This randomized clinical trial compared the effects of 20% mannitol versus 3% hypertonic saline on controlling intracranial pressure in children with raised ICP due to acute CNS infection. The study found that 3% hypertonic saline was more effective at achieving the target ICP < 20 mmHg within 72 hours and resulted in better neurological outcomes, shorter duration of mechanical ventilation and PICU stay, and less severe disability compared to 20% mannitol. While hypernatremia was more common with hypertonic saline, both treatments had a similar safety profile otherwise. The study demonstrated that 3% hypertonic saline is superior to 20% mannitol for managing raised ICP in pediatric CNS

1. JOURNAL CLUB
PRESENTER- DR.SASIDHARAN
MODERATOR- DR.NARAYANAN

2. BASIC IDEA
▪ Research question
▪ Study design
▪ Validity
▪ Results
▪ General and local applicability
2

3. TITLE OF THE STUDY
▪ Randomized clinical Trial of 20% Mannitol
Versus 3% Hypertonic Saline in Children With
Raised Intracranial Pressure Due to Acute CNS
Infection
3

4. Published in pediatric
critical care medicine
journal in 2020
6

5. BACKGROUND
▪ Both Mannitol and hypertonic saline used as a
osmotherapy in Raised Intracranial Pressure
▪ Side effects of Mannitol are significant
▪ We compare the effect of 3% saline vs mannitol in
raised ICP in pediatric acute CNS infection
5

6. CNS INFECTION IN PEDIATRIC PATIENTS
▪ Central nervous system (CNS) infections are an important cause of morbidity and
mortality in children. Estimated incidence of acute encephalitis syndrome in children
is 10.5–13.8/100000 [1].
▪ The case fatality rate is 30% and neurological disabilities occur in one–third of
survivors [2]. Global burden of disease network (WHO) estimated that in 2010
meningitis caused approximately 422,900 deaths and encephalitis, 143,500 deaths
[3].
6

7. RAISED ICP AND PEDIATRIC CNS INFECTION
Acute CNS infection in children are commonly
associated with high mortality
Raised ICP (ICP≥20mmHg) is seen ¾ of comatose
children with acute CNS infection
So raised ICP monitoring plays a vital role in improving
neurological outcome
8

8. REASON FOR RAISED ICP MONITORING IN CNS
INFECTION
Raised ICP is a significant predictor of neurological outcome
in CNS infection
Complication related to raised ICP usually occurs in first 48 –
72 hours of illness
Targeting ICP less than 20mmHg is associated with
increased survival in pediatric acute CNS infection
8

9. RAISED ICP - MECHANISM OF ACTION IN CNS
INFECTION
▪ In acute bacterial meningitis, diffuse inflammatory
edema is the reason for raised ICP
▪ In Viral meningitis, cytotoxic brain edema followed by
vasogenic and osmotic brain edema in the later stage is
the reason for raised ICP
9

10. 10

11. 20 % MANNITOL (SUGAR) VS 3% SALINE (SALT) IN
CONTROLLING ICP
▪ MANNITOL: lower ICP through 2 distinct effect in the Brain
▪ 1. reduces blood viscosity, promotes plasma expansion and cerebral oxygen delivery in
response to cerebral vasoconstriction and decrease in cerebral blood volume occurs due
to auto regulation.
▪ 2. creates a osmotic gradient across Blood Brain Barrier , leading to movement of water
from parenchyma to intravascular space .
▪ HYPERTONIC SALINE : HTS creates a osmotic shift of fluid from intracellular space to
interstitial and intravascular space. Usual plasma osmolarity ranges between 280 and 295
mosm/ L, while HTS osmolarity vary from 1026 to 8008 mosm/L depending on HTS
concentration (3-23.4%)
11

12. 12

13. 13

14. OVERALL GOALS
▪ To evaluate the effect of 20 %mannitol and 3% saline in
pediatric acute CNS infection
▪ To compare which one has a better outcome over
another in clinical improvement
14

15. PRIMARY OBJECTIVES
▪ We compare effect of 3% Hypertonic Saline versus 20% Mannitol
in Raised ICP control over 48-72 hrs
15

16. SECONDARY OBJECTIVES
▪ To find out which one has a better neurological outcome
▪ To decrease the PICU stay and duration of mechanical
ventilation
16

17. STUDY DESIGN
Open – label Randomized Control Trial
Two group
1. Receiving 20% Mannitol
2. Receiving 3% Hypertonic Saline
17

18. STUDY POPULATION
Children 1-12 years old , with raised Intracranial Pressure
and modified Glasgow coma scale less than or equal to 8
were enrolled.
18

19. STUDY POPULATION AND TIME PERIOD
▪ The study Was conducted at Pediatric Intensive
Care Unit of a Quaternary care academic institute
in North India
▪ Study population : assessed for eligibility 109
▪ randomized – 57
▪ Time duration : August 2011 to April 2014
19

20. SAMPLE SIZE
▪ Primary outcome (proportion of patient to achieve target ICP < 20 mmHg
during 72 hrs ) was 50% in the Mannitol group (unpublished Data, 2011) .
Assuming that HTS therapy increases primary outcome to 85%, a two sided
alpha level of 5% and 80% power (1:1) allocation , 28 patient were needed in
each group, including 10% attrition for cross over and loss to follow up
20

21. DEFINITIONS
▪ Diagnosis of Acute CNS infection was considered in presence of fever and CNS dysfunction
▪ Acute bacterial meningitis was diagnosed if patient additionally had any of the following
1.CSF showing Bacteria on culture or gram stain or bacterial antigen
2.positive blood culture plus CSF showing > 5 leucocytes / mm3
glucose less than or equal to 40 mg/ dl or CSF/ serum glucose ratio ≤ than .5
Protein ≥100mg/dl
3.any three of following changes
CSF showing ≥ 100 wbc / mm3 (predom neutrophils)
CSF glucose less than or equal to 40 mg/ dl or CSF/ serum glucose ratio ≤ than .5
Protein ≥100mg/dl
CRP ≥ 40 mg/dl (negative tuberculin and cxr negative for PTB ) 21

22. CONTI..
▪ The etiological diagnosis was made based on
microbiological evidence of specific virus (JE, HSV,
ENTERO) and radiological evidence on CT or MRI
22

23. ETHICAL STATEMENT
▪ Approved by the Institutional Ethical Committee
23

24. INCLUSION CRITERIA
▪ All children aged 1-12 years old with acute CNS infection
History ≤ 7 days
clinical or radiological evidence of Raised ICP
modified Glasgow coma scale (m-GCS) score
less than or equal to 8
Informed written consent obtained from parent or legal
guardian
24

25. EXCLUSION CRITERIA
▪ Children with neurodevelopmental delay
▪ Chronic neurologic illness
▪ Contraindication to ICP catheter insertion
▪ Clinical brain death
▪ Already received mannitol or hypertonic saline
▪ Parents refuse participation in the study
▪ Were excluded from the study
25

26. RANDOMIZATION AND BLINDING
▪ After initial stabilization in emergency department, patient shifted to PICU and
were randomized into 20% mannitol and 3% hypertonic saline group by variable
size block randomization
▪ A computer generated randomization list was generated by a person blinded to
protocol
▪ Codes were placed in a serially numbered , sealed, opaque envelope opened
after getting written consent for enrollment
▪ Statistician and clinical outcome assessors were blinded to treatment
assessment
26

27. CONTROL AND INTERVENTION
▪ Control Arm : in mannitol group, 20% mannitol was administered @ 0.5 gm / kg
bolus over 20 mins as and when required but not less than 4 hrs of previous dose.
Diuresis induced by mannitol was replaced with isotonic saline to maintain
hemodynamic status
▪ Intervention Arm: In hypertonic saline group, 3% HTS was administered @ 10ml/kg
loading dose over 20 mins followed by continuous infusion of 0.5- 1 ml /kg / hr
infusion ( hiked at 0.1ml/kg/hr) . HTS was increased every hour if the ICP value was
not decreased by more than 25 % from previous value and above 20 mmHg
27

28. DATA COLLECTION
▪ Demographic and baseline data collected
▪ Severity of illness using PRISM – III score
▪ Neurological examination at 24,48and 72 hrs
▪ Vasoactive inotrope score measured 6th hourly
▪ Maximum accepted osmolarity was 330 mosm/l
▪ In HTS, serum sodium measured every 6th hourly for 72 hrs and maxi
accepted 160meq/l
▪ Discontinuation of osmotherapy : 1. hypotension 2. osmolarity above
accepted level 3. serum sodium above accepted level4. AKI requiring RRT 5.
Hemolysis or coagulopathy
26

29. General Care and Monitoring
▪ Management of raised ICP and mechanical ventilation
were similar in both groups
▪ ICP transducer probe was used for monitoring of ICP
▪ Cerebral perfusion pressure was calculated as MAP- ICP
▪ On a average, 2 hrly monitored and ICP transducer probe
removed when ICP remains less than 20mmHg
continuously minimum of 24 hrs. 29

30. PRIMARY OUTCOMES
▪ Proportion of patient achieved target average
ICP less than 20 mmHg during 72 hrs
30

31. STATISTICAL METHODS
▪ The normality of data was checked with the Kolmogorov –
Smirnov Z test
▪ Continuous normally distributed data were compared by
Student t test, nonnormally distributed data by the Mann –
Whitney U test
▪ The proportions was compared by the chi- square chart and
expressed as RR with 95% CI and Fisher exact test if the cell
frequencies were small ass appropriate
31

32. SECONDARY OUTCOMES
▪ m- GCS score at 72 hrs and PICU discharge
▪ Proportion of patients with complication requiring
discontinuation or withholding of osmotherapy
▪ Duration of mechanical ventilation and PICU stay
▪ All cause PICU – morality
▪ Functional status at PICU discharge
32

33. TRIAL FLOW
33

34. POPULATION FOR ANALYSIS
▪ Intention to treat analysis – was used
34

35. ▪ Intention to treat
analysis
▪ Every patient randomized to the
clinical study should enter the
primary analysis
▪ Potential bias due to exclusion of
patients is avoided
▪ Recommended method in superiority
trialShah PB. Intention-to-treat and per-protocol analysis. CMAJ. 2011;183(6):696.

36. STATISTICAL ANALYSIS
▪ Statistical analyses were performed with SPSS
software 20.0 (SPSS, Chicago, IL) and Epi info 7
(7.0.9.7; Cente for Disease Control and Prevention,
Atlanta, GA ) were used for data analysis
36

37. STATISTICAL METHODS
▪ The trend of MABP and ICP and change (delta – ICP), CPP and change
( delta- CPP), Vasoactive score, vital signs, and laboratory variables
in the first 72 hrs between the groups were analyzed using general
linear model repeated measures analysis of variance
▪ Time to event data ( resolution of coma, mechanical ventilation , ICP
transducer probe removal, death and PICU discharge ) were
analyzed using Kaplan – Meier and log – rank test followed by cox
regression analysis to adjust for prespecified baseline factors ( age,
sex, diagnosis) and expressed as an adjusted hazard ratio with 95%
CI 37

38. STATISTICAL METHODS
▪ All test were two tailed, and a p value of less than 0.05 was
taken as a statistically significant
38

39. RESULTS
39

40. BASELINE
CHARACTERISTICS

41. BASELINE CHARACTERISTICS
41

42. 42

43. 43

44. 44

45. PRIMARY OUTCOMES
45

46. 46

47. SECONDARY OUTCOMES
47

48. 48

49. 49

50. 50

51. 51

52. SUMMARY OF RESULTS

53. PRIMARY OUTCOMES
▪ Proportion of patient achieved the target average ICP (< 20
mmHg ) during 72 hours was significantly higher in HTS group
▪ Mean ICP in the first 72 hrs was significantly lower and CPP was
higher in the HTS group.
▪ Mean delta- ICP was significantly more negative and mean
delta- CPP was significantly positive in HTS group
53

54. SECONDARY OUTCOMES
▪ Median (interquartile range) m-GCS score at 72hrs and at PICU discharge
and proportion of patients with m-GCS score ≥ 9 at above time points
were significantly higher in HTS group .
▪ In HTS group, proportion of patients who developed rebound raised ICP or
complications requiring temporary discontinuation or withholding
osmotherapy was significantly lower than in Mannitol group.
▪ Proportion of patients who developed therapy related hypotension were
significantly lower in HTS group.
▪ Severe hypernatremia (>160mEQ/l ) was seen in higher number of patients
in HTS group
54

55. SECONDARY OUTCOMES
▪ Frequency of AKI was similar in both groups
▪ One patient in each group had evidence of haemolysis
▪ The coagulopathy ( no clinical bleeding only lab evidence
) was similar in both groups
▪ On Kaplan Meir analysis, HTS group has a shorter
median duration of Mechanical ventilation and PICU stay
55

56. SECONDARY OUTCOMES
▪ In the HTS group, three of six deaths(50%) were
attributed to refractory raised ICP in contrast to 6 of
10 deaths in mannitol group (60%)
▪ At PICU discharge, HTS group has more number of
patients with mild or no neurodisability and
significantly lesser number of patients with severe
disability
56

57. OTHER OUTCOMES
▪ Proportion of patients who received short term
hyperventilation was similar in both groups. The
median number of ICP spikes managed with
Hyperventilation and duration of hyperventilation
(5min vs 13 min) was lesser in HTS group
57

58. ADVERSE EVENTS
▪ No procedural complications were
encountered during the insertion of ICP
transducer probe.
▪ No serious adverse events related to trial
intervention occured
58

59. STRENGTHS
▪ Good study design
▪ Follow up for neurological examination
▪ Newly tried RCT on pediatric CNS infection ICP
management
59

60. LIMITATIONS
▪ Blinding of investigator was difficult because of nature of study
▪ No further analysis on Cerebral hemodynamics and metabolism
▪ Fixed and intermittent dosing strategy of 20% mannitol and different
osmolar load of 3% HTS .
▪ No subgroup analysis of etiology
60

61. CONCLUSION
▪ In pediatric CNS infection 3% HTS was superior to
Mannitol in view of
1. better reduction in ICP
2. improvement in m-GCS
3. Decrease in duration of mechanical
ventilation and PICU stay
4. decrease in severe neurological outcome
61

62. CONSORT CHECKLIST
62
CHECK LIST ITEM YES/NO
Identification as a randomised trial in the title YES
Structured summary of trial design, methods, results & conclusions YES
Scientific background and explanation of rationale YES
Specific objectives or hypotheses YES
Description of trial design YES
Eligibility criteria for participants YES
Settings and locations where the data were collected YES
The interventions for each group with sufficient details to allow replication,
including how and when they were actually administered
YES
Completely defined pre-specified primary & secondary outcome
measures, including how & when they were assessed
YES

63. 63
CHECK LIST ITEM YES/NO
How sample size was determined YES
When applicable, explanation of any interim analyses & stopping guidelines NA
Method used to generate the random allocation sequence YES
Type of randomisation; details of any restriction (such as blocking and block size) YES
Who generated the random allocation sequence, who enrolled participants, and who assigned
participants to interventions
YES
If relevant, description of the similarity of interventions YES
Statistical methods used to compare groups for primary and secondary outcomes YES
For each group, the numbers of participants who were randomly assigned, received intended
treatment, and were analysed for the primary outcome
YES

64. 64
CHECK LIST ITEM YES/NO
Losses & exclusions after randomisation, together with reasons No
Dates defining the periods of recruitment and follow-up YES
A table showing baseline demographic and clinical characteristics for each group YES
Number of participants (denominator) included in each analysis and whether the analysis was
by original assigned groups
YES
For each primary and secondary outcome, results for each group, and the estimated effect
size and its precision (such as 95% confidence interval)
YES
All important harms or unintended effects in each group YES
Trial limitations, addressing sources of potential bias, imprecision, and, if relevant, multiplicity
of analyses
YES
Registration number and name of trial registry YES
Sources of funding and other support (such as supply of drugs), role of funders No

66. QUESTIONS COMMENTS YES NO CAN’T
TELL
1.Did the study address
a clearly focused
question?
They clearly mentioned the population, and
intervention and the comparator was chosen.
The study tried to assess the superiority of
HTS vs mannitol as osmotherapy
Yes
2. Was the assignments
of participant to
interventions
randomized ?
Randomization was carried out appropriately
with an view to eliminate systematic bias
Yes
3. Were all participants
who entered the study
accounted for at its
conclusion?
There were 52 participants who were not been
included in the conclusion as they are not
randomized
NO

67. QUESTIONS COMMENTS YES NO
CAN’T
TELL
4.Were the participants
‘blind’ to intervention they
were given
Yes
Were the investigators
‘blind’ to the intervention
they were giving to
participants?
NO
Were the people
assessing/analysing
outcome/s ‘blinded’
Yes

68. QUESTIONS COMMENTS YES NO
CAN’T
TELL
5.Were the study groups
similar at the start of the
randomised controlled
trial?
The baseline characteristics of each study
groups were similar and there are no
differences between the study groups that
could affect the outcome.
Yes
6.Apart from the
experimental intervention,
did each study group
receive the same level of
care?
There was clearly defined protocol and the
follow up intervals were similar for each
group
Yes
7.Were the effects of
intervention reported
comprehensively?
Yes

69. QUESTIONS COMMENTS YES NO
CAN’T
TELL
8.Was the precision of the
estimate of the intervention
of treatment effect
reported?
Confidence intervals were reported.
Yes
9.Do the benefits of the
experimental intervention
outweigh the harms and
costs?
Can’t tell
10. Would the
experimental intervention
provide greater value to the
people in your care than
any of the existing
Yes

70. 70

71. 71

72. 72
Thank
you