compare the effect of mannitol and hypertonic saline (nacl3%) in treatment of acute elevated intracranial pressure in stroke patient

We conducted the study of “Compare the effect of mannitol and hypertonic saline NaCl3% in treatment of acute elevated intracranial pressure in stroke patient” in the purpose of 1- Compar

Raised intracranial pressure is a complication of the patientwith stroke Intracranial pressure is normally under 15mmHg,pathologic status happens when it increases above 20mmHg thatneed to be cured Some treatments are recommended by RCT studies,but most of them are base on clinical experiences Successfultreatment demands the cooperation of multiple specialties

Osmotic therapy has been implied since 1960s, however,indication and effectiveness remains controversial Some argued thatmannitol can break-through the injured blood brain barrier,accumulated in brain parenchyma drawing water inversely causemiddle-line shift and herniation Hyperosmotic sodium wasinvestigated as a substitution, but different mechanism may notassure the target

In Vietnam, the application of osmotic agents is popular,specially at the local medical center Due to some limitation ofmannitol was reported, the replacement agent should be studied.There is some study on mannitol compare with hyperosmotic sodiumcarrying in several surgical units, but not the internal ward We

conducted the study of “Compare the effect of mannitol and hypertonic saline (NaCl3%) in treatment of acute elevated intracranial pressure in stroke patient” in the purpose of

1- Compare the effect of reduce intracranial pressure bymannitol and NaCl3% in the acute elevated intracranial pressure onstroke patient

2- Record the change in the hemodynamic status andlaboratory date during the treatment of osmotic therapy

*The urgent and demand of the study

Stroke is common disease with high mortality The protocoltreatment of elevated intracranial pressure includes osmotic therapy.Althought the long-term use of it, controversial still remains.Hypertonic saline was recently implied to treat intracranial

hypertension, but most of the patients were suffer from brain injury.The administration on the stroke patient is becoming up-to-date andcontaining scientific issue

* The new contribution of the study

- The first study in Vietnam to evaluate the effect of hypertonicsaline on treatment of stroke

- Evaluated the impact of mannitol and NaCl3% on strokepatient With the dose of 250 ml bolus, Mannitol was able tosuccessfully decrease the intracranial pressure to below 25 mmHg in73.9% and NaCl3% was successful in 74.2% of the the patient

- Mannitol appeared to be prior to NaCl3% in the first minute, however, the duration of the intracranial pressure underthreshold of 25mmHg in the NaCl3% group was longer than that ofmannitol group (150 minute average in NaCl3% group vs 85 minute

30-in mannitol group)

- Both agents caused the raise in plasma osmolality as well asserum sodium, the difference was significant before and afterinfusion The brain hemodynamics was also improved, shown by theincrease of cerebral perfusion pressure and the decrease of pulsatilityindex on Transcranial Doppler, which meant the improvement ofbrain compliance

* The presentation of the study

The thesis includes 112 pages, with introduction, conclusionand recommendation Chapter one: overview 38 pages, chapter two:subject and method 15 pages; chapter three: results 20 pages; chapterfour: discussion 34 pages There are 29 tables of data, 5 charts, 8pictures and figures The reference section includes 143 articles inEnglish and Vietnamese version

Chapter one

1.1 Pathology of elevated intracranial pressure (ICP) on stroke patient

1.1.1.Pathology of raised intracranial pressure

If the ICP is greater than 20 mmHg, the pathological changehappens Middle increase of ICP is consider as 20-30 mmHg,however with the mass lesion, the herniation can be occurred with theICP even under 20 mmHg The ICP above 25 mmHg need to becontrolled and the ICP above 40 mmHg could be life threatening

The etiology of raised ICP on stroke patient

Intracranial hematoma:

The formation and the size of the hematoma will define theseverity of increasing ICP The clinical manifestation includes:subarachnoid hemorrhage, intracranial hemorrhage, intra-ventricularhemorrhage

Vascular tone disorder:

location or surrounding the lesion, or the whole brain, causediffuses brain edema Brain edema and brain vessel vasodilation canworsening the primary lesion

Brain edema:

Brain edema is defined as increase of water content of thebrain, shown as a hypo-density on CT scanner image Brain edemahappens on the white matter (68% total brain), the gray matter hashigher density so the edema is harder to be seen

The type of brain edema:

Angioma edema: serum content protein leak to interstitialspace due to injured blood brain barrier The expansion depends onblood pressure

Edema by toxic of the cell: hypoxemia deactivate the natripump (ATP depended) intracellular Sodium will be accumulated

intracellular draw the water from extracellular to enter intra-cellEdema cause by hydrostatic pressure: blood pressure contributes todilation of brain vessel (despite intact blood brain edema)

Other types: Hyponatremia, excess infusion of glucose causehypo-osmotic status of the serum The edema cause byhydrocephalus, cerebral-spinal fluid leak to surrounding tissue

1.1.2 The consequence of elevated intracranial pressure

Reduce of cease of blood flow to the brain

When intracranial pressure reach the mean arterial bloodpressure, the flow to the brain will stop, it similar to cardiac arrest

As Pitts state, if the intracranial pressure greater than the bloodpressure in 5-10 minute, brain dead will be assured There is strongrelationship between elevated intracranial pressure and mortality inthe severe brain injury

Compress and herniation:

The herniation appears when the brain tissue goes through theholes inside the skull The ulcus, the temporal lobe, the cerebellartonsils are the common parts of this complication

The clinical symptom rely on the location of the herniation includes:pupil dilation, hemiplegia, decorticate, decerebrate and dead Othercomplications could make the manifestation worsen

1.2 Treatment of elevated intracranial pressure

resolute the cause of it

Diuretics

Furosemide IV, synergic the effect of mannitol

Glycerol and ure infusion were used to reduce intracranialpressure, however, the implication of those agents is rare due tolimitation of the effect on clinical relevant

1.3 Osmotic therapy (mannitol and NaCl3%)

1.3.1 Mechanism of action

The mechanism of osmotic agents will be the subject ofcontroversial, however, there are 3 hypothesis have been consensus

as below:

- Draw the water out of the brain tissue

- Osmotic agents make hypertension, vasoconstriction, thenreduce the cerebral blood flow

- Hyperdilution, reduce blood flow

Although the hypothesis are for mannitol, it also can be apply forhypertonic saline

1.3.2 The study compare effectiveness of mannitol to hypertonic

2.1 Subjects

Those patient over 18-year-old who were monitored byintracranial pressure monitoring device at emergency department, atBachmai hospital from Jan, 2010 to March, 2014

Include criteria

* Had stroke with GCS below 8 points, were placedintracranial pressure monitoring by camino or extraventricularcatheter:

- MCA infarction or carotid occlusion with the lesion areagreater than one third of the hemisphere on imaging

- Intracranial hemorrhage or intraventricular hemorrhage

- Subarachnoid hemorrhage

*Acute elevated intracranial pressure

- ICP number greater than 25 mmHg over 5 minutes afterbeing treated by conventional method

Exclude criteria

- Decompressive hemicraniotomy

- Systolic blood pressure under 90 mmHg

- Renal failure grade II and above

- Serum sodium >155 mmol/l and/or serum osmotic >320mosm/kg

- Mannitol or hypertonic saline administrated 6 hours before

- Complication of ICP monitoring

- Patient or surrogate was not consent

With 95% confidence interval was 95%,

α = 0.05, Zα/2 = 1.96; β = 0.1, Zα/2 = 1.96; β = 0.1, Zα/2 = 1.96; β = 0.1, Z1-β = 1.28; the constants of αand β was C (α, β) = 10,5

The minimum size for to detect the difference between twoagents was formulate as:

N = 2 x C (α, β)/(ES)α, β)/(ES))/(α, β)/(ES)ES) 2 = 2 x 10.5/ (α, β)/(ES)0,67) 2 = 46

We conducted the study on 122 patient with 58 patient inmannitol group and 64 patients on NaCl3% group, satisfactory thesample size

2.2.3 The study protocol

Place the intracranial pressure monitoring

Patient elevation

Mechanical ventilation maintain PaCO 2 35-38 mmHg, SaO 2 >95%

Control temperature by acetaminophen, cool method

Sedation: midazolam, fentanyl

Hypertension control: per protocol

Anti-epilepsy

Nimodipin for SAH

The target of this bundle is to maintain intracranial pressurebelow 25 mmHg, CPP over 70 mmHg If the intracranial pressure isgreater than 25 mmHg over 5 minute without any anticipating factor(suction, poor synconized, mucus occlusion), the ventricular catheterwas opened (hydrostatic level of 15 cmH2O) After opening ofextraventricular drainage, intracranial pressure was still above 25mmHg over 5 minute, then osmotic agents would be indicated

Osmotic therapy protocol

Patient was allocated randomized into two groups

We allocate the patient randomize by the computer software.Because of the difference of bottled package so double blind couldnot be established

Data collection

General and demographics data: age, sex, weight, Glasgow

coma scale, the type of stroke, mortality

The record of intracranial pressure

The intracranial pressure was recorded before infusion(regarding as starting of the study or T0), after 30 minutes (T30), 60minutes (T60), 90 minutes (T90) and 120 minutes (T120) Then theintracranial pressure was monitor every hour until 6 hour (T180,T240, T300 and T360) If intracranial pressure below 25 mmHg, thenumber was recorded every 60 minutes for 24 hours

- The trend of intracranial pressure was documented, thenumber of success, and the time below threshold

- The intracranial pressure in types of stroke, in level ofelevated intracranial pressure

The data of hemodynamics status:

- Heart rate before and after osmotic therapy every 30 minutescoincide of intracranial pressure documentary

- The mean arterial blood pressure: documented whenrecording intracranial pressure

- Cerebral perfusion pressue

- Central venous pressure

- Urine output every hours until 6 hours after infusion

Laboratory data

- Serum sodium at T0 and T120

- Serum osmolality at T0 and T120, calculate osmotic gap

- Serum creatinin and blood sugar at T0 and T120

Transcranial Doppler waveform

- The max velocity (FVs: flow velocity systolic), FVd: flowvelocity diastolic, and pulsatility index (PI) were recorded at T0,T30, T60, T90 and T120

Chapter three MAIN RESULTS

3.1 Demographics of the study group

Table 3.1: the demographics features of the group

Method of monitoring

bolt/EVD

39/19(67.2%/32.8%)

36/28(56.3%/43.7%) 0.213Remark: the demographics feature is not significant different

3.2 Intracranial pressure control effectiveness

3.2.1 The trend of intracranial pressure per records

Chart 3.1: chart of trend of intracranial pressure per recordHighlight: the two solution had reduced intracranial pressure

of all recording times

3.2.2 The successful rate of reducing intracranial pressure below

25 mmHg

Table 3.2: The successful rate of intracranial pressure below 25

mmHg of the two groups

Status

Groupmannitol(n=58)

GroupNaCl3%(n=64)

Remark: the difference was not significant, p= 0.955

3.2.3 The successful rate per type of stroke

Table 3.3: The successful rate on three types of stroke

Type of stroke

Group mannitol (No.of infusion = 88)

Table 3.4: Compare the effectiveness on 3 level of raised

intracranial pressure Level of ICP Group

Mannitol

Group NaCl3%

p

Above 50 mmHg 4/14 (28.6%) 1/15 (6.7%) 0.16940-49 mmHg 23/26 (88.5%) 25/28 (89.3%) 0.92326-39 mmHg 38/48 (79.2%) 46/54 (85.2%) 0.426Total 65/88 (73.9%) 72/97 (74.2%) 0.955Highlight: There was no significant difference between twogroups

3.2.5 Duration keeping intracranial pressure below the threshold

of 25mmHg

Table 3.5: Duration of action below 25 mmHg

Group Duration

Group mannitol Group NaCl3%

3.2.6 Mortality rate of the two group

Table 3.6: overall mortality rateGroup

- The overall mortality rate was 42.6%

- There was no significant difference between the two group,

Mortality Group

NaCl3% Mortality pAbove 50

6/6

6/6(100%) > 0.0540-49

10/12

10/13(76.9%) > 0.0526-39

11/40

9/45(20%) 0.268

25(39.1%) 0.404Remark:

- 100% patient with intracranial pressure above 50 mmHg died

3.3 Hemodynamic changes of the two groups

3.3.1 Change of mean arterial blood pressure

Table 3.8: Change of mean arterial blood pressure

Group Time

0.256

16.022

108.84 ±16.550

0.911

16.009

107.91 ±16.526

0.897

15.187

108.57 ±17.154

0.605

18.187

108.45 ±17.265

0.781Remark:

- Middle increase of mean arterial blood pressure in two groupTable 3.9: Change of cerebral perfusion pressure

Group Time

Cerebral perfusion pressure

0.003

17.35881

82.2935 ±19.00176

0.694

18.64236

84.4130 ±19.23033

0.024

21.77245

83.4043 ±19.89560

0.005

Remark:

- Cerebral perfusion pressure reach the maximum at T30 inmannitol group and at T90 in NaCl3% group

3.3.2 Urine output before and after 6 hours of the infusion

Table 3.10: Urine output of the two groups

- The urine output for 6 hours of mannitol was greater thanNaCl3% group, the difference was significant p=0.03

3.3.3 Change of serum sodium after 2 hours

Table 3.11: Change of serum sodium at T120 in two group

Time

Mannitol

´

X ± SD(min, max)

NaCl3%

´

X ± SD(min, max)

3.3.4 Change of serum osmolality at T120

Table 3.12: Change of serum osmolality at T120

Time

Mannitol

´

X ± SD(min, max)

NaCl3%

´

X ± SD(min, max)

Serum osmolality was increased significantly, p<0.01

3.3.5 Change of Hb, Hct and creatinin at T0 and T120

Table 3.13: Change of Hb, Hct and creatinin

0.40880 ±0.0482720.330 – 0.470

0.476

0.0432920.315 – 0.476

0.37720 ±0.0625440.318 – 0.450

0.558

Creatinin at T0

(μmol/l)mol/l) 87,45±10.965-112 79,5±14.259-107 0.421Creatinin at T120

(μmol/l)mol/l) 89,2 ± 12.462-121 76.02±10.160-115 0.246

PHb; PHct; Pcreat 0.003; 0.006;

0.192 0.041; 0.137;0.227

- Hb and Hct reduced in two significantly statistics, but the meanvalue was within the normal range

- Difference of creatinin was not significant

3.4 Transcranial doppler data

Table 3.14: Change of FVd by percentage of T0 value

T120 2.2 ± 1.2 0.04 1.91 ± 1.1 0.02 0.495Highlight: The PI reduced during the treatment significantly