SIRS and Brain Injury - Dr Eka Musridharta

Dr. Eka Musridharta, SpSData Pribadi

Tempat/Tgl Lahir : Jakarta, 1 Mei 1975

Alamat : Bulu Perindu Raya Blok N-3

Pondok Bambu, 13430

+68551075488

musridharta@yahoo.com

Pendidikan

Pendidikan Dokter Umum FKUI, Lulus 2009

Pendidikan Dokter Spesialis Neurologi FKUI, lulus 2006

Pendidikan Konsultan Intensive Care FKUI, Lulus 2009

Jabatan

Staff Medik Departemen Neurologi RSCM

Konsultan Neurofisiologi RS. Pusat Pertamina

Konsultan Neurofisiologi RS. Menteng Mitra Afia

SIRS and Brain Injury

Dr Eka Musridharta, SpS KIC

Sepsis: Defining a Disease Continuum

A clinical response arising from a nonspecific insult, including 2 of the following:

• Temperature 38oC or 36oC

• HR 90 beats/min

• Respirations 20/min

• WBC count 12,000/mm3 or4,000/mm3 or >10% immature neutrophils

SIRS = Systemic Inflammatory Response Syndrome

SIRS plus/with a presumed or confirmed infectious process

SepsisSIRSInfection/

Trauma/shock Severe Sepsis

Adapted from: Bone RC, et al. Chest 1992;101:1644Opal SM, et al. Crit Care Med 2000;28:S81

Sepsis: Defining a Disease Continuum

Bone et al. Chest 1992;101:1644; Wheeler and Bernard. N Engl J Med 1999;340:207

SepsisSIRSInfection/

Trauma/shock Severe Sepsis

Sepsis with 1 sign of organ failureCardiovascular (refractory hypotension)

Renal

Respiratory

Hepatic

Hematologic

CNS

Metabolic acidosis

Septic Shock

ACCP/SCCM Consensus

Definitions

O InfectionO Inflammatory response to

microorganisms, or

O Invasion of normally sterile tissues

O Systemic Inflammatory

Response Syndrome (SIRS)O Systemic response to a variety of

processes

O SepsisO Infection plus

O 2 SIRS criteria

O Severe SepsisO SepsisO Organ dysfunction

O Septic shockO SepsisO Hypotension despite fluid

resuscitation

O Multiple Organ Dysfunction Syndrome (MODS)O Altered organ function in an

acutely ill patientO Homeostasis cannot be

maintained without intervention

Bone RC et al. Chest. 1992;101:1644-55.

Clinical presentation

Sepsis / SIRS

SEPTIC SHOCK/MOF

Biologic sequelae

Monocyte activation

Monocyte deactivation

TNF-IL-1ßIL-6IL-8PAFiNOSCOX2

IL-1 raIL-10sTNFr-1/11TGF-IL-4

PROINFLAMMATORY

PROINFLAMMATORY

ANTI-INFLAMMATORY

ANTI-INFLAMMATORY CELL HYPORESPONSIVENESS / IMMUNOPARALYSIS

TNF-IL-1ßIL-6IL-8PAFiNOSCOX2

IL-1 raIL-10sTNFr-1/11TGF-IL-4

Imbalance between Pro-Inflamatory and Anti-inflamatory response

SIRS =SYSTEMIC INFLAMATORY

RESPONSE SYNDROME

CARS =COMPENSATED

ANTI-INFLAMATORYRESPONSE SYNDROME

Mortality

Septic

Shock53-63%

20-53%Severe Sepsis

300,000

7-17%

Sepsis

400,000

Incidence

Balk, R.A. Crit Care Clin 2000;337:52

Mortality Increases in Septic Shock Patients

2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definition Conference. CCM 2003;31:1250-1256

CEREBRAL ENERGY METABOLISM

The brain comprises only 2% of body weight, but

receives 15% of cardiac output and uses 20%

of total body oxygen and 25% of total body

glucose.

Within normal levels of global CBF the brain

extracts about 50% of the oxygen and 10% of

the glucose from arterial blood.

Elevation of body temperature

occurring as a result of

hypothalamic coordination of

autonomic, neuroendocrine, and

behavioral responses in reaction to

physiological injury or invasion is

generally known as fever

Traditional thought is that the

“febrile response” is beneficial in

preventing the proliferation of

invading microorganisms, but

some caregivers consider fever

to be harmful

Fever and Brain Injury

“ Moreover, increasing evidence

suggest that fever (irrespective of

its cause) can directly and

adversely affect neurological

outcome in various types of

neurological injury”

Polderman, Lancet,2009

Pathophysiology of Fever

O Rise in temperature due to regulated increase in patient’s hypothalamic set point

O oxygen consumption

O metabolic rate

O heart rate

O cardiac output

O leukocyte count

O levell of C-Reactive Protein

O May be detrimental to a critically ill patient

Brain Temperature

Local brain temperature may exceed

core temperature by up to 2°C

This variance may increase in the injured brain

due to hyper-metabolism in injured areas

Polderman, Lancet,2009

Prevalence of Hyperthermia

O Defined as temperature increase of > 38.3°C or one full degree above baseline

O Occurs in up to 70% of all neurologically-injuries patients

O Typically not an isolated event but a sustained response for as long as 2 weeks

O Risk of hyperthermia may increase by 32% for each additional day in ICU

O Evidence suggests that fever worsens injury after ischemia or trauma

Mc Ilvoy,AACN Clin.Issues,2006Badjatia, Current Neur and Neurosurg Reports, 2009

Neurogenic Fever

O Non infectious source of fever

O Results from disruption in the hypothalamic

set point

O Injury to hypothalamus; unclear mechanism

O Patient response

O Increased temperature (may plateau),

resistant to antipyretics

O Absence of perspiration.

Elevated temperature exacerbates neuronal

injury caused by cerebral ischemia or

traumatic brain injury (TBI) and, conversely,

hypothermia acts as a neuroprotectant in such

cases.

Well-controlled animal models of global and

focal ischemia demonstrate a significantly

detrimental effect of hyperthermia on clinical

outcome and neuropathological changes

hyperthermia worsens outcome in cerebral ischemia:

increased neurotransmitter release

increased free radical production

opening of the blood-brain barrier

increased depolarizations within the

penumbra

impaired brain metabolism and second

messenger inhibition

cytoskeletal degradation

“the action of otherwise

neuroprotective drugs in ischemia may

be nullified by mild hyperthermia.”

brain temperature monitoring and treatment

of elevated temperature in patients suffering

from neurological insult may, therefore, help

prevent secondary injury.

Ischemic Stroke and Fever

O Fever on admission has been correlated with larger infarct sizes and increased mortality.

O Each 1°C increase in temperature “doubles the relative risk for poor functional outcome”

O Neuronal loss may be increased even when occurring 24 hours after original insult

O Maintaining normothermia after ischemia stabilizes the blood-brain barrier and reduces cerebral metabolism

Badjatia, CCM, 2009

Temperature elevations aggravate ischemic neuronal injury and exacerbate brain edema

TBI and Hyperthermia

O Intracranial blood volume increases with rise in temperature

O Causes a reduced compliance and increases ICP

O Elevates risk for further neuronal injury

O 13% increase in metabolic rate associated with every 1°C increase in body temperature

O Increases risk of secondary injury

O Rates as high as 68% have been reported within 72 hours of TBI

Thompson et all. J. Neurol Neurosurg Psychiatry, 2003.

TBI and Hyperthermia

O Fever occurring within first week of injury

has been associated with:

O Increased ICP

O Neurologic impairment

O Prolonged ICU stay

O Long-term poor outcome

O Recommendation is to treat fever

aggressively in this patient population

Badjatia, CCM, 2009

SAH and Hyperthermia

O Occurs in up to 70% of all patients in first 10

days

O Hyperthermia has been linked to increased

ICP after SAH

O Fever occurring late (4 to 6 days after injury)

in SAH patients has been associated with

cerebral vasospasm

Badjatia, CCM, 2009

Treating Fevers

O Pharmacological: O Linked to intact thermoregulatory

mechanismsO Such as Acetaminophen, Ibuprofen.

O Surface Cooling O Water blankets O Hydrogel pads

O IntravascularO Endovascular cathetersO Iced saline

Controled Normothermia

O “Traditional Therapy” has consisted of water

blankets and antipyretic, which have been

proven to have <40% success rates

O Advanced technology

O 75% reduction in fever.

Induced Hypothermia

Advanced Technology

Acetaminophen

32

Arachidonic Acid Cascades

PLA-2

COX-1

Constitutive

COX-2

Inducible

Lipoxyge-

nase

COX-3

Leukotriene Prostaglandin ProstaglandinProstacyclin

GI Mucosal

Protection

GI Mucosal

Immun

System

Inflamm

Plat aggreg and

Hemostasis

Vasodil &

endothelial

function

Platelet

Thromboxane

TXA-2 Mediate pain,

inflammation,

fever & regulate

cell growth

Brain

Mediate pain

and Fever

Acetamino

phen

Botting et al 2005: Benarroch, 2006

Vascular

COX-3

Acetaminophen

Acetaminophen

O Acetaminophen is generally considered to be a weak inhibitor of the synthesis of prostaglandins (PGs).

O Acetaminophen also decreases PG concentrations in vivo, but, unlike the selective COX-2 inhibitors, acetaminophen does not suppress the inflammation of rheumatoid arthritis.

O Acetaminophen is a weak inhibitor of PG synthesis of COX-1 and COX-2 in broken cell systems, but, by contrast, therapeutic concentrations of acetaminophen inhibit PG synthesis in intact cells in vitro when the levels of the substrate arachidonic acid are low (less than about 5 μmol/L).

Graham, Garry G.; Scott, Kieran F. Am J of Therapeutics: 2005.12 - Issue 1: 46-55

Acetaminophen

O COX-3, a splice variant of COX-1, has been

suggested to be the site of action of

paracetamol.

O There is considerable evidence that the

analgesic effect of paracetamol is central

and is due to activation of descending

serotonergic pathways, but its primary site of

action may still be inhibition of PG synthesis.

Graham, Garry G.; Scott, Kieran F. Am J of Therapeutics: 2005.12 - Issue 1: 46-55

Acetaminophen and Clinical Settings

37

Acetaminophen Penetrates Readily Into the CSF of Children After I.V

Administration

O The children, aged 3 months to 12 years, who were undergoing surgery in the lower body using spinal anesthesia were given a single IV inject of paracet (15 mg/kg).

O CSF and venous blood samples were obtained between 5 min and 5 hours after injection.

O Paracetamol concentrations were determined by using a fluorescence polarization immunoassay.

Elina Kumpulainen, BMa,b, et al. Published online April 2, 2007PEDIATRICS Vol. 119 No. 4 April 2007, pp. 766-771 (doi:10.1542/peds.2006-3378)

Results

O Acetaminophen was detected in CSF from the earliest sample at 5 minutes, although in this sample acetaminophen concent was below the limit of quantification of 1.0 mg/L.

O Subsequent CSF acetaminophen concentr ranged between 1.3 and 18 mg/L (median: 7.2 mg/L), plasma concentr ranged between 2.4 and 33 mg/L, and CSF/plasma ratios ranged between 0.06 and 2.0.

O The highest CSF acetaminophen concentr was detected at 57 minutes.

Study Conclusions

O Acetaminophen permeates readily into the

CSF of children.

O This fast and extensive transfer enables the

rapid central analgesic and antipyretic

action of IV acetaminophen.

Summary• Hyperthermia may caused of increased O2 Consumption and

metabolism rate and may be detrimental to a critically ill

patient

• Occurs in up to 70% of all neurologically-injuries patients

• Hyperthermia poor outcome in brain injury.

• The modalities of treatment of hyperthermia are

pharmacological therapy, surface cooling and intravascular

cooling.

• Acetaminophen intravenous is the choice of drug if the

patient is unable to take oral or rectal and NSAIDs are

contraindicated.

Thank You