SERUM RESISTIN AS A PREDICTOR OF OUTCOME IN TRAUMATIC HEAD-

INJURED PATIENTS IN INTENSIVE CARE UNIT OF SUEZ CANAL

UNIVERSITY HOSPITAL

By

Hosam m atef ;MD

Anesthesia&ICU

Introduction

• The incidence of traumatic head injury is high in both industrialized and

non-industrialized countries and has been estimated variously to be

between150–250 cases per100,000 population per year.

• The Glasgow Coma Scale (GCS), the most commonly used system for

classification of traumatic head injury severity, grades a person's level of

consciousness on a scale of 3–15 based on verbal, motor, and eye-

opening reactions to stimuli. It is generally agreed that a traumatic head

injury with a GCS of 13 or above is mild, 9–12 is moderate, and 8 or

below is severe .

• Clinical and radiological tools for assessment of head injury severity and

predicting outcome lack sensitivity and specificity.

• Routinely performed CT in all patients with head injury may cause a

logistic and financial challenge in many emergencies unites.

• Identifying a high-risk group for adverse outcome after head trauma

would allow after care to be targeted at those with most to gain.

• High biomarker levels may also identify patients who are at highest risk

for secondary deterioration and who would benefit from repeat imaging,

monitoring, and increased surveillance.

• Resistin belongs to a novel family of cysteine-rich proteins called

resistin-like molecule or found in inflammatory zones proteins .

• In humans, resistin is expressed primarily in inflammatory cells,

especially macrophages. Furthermore, resistin has been shown to be

involved in inflammatory processes.

• However, it is evidenced that resistin could be produced by the brain and

pituitary gland.

• Furthermore, resistin mRNA was increased in the cortex of hypoxic,

ischemic and traumatic animal brain. In the patients with ischemic

stroke, high plasma resistin level has been associated with mortality and

disability.

• Recently, it is reported that high levels of resistin are present in the

peripheral blood of patients with intracerebral hemorrhage and are

associated with poor outcome.

Aim of the Work

The aim of this work is to study serum resistin level as a predictor of outcome in ICU patients with traumatic head injury in Suez Canal university hospital. This is in a trial to improve outcome among traumatic head - injured patients.

Patients and Methods

After obtaining approval by the Research Ethics Committee, a written informed consent from the first degree relatives of patients was taken with an explanation regarding the purpose, methods, effects, and complications.

Type of study :• A prospective descriptive study.

Site of study :• This study was held in ICU in Suez Canal University Hospital.

Target population:• Patients attended to ICU in Suez Canal University Hospital, over one year with

severe head injury fulfilling the inclusion criteria were included in this study. Sample size was 48 patients.

Inclusion criteria:

• History of traumatic head injury justified by Cranial Computed

Tomography (CCT) .

• GCS on admission : < 8/15 .

• Age : between 18 - 60 years old.

• Gender : both males and females .

Exclusion criteria:

• Pregnancy.

• Obesity (BMI >30kg/m2).

• Previous neurological disease.

• Patients with either of the following:

1) Diabetes Mellitus. 2) Hypertension.

3) Chronic heart disease. 4) Chronic lung disease.

5) Renal impairment. 6) Liver cirrhosis.

Methods of data collection:This was done via questionnaire included the following data

1. Demographic data: The patient’s age, gender, and BMI were recorded.

2. Patient evaluation:All patients were assessed clinically by:

(1) Medical History: Detailed history from the patient's first degree relatives including:

- Mechanism of head injury. -Time of trauma.

-History of chronic illness. -History of any medications taken.

-Manifestations: vomiting, fits and disturbed level of consciousness

-History of previous neurological diseases and medications.

(2) Examination including:

• General examination :

-Vital signs: ( Blood Pressure, Pulse, Respiratory Rate)

-Temperature monitoring.

-Head and neck examinations.

-Upper and lower limb examinations.

• Chest examination.

• Cardiac examination.

• Abdominal examination.

(3) Neurological assessment :

- Consciousness (Glasgow coma scale).

- Pupillary reflex.

- Signs of lateralization.

- Signs of fracture base of skull.

- Motor and sensory examination.

(4) Investigations including:

Laboratory: – CBC, RBS– PT, PTT, INR– AST,ALT, total &direct bilirubin,

albumin– Serum creatinine– Serum Na+ ,K+ ,Ca++

– Serum level of resistin protein– Arterial blood gases (ABG)

All samples were taken on admission and according to the protocol of ICU management till time of discharge from ICU. Resistin samples were drawn only on admission,3rdand 5th days.

Radiological Imaging:

-

Chest X-ray

-

Non-contrast brain CT

Others :

-

Electrocardiography (strip ECG)

The procedures in ICU department :

1. Monitoring :

Vital signs including: BP , Pulse , SpO2. Continuous temperature monitoring. Daily monitoring of blood gases via ABG.

• We recorded dynamic parameters every 2hours over the 24hours then the mean reading of them was taken in our study.

2. Management :

-After cannulation , intubation was done using heavy sedation then

ventilation was done.

- Head up position 45 degree. - Deep sedation.

- Management of hyperthermia. - Adequate nutritional support.

- Peptic ulcer prophylaxis. - Proper glycaemic control.

- DVT prophylaxis. - Seizures control.

- Dehydrating measures.

• After collecting all the blood samples, analysis was done by the specific

resistin protein kits using ELISA .

End point

• Outcome was assessed as 14 days morbidity and mortality in ICU.

• Through Glasgow outcome scale (GOS).

• On discharge, survived patients were neurologically reassessed and ICU

length of stay was recorded.

Number Percentage

Age

20 – 24 50%

30– 12 25%

40 – 48 12 25%

Mean ± SD 32.3 ± 8.1

Range 20 – 48

BMIMean ± SD 25.4 ± 2.7

Range 22.4 – 31.1

Table (1): Demographic characteristics among the studied patients:

Results

Female8.3%

Male92.7%

FemaleMale

Figure (1) Sex distribution among the studied patients

Table (2): Baseline clinical characteristics among the studied patients:

Number Percentage

Pupils react to light

Both 16 33.3%

One 28 58.4%

None 4 8.3%

Signs of lateralization

Present 8 16.7%

Absent 40 83.3%

HypoxiaNo 48 100%

Yes 0 0%

Table (3): Glasgow coma scale (GCS) among the studied patients on

admission and on follow up:

Mean ± SD Median (Range)

On admission 6 ± 1.3 b 5.5/15) 4/15 – 8/15(

On day 3 4 ± 1.9 a 4/10T (2/10T – 7/10T)

On day 5 5.6 ± 3.6 b 5.5/10T (2/10T – 15/15)

p-value 0.001*

Table (4): Hemodynamics and vital signs among the studied patients

on admission and on follow up:

On admission On day 3 On day 5 p-value

SBP(mmHg) 118.1 ± 16.9 a127.3 ± 13.7

b122 ± 7.4 a 0.004*

DBP(mmHg) 75.6 ± 10.5 a 75.4 ± 4.2 a 70.1 ± 6.6 b 0.001*

Mean arterial blood pressure(mmHg)

87.5 ± 14.4 a 92.6 ± 6.6 b 87.5 ± 6.1 a 0.02*

Heart rate(beat/minute) 101.1 ± 22.5 a 95.8 ± 14.5 a 86 ± 15.5 b 0.001*

Respiratory rate(cycle/minute)

18.1 ± 6.5 a 15.1 ± 3.3 b 14 ± 3.1 b 0.001*

Temperature(0C) 37.4 ± 0.6 a 36.9 ± 0.5 b 36.5 ± 0.5 b 0.001*

Table (5): CT findings on admission and follow up among the studied patients:

 Number Percentage

CT brain on admission

Fracture skull base 4 8.3%

Subdural hemorrhage 20 41.7%

Subarachnoid hemorrhage 12 25%

Severe brain edema 16 33.3%

Inter-ventricular hemorrhage 4 8.3%

Brain contusions 12 25%

Number of abnormality on CT

Single finding 20 41.7%

Multiple abnormalities 28 58.3%

Finding of CT follow-up

No recent events 16 33.3%

Resolving 24 50%

New event 8 16.7%

Table (6): Serum resistin level (ng/ml) among the studied patients on admission and on follow up:

Mean ± SD Median (Range)

On admission 0.79 ± 0.4 b 0.62) 0.413 – 1.82(

On day 3 1.34 ± 0.3 a 0.78) 0.425 – 1.45(

On day 5 0.75 ± 0.45 b 0.59) 0.321 – 1.92(

p-value 0.001*

Death

Persis

tent

Veg

etat

ive S

tate

Sever

e Disa

bility

Mod

erat

e Disa

bility

Goo

d Rec

over

y0%5%

10%15%20%25%30%35%40%45%

25.00%

8.30%

41.70%

0.00%

25.00%

Figure (2): Outcome among the studied patients according to Glasgow outcome 5- points scale (GOS) after 14 days:

Table (7): Comparison between patients with good recovery and patients with poor outcome (vegetative and disability) after 14 days :

Good recovery)n=12(

Poor outcome#)n=24(

p-value

Age (years) Mean ± SD 23.4 ± 4.8 31.5 ± 6.3 0.001*GCS on admission

Mean ± SD 7.5/15 ± 0.8 6.1/15 ± 0.5 0.001*

Number of abnormality on CT

Single finding 9 75% 8 33.3%

0.03*Multiple abnormalities

3 25% 16 66.7%

Finding of CT follow-up

No recent events 2 16.7% 9 37.5%0.3) NS(

Resolving 10 83.3% 14 58.3%New event 0 0% 1 4.2%

Baseline resistin level (ng/ml)

Mean ± SD 0.48 ± 0.2 1.02 ±0.5 0.01*

End tidal CO2

(mmHg)Mean ± SD 35.3 ± 1.8 36.4 ± 2.9 0.2) NS(

RBS (mg/dl) Mean ± SD 145.5 ± 29.8 198.9 ± 41.5 0.004*

Pupils reactivity

Both 8 66.7% 6 25%0.03*One 4 33.3% 18 75%

None 0 0% 0 0%

Figure (3): ROC curve showing predictive values of baseline resistin level for 14 days mortality:

Baseline Resistin

0 20 40 60 80 100

100

80

60

40

20

0

100-Specificity

Sensitiv

ity

Discussion

• In the model used in this study, multiple clinical and laboratory

variables have been used as predictors e.g. Glasgow coma scale

(GCS), pupil reactivity, hemodynamic and vital sign values, the

presence of a CT scan lesion, random blood sugar (RBS) and

serum resistin level.

• In a systematic review, Perel et al. in 2006 showed that GCS was

the most common predictor included in the models (50%)

followed by age (46%) and pupil reactivity (26%).

• In the current study, mortality at 14 days was 25% with a significant

difference between survival (36 patients) and non-survival group (12

patients) regarding mean age (29.1 and 34.5 years respectively), mean

GCS on admission (7.2/15 and 5.6/15 respectively), mean baseline

resistin level (0.69 and 1.12 ng/ml; p=0.03 respectively), mean RBS

(186.9 and 246.7 mg/dl respectively) and pupils reactivity. While pupils

were bilaterally reactive in 38.9% and unilaterally reactive in 61.1% in

the survival group patients, there were no reported cases with

nonreactive pupils. Pupils were bilaterally reactive in 16.7% and

unilaterally reactive in 50% in the non-survival group patients, while

there were 4 reported cases (33.3%) with nonreactive pupils.

• Similarly, Dong et al. in 2010 found that Twenty-six patients

(27.7%) died from TBI within 1 month. Baseline plasma resistin

level in the non-survival group was significantly higher than that in

the survival group (39.4 ± 12.4 vs. 23.8 ± 9.0 ng/mL; p< 0.001).

The neurological condition upon admission using GCS score and

unreactive pupils was statistically significantly different (both <

0.001) between the two groups. A higher proportion of patients in

the non-survival group suffered from hyperglycemia (p = 0.003).

• In the present study, multivariable predictive model for mortality at

14 days has shown that GCS on admission < 7/15, baseline

resistin level > 0.618ng/ml, RBS on admission > 200mg/dl and

nonreactive pupils on assessment are significant predictors while

age was not a significant predictor. Multiple logistic regression

model for poor GOS outcome has shown that GCS on admission

<7/15, unilaterally reactive pupil and baseline resistin level >

0.527 are significant .

• In the United States, Marshall et al. studied the relationship of

the initial GCS score with outcome and found the morality rate for

those with an initial post-traumatic GCS score of 3 was 78.4%;

initial GCS score of 4, 55.9%; and initial GCS score of 5, 40.2%.

of note, however, is that 4.1%, 6.3%, and 12.2% of the three

groups, respectively, had a good outcome.

• Dong et al. in 2010 introduced significant variables into

multivariate logistic model and selected GCS and plasma resistin

level as the independent predictors for 1-month mortality of

patients.

• In the present study, there is a significant correlation emerged

between plasma resistin level and GCS on admission, pupils

reactivity, mean arterial blood pressure and RBS. The present

study has also shown that a value of resistin level on admission

of TBI patient to ICU > 0.618 ng/ml was a significant predictor for

mortality at 14 days with sensitivity of 100%, specificity of 77.8%,

Positive predictive value of 60% and Negative predictive value of

100%( according to the ROC curve).

• Similar results in Dong et al. study in 2010, they found a

significant correlation between plasma resistin level and GCS

score on admission, pupils non-reactive on admission, and blood

glucose level ( p-value<0.02). A receiver operating characteristic

(ROC) curve identified plasma resistin cutoff level (30.8 ng/mL)

that predicted 1-month mortality with the optimal sensitivity

(84.6%) and specificity (75.0%) values ( P < 0.001) .

Conclusion

• A value of resistin level on admission of TBI patients to ICU > 0.618 ng/ml is a significant predictor for 14 days mortality with sensitivity of 100%, specificity of 77.8%, PPV of 60% and NPV of 100%.

• Resistin could possibly used as a novel biomarker in TBI as adjuvant prognostic tool to predict poor outcome.

Recommendations

• Use of resistin as a novel biomarker in TBI as adjuvant

diagnostic and prognostic tools to predict poor outcome.