 6 hours for infants, and 3 hours for older child Then choose the most appropriate Plan (A, B, or C) to continue treatment.
Is I/V or I/O Yes • Send the patient for I/V treatment treatment immediately. available nearby • If the patient can drink, provide the mother within 30 with ORS and show her how to feed the minutes? child on the journey.
Arrange and send the patient to the nearest hospital or clinic
(where IV or IO assess can be given) as you start to
No rehydrate the child via NG or oral feed at your centre.
Continue rehydration along the journey
• Start rehydration by tube with ORS Are you trained Yes solution, give 20 ml/kg/hour for 6 hours to use NG tube (total 120 m/kg) for rehydration? • Start re-hydration by mouth with ORS Yes solution, give 20 ml/kg/hour for 6 hours (total 120 m/kg) No
Then Can the patient drink? • Reassess the patient at 1 to 2 hours intervals
No • If there is repeated vomiting or increase of abdominal distension, give the fluid more slowly. URGENTLY send the patient for IV or • Reassess the patient after six hours, then NG treatment. select the most appropriate treatment plan.
• If possible, observe the patient at least 6 hours after re-hydration making sure that the mother maintains hydration by feeding ORS fluid • If there is an outbreak of cholera in your area, give an appropriate oral antibiotic after the patient is alert.
D. Criteria for admission to Hospital
Inpatient care is indicated for children if: • Caregivers cannot provide adequate care at home • Substantial difficulties exist in giving ORS including intractable vomiting, ORS refusal or inadequate ORS intake • Concern exist for other possible illness complicating the clinical course • ORS treatment fails including worsening diarrhoea or dehydration despite adequate volume • Severe dehydration (> 9% of body weight) • Social or logistical concerns that might prevent return evaluation if necessary • Factors especially young age, unusual irritability/drowsiness, progressive course of symptoms, or uncertainty of diagnosis that might need closer observation
E. When oral rehydration fails
In about 5% of children the signs of dehydration do not improve during ORT, or they worsen after initial improvement. The usual causes are : • Continuing rapid stool loss ( > 15-20ml/kg/hour ) • Insufficient intake of ORS solution owing to fatigue or lethargy • Frequent , severe vomiting
Treatment : Give ORS solution by nasogastric tube Or IV Hartmann solution (amount to be given depend on the degree of dehydration)
F. When oral rehydration should not be given • All children who are severely dehydrated and in state of shock or near shock require immediate iv therapy • Unconscious child • Abdominal distension with paralytic ileus , usually caused by opiate drugs ( e.g. codeine, loperamide ) and hypokalaemia • Glucose malabsorption – indicated by marked increase in stool output, failure of the signs of dehydration to improve and a large amount of glucose in the stool when ORS solution is given.
Treatment : • Rehydration should be given IV • NG therapy should not be used
G. Electrolytes disturbances
Knowing the levels of serum electrolytes rarely changes the management of children with diarrhoea. The disorders described below are all adequately treated by using ORS solution.
1. Hypernatraemic dehydration
Def : serum Na > 145mmol/l
Clinical features : Clinical presentation is notoriously deceptive Shock is late and ominous sign Skin having a characteristic doughy appearance Anterior fontanelle is typically not sunken
Treatment : a. Resuscitation If in shock , give normal saline/Ringer’s lactate 20ml/kg intravenously over ½ to 1 hour and repeat as necessary b. Rehydration
Aim : reduce sodium slowly , dramatic fall results in cerebral oedema and convulsions Rehydrate over 48 to 72 hours Reduction in plasma sodium should not exceed 10 mmol/L per 24 hours
Oral rehydration is the method of choice and the safest. Only if this fails is slow IV rehydration necessary
Calculate the fluid deficit and give together with maintenance fluids over at least 48 hours. If fluid was given to resuscitate, the amount given should be subtracted from the fluid deficit. This is particularly important in hypernatraemic dehydration to avoid giving too much fluid
* use ½ normal saline/5%dextrose for the duration of fluid replacement after this if the Na is still > 145mmol/l, continue using this fluid until the serum sodium is < 145mmol/l, after which 0.18%saline/5%dextrose may be used. Add KCL when child PU and review BUSE.
Monitor BUSE 6 HOURLY
2. Hyponatraemia • ORS solution is safe and effective therapy for nearly all children with hyponatraemia EXCEPT those with oedema
3. Hypokalaemia • can be prevented, and the potassium deficit corrected, by using ORS solution for rehydration therapy and by giving food rich in potassium during diarrhoea and after it has stopped.
If intravenous drip is required:- Notes: Fluid deficit (mls) = percentage dehydration X body weight in grams
• Correction of metabolic acidosis if pH < 7.1. Otherwise metabolic acidosis self corrects with rehydration • Administration of IV 8.4% NaHCO3 (mEq or ml)= 1/3 x base deficit x weight * usually only ½ correction is given. Review with a repeat blood gas • Maintenance fluid using 0.18% saline 5% dextrose solution (up to 2 years) , ½ normal saline 5% dextrose (children) +/- KCL in drip
Less than 6 months = 150 ml/kg/day: 6 months to 1 year = 120 ml/kg/day More than 1 year (according to weight): 1st 10 kg = 100 ml/kg; 10-20 kg = 1000 ml for first 10 kg + 50 ml/kg for any subsequent kg Over 20kg = 1500 ml for first 20kg and 20 ml/kg for any subsequent kg.
• Normal daily requirement of K+ = 3 mmol/kg/day x body weight (kg) • Normal daily requirement of Na+ = 3 mmol/kg/day x body weight (kg) • Sodium deficit (mmol) = (140 - patient’s serum Na level x 0.6 x wt (kg)
H. Management of acute bloody diarrhoea (Dysentery )
1. Assessment for amount of dehydration and treat accordingly 2. Treat for 5 days with an antimicrobial.
Trimethoprim (TMP) 5 mg/kg and sulfamethoxazole(SMX) 25 mg/kg twice a day for 5 days OR Ampicillin 25 mg/kg 4 times a day for 5 days
3. May consider discharging if • Disappearance of fever • Less blood in the stool • Passage of fewer stools • Improved appetite • Return to normal activity
*check for sensitivities of local strain *
I. Other problems associated with diarrhoea
1. Fever It may be due to • Another infection • Dehydration
Always search for the source of infection if there is fever, especially if it persists after the child is fully rehydrated
2. Convulsion Consider : Febrile convulsion ( evaluate for possible meningitis ) Hypoglycaemia Hyper – or hyponatraemia
3. Lactose intolerance
Usually formula-fed babies less than 6 months old with infectious diarrhoea
Clinical features: • Persistent loose stool • Abdominal distension • Increased flatus • Perianal excoriation
Diagnosis • History • Clinitest • Benedict’s test
Collect stool fluid in diapers lined with plastic. Dilute 5 drops of stool fluid with 10 drops of water in a test tube Clinitest – Add a Clinitest tablet into the resultant mixture. A colour reaction indicating over 0.5% reducing substances suggests the diagnosis Benedict’s test – 5 ml of Benedict solution is mixed with 0.5ml of liquid stool. The resultant solution is boiled for about 5 minutes. A colour reaction indicating over 0.5% reducing substances suggests the diagnosis
Treatment If diarrhoea is persistent and watery ( over 7-10 days ) and there is evidence of lactose intolerance, a lactose free formula may be given The usual formula can usually be reintroduced after 3 – 4 weeks
J. Pharmacological Agents
1. Anti microbial medication Not indicated as majority of diarrhoea are caused by viruses. Even when bacterial cause is suspected, antimicrobial therapy is not indicated among children because in majority of cases diarrhoea are self limited. Exceptions involve special needs of individual children (e.g.. Immune compromised host, premature infants or children with underlying disorder)
2. Antidiarrheal compound As a general rule, these pharmacologic agents should not be used to treat acute diarrhoea
3. Supplemental zinc Number of trials have supported zinc supplementation as an effective agent in treating and preventing diarrhoea, Further research is needed to identify mechanism of action and to determine optimal delivery.
4. Probiotic - Lactobacillus containing compounds currently are not recommended in the treatment of acute diarrhoea in children ( based on limited scientific evidence; efficacy has not been shown, although toxic effects are not a concern ACUTE HEPATIC FAILURE IN CHILDREN
A. DEFINITION Fulminant hepatic failure - Hepatic dysfunction (hepatic encephalopathy and coagulopathy) within 8 weeks of evidence of symptoms of liver disease and absence of pre existing liver disease in any form. Hyperacute /Fulminant HF - encephalopathy within 2 weeks of onset of jaundice Subfulminant HF - encephalopathy within 2 12 weeks of onset of jaundice. Subacute/Late-onset HF- encephalopathy later than 8 weeks 6 months of onset of symptoms. B. SALIENT FEATURES 1. Jaundice with impalpable liver or a liver of reducing size. 2. Encephalopathy may worsen rapidly (needs frequent review). Coma Level Grade 1 irritable/ lethargic Grade 2 mood swings, aggressive, photophobia, not recognise parents, flap. Grade 3 sleepy but rousable, incoherent, sluggish pupils, hypertonia ± clonus, extensor spasm. Grade 4 coma, decerebrate/ decorticate/ no response to pain 3. Bruising/petechiae/bleeding due to deranged clotting unresponsive to vitamin K. 4. Failure to maintain normoglycaemia (which aggravates encephalopathy) / presence of hyperammonaemia 5. Increased intracranial pressure (fixed dilated pupils/bradycardia/hypertension/ papilloedema) Investigate causes In Comatose patient 1. Infection hepatitis A, B, non A non 1. In presence of sudden coma, B, CMV, Leptospirosis, Dengue Consider intracranial bleed 2. Drugs Carbamazepine, Valproate, Order CT Brain.
Paracetamol, Halothane 2. Patients in Grade 3 or 4 coma 3. Ingested toxins mushrooms, Amanita require ventilation to maintain Phalloides normal cerebral perfusion pressure. 4. Metabolic Fructosaemia, Galactosaemia, tyrosaemia, Wilson’s. 5. Ischaemic shock e.g. Gram negative
septicaemia, Budd Chiari. 6. Tumour Histiocytosis, lymphoproliferative disorder
C. MANAGEMENT OF ACUTE HEPATIC FAILURE IN CHILDREN Supportive Treatment 1. Nurse in quiet darkened room with head end elevated at 20 0 with no neck flexion (to decrease ICP and minimise cerebral irritability). 2. DO NOT SEDATE unless already ventilated this may precipitate respiratory failure and death. 3. Maintain blood glucose between 6 9 mol/l using minimal fluid volume (40 60 ml/kg/day crystalloid) with high dextrose concentrations e.g. 10 20%. Add K + as necessary. 4. Check dextrostix 2 4 hourly. 5. Strict monitoring of urine output and fluid balance. Catheterise if necessary. 6. Check urinary electrolytes, serum urea, creatinine electrolytes and osmolarity. 7. Frequent neurological observations (1 4 hourly). 8. Maintain oxygenation with facial oxygen. 9. Give vitamin K to attempt to correct prolonged PT. If frank bleeding (GIT/oral) occurs, consider prudent use of FFP or iv cryoprecipitate at 10 ml/kg. 10. Prophylactic ranitidine plus oral antacid to prevent gastro/duodenal ulceration. 11. Full septic screen (excluding LP) on admission, CXR. Treat sepsis aggressively, monitoring levels of aminoglycosides frequently. 12. Stop oral protein initially. Gradually reintroduce 0.5 1g/kg/day. 13. Lactulose to produce 3 4 loose stools per day. 14. *Strict fluid balance is essential aim for urine output not less than 0.5 ml/kg/hour. 15. Consider N acetylcysteine. Notes on fluid management in Liver Failure Normal Liver Function Liver Failure 1. Volume given if child not dehydrated and losses are not abnormal • Body Weight a. < 10 kg 120 150 ml/kg/day 60 80 ml/kg/day b. 10 20 kg 90 120 ml/kg/day 40 60 ml/kg/day c. > 20 kg 50 90 ml/kg/day 30 50 ml/kg/day 2. Fluid Type Dextrose 4 – 5 % Dextrose ≥ 10% (adjust according to Destrostix readings) 3. K + 1 3.5 mmol/kg/day NIL WHILE ANURIC 4. Na + 1.5 3.5 mmol/kg/day NIL ADDED 5. Other Fluids Albumin 20% 5 ml/kg Albumin 20% 5 ml/kg 6. For Transfusion FFP 10 20 ml/kg FFP 10 20 ml/kg 7. Volume (ml) blood = Number of grams Hb you want to raise Hb by x body weight in kg x F. Where F = 6 for whole blood, F = 4 for packed cells GASTROINTESTINAL BLEEDING
DEFINITION Haemetemesis - vomiting out blood whether fresh or stale Malaena - passing out tarry black stools per rectum Haemetemesis / malaena is a medical emergency and carries significant mortality.
SALIENT FEATURES • Duration and severity of haemetemesis and/or malaena • Evidence of hypovolaemic shock • Rule out bleeding diathesis
MANAGEMENT Acute resuscitation Acute GI bleeding
Quick assessment of cardiovascular status (Pulse, BP, Respiration)
Largest possible bore intravenous cannula inserted immediately (CVP line may be required)
Resuscitate with iv volume expander e.g. Take blood for GXM. At least 1-2 units of half/normal saline, plasmatein, (FFP) or packed cells should be kept available at all 5% albumin to stabilise BP/HR (while times during acute period. waiting for blood to be available)
Hb/ platelet counts/ haematocrit Renal profile Large. bore NG tube passed to aspirate Coagulation profile fresh/ clotted blood, then tube removed Other investigations relevant to cause of bleeding
Transfuse blood to maintain BP/HR, urine output and Monitor BP/HR/Pulse volume/Temperature/ Hb. (Be aware of complications of massive transfusion urine output/ CVP hourly until stable and such as acidosis, hypoglycaemia, hypothermia) continue to observe for ongoing bleeding. If required calcium gluconate10% and sodium bicarbonate can be given intravenously)
FFP, cryoprecipitate and platelet concentrates may be ne eded to correct coagulation disorders, DIVC, etc.
Reassessment of patients Diagnostic measures to localise source of bleeding 1. When patient’s condition is stable and 1. Oesophagogastro-duodenoscopy (OGDS) or resuscitative measures have been colonoscopy can be performed when patient’s instituted, assess patient for condition is stable. • cause of bleeding • need for surgery 2. Double contrast barium study less useful than endoscopy but may be indicated in patients 2. History is reviewed. Ask for history of when endoscopy cannot precisely locate the chronic liver disease, dyspepsia, chronic or source of bleeding (e.g. in intussusception) intermittent GIT bleeding (e.g. polyps), drug ingestion (anticoagulants, aspirin), or acute fever (dengue haemorrhagic fever), easy 3. Visceral angiography can precisely locate the bleeding tendencies, etc. source of bleeding. But is only reserved for patients with a difficult bleeding problem. 3. Physical exam should be directed towards looking for signs of chronic liver disease (spider angiomata, palmer erythema, portal hypertension, splenomegaly) or telengiectasia/angiomata in mouth, trunk, etc.)
Definitive Measures to Management of GIT Bleeding Medical cause Surgical Cause 1. Bleeding peptic ulcer When surgical cause is suspected, early i) Start H2 receptor antagonist (e.g. referral to the surgeon is important so that a cimetidine or ranitidine) team approach to the problem can be adopted. ii) If biopsy shows presence of Helicobacter pylori infection, treat accordingly. 1. Intussusception requires immediate iii) Stop all incriminating drugs e.g. aspirin, surgical steroids, anticoagulant drugs if possible. referral and intervention. 2. Meckel’s diverticulum 2. Bleeding oesophageal varices 3. Malrotation • Do not transfuse blood too rapidly as this will lead to increase in CVP and a rapid increase in portal pressure will precipitate further bleeding. • Refer paediatric surgeon and paediatric gastroenterologist to consider use of octreotide.
3. Psudomembranous colitis i) Stop all antibiotics ii) Start oral metronidazole or oral vancomycin immediately.
SEPSIS, SEPTIC SHOCK
Definitions (based on American College of Chest Physicians and Society of Critical Care Medicine consensus)
SIRS Non specific systemic inflammatory response (Systemic Inflammatory Response Syndrome) to infection, trauma, burns, surgery etc. Characterised by 2 or more of the following: changes in • body temperature • heart rate • respiratory function • peripheral leucocyte count Sepsis SIRS due to infection. Characterised by features of SIRS AND clinical evidence of INFECTION Severe sepsis Sepsis associated with decreased end organ perfusion: • respiratory – hypoxaemia • CNS – altered sensorium • renal – oliguria • metabolic – lactic acidosis Septic shock Severe sepsis with haemodynamic and circulatory compromise i.e. hypotension (systolic blood pressure [SBP] drops below 5 th centile for age). Early septic shock (WARM shock) Compensated warm phase of shock. Prompt response to fluids and pharmacologic treatment. Refractory septic shock (COLD shock) Late decompensated phase. Shock lasting more than 1 hours despite vigorous therapy necessitating vasopressor support. Incidence Non hospitalized immunocompetent children may develop community acquired sepsis. More commonly, hospitalized immunocompromised patients are at higher risk of developing serious nosocomial sepsis.
Pathophysiology Infection Activation of immunological system Release of inflammatory chemical mediators Systemic vasodilation Capillary leakage Intravascular volume depletion Maldistribution of intravascular volume Impaired myocardial function Clinical features Sepsis, severe sepsis and septic shock are a clinical continuum . SEPSIS is present when 2 or more of the following features are present • Fever ( > 38.5 oC) or hypothermia often in neonate <36 oC • Hyperventilation • Tachycardia • White blood count abnormalities: leukocytosis or leukopenia and there is clinical evidence of infection.
Other constitutional symptoms poor feeding, diarrhea, vomiting, lethargy may be present With progression to SEVERE SEPSIS, there are features of compromised end organ perfusion
Neurology altered sensorium irritability, agitation, confusion unresponsive coma Respiratory tachypnoea increase breathing effort. apnoea / respiratory arrest, cyanosis (late sign) Renal oliguria less than 0.5ml/kg per hour When SEPTIC SHOCK sets in, WARM shock COLD shock Peripheries warm, flushed cold, clammy, cyanotic Capillary refill < 2 sec > 2 sec Pulse bounding weak, feeble Heart rate tachycardia tachycardia or bradycardia Blood pressure relatively maintained hypotension Pulse pressure widened narrowed Look out for localizing signs - most useful but not always present CNS meningism , encephalopathy Resp – localized crepitations, evidence of consolidation Cardiac changing murmurs GIT –focal or rebound tenderness, guarding Bone and soft tissue – focal erythema, tenderness and oedema Head and neck – cervical lymphadenopathy, stridor, inflamed tympanic membrane, sinus tenderness, exudative pharyngotonsillitis Skin – pustular lesions Complications Multiorgan Failure • Acute respiratory distress syndrome • Acute renal failure • Disseminated intravascular coagulopathy • CNS dysfunction • Hepatic failure INVESTIGATIONS
Septic work up Blood cultures and sensitivity Urine C&S CSF C&S ) Tracheal aspirate C&S ) when appropriate Pus / exudate C&S ) Fungal cultures ) Serology, viral studies ) Imaging studies i.e. CXR, ultrasound, CT scan )
Supporting evidence of infection: FBC: leukocytosis or leukopenia FBP: increase in immature neutrophil count CRP: raised c reactive protein Monitoring severity and progress: To monitor: • Full blood count • Renal profile • Electrolytes, Ca 2+, Mg2+ • Blood sugar • Blood gases • +/ lactate levels • Coagulation profile • Liver function test MANAGEMENT: Initial Resuscitation ABC Secure airway Support breathing Restore circulation Caution: the use of sedation in septic or hypotensive children may result in crash of blood pressure. If sedation is required, use low dose IV Midazolam or Ketamine, volume infusion should be continued and inotropes should be initiated, if time permits Fluid therapy Aggressive fluid resuscitation with crystalloids or colloids at 20 mls/kg as rapid IV push over 5 10 mins can be repeated up to 60 mls/kg or more Inotropic Support If still hypotensive, consider more fluid resuscitation, and start inotropes – IV Dopamine 5 15 g/kg min and later may add IV Dobutamine 5 15 g/kg min If warm and vasodilated, consider vasopressors – IV Noradrenaline 0.05 – 1.0 g/kg min If cold and peripherally vasoconstricted and refractory hypotension, consider adding IV Adrenaline 0.05 – 1.0 g/kg min Inotropes should be infused via a central line (whenever possible) or a large bore peripheral canula. Use dedicated line or lumen. Avoid concurrent use for other intravenous fluids / medication. Fluids and inotropes to be titrated to optimal vital signs, urine output and conscious level. Antimicrobial therapy IV antibiotics should be administered immediately after appropriate cultures are taken empirical, broad spectrum to cover all likely pathogens, considering risk factors of patient and underlying illness local organism prevalence and sensitivity patterns protocols of the institution Antibiotic regime to be modified accordingly once C&S results are back Source control Evaluate patient to identify focus of infection Drainage, debridement or removal of infected devices to help control infection Respiratory Support
Use minimum PEEP and FIO 2 to keep SaO 2 > 90% PaO 2 > 80 mmHg Caution: high PEEP results in raised intrathoracic pressure can compromise venous return and worsen hypotension Supportive Therapy HB packed cells transfusion if Hb <10g% PLT platelet concentrate transfusion if platelet count < 20 000 If overt clinical bleeding, to correct coagulopathy or DIVC Bicarbonate therapy give bicarbonate only in refractory metabolic acidosis, if pH < 7.1 (ensure adequate tissue perfusion and ventilation to clear byproduct CO 2) Electrolytes and Sugar aim to maintain normal values Monitoring:
Frequent serial reevaluation is essential to guide therapy and gauge response Clinical: Laboratory: Vital signs: (as outlined above) HR via cardiac monitor Capillary return Skin temperature Pulse volume BP non invasive invasive – ideal if available SaO 2 via pulse oximeter CVP Urine output via continuous bladder drainage Head chart References: Nelson Textbook of Paediatrics Dellinger RP, Carlet JM, Masur H, et al. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med 2004;32(3):858 873 Warrick Butt. Septic Shock. Ped Clinics North Am 2001;48(3) Andrew Macnab. Care of the Critically Ill Child Paediatric HIV
A. Screening of Paediatric Cases for HIV status
In New-borns / children, the following groups need to be tested: • Abandoned babies/ street children • Babies of mothers with high risk behaviour (e.g. drug addicts/ prostitutes/ multiple sex partners/ single -teenage or underage) • Babies of HIV positive mothers • Sexually abused children and children with sexually transmitted disease • Children receiving regular blood transfusions/blood products e.g. Thalassemias
B. Deliveries and Infant Nursing
Standard Precautions must be observed at all times. It is vital to use protective barriers such as arm length gloves, mask, goggles and gown with waterproof sleeves. Boots are to be used for institutional deliveries. • During deliveries. • During handling of placenta tissue • During handling of babies such as wiping liquor off babies.
All equipment used during this procedure including resuscitation equipment should be cleaned and sterilised. Cord blood sample must be collected using a syringe and needle (except collection of blood for G6PD which can be done by dripping the cord blood directly onto the filter paper)
Nursery • Gloves must be worn • During admission of new-borns to SCN / NICU or postnatal wards. • During all blood taking and intravenous drip setting. • During suction and while doing nursing procedures like top and tail as well as changing nappies for high-risk babies including abandoned babies. • Gloves must be changed and hand washing done after each patient.
• Thermometer must be of individual use and suction catheters should be of single use. • Disposable diapers need to be used for babies whenever possible. If they are born to HIV positive mothers, disposable liners are done in the usual manner as for other babies. • Contact with body secretions such as faeces, urine, saliva and sweat are washed off with soap and water since the risk of transmission is low. • Finally all sharps are disposed according to the Ministry of Health’s guidelines
For parents or relatives, gloves are given when they are taking placenta back on discharge or during burial of stillbirth or dead babies at home. The placenta from HIV positive mothers should be soaked in formalin solution before disposal.
For home deliveries, battery operated suction device should be used. C. Immunisation
• Vaccines are generally well tolerated • All routine vaccinations can be given according to schedule • In addition, pneumococcal vaccine is given for a child >2 years of age. Booster dosing is required every 3-5 years intervals • Some special precautions for live vaccines i.e. BCG, OPV and MMR: • BCG – safe if the child is asymptomatic and not immunosuppressed (e.g. at birth); omit if symptomatic or immunosuppressed • OPV – safe but small theoretical risk of transmission to other immunocompromised family members. Preferably give IPV (killed polio vaccine) if available • MMR & (Varicella-zoster vaccine when available)– given in asymptomatic children, omit with severe immunosuppression (CD4<15%) Long term protection may not be achieved in severe immune suppression
D. Intervention to limit Perinatal Transmission Vertical transmission of HIV may occur while in utero, during the birth process or through breast-feeding. The rates of transmission vary from 25 – 30 % in most countries. Breast-feeding by HIV +ve mother gives a 14% additional rate of transmission. Therefore newborn breast-feeding is contraindicated in HIV positive mothers.
Factors associated with higher transmission rate • Mother with low CD 4 counts, high antigenemia, advanced disease and seroconversion during pregnancy. • Premature delivery of the baby (2.4X higher) • Invasive procedures such as episiotomy, foetal scalp electrodes, foetal blood sampling and amniocentesis. • Vaginal delivery 2.2X higher than LSCS • PROM > 4 hours. Chorioamnionitis .
As blood transfusion is an important method of HIV transmission it should be given judiciously in babies and mothers. Whenever possible autologous blood transfusion is recommended
The use of Zidovudine after the first trimester and during labour in the mother as well as in her new-born for the first six weeks has been shown to reduce perinatal transmission by 67.0% in PACTG076 study (i.e. 8.0% transmission compared to 25% in untreated group). This regime has been implemented in all KKM hospitals:
Antenatal: AZT 300mg bd p.o. starting from 14 weeks of gestation till delivery
In Labour: AZT loading 2 mg/kg IV in first hour; 1 mg/kg/hour infusion until delivery; substitute with oral AZT 300mg 3 HOURLY IF IV AZT is not available
Induction of labour: begin AZT at time of induction
Elective caesarean section: begin AZT 4 hours before surgery
Infant: Syrup AZT 2 mg/kg/dose 6 hourly beginning from < 8 to 12 hours of life (not > than 24 hours of life) until 6 weeks of age . E. Management of Babies Born to HIV Infected Mother
Children born to HIV positive mothers are usually asymptomatic at birth. However, all will have acquired maternal antibodies via the placenta and therefore will test antibody positive at birth. The median time for losing this antibody, if the child is not infected, is around 10 months but may be as late as 18 months.
During pregnancy Counseling of mother – discuss the following: • Transmission rate (natural course without intervention) – 25 to 30%. use of prophylactic AZT – reduces transmission to 8%, elective LSCS with prophylactic AZT – reduces transmission to ~3%. • Advise on bottle feeding as breast feeding can double the risk of transmission • Difficulty in making early diagnosis because of presence of maternal antibody in babies of HIV positive mothers. Stress importance of regular blood tests and follow-up.
Neonatal period • Admit all cases to nursery. • Examine the child – look for evidence of congenital infections other than HIV and symptoms of drug withdrawal if appropriate. • Start on Syrup Zidovudine (AZT) 2mg/kg/dose 6 hourly for 6 weeks within the first 8 hours and certainly no later than 24 hours. (Dose for premature baby >30 weeks: 2mg/kg 12hourly for 2 weeks, then 2mg/kg 8hourly). If oral feeding is contraindicated, then use IV AZT at 1.5mg/kg/dose. • Take blood for: - HIV DNA PCR (need arrangement with IMR, do not take from cord blood. Sensitivity reaches 90% by 1 month of age) - FBP, LFT, RP - HBsAg, Hepatitis C serology - TORCHES (esp. toxoplasmosis & CMV), VDRL
F. Management of HIV Infected Children
Clinical Features Common presenting features are: • Persistent/ generalized lymphadenopathy • Hepatosplenomegaly • Failure to thrive • Recurrent infections (respiratory, skin, gastrointestinal) • Developmental delay / regression
Follow up Schedule for Infants of HIV Infected Mother
Mother HIV +ve
• PCR of Baby at 2 weeks (2.5ml venous blood in EDTA bottle) • 2 weekly follow-up with FBC until 6 weeks. • Start PCP prophylaxis at 6 weeks till HIV status resolved PCR+ ve (Co-trimoxazole150mg/m 2/day TMP given PCR - ve once daily on 3 alternate days weekly)
Repeat as soon as Repeat HIV PCR at 6 possible weeks of age
+ ve - ve Infected Repeat HIV PCR between 4 – 6 months of age
• PCP - ve Prophylaxis up to 12 months (or for life If • Not infected. develop PCP • Stop co-trimoxazole. or low CD4 for • 3 monthly F/U until 18 age) months. • Antiretroviral • Ensure that the baby's therapy (ART) HIV IgG status is and follow up negative by 18 months • Then yearly follow-up until adulthood. 1994 Revised HIV Paediatric Classification (adapted from MMWR)
a. Clinical categories
Category A: Mildly Symptomatic Children with 2 or more of the following conditions but none of the conditions listed in categories B and C: • Lymphadenopathy (< 0.5cm at more than 2 sites; bilateral=one site) • Hepatomegaly • Splenomegaly • Dermatitis • Parotitis • Recurrent or persistent URTI, sinusitis or otitis media
Category B: Moderately Symptomatic Children who have symptomatic conditions other than those listed for category A or category C that are attributed to HIV infection. Examples of conditions in clinical category B include but are not limited to the following: • Anaemia (<8g/dl), neutropenia (1000/mm3), or thrombocytopenia (<100 000/mm3), persisting > 30 days • Bacterial meningitis, pneumonia, or sepsis (single episode) • Persistent oropharyngeal candidiasis (i.e. thrush) • Cardiomyopathy • Cytomegalovirus infection with onset before age 1 month • Diarrhoea, recurrent or chronic • Fever lasting > 1 month • Hepatitis • Herpes simplex virus (HSV) stomatitis, recurrent (i.e. more than 2 episodes within 1 year) • HSV bronchitis, pneumonitis, or oesophagitis with onset before age 1 month • Herpes zoster (i.e. shingles) involving at least 2 distinct episodes or more than one dermatome • Leiomyosarcoma • Lymphoid interstitial pneumonitis (LIP) or pulmonary lymphoid hyperplasia complex • Nephropathy • Nocardiosis • Toxoplasmosis with onset before age 1 month • Varicella, disseminated (i.e. complicated chickenpox)
Category C: Severely Symptomatic Children who have any condition listed in the 1987 surveillance case definition for acquired immunodeficiency syndrome, with the exception of lymphoid interstitial pneumonitis (LIP- which is a category B condition)
b. Immune categories
Immune category < 12 months 1 – 5 years 6 – 12 years No. / uL (%)* No. / uL (%)* No. / uL (%)* Category 1 > 1 500 (> 25) > 1000 (>25) > 500 (>25) No suppression Category 2 750 – 1499 (15-24) 500-999 (15-24) 200-499 (15-24) Moderate suppression Category 3 < 750 (<15) < 500 (<15) < 200 (<15) Severe suppression * CD4+ T-lymphocyte counts
Diagnosis of HIV infection • In children > 18 months old, need 2 consecutive positive HIV antibody tests. • In children < 18 months, need at least 2 positive HIV DNA PCR tests.
Monitoring • Monitoring of disease progression is through clinical, immunological (CD4+) and viral load status. Viral load assay is available in regional centers. • CD4+ count and viral load assay are done at diagnosis, about 1 month on initiation/ change of ART and every 3-4 months (more frequently if change of therapy is made or progression of disease occurs).
Antiretroviral Therapy Clinical outcome following the introduction of highly active antiretroviral therapy (HAART) in children is excellent, with dramatically reduced mortality reported from various cohorts. However, this needs to be balanced with: the failure of current drugs to eradicate the infection, side effects especially on prolonged therapy and compliance- adherence issues.
3 main categories of antiretroviral drugs are available in Malaysia:
Nucleoside reverse Non nucleoside reverse Protease inhibitors transcriptase inhibitors (NRTI) transcriptase inhibitor (NNRTI) • Zidovudine (AZT) • Nevirapine (NVP) • Ritonavir • Stavudine(d4T) • Efavirenz (EFZ) • Indinavir • Lamivudine (3TC) • Lopinavir/Ritonavir • Didanosine (ddI) (Kaletra) • Zalcitabine (ddC) • Saquinavir • AZT-3TC combined tablet (Combivir/ Duovir)
Goals of therapy
Decrease viral replication
Preservation of immune system
Diminish viral replication
Improved quality of live & Increase survival
Optimizing growth & development Reduced opportunistic infections
When to start? Starting ART is very rarely an emergency. Before starting ART, intensive education to parents/ care givers and older children-patients (esp. school going) need to be stressed. Do not start in haste as we may repent at leisure! Assess the family’s capacity to comply with often difficult & rigid regimens. Stress that non-compliance & non-adherence to medications allows continued viral replication and encourages the emergence of drug resistance and subsequent treatment failure.
Infants younger than 12 months Clinical Category CD4 cell % Viral load Recommendation Symptomatic OR < 25% Any Treat (category A, B, or C) (category 2 or 3) Asymptomatic AND > 25% Any Consider treatment (category N) (category 1)
Young infants have a much higher risk of disease progression to clinical AIDS or death when compared to older children or adults and hence the treatment recommendations are more aggressive.
Children aged 12 months or older Clinical Category CD4 cell % Viral load Recommendation AIDS OR < 15% Any Treat (category C) (category 3) Mild-to-moderate OR 15% - 25% OR > 100,000 Consider symptoms (category 2) copies/ml treatment (category A or B) Asymptomatic AND > 25% AND < 100,000 Defer therapy & (category N) (category 1) copies/ml close follow up
Please consult a specialist/consultant before starting treatment.
Which drugs to use?
Always use combination of at least 3 drugs .
Either • 2 NRTI* + 1 PI (Kaletra / Ritonavir / Indinavir) or • 2 NRTI* + 1 NNRTI (Efavirenz or Nevirapine)
[Note: i) there is a trend now to use PI for older children; ii) efavirenz usually initiated in children > 3 years of age; iii) nevirapine has a higher chance of developing rash (need dose adjustment)]
*Dual NRTI combination
Recommended: AZT + 3TC, AZT + ddI, d4T + 3TC, ddI + 3TC
Use in special circumstances d4T + ddI - has higher incidence of side effects AZT + ddC - ddC less potent NRTI than other NRTIs
Not Recommended Any monotherapy (except MTCT prophylaxis during neonatal period) d4T and AZT - pharmacologic and antiviral antagonism ddC and ddl ddC and d4T less potent combinations ddC and 3TC
When to change? • Treatment failure based on clinical, virologic and immunological parameters e.g. deterioration of condition or dropping of CD4 count. • Toxicity or intolerance of the current regimen o If due to toxicity or intolerance: Choose drugs with toxicity profiles different from the current regimen Changing a single drug is permissible If the dose is reduced, avoid reducing dose below lower end of therapeutic range for that drug o If due to treatment failure; Assess and review compliance & adherence Preferable to change all ART (or at least 2) to drugs that the patient had not been exposed before. Choices are very limited! Do not add a drug to a failing regime. Consider potential drug interactions with other medications When changing therapy because of disease progression in a patient with advanced disease, the patient's quality of life must be considered. • Consult Infectious diseases specialist. Follow up • Usually every 3 – 4 months • Ask about medication: o Compliance (who, what, how and when of taking medications) o Side effects e.g. vomiting, abdominal pain, jaundice • Examine: growth, head circumference, pallor, jaundice, oral thrush, lipodystrophy syndrome (if on d4T & PI) • Take FBC, CD4 count and viral load every 3 months, RFT, LFT, Ca/Po4 (amylase if on ddI) every 6 months. If on PI also do fasting lipid profiles and blood sugar yearly. • Explore social, psychological and financial issues e.g. schooling, home environment etc. Many children are orphans (single/ double), live with relatives, adopted and some are under NGO’s care / fostering. Referral to social welfare is usually required. Compliance & adherence to HAART are strongly linked to these issues.
Other issues • HIV / AIDS is a notifiable disease. Notify health office within 1 week of diagnosis. • Screen other family members for HIV. • Refer parents to Physician Clinic if they are HIV infected and not yet followed up. • Disclosure of diagnosis to the child (would be teenager, issues on sexual rights)
G. Horizontal Transmission Within Families Although HIV has been found in the saliva, sweat, tears and urine, there is no evidence that HIV can be acquired from these sources. Despite sharing of household utensils, linen, clothes, personal hygiene products; and daily interactions including biting, kissing and other close contact - repeated studies have failed to demonstrate transmission (except in cases with specific exposure to well defined body fluids especially blood, semen or vaginal fluids).
It is important to stress that the following has not transmitted infection: • casual contact with an infected person • droplets coughed or sneezed into the air • the sharing of utensils such as cups and plates • swimming pools • toilet seats • insect bites
It is difficult to isolate the virus from urine and saliva of seropositive children. So day care settings do not constitute a risk. However because of the theoretical risk of direct inoculation by biting, aggressive children should not be sent to day care. Teachers should be taught to handle cuts/grazes with care.
H. Guidelines for post exposure prophylaxis
Goal of post exposure care: 1. to prevent HIV infection among those sustaining exposure 2. to provide information and support during the follow up interval until infection is diagnosed or excluded with certainty
Risk for occupational transmission of HIV to Health Care Workers
• the average risk for HIV transmission after a percutaneous exposure to HIV infected blood is approximately 0.3% and after mucous membrane exposure is 0.1%. • risk is dependant on : o type of body fluid involved o type of exposure that has occurred o volume of fluid involved o disease stage o viral load of the source patient
Treatment of an Exposure Site • Wounds and skin sites that have been in contact with blood or body fluids should be washed with soap and water • mucous membranes should be flushed with water. • Immediate supervisor need to be notified and the HCW should be referred to the appropriate physician/doctor as per each hospital needle stick injury protocol.
References
1. Consensus on Antiretroviral Treatment (2 nd Edition) Year 2001. (Malaysian consensus) 2. Sharland M, et al. PENTA guidelines for the use of antiretroviral therapy, 2004. HIV Medicine 2004;5(Suppl 2):61-86. 3. The Working Group on Antiretroviral Therapy. Guidelines for the use of antiretroviral agents in Paediatric HIV infection. http://www.aidsinfo.nih.gov/guidelines/ (accessed on 1 st August, 2004)
APPENDIX
Antiretroviral drugs dosages and common side effects
Drug Dosage Side effects Comments Zidovudine (AZT) 160mg/m 2/dose, tds Anaemia, neutropenia, Large volume of Neonate:2mg/kg/dose headache syrup not well 6H tolerated in older children Didanosine (ddI) 90-120mg/m 2/dose, bd Diarrhoea, abdo pain, Ideally taken on peripheral neuropathy empty stomach (1hr before / 2hr after food) Lamivudine (3TC) 4mg/kg/dose, bd Diarrhoea, abdo pain; Well tolerated pancreatitis (rare) Use oral solution within 1 month of opening Stavudine (d4T) 1mg/kg/dose, bd Headache, peripheral Capsule may be neuropathy, opened and sprinkle pancreatitis (rare) on food or drinks Efavirenz (EFZ) 17 yrs or under Rash, headache, Inducer of CYP3A4 13-15kg 200mg insomnia hepatic enzyme; so 15-20kg 250mg has many drug 20-25kg 300mg interactions, monitor 25-32kg 350mg liver enzymes when 33-40kg 400mg given with lopinavir/ > 40kg 600mg od ritonavir Capsules may be opened and added to food Nevirapine (NVP) 150-200mg/m 2/day od for Severe skin rash, Few data on use with 14 days, then increase to headache, diarrhea, PI. Practice is to 300-400mg/m 2/day, bd nausea increase PI dose by about 30% Ritonavir (RTV) 400mg/m 2/dose, bd Vomiting, nausea, Take with food to headache, diarrhoea; increase absorption hepatitis (rare) and reduce GI side effects Solution contains 43% alcohol and is very bitter! Kaletra 230/57.5mg/m 2/dose, bd Diarrhea, asthenia Low volume, but a (Lopinavir/ritonavir) 7 -14kg 12/3 mg/kg, bd bitter taste. 15-40kg 10/2.5mg/kg, bd Higher dose used > 40kg 400/100mg, bd with NNRTI(efavirenz) Indinavir (IDV) 500mg/m 2/dose, tds Headache, nausea, Use in older children abdominal pain, that can swallow hyperbilirubinemia, tablet; renal stone Take on an empty stomach Advise to drink more fluid