Dr. Surendra Godara

Presented By :

Protocol on Neonatal Sepsis & Hypocalcemia

References AIIMS protocol NICU 2010PGI Chandigarh Protocol NICU 2010Manual of neonatal care

John P Cloherty

Avery’s Disease of newborn8th Edition

Foranoff & MartinNeonatal & perinatal medicine, Volume II 8th Edition

Neonatal sepsis is a clinical syndrome characterized by signs and symptoms of infection with or without accompanying bacteremia in the first month of life. It include:-

septicemia,

meningitis,

pneumonia,

arthritis,

osteomyelitis, and

urinary tract infections.

Superficial infections like conjunctivitis and oral thrush are not usually included under neonatal sepsis.

Definition

Neonatal sepsis

COMMONEST CAUSE OF NEONATAL DEATHS

Sepsis52%

As-phyxia20%

Others13%

Prema-tu-rity15%

Common organisms Klebsiella pneumoniae Escherichia coli Staphylococcus aureus PseudomonasGroup b streptococus

Early vs Late onset sepsisEarly Late

Onset Upto 72 hrs After 72 hrs

Source Maternal Postnatal environment

Presentation Fulminant multisystemPneumonia frequent

Slowly progressive,focalMeningitis frequent

Mortality 15-50% 10-20%

Clinical manifestations of neonatal sepsis Lethargy Refusal to suckle Poor cry Not arousable, comatosed Abdominal distension Diarrhea Vomiting Hypothermia Poor perfusion Sclerema Poor weight gain Shock Bleeding Renal failure

Cyanosis* Tachypnea* Chest retractions* Grunt* Apnea/gasping* Fever+ Seizures+ Blank look+ High pitched cry+ Excessive crying/irritability+ Neck retraction+ Bulging fontanel+

* Particularly suggestive of pneumonia+ Particularly suggestive of meningitis

Approach to EOSRisk factor

1. Low birth weight (<2500 grams) or prematurity

2. Febrile illness in the mother with evidence of bacterial infection within 2 weeks prior to delivery.

3. Foul smelling and/or meconium stained liquor.

4. Rupture of membranes >24 hours.

5. Single unclean or > 3 sterile vaginal examination(s) during labor

6. Prolonged labor (sum of 1st and 2nd stage of labor > 24 hrs)

7. Perinatal asphyxia (Apgar score <4 at 1 minute)

Presence of foul smelling liquor or three of the above mentioned risk factors warrant initiation of antibiotic treatment. Infants with two risk factors should be investigated and then treated accordingly.

Risk score generated in PGIRisk factor Score

IP per vaginal examinations >3

6

Clinical chorioamnionitis 6

BW <1.5kg 3

Male gender 3

Not received IP antibiotics 2

Gestation <30 wks 2

If - score 0-6 monitoring 7 or >7 antibiotics , blood cultureExtreme risk factor – prom>72hr

-prolonged labor>24hr -unclean vaginal exam’ - Maternal septisemia

Approach to LOS

Neonates who become symptomatic after 72 h must be evaluated for LOS..

Based on clinical assessment the neonate must be categorized into low probability of sepsis or high probability of sepsis. “Low probability” represents situations where the clinician would be willing to withhold antibiotics if-the sepsis screen is negative.

Those with low probability of sepsis (e.g. single episode of apnea, but otherwise well) should undergo a sepsis screen. The purpose of the sepsis screen is to rule out sepsis rather than to rule in sepsis. The sepsis screen consists of:TLC, CRP, ANC. ITR and micro-erythrocyte sedimentation rate (m-ESR).

o CRP: It is done by quantitative ELISA or by a bedside semi-quantitative latex agglutination kit. More than 1 mg/dL is positive.

o ANC: It must be read off Manroe’s charts, Schelonka’s chart or Mouzinho’s chart, depending on whether it is a term baby or a preterm baby respectiveIy.

Components Abnormal values

Total leukocyte count Absolute neutrophil count Immature /total neutrophilMicro-ESRC reactive protein (CRP)

<5000/mm3

<1750/mm3

>0.2>10 mm in 1st hour>1mg/dL

12

o ITR: It is considered to be positive if>20%. ITR is defined as

 Immature PMN (band forms, metamyelo & myelocytes)

Mature + immature neutrophils

Mature neutrophil Band cell

o mESR, Value (in mm in first hour)> “3+age in days” in the 1 wk of life or >10 thereafter is considered positive.

Two systematic reviews on sepsis screens reached the same conclusions- that there is no ideal test or combination of tests. Among the various tests, quantitative CRP is the best, followed by qualitative CRP and ITR.

If all the parameters of the sepsis screen are negative in a neonate assessed to have low probability of LOS, antibiotics may not be started and the neonate must be monitored clinically. The screen must be repeated after 12-24h. Two consecutive completely negative screens are suggestive of no sepsis.

Since CRP is the key parameter in the sepsis screen, a pragmatic approach is that if the CRP alone is positive or any two parameters of the sepsis screen are positive, a blood culture must be drawn and empirical antibiotics must be started. A CSF examination must be performed.

Neonates assessed to have a high clinical probability of sepsis may not be subjected to a sepsis screen, because a negative screen would not alter the decision to start antibiotics. A CSF examination must be performed.

Investigations

Sepsis screenBlood cultureLP Revised guideline for empirical treatment of meningitis based on csf

parameterAmong neonates with suspected sepsis

Among neonates with blood culture proven sepsis

Cut-off values to diagnose meningitis

Preterm babies

•WBC >25 AND protein >170 OR•WBC>100 •OR•Glucose <25

•WBC >10• OR•Glucose <25OR•Protein >170

Term babies

•WBC >21• OR•Glucose <20

•WBC >8 OR•Glucose <20 OR•Protein >120

Radiology

X-ray chest

X-ray Abdomen

CT scan

Neurosonogram

Urine analysis

Protocol on Sepsis

ManagementEmpirical antibiotic

First line: Ciprofloxacin + Amikacin (covers - 75% isolates) . If meningitis is suspected, replace Ciprofloxacin. by Cefotaxime-sulbactam (see section D24)

Second line: Vancomycin + Piperacillin-Tazobactam (covers -90% isolates)

Third line: Vancomycin + Meropenem (covers - 95-100%)The antibiotic policy is reviewed periodically and may change after the next review. Cephalosporins rapidly induce the production of extended spectrum b-lactamases, cephalosporinases and fungal colonization, and hence, are best avoided as empirical antibiotics.

Starting empirical antibiotics

Empirical upgradation must be done if the expected clinical improvement with the ongoing line of antibiotics does not occur. A minimum of 48-72 h of observation should be allowed before declaring the particular line as having failed. The duration may be longer for Vancomycin compared to the Penicillin group and Aminoglycosides

In case the neonate is extremely sick or deteriorating very rapidly and the treating team feels that the neonate may not able to survive 48 h in the absence of appropriate antibiotics, a decision may be taken to bypass the first line of antibiotics and start with the second- line of antibiotics

Upgradation of empirical antibiotics

Antibiotic therapy once culture report available

If the growth is a non-contaminant, the antibiotic sensitivity must be assessed to decide whether antibiotics need to be changed or not. The following guidelines must be adhered to:o If the organism is sensitive to an antibiotic with a narrower

spectrum or lower cost, therapy must be changed to such an antibiotic, even if the neonate was improving with the empirical antibiotics.

o If possible, a single sensitive antibiotic must be used, the exception being Pseudomonas for which 2 sensitive antibiotics must be used. Two sensitive antibiotics (a Penicillin + an Aminoglycoside) may also be used for S aureus and E. fecalis.

o If the empirical antibiotics are reported sensitive, but the neonate has

worsened on these antibiotics, it may be a case of in vitro resistance.

Antibiotics may be changed to an alternate sensitive antibiotic with the

narrowest spectrum and lowest cost.

o If the empirical antibiotics are reported resistant but the neonate has

improved clinically, it may or may not be a case of in-vivo sensitivity. In

such cases a careful assessment must be made before deciding on

continuing with the empirical antibiotics. One must not continue with

antibiotics with in vitro resistance in case of Pseudomonas, Kiebsiella and

MRSA; and in cases of CNS infections and deep-seated infections.

o If no antibiotic has been reported sensitive, but one or more has been

reported moderate1y sensitive’, therapy must be changed to such

antibiotics at the highest permissible dose. Use a combination, in such

cases.

Dosage and root of administration of common antibiotic in newborn

Supportive care of sick septic newborns

The survival of a sick septic newborn often depends upon aggressive supportive care. Oxygen saturation should be maintained in the normal range and

mechanical ventilation may be required in case of increased work of breathing.

Anemia, thrombocytopenia, and DIC are treated with appropriate transfusions. Packed red cells and FFP might have to be used.

Septic infants should be screened for hypoglycemia and treated appropriately.

Management of Septic Shock

Adjunctive Therapies

IVIG The currently available evidence does not support the use of IVIG. IVIG may be used in a difficult situation, after discussion with the consultant.Dose : pentaglobin 5 mL/kg/d for 2 d (IgM 6 mg, IgA 6 mg and IgG 38 mg/ml).Among patients with clinically suspected infection, the reduction of mortality with IVIG is of borderline significance [typical RR 0.63 (95% CI; 0.40, 1.00)]. In cases of subsequently proven infection the reduciton in mortality is statistically but has very wide Cl [typical RR 0.55 (95% Cl; 0.31, 0.98)].

Exchange transfusion (ET): Sadana et al have evaluated the role of double volume exchange transfusion in septic neonates with sclerema and demonstrated a 50% reduction in sepsis related mortality in the treated group. We perform double-volume exchange transfusion with cross-matched fresh whole blood as adjunctive therapy in septic neonates with sclerema.

.Granulocyte-Macrophage colony stimulating factor (GM-CSF): This mode of treatment is still experimental.

NS- 26Teaching Aids: NNF

Prevention of infections Exclusive breastfeeding

Keep cord dry

Hand washing by care givers

Hygiene of baby

No unnecessary interventions

NS- 27Teaching Aids: NNF

Control of hospital infections Hand washing by all staff

Isolation of infectious patient

Use plenty of disposable items

Avoid overcrowding

Aseptic work culture

Infection surveillance

NS- 28Teaching Aids: NNF

Work culture Sterile gowns and linen for babies Hand washing by all Regular cleaning of unit No sharing of baby belongings Dispose waste-products in separate bins

Hypocalcemia

DefinitionDefined as total serum calcium concentration of <7 mg/dL or an ionized calcium concentration of <4 mg/dL (i.e. 1 mEq/L). umbilical calcium level is 10-11mg/dLfirst 24-48h-7.5-8.5 mg/dL .Classification: early onset (<3 d) and late onset (>3 d)Causes:Early onset: Prematurity, 1DM, perinatal asphyxia, maternal intake of anticonvulsants, IUGR. If hypocalcemia does not resolve within 72 h of therapy investigate for causes of late onset hypocalcemia.

TreatmentMaintenance: 4-6 mL/kg/d of Ca gluconate IV (added in last 2 h of 6 hourly IVF)Preparation: Ca-gluconate 10% (IV)- 9 mg/mL (preferred), Ca-chloride (IV)-27 mg/mLTherapeutic:Asymptomatic: increase maintenance to 8-12 mL/kg/d of Ca-gluconateSymptomatic: 2 mL/kg of Ca-gluconate diluted in 1:1 dilution with NS or 5% D IV over 10-15 mm under strict cardiac monitoring (stop infusion if HR drops for >20 beats/mm than baseline or any other arrhythmia appears on ECO). Start maintenance calcium after bolus dose.

Management of early neonatal hypocalcemiaHypocalcemia

Total serum Cal <7 mg/dl

Asymptomatic80 mg/kg/day for 48 hrs

(8 mL/kg/day of 10% calcium gluconate )

Taper to 40 mg/kg/day for one dayThen stop

SymptomaticBolus of 2 mL/kg calcium gluconate 1:1 diluted with 5 % dextrose over 10 minutes under cardiac monitoring

Followed by continuous infusion 80 mg/kg/day for 48 hrs (8 mL/kg/day of 10% calcium gluconate )Document normal calcium at 48 hrs

Then taper to 40 mg/kg/day for one dayThen stop

ProphylacticPreterm< 32 wks, sick IDM, severe asphyxia 40 mg/kg/day for 3 days

(4ml/kg/day of 10% calcium gluconate ) IV or oral if can tolerate per oral

Treatment is for 72 hours Continuous infusion is better than bolus Symptomatic babies treatment is 48 hrs continuous infusion

Prolonged or resistant hypocalcemiaThis condition should be considered in the

following situations:Symptomatic hypocalcemia unresponsive to

adequate doses of calcium therapyInfants needing calcium supplements beyond 72

hours of ageHypocalcemia presenting at the end of the first

week.These infants should be investigated for causes

of LNH

Causes of late onset hypocalcemia Increased phosphate load--Cow milk, renal insufficiency Hypomagnesemia Vitamin D deficiency Maternal vitamin D deficiency Malabsorption Renal insufficiency Hepatobiliary disease PTH resistence--Transient neonatal pseudohypoparathyroidism Hypoparathyroidism Primary Hypoplasia, aplasia of parathyroid glands - (Di George’s syndrome), CATCH 22 syndrome (cardiac anomaly, abnormal facies, thymic aplasia, cleft palate, hypocalcaemia with deletion on chromosome 22) Activating mutations of the calcium sensing receptor (CSR) Secondary Maternal hyperparathyroidism

Metabolic SyndromesKenny-caffey syndromeLong-chain fatty acyl CoA dehydrogenase

deficiencyKearns-sayre syndromeIatrogenicCitrated blood productsLipid infusionsBicrbonate therepyDiueretics (loop diuretics)GlucocorticosteriodsPhosphate therepyUse of Aminoglycosides (mainly gentamicin) as

single doseAlkalosisPhototherapy

First lineSerum phosphateSerum alkalinephosphatase (SAP)Liver function testsRenal function testsX ray chest/ wristArterial pH

Second lineSerum magnesiumSerum parathormonelevels (PTH)Urine calcium creatinineratioMaternal calcium,phosphate, and alkalinephosphatase

OthersCT brain for calcificationEchocardiographyVitamin D levels (1,25D3)Hearing evaluationSerum cortisolThyroid function tests

S.No. Disorder causing hypocalcemia

Findings

1 Hypoparathyroidism High : PhosphateLow : SAP, PTH, 1,25 D3

2 PseudoHypoparathyroidim

High : SAP, PTH, PhosphateLow : 1,25 D3

3 Chronic renal failure High : phosphate, SAP, PTH, pH (acidotic), deranged RFTLow : 1,25 D3

4 Hypomagnesemia High : PTHLow : Phosphate, Mg,1,25 D3

5 VDDR1 High : SAP, PTHLow : Phosphate, 1,25 D3

6 VDDR2 High : SAP, 1, 25 D3, PTHLow : Phosphate

Investigation required

Treatment of LNH

The treatment of LNH is specific to etiology and may in certain diseases be lifelong.1. Hypomagnesemia: Symptomatic hypocalcemia unresponsive to adequate doses of IV calcium therapy is usually due to hypomagnesemia. It may present either as ENH or later as LNH. The neonate should receive 2 doses of 0.2 mL/kg of 50% MgSO4 injection, 12 hours apart, deep IM followed by a maintenance dose of 0.2 mL/kg/day of 50% MgSO4, PO for 3 days.2. High phosphate load: These infants have hyperphosphatemia with near normal calcium levels. Exclusive breast-feeding should be encouraged and top feeding with cow’s milk should be discontinued. Phosphate binding gels should be avoided.

Treatment of LNH3. Hypoparathyroidism: These infants tend to be hyperphosphatemic and hypocalcemic with normal renal function. Elevated phosphate levels in the absence of exogenous phosphate load (cow’s milk) and presence of normal renal functions indicates parathormone inefficiency. It is important to realize that if the phosphate level is very high, then adding calcium will lead to calcium deposition and tissue damage. Thus attempts should be made to reduce the phosphate (so as to keep the calcium and the phosphate product less than 55). These neonates need supplementation with calcium (50 mg/kg/day in 3 divided doses) and 1,25(OH)2 Vitamin D3 (0.5-1 mg/day). Syrups with 125 mg and 250 mg per 5ml of calcium are available.1,25(OH)2 vitamin D3 (calcitriol) is available as 0.25 mg capsules. Therapy may be stopped in hypocalcemia secondary to maternal hyperparathyroidism after 6 weeks.

Treatment of LNH

4. Vitamin D deficiency states: These babies have hypocalcemia associated with hypophosphatemia due to an intact parathormone response on the kidneys. They benefit from Vitamin D3 supplementation in a dose of 30-60 ng/kg/dayMonitoringThe baby is monitored for the SCa, and phosphate, 24 hour urinary calcium, and calcium creatinine ratio. Try to keep the calcium in the lower range as defective distal tubular absorption leads to hypercalciuria and nephrocalcinosis.

Treatment of LNH

Prognosis and outcomeMost cases of early neonatal hypocalcemia resolve within 48-72 hours without any clinically significant sequelae.Late neonatal hypocalcemia secondary to exogenous phosphate load and magnesium deficiency also responds well to phosphate restriction and magnesium repletion. When caused by hypoparathyroidism, hypocalcemia requires continued therapy with vitamin D metabolites and calcium salts. The period of therapy depends on the nature of the hypoparathyroidism which can be transient, last several weeks to months, or be permanent.