Adjunct therapies for neonatal sepsis

1
Adjunct therapies for neonatal sepsis

• Dr Rajesh
• 26/03/08

2

• IVIG
• Exchange Transfusion
• G-CSF, GM-CSF

3
IVIG rationale

• Maternal IgG tranfer ocuurs after 32 wks GA,
• The rationale for treating neonatal infections
  with intravenous immunoglobulin (IVIG) is based
  on the evidence that administration of IVIG
  provides IgG that can bind to cell surface
  receptors,
• provide opsonic activity,
• activate complement,
• promote antibody dependent cytotoxicity,
• improve neutrophilic chemo luminescence

4
Meta-analyses of the effectiveness of intravenous
immune globulin for prevention and treatment of
neonatal sepsis.Pediatrics. 1997 Feb99(2)E2

• Meta-analysis of 4933 evaluable newborns in 12
  studies of IVIG prophylaxis showed a
  statistically significant negative association
  with the incidence of sepsis in premature low
  birth weight newborns given IVIG shortly after
  birth (P .0193, two-sided).
• Meta-analysis of 110 evaluable cases of neonatal
  sepsis in three studies of IVIG treatment of
  neonatal sepsis showed a significant decrease in
  the mortality rate for neonates with sepsis given
  IVIG (P .007, two-sided). The common odds ratio
  was .173 (95 confidence interval .031 to
  .735).

5
Meta-analyses of the effectiveness of intravenous
immune globulin for prevention and treatment of
neonatal sepsis.Pediatrics. 1997 Feb99(2)E2

• CONCLUSIONS Using conservative and objective
  outcome rating criteria, the addition of IVIG to
  standard therapies is of minimal but demonstrable
  benefit in preventing sepsis when administered
  prophylactically to premature low birth weight
  newborns,
• And of unequivocal benefit in preventing death
  when administered therapeutically for early-onset
  neonatal sepsis. The likelihood of newborns with
  sepsis living past the neonatal period was
  improved nearly sixfold when IVIG was
  administered in addition to standard therapies.

6
(No Transcript)
7
Dosage used

• a single dose of 500 mg/kg of Intraglobin (Chen
  1996)
• single dose of 750 mg/kg of Gamimmune-N
  (Christensen 1991)
• 5ml /kg/day of Pentaglobin for three days
  (Erdem1993)
• 5 ml/kg/d of Pentaglobin for four days (Haque
  1988)
• single dose of 500 mg/kg of Gamimmune-N
  (Mancilla-R 1992)
• daily dose of 0.5 - 1 g for six days of
  Immunoglobulin SRK
• (Sidiropoulos 1981)
• 1g/kg of Sandoglobulin on three consecutive days
  (Shenoi 1999)
• single dose of 500 mg/kg of Sandoglobulin
  (Weisman 1992).

8
(No Transcript)
9
(No Transcript)
10
Main Results

• Nine studies,530 neonayes from 7 countries
• Six studies (n 318),suspected infection. A
  reduction in mortality following IVIG treatment
  typical RR 0.63 (95 CI 0.40, 1.00), of
  borderline statistical significance.
• Seven trials, (n 262),proven infection did
  result in a statistically significant reduction
  in mortality typical RR 0.55 (95 CI 0.31,
  0.98).
• In spite of different geographical locations of
  the studies, differences in the mortality in the
  control groups (range 0 - 43.8), the use of
  different IVIG preparations, and different dosing
  regimens, there was no statistically significant
  between-study heterogeneity for the outcome of
  mortality in the two analyses.

11
Authors Conclusion

• There is insufficient evidence to support the
  routine administration of IVIG preparations
  investigated to date to prevent mortality in
  infants with suspected or subsequently proved
  neonatal infection.

12
Exchange Trnsfusion
13
Rationale

• Providing immunoglobulin, Complement,
  Granulocyts, Platelets
• Removal of toxins
• Providing adult Hb for better tissue oxygenation

14
Indian Pediatr. 1991 Aug28(8)956-7. Indian
Pediatr. 1991 Jan28(1)39-43.

• 53 neonates with severe or unresponsive sepsis
  were subjected
• There were 32 low birth-weight (LBW) and 21
  non-LBW infants and 51/53 subjects had sclerema.
• The mean time for recovery following ET was 19.6
  /- 12.4 h (range 1-48 h).
• The overall survival was 77.4 and the survival
  rates for LBW and non-LBW infants were 73.6 and
  68.2,

15
Exchange transfusion in septic neonates with
sclerema effect on immunoglobulin and complement
levels.Indian Pediatr. 1997 Jan34(1)20-5

• Consecutive culture positive septic neonates with
  sclerema were enrolled and were randomized to
  undergo ET (study group, n 20) or no ET
  (controls, n 20).
• RESULTS Mortality was 50 in the study group and
  95 in controls. Gram negative organisms
  accounted for 85 in study group and 90 in
  controls.
• IgG, IgA and IgM levels rose significantly while
  C3 levels did not show significant rise 12-24
  hours after ET. Ig and C3 levels did not change
  significantly in the controls.

16
Exchange transfusion in neutropenic septicemic
neonates effect on granulocyte functions.Acta
Paediatr. 1993 Nov82(11)939-43

• Study group 20, Control 20
• Granulocyte functions by NBT reduction test and
  the staphylococcidal index.
• Mortality was 35 in the study group and 70 in
  controls. Gram-negative organisms accounted for
  80 in the study group and 90 in controls.
• TLC and ANC increased significantly immediately
  after exchange transfusion and 6 h later.
  Absolute band count decreased significantly
  immediately after exchange transfusion and
  increased 6 h later.
• NBT reduction in septicemic neonates in the study
  group, as well as in controls, was significantly
  decreased as compared to donor cells. NBT
  reduction improved significantly immediately
  after exchange transfusion and 6 h later. The
  values of the percentage of viable staphylococci
  recovered from neutrophils also improved
  significantly immediately after exchange
  transfusion and 6 h later.

17
Exchange transfusion or intravenous
immunoglobulin therapy as an adjunct to
antibiotics for neonatal sepsis in developing
countries a pilot study.Ann Trop Paediatr. 2006
Mar26(1)39-42.

• 88 infants with sepsis and GA 32 to lt37 wks
• Numbers ET33, IVIG 33, Control 22
• Deaths 9 (27) in the IVIG , 7 (21) in the ET
  and 9 (41) in the control group (pgt0.05)
• IgG levels rose significantly 12 hours after
  administration of IVIG (plt0.01). There were no
  differences between the initial and 24-hour IgG
  levels in the IVIG group.
• IgG levels did not change significantly in the ET
  and control groups. IgM levels rose significantly
  12 hours after ET and elevated IgM levels
  persisted for over 24 hours.

18
(No Transcript)
19
(No Transcript)
20
(No Transcript)
21
(No Transcript)
22
(No Transcript)
23
Main Results

• Statistically significant reduction (p 0.02) in
  sepsis, typical RR 0.85 (95 CI 0.74,0.98), NNT
  33. There was statistically significant
  between-study heterogeneity (p 0.02)
• Statistically significant reduction was found for
  any serious infection, one or more episodes, when
  all studieswere combined typical RR 0.82 (95 CI
  0.74, 0.92) NNT 25 (95 CI, 17, 50).
• No major adverse effects of IVIG were reported in
  any of the studies.

24
Authors Conclusion

• IVIG administration results in a 3 reduction in
  sepsis and a 4 reduction in one or more episodes
  of any serious infection,
• But is not associated with reductions in other
  important outcomes NEC, IVH, or length of
  hospital stay.Most importantly, IVIG
  administration does not have any significant
  effect on mortality from any cause or from
  infections.
• Prophylactic use of IVIG is not associated with
  any short-term serious side effects. From a
  clinical perspective a 3 - 4 reduction in
  nosocomial infections without a reduction in
  mortality or other important clinical outcomes is
  of marginal importance.
• The decision to use prophylactic IVIG will depend
  on the costs and the values assigned to the
  clinical outcomes. There is no justification for
  further RCTs

25
(No Transcript)
26
(No Transcript)
27
(No Transcript)
28
(No Transcript)
29
(No Transcript)
30
Main Results

• No significant survival advantage was seen at 14
  days from the start of therapy
• who, in addition to systemic infection, had
  clinically significant neutropenia at trial
  entry, does show a significant reduction in
  mortality by day 14 RR 0.34 (95 CI 0.12, 0.92)
  NNT 6 (95 CI 3-33).
• Prophylaxis studies have not demonstrated a
  significant reduction in mortality in neonates
  receiving GM-CSF RR 0.59 (95 CI 0.24,1.44) RD
  -0.03 (95 CI -0.08,0.02). The identification of
  sepsis as the primary outcome of prophylaxis
  studies has been hampered by inadequately
  stringent definitions of systemic infection.
• However, data from one study suggest that
  prophylactic GMCSF may provide protection against
  infection when given to preterminfants who are
  neutropenic or at high risk of developing
  postnatal neutropenia.

31
Authors Conclusion

• There is currently insufficient evidence to
  support the introduction of either G-CSF or
  GM-CSF into neonatal practice, either as
  treatment of established systemic infection to
  reduce resulting mortality, or as prophylaxis to
  prevent systemic infection in high risk neonates.
  
• No toxicity of CSF use was reported in any study
  included in this review.
• The limited data suggesting that CSF treatment
  may reduce mortality when systemic infection is
  accompanied by severe neutropenia should be
  investigated further in adequately powered trials
  which recruit sufficient infants infected with
  organisms associated with a significant mortality
  risk.

32
Conclusion

• Exchange transfusion to be done in neonates with
  sepsis and sclerema
• IVIG may be used, considering its limited
  usefulness
• In neutropenic IUGR preterms G-CSF or GM-CSF can
  be helpful