Journal Reading Aminophylline

JOURNAL READING :
“EFFECT OF AMINOPHYLLINE AS
REVERSAL AGENT”
PPDS : Kinanti Narulita Dewi

Pembimbing : dr. Arie Zainul F, Sp.An KIC
●
General Issue
Phase of recovery ●
Pharmacodynamic
Risk factors ●
Understanding of PDE &
Delay awakening / Adenosine
Aminophylline as
emergence from GA
●
anesthesia agent’s reversal
Recovery Issue of
from Amino-
Anesthesia phylline
EBM Bispectral Index
Validity
Importance ●
Range of BIS
Applicable
RECOVERY FROM
ANESTHESIA
Delayed awakening from anesthesia remains one of the biggest
challenges that involve an anesthesiologist. With the general
use of fast‑acting anesthetic agents, patients usually awaken
quickly in the postoperative period.
“Recovery from anesthesia may be defined as a state of

consciousness of an individual when he is awake or easily
arousable and aware of his surroundings and identity.”
Awakening results from elimination of anesthetic agents from
the brain.
Patients usually respond to verbal stimuli when alveolar
anesthetic concentration is decreased to about 30% of
minimum alveolar concentration (MAC) (MAC awake) if
unimpeded by other factors. Recovery from intravenous (IV)
opioids and hypnotics may be more variable and difficult to
quantify than recovery from inhalational and neuromuscular
blocking
Misal, U.S., Joshi, S, A., Shaikh, M.M., 2016. Delayed recovery agents.
from anesthesia. Anesthesia: Essays and Researches;
PHASES OF RECOVERY FROM ANESTHESIA
1. Immediate recovery
• This consists of return of consciousness, recovery of
protective airway reflexes, and resumption of motor
activity. This stage usually lasts for a short time.
2. Intermediate recovery
• During this stage, the patient regains his power of
coordination and the feeling of dizziness disappears.
This stage usually lasts for 1 h after short anesthetic.
Outpatient may be considered fit for discharge with a
responsible escort.
Misal, U.S., Joshi, S, A., Shaikh, M.M., 2016. Delayed recovery from anesthesia. Anesthesia: Essays and Researches;
PHASES OF RECOVERY FROM ANESTHESIA
3. Long‑term recovery
• There is a full recovery of coordination and higher
intellectual function. It may last for hours or even days.
RISK FACTORS
RISK FACTORS
Gaeriatri
c
RISK FACTOR
F>M
RISK FACTORS
Liver disease
Kidney
disease
RISK FACTORS
Drugs inhibitor
Drugs inducer
CYP 450
DELAYED AWAKENING OR EMERGENCE FROM GA :
DRUG FACTORS/PHARMACOLOGICAL CAUSES
Delayed awakening after GA is most commonly caused by
anesthetic overdose. Administration of an ideal dose to one
patient may have a very different effect on an apparently
similar patient.
Residual drug effects : A heavy premedication or the relative
overdose of general anesthetic agents may be the cause of
delayed awakening.
Potentiation by other drugs : Prior ingestion of opioids & BZDs
or nonanesthetic drugs that affect cognitive function such as
tranquilizers, antihypertensives, anticholinergics, clonidine,
antihistamines, penicillin‑derived antibiotics, amphotericin B,
immunosuppressants, lidocaine, & alcohol will potentiate the
CNS depressant effects of anesthetic drugs & delay
emergence from anesthesia.
DELAYED AWAKENING OR EMERGENCE FROM GA :
DRUG FACTORS/PHARMACOLOGICAL CAUSES
Drug interactions :
MAOIs / SSRIs may experience severe drug interactions
with IV agents that can result in hyper/ hypotension &
postoperative coma or a full‑blown serotonergic syndrome.
A large number of pharmacological interactions with NMBA
such as aminoglycosides, diuretics, calcium channel
antagonists, lithium, polymyxin B, echothiophate, oral
contraceptives, LAs etc., will prolong neuromuscular block
(NMB).
Neurotoxic effect of chemotherapeutic drugs such as
l‑asparaginase & vincristine can also produce CNS
depression.
OPIOIDS
Direct sedation through opioids receptor also

prolongs recovery.
Active metabolites of morphine and meperidine
prolong the duration of action, especially in the
presence of renal failure.
Patient with hepatic insufficiency may develop
hepatic coma after morphine and prolong
sedation after thiopentone.
BENZODIAZEPINES
They potentiate CNS depressant effects of
anesthetic drugs and may delay emergence from
anesthesia.
Benzodiazepines combined with high‑dose opioids
can produce respiratory depression, hypercapnia,
and coma.
Midazolam is metabolized by the same CYP450 isoenzymes as alfentanil such
that co‑administration prolongs the action of both drugs. Midazolam is
biotransformed to alpha hydroxyl midazolam, which have clinical potency 20–
30% of midazolam & cause profound sedation in patients with renal
impairment.
Diazepam forms two active metabolites,
oxazepam and desmethyl diazepam, that prolong
its effect.
VOLATILE ANESTHETIC AGENTS
The speed of emergence is Hypoventilation lengthens

directly related to alveolar the time taken to exhale
ventilation and inversely the anesthetic agent and
related to blood gas delays recovery.
solubility.
NEUROMUSCULAR BLOCKERS
Residual NMB results in paralysis that is indistinguishable
from delayed awakening though the patient is conscious &
1 aware. This occurs secondary to absolute or relative overdose
or incomplete reversal of nondepolarizing muscle relaxants or
in a patient with suxamethonium apnea.
Inability to maintain head lift for 5 s in a patient
indicates residual NMB of >30% of receptors. The patient
2 may become distressed or agitated, typically twitchy
movements of partial reversal may also be seen.
A large number of pharmacological interactions with

3 neuromuscular blocking agents prolong NMB.
ISSUES OF
AMINOPHYLLINE.....
Aminophylline is a derivative of methylxanthine. Mx’s
antagonise adenosine (a nonselective
adenosine receptor antagonist) which is a NT in
the adenosinergic neuromodulater system in the
CNS.1
Aminophylline has excitatory effects on neuronal
activity, and stimulates the CNS to induce vigilance
and increase the time spent awake.2
Turan et al (2004) hypothesize that modulation of the
adenosine function may be one of the mechanisms
of action for some anesthetic drugs.1
The mechanism for the antihypnotic effect of
aminophylline is thought to be suppression of central
adenosine receptors.3
1. Turan, A., Memis, D., Karamanlyoalu, B., Pamukcu, Z., Sut, N, 2004. Effect of aminophylline on bispectral index. Acta Anaesthesiol Scand, 48, 408-411.
2. Moon, S., Baik, H.J., 2018. Aminophylline and Ephedrine, but Not Flumazenil, Inhibit the Activity of the Excitatory Amino Acid Transporter 3 Expressed in
Xenopus Oocytes and Reverse the Increased Activity by Propofol. Hindawi BioMed Research International, 2018, 1010.
3. Turan, A., Kasuya, Y., Govinda, R., Obal, D., Rauch, S., Dalton, J.E., Acka, O., Sessler, D.I., 2010. The Effect of Aminophylline on Loss of Consciousness,
Bispectral Index, Propofol Requirement, and Minimum Alveolar Concentration of Desflurane in Volunteers. International Anesthesia Research Society, 110,
CELLULAR PHARMACODYNAMIC OF
AMINOPHYLLINE
The methylxantines cAMP is the

inhibit postsynaptic second
phosphodiesterase messenger in alpha
(PDE), the enzyme that adrenergic stimulation
degrades cAMP to AMP system whose clinical
and thus increase effects are similar to
cAMP. adrenergic stimulation.
Aghabklooei, A, 2018. The Efficacy of Aminophylline in Raising Consciousness in Benzodiazepines-Intoxicated Patients. Asia Pac J Med
1
Trevor, Anthony J., Katzung, Betram G., Kruidering-Hall, Marieke., 2015. Pharmacology Examination & Board Review – Possible mechanism of β agonists,
muscarinic antagonist, theophylline, and leukotriene antagonists in altering bronchial tone in asthma. Mc Graw Hill. 171.
AC : adenylyl cyclase, PDE : phosphodiesterasec.
UNDERSTANDING
OF PDE
• Phosphodiesterase is
responsible for
degradation of
intracellular cAMP
(cyclic adenosine
monophosphate).2
1. Omori, Kenji., Kotera, Jun., 2006. Overview of PDEs and Their Regulation. Molecular and Physiological Characteristics of PDEs. Circulation Research, 309-
327.
UNDERSTANDING OF ADENOSINE
• Adenosine is present in all cells and its receptors are
distributed in all brain cells.1
• Change in adenosine function may be one of the
mechanisms of action for some anesthetics.1
• Four subtypes of adenosine receptors are expressed in the
CNS : A1, A2A, A2B and A3. Several lines of evidence
indicate that both A1R and A2AR subtypes promote sleep.
A1 and A2A receptors modulate cortical ACh release,
• The mechanism
behavioral arousal,for the and antihypnotic
sleep. 1 effect of aminophylline
is thought to be suppression of adenosine receptors in the
CNS. 2
1. Ghaffaripour S, Khosravi M.B, Rahimi A, Sahmedini M.A, Chohedri A, Mahmoudi H, Kazemi, M.R, 2014. The effects of aminophylline on clinical recovery
and bispectral index in patients anesthetized with total intravenous anaesthesia. Pak J Med Sci, 30(6), 1351-1355.
2. Turan, A., Kasuya, Y., Govinda, R., Obal, D., Rauch, S., Dalton, J.E., Acka, O., Sessler, D.I., 2010. The Effect of Aminophylline on Loss of Consciousness,
Bispectral Index, Propofol Requirement, and Minimum Alveolar Concentration of Desflurane in Volunteers. International Anesthesia Research Society, 110,
MSN : MEDIUM SPINY NEURONS
Huang, Zhi-Li., Urade, Yoshihiro., Hayaishi, Osamu., 2011. The Role of Adenosine in the Regulation of Sleep. Current Topics in Medicinal Chemistry, 11, 1047-1057.
MOLECULAR MECHANISM OF SLEEP–WAKE
REGULATION
Huang, Zhi-Li., Urade, Yoshihiro., Hayaishi, Osamu., 2011. The Role of Adenosine in the Regulation of Sleep. Current Topics in Medicinal Chemistry, 11, 1047-1057.c
VLPO neurons were inhibited uniformly by two
arousal neurotransmitters, noradrenaline and
acetylcholine
Both the adenosine A1 receptor (A1R)

and A2AR are involved in sleep
induction
• The endogenous somnogen PGD2 (green) is produced by L-PGDS, circulates
within the CSF, stimulates DP1R (light blue) on the ventral surface from the
basal forebrain to the hypothalamus, and increases the level of extracellular
adenosine.
• Adenosine (purple) diffuses into the brain parenchyma as the secondary
somnogen, inhibits arousal neurons in the basal forebrain (orange area) and
TMN (red area) via A1R (blue lines), and activates sleep–active VLPO neurons
(blue area) via A2AR (red arrows) to induce sleep.
• The flip–flop switch of sleep–wakefulness regulation between the VLPO and
TMN is stabilized by their OX/Hcrt mediated activation and adenosine A1R-
mediated suppression.
Ach: Acetylcholine; EP4: Prostaglandin E2 receptor, subtype EP4; H1R: Histamine H1 receptor; Hcrt: Hypocretin; L-PGDS: Lipocalin-type prostaglandin D
synthase; Ox: Orexin; TMN: Tuberomammillary nucleus; VLPO: Ventrolateral preoptic area. Adapted and modified from Urade and Hayaishi [5] with
permission.
DOES AMINOPHYLLINE REVERSE ANESTHESIA AGENTS ?
Aminophylline has been used successfully as

diazepam, midazolam, barbiturate, and ketamine
antagonists in surgical patients.1
Central effects of aminophylline, such as the
excitatory effects on neuronal activity and CNS
stimulation, antagonism of the sedative effects of
several anesthetics.2
In previous studies aminophylline has been
shown to be effective in improving recovery from
volatile anesthetics by using eye opening, time to
extubation, response to command & perform 3
simple arithmetic calculations, however, BIS
values were not evaluated.2
1. Turan, A., Memis, D., Karamanlyoalu, B., Pamukcu, Z., Sut, N, 2004. Effect of aminophylline on bispectral index. Acta Anaesthesiol Scand, 48, 408-411.
2. Moon, S., Baik, H.J., 2018. Aminophylline and Ephedrine, but Not Flumazenil, Inhibit the Activity of the Excitatory Amino Acid Transporter 3 Expressed in
Xenopus Oocytes and Reverse the Increased Activity by Propofol. Hindawi BioMed Research International, 2018, 1010.
DOES AMINOPHYLLINE REVERSE NMBA ?
Theophylline has been reported to enhance resting calcium

concentrations in skeletal muscles by antagonizing adenosine
receptors and subsequently enhancing twitch tension upon
electrical stimulation in animals.
Its action on skeletal muscles to counteract fatigue and /or
paralysis is through increasing acetylcholine release from
motor nerve ending and increasing calcium concentrations
within the muscle fiber itself. These combined effects
therefore can antagonize nondepolarizing neuromuscular
blockers through competitive antagonism in generally
anesthetized patients.
El-Hamamsy, M.M.E., Botros, J.M., Yassen, H.M., Mohammed, M.I, 2018. Effect of Aminophylline on Atracurium Induced Neuromuscular Block. The Egyptian
Journal of Hospital Medicine, 71 (5), 3254-3260.
DOES AMINOPHYLLINE REVERSE NMBA ?
It had been reported to enhance diaphragmatic contractility and
enhance neurotransmitter release at the motor nerve terminals in
animals. So, it has been used recently in anesthesia to antagonize
the neuromuscular blocking effect of non-depolarizing
neuromuscular blockers. It had been reported that theophylline
antagonizes the effect of pancuronium.
Theophylline antagonizes atracurium induced neuromuscular

blockade by several mechanisms either at the prejunctional or
postjunctional level by AR antagonism or PDI or by RyR channel
activation.
El-Hamamsy, M.M.E., Botros, J.M., Yassen, H.M., Mohammed, M.I, 2018. Effect of Aminophylline on Atracurium Induced Neuromuscular Block. The Egyptian
Journal of Hospital Medicine, 71 (5), 3254-3260.
BISPECTRAL INDEX (BIS)
• The main role of bispectral index (BIS), which
was developed from a processed
electroencephalogram, is measuring depth of
anesthesia and adjusting
• The bispectral indexthe dosage
ranges of 0sedating
from to 100. It is
medications.
believed that there is a relationship between the
BIS and responsiveness. A score of 95 to 100
correlates with an awake state and zero shows
no EEG• During
activity.general anesthesia, a BIS index of less
than 55 is recommended. Intense surgical
stimulation increases the BIS and also heart rate
and blood pressure.
Ghaffaripour S, Khosravi M.B, Rahimi A, Sahmedini M.A, Chohedri A, Mahmoudi H, Kazemi, M.R, 2014. The effects of aminophylline on clinical recovery and
bispectral index in patients anesthetized with total intravenous anaesthesia. Pak J Med Sci, 30(6), 1351-1355.
BISPECTRAL INDEX
(BIS)
BIS values :
• 65 – 85 have been
recommended for sedation
• 40 – 65 have been
recommended for general
anesthesia
• <40 : cortical suppression
becomes discernible in a
raw encephalogram as a
burst pattern
EVIDENCE BASED MEDICINE
STEPS OF EVIDENCE BASED MEDICINE
Melakukan
Mencari
Identifikasi Dan
Formulasi Masalah
Bukti
Critical
dengan Jurnal
Menyusun
Pertanyaan Klinik
Penelitian
Appraisal
(PICO)
Me
ner
apk
an
Buk
ti
Ter
bai
k
unt
uk
pas
ien
(me
ngi
nte
gra
sik
an
buk
ti
ter
bai
k,
pen
get
ahu
an
dan
ket
ram
pila
n
klin
ik
dan
nila
i/pe
rti
mb
ang
an
pas
ien)
PICO
Patient / Patient who are scheduled for

Problem elective surgery with General
Anesthesia
Intervention Aminophylline
Comparison Placebo
Outcome Improving recovery time from
GA
PICO
PATIENT : 92 adult male & female patients, ages 18-50 years
old and American Society of Anesthesiologists (ASA) physical
status I and II, who were scheduled for elective
herniorrhaphy with a duration of less than one hour were
enrolled in this study
INTERVENTION : 4mg/kg of aminophylline at the end of
surgery
COMPARISON : placebo
OUTCOME : BIS, time to eye opening in response to vocal

request, time to extubation and response to command (hand
squeezing)
CLINICAL QUESTION
Does aminophylline administration is
more effective than placebo in improving
BIS, time to eye opening (in response to
vocal request), time to extubation and
response to command (hand squeezing) ?
CRITICAL APPRAISAL
APPLICABLE VALIDITY
IMPORTANCE
VALIDITY
I. APAKAH KELOMPOK PERLAKUAN DAN KELOMPOK
KONTROL TERWAKILI (REPRESENTATIVE) DAN SEBANDING ?
A. Apakah pemilihan subjek dilakukan secara random ?
YES √
VALIDITY
B. Apakah kedua kelompok tersebut sama dan sebanding sejak

awal penelitian ?
YES √
VALIDITY
1. APAKAH KELOMPOK PERLAKUAN DAN KELOMPOK
C. Apakah kedua kelompok mendapatkan perlakuan yang sama

(di luar perlakuan eksperimen yang akan dibandingkan)?
YES √
VALIDITY
II. APAKAH PENGUKURANNYA AKURAT?
A. Apakah menggunakan single blind / double blind (baik subjek

dan investigator tidak mengetahui treatment yang diberikan
kepada tiap subjek)?
YES √
VALIDITY
B. Apakah outcome penelitian diukur dengan cara yang sama

pada seluruh kelompok ?
YES √
VALIDITY
III. APAKAH KELOMPOK KONTROL MEMPEROLEH PLASEBO ?
YES √
VALIDITY
IV. APAKAH HASILNYA KARENA FAKTOR PELUANG ?
P
value √
CI √
INTERVAL KEPERCAYAAN (CONFIDENCE
INTERVAL)
Adalah perhitungan estimasi dari rentang nilai, yang

nilai sesungguhnya berada dalam rentang tersebut. Jika
rentang CI kelompok kontrol dan perlakuan sempit dan
tidak overlap, kita yakin bahwa hasil tersebut real. Jika
hasil rentang nilai tersebut lebar dan saling overlapping
maka kita tidak yakin bahwa hasilnya real.
Kelemahan
Kelemahan: :peneliti
penelititidak
tidakmenyebutkan
menyebutkanrentang
rentangCI
CI
kelompok
kelompokkontrol
kontroldan
danperlakuan
perlakuanpada
padajurnal
jurnaltersebut,
tersebut,hanya
hanya
ada
adarentang
rentangCICIpada
padamasing2
masing2variable.
variable.
IMPORTANCE
A. Seberapa besarkah efek terapi tersebut ?
• Relative Risk (RR)

• Absolute Risk Reduction (ARR)
• Number Need to Treat (NNT)  membutuhkan data
pasien yang meninggal dalam waktu 2 tahun setelah
perlakuan
• Number Need to Harm (NNH)
IMPORTANCE
Meningga Hidup Jumlah

l
Perlakuan ya Tidak ada Tidak ada 46
(kelompok data data
perlakuan)
Perlakuan tidak Tidak ada Tidak ada 46
(kelompok
Pada jurnalkontrol) data
ini tidak didapatkan data pasien yang meninggal
data
Pada jurnal ini tidak didapatkan data pasien yang meninggal
dalam
dalamkurun
kurunwaktu
waktu22tahun
tahunsetelah
setelahmendapatkan
mendapatkanperlakuan
perlakuan
APPLICABLE
Apakah pada pasien kita terdapat YA TIDAK

perbedaan bila dibandingkan dengan
yang terdapat pada penelitian sehingga
hasil penelitian tersebut tidak dapat
diterapkan pada pasien kita ? √
Usia
√
Comorbidity/ASA
Jenis operasi √
Durasi operasi √
APPLICABLE
Apakah obat tersebut dapat diterapkan YA TIDAK

pada pasien kita (our setting) ?
Kondisi demografis yang berbeda ?
√
Setting klinis yang berbeda (di RS/IGD) ?
√
Obat tersebut tersedia di tempat kita ?
Melakukan monitoring setelah √
menggunakan obat tersebut ? √
Pasien bersedia diberikan terapi obat
tersebut ? √
PICO
PATIENT : Patients aging 20-50 years old have undergone
elective surgeries expected to be about one-hour duration, with
American society of Anesthesiology (ASA) classification I and II
physical status.
INTERVENTION : theophylline 5 mg/kg over 10 minutes with
induction of anesthesia, and if TOFR has not returned to a value
of >90% at the end of the operation, intravenous atropine 0.02
mg/kg and Neostigmine 0.035 mg/kg were given.
COMPARISON : Neostigmine 0.035 mg/kg and Atropine 0.02

mg/kg at the end of operation (control)
OUTCOME : time to return of the four twitches of TOF & time
to the return of TOFR to 25%, 50% and 75% of its value
CLINICAL QUESTION
• Does theophylline administration could
facilitating the recovery from atracurium induced
neuromuscular blockade ?
VALIDITY
A. Apakah pemilihan subjek dilakukan secara random ?
YES √
VALIDITY
B. Apakah kedua kelompok tersebut sama dan sebanding sejak

awal penelitian ?
YES √
VALIDITY
1. APAKAH KELOMPOK PERLAKUAN DAN KELOMPOK
C. Apakah kedua kelompok mendapatkan perlakuan yang sama

(di luar perlakuan eksperimen yang akan dibandingkan)?
YES √
VALIDITY
A. Apakah menggunakan single blind / double blind (baik subjek

dan investigator tidak mengetahui treatment yang diberikan
kepada tiap subjek)?
Not mentioned
VALIDITY
B. Apakah outcome penelitian diukur dengan cara yang sama

pada seluruh kelompok ?
YES √
VALIDITY
III. APAKAH KELOMPOK KONTROL MEMPEROLEH PLASEBO ?
YES √
VALIDITY
P
value √
CI -
VALIDITY
P
value √
CI -
IMPORTANCE
A. Seberapa besarkah efek terapi tersebut ?
• Relative Risk (RR)

• Absolute Risk Reduction (ARR)
• Number Need to Treat (NNT)  membutuhkan data
pasien yang meninggal dalam waktu 2 tahun setelah
perlakuan
• Number Need to Harm (NNH)
IMPORTANCE
Meningga Hidup Jumlah

l
Perlakuan ya Tidak ada Tidak ada 30
(kelompok data data
perlakuan)
Perlakuan tidak Tidak ada Tidak ada 30
(kelompok kontrol) data data
Pada
Padajurnal
jurnalini
initidak
tidakdidapatkan
didapatkandata
datapasien
pasienyang
yangmeninggal
meninggal
dalam
dalamkurun
kurunwaktu
waktu22tahun
tahunsetelah
setelahmendapatkan
mendapatkanperlakuan
perlakuan
APPLICABLE
Apakah pada pasien kita terdapat YA TIDAK

perbedaan bila dibandingkan dengan
yang terdapat pada penelitian sehingga
hasil penelitian tersebut tidak dapat
diterapkan pada pasien kita ? √
Usia
√
Comorbidity/ASA
Jenis operasi √
Durasi operasi √
APPLICABLE
Apakah obat tersebut dapat diterapkan YA TIDAK

pada pasien kita (our setting) ?
Kondisi demografis yang berbeda ?
√
Setting klinis yang berbeda (di RS/IGD) ?
√
Obat tersebut tersedia di tempat kita ?
(theophylline intravena tidak tersedia) √
Melakukan monitoring setelah
menggunakan obat tersebut ? √
Pasien bersedia diberikan terapi obat
tersebut ? √
CONCLUSION
• Aminophylline improves early recovery and BIS values after
general anesthesia.
• Mechanisms which demonstrate theophylline action in
improving muscle contraction, include :
1. Antagonism of adenosine A1 receptors at the presynaptic
membrane
2. PDE inhibition leading to increase intracellular cAMP
3. RyR channel activation in the motor nerve ending
All these mechanisms lead to increase acetylcholine release
that competes with atracurium.
• The journal aboves are appropriate and valid for applying to
our patients.

Journal Reading Aminophylline

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Journal Reading Aminophylline

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JOURNAL READING :

PPDS : Kinanti Narulita Dewi

anesthesia agent’s reversal

EBM Bispectral Index

“Recovery from anesthesia may be defined as a state of

Direct sedation through opioids receptor also

The speed of emergence is Hypoventilation lengthens

A large number of pharmacological interactions with

The methylxantines cAMP is the

Both the adenosine A1 receptor (A1R)

Aminophylline has been used successfully as

Theophylline has been reported to enhance resting calcium

Theophylline antagonizes atracurium induced neuromuscular

Patient / Patient who are scheduled for

OUTCOME : BIS, time to eye opening in response to vocal

A. Apakah pemilihan subjek dilakukan secara random ?

B. Apakah kedua kelompok tersebut sama dan sebanding sejak

C. Apakah kedua kelompok mendapatkan perlakuan yang sama

A. Apakah menggunakan single blind / double blind (baik subjek

B. Apakah outcome penelitian diukur dengan cara yang sama

Adalah perhitungan estimasi dari rentang nilai, yang

A. Seberapa besarkah efek terapi tersebut ?

• Relative Risk (RR)

Meningga Hidup Jumlah

Apakah pada pasien kita terdapat YA TIDAK

Apakah obat tersebut dapat diterapkan YA TIDAK

COMPARISON : Neostigmine 0.035 mg/kg and Atropine 0.02

B. Apakah kedua kelompok tersebut sama dan sebanding sejak

C. Apakah kedua kelompok mendapatkan perlakuan yang sama

A. Apakah menggunakan single blind / double blind (baik subjek

B. Apakah outcome penelitian diukur dengan cara yang sama

A. Seberapa besarkah efek terapi tersebut ?

• Relative Risk (RR)

Meningga Hidup Jumlah

Apakah pada pasien kita terdapat YA TIDAK

Apakah obat tersebut dapat diterapkan YA TIDAK

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