Haemodynamic Effects of Paracetamol (Acetaminophen) as Extended Intravenous Infusion Versus Intravenous Bolus in Septic Shock Patients
Phase: PHASE4
Conditions: Septic Shock, Sepsis
Sponsor: Ayah Mohammed Khalil

This pdf / A file is a protocol of thesis under the title
Haemodynamic Effects of Paracetamol (Acetaminophen)
as Extended Intravenous Infusion Versus Intravenous
Bolus in Septic Shock patients.
30/8/2020
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A Thesis
Under The Title
Haemodynamic Effects of Paracetamol (Acetaminophen)
as Extended Intravenous Infusion Versus Intravenous
Bolus in Septic Shock patients
Submitted by
Clinical pharmacist: Ayah Mohammed Khalil Ibrahem
B.Sc.of clinical pharmacy,Faculty of Pharmacy,Cairo university (2014)
American board pharmacotherapy certified
Supervisor clinical pharmacist in trauma and surgical emergency
kasr al ainy school of medicine
Submitted For the Master Degree in Pharmaceutical Sciences
(Clinical Pharmacy)
Under Supervision of
Prof. Dr. Zeinb El Kassapy Mahmode Zalat
Professor and Head of Clinical Pharmacy department,
Faculty of Pharmacy (Girls), Al-Azhar University
Prof.Dr.Ahmed Mohamed Mukhtar
Professor of Anesthesia , Intensive care and Pain management
Faculty of Medicine,Cairo university
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Introduction:
Sepsis, inflammatory response to infection, contributes directly or
indirectly to mortality in the majority of critically ill patients. An elevated
cardiac index and a decreased systemic vascular resistance leading to
hypotension and hypo perfusion of vital organs characterize the early stage
of septic shock. The hypotensive state is often not amenable to fluid
resuscitation alone and requires institution of vasoactive agents to counter
the profound fall in systemic vascular resistance, which is an integral
feature of septic shock [1, 2] .
Acetaminophen is the antipyretic and analgesic that is most often
given to hospitalized patients, including those in critical care units. The
mechanism of action of acetaminophen remains incompletely understood,
but the antipyretic response appears to be due to blocking cyclooxygenase-II
and inhibiting prostaglandin-II synthesis in the central nervous system [3].
Intravenous (IV) acetaminophen has gained popularity for inpatient
management of acute pain for its practical and clinical advantages. IV
administration is associated with more predictable pharmacokinetic
performance compared with rectal (30%-40% bioavailability) and oral
dosage forms of acetaminophen (60%-70% bioavailability) [4-7].
Predictable kinetics as well as ease of IV administration has made it
an especially attractive option in the critically ill patients who have altered
gut absorption secondary to numerous pathophysiological and therapeutic
influences.
IV acetaminophen has shown promise in improving patient
satisfaction, managing fever, and decreasing postoperative opioid
requirements. These features have made it one of the most widely ordered
medications within critical care and surgical services [8].
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Product information for IV acetaminophen lists mild effects such as
nausea or vomiting among the most common adverse events (incidence ≥
5%), with the estimated incidence of more serious adverse effects such as
hypotension being <1%. However, there have been an increasing number
of randomized controlled trials which indicated that the incidence of IV
acetaminophen–induced hypotension may be higher than previously
reported by manufacturers. These publications have prompted investigators
to look more closely at the possible untoward effects of IV acetaminophen
across a variety of populations. . None of these studies examined whether
the extended infusion of IV paracetamol can minimize the degree of
hypotension in critically hemodynamic unstable patients [9-10] .
Aim of the Work:
To assess the incidence of hypotension of the extended intravenous
paracetamol (acetaminophen) infusion in comparing with intravenous
paracetamol bolus in haemodynamically unstable patients (septic shock).
Hypothesis:
Extended intravenous paracetamol infusion will minimize the incidence
of hypotension compared to intravenous bolus.
Ethical considerations:
The study protocol was approved by the Research Ethics Committee
(REC), Faculty of Pharmacy (Girls), Al-Azhar University, REC.No.277.
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Methodology :
Study design: Open labeled, Paralled, Randomized, Controlled
study.
Study Setting and location: Emergency department, Intensive care
units, Cairo University Hospitals (kasr alainy), Cairo, Egypt.
Study population: Patients critically ill hemodynamically unstable
(septic shock).
Eligibility Criteria: Patients eligible for the study fulfilled the
following inclusion criteria and exclusion criteria:
Inclusion criteria:
The prescribed paracetamol will be at the discretion of the treating ICU
clinician for either fever or pain, were eligible for enrolment.
1- Age more than 18 years old
2- Patient fulfill criteria of septic shock definition:
 Sepsis need vasopressor therapy.
 Serum lactate level greater than 2 mmol/l (SSC 2016).
3- Patient with contractility greater than 40%
Exclusion criteria:
1-paracetamol hypersensitivity or allergy.
2- Acute liver injury or failure.
3-Childs-Pugh C liver disease.
4-Heat stroke.
5-Malignant hyperthermia.
6-Neuroleptic Malignant Syndrome.
7-Continous renal replacement therapy.
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8-Around the clock scheduled of acetaminophen containing medications
administration or non-steroidal anti-inflammatory drugs.
9- ventricular assist device
Study procedures
1. Randomization
Randomization will be done by computer generated numbers and
concealed by serially numbered, opaque and sealed envelopes.
2. Study protocol
After institutional ethical committee approval, patients with septic shock
will be investigated for exclusion criteria.
The recruited patients will be allocated randomly into group I (paracetamol
1 g infused over 3 hours ) , group II (paracetamol 1 g infused over 15min)
or control group ( normal saline 100ml infused over 15 min ).
Baseline values of cardiac output, blood pressure (SBP + DBP + MAP)
,temperature and vasopressor inotropic score will collect immediately
before (paracetamol or normal saline ) administration and 60 ,180, 360 min
after and need for inotropic support or intravenous fluid bolus during 360
min after administration.
3. Measurement tools
Temperature: electronic sensor
Cardiac output: cardiometry
Study outcomes:
Primary outcome
The incidence of hypotension, defined as decrease in SBP ≥ 20٪ from
baseline, by extended infusion of intravenous paracetamol.
 Secondary outcome
a. Changes in mean arterial pressure, diastolic blood pressure, cardiac
output and heart rate.
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b. Changes in the body temperature, defined as the greatest difference
in the temperature between preinfusion temperature and temperature
during 60,180,360 min after
c. Changes in vasopressor dose , defined by vasopressor infusion rate
(mcg/min)
d. Changes in need of fluid boluses.
Statistical analysis
Sample size:
Sixty patients with hemodynamic instability (septic shock) will be
enrolled in the study according to the inclusion and exclusion criteria.
Patients will be randomized into three groups each group includes 20
patients:
Control Group: Twenty patients will receive normal saline with their
standard analgesia (15 min ).
Tested Group I: Twenty patients will receive extended IV paracetamol
infusion ( 3 hours).
Tested Group II: Twenty patients will receive IV paracetamol bolus (15
min).
Statistical Methods:
SPSS statistical software package recent version.
Data will be expressed as Mean ± SD for quantitative measures and
both number and percentage for categorized data.
The probability of error at 0.05 will be considered significant, while
at 0.01 and 0.001 are highly significant.
Suitable statistical tests will be used to enable the comparison
between the results of the three study groups.
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References
1.
Sakr, Y., et al., Does dopamine administration in shock influence outcome?
Results of the Sepsis Occurrence in Acutely Ill Patients (SOAP) Study. Crit Care Med,
2006. 34(3): p. 589-97.
2.
Dellinger, R.P., et al., Surviving Sepsis Campaign: international guidelines for
management of severe sepsis and septic shock: 2008. Intensive Care Med, 2008. 34(1):
p. 17-60.
3.
Schell-Chaple, H.M., et al., Effects of IV Acetaminophen on Core Body
Temperature and Hemodynamic Responses in Febrile Critically Ill Adults :A
Randomized Controlled Trial. Crit Care Med, 2017. 45(7): p. 1199-1207.
4.
Jibril, F., et al., Intravenous versus Oral Acetaminophen for Pain: Systematic
Review of Current Evidence to Support Clinical Decision-Making. Can J Hosp Pharm,
2015. 68(3): p.47-238 .
5.
Singla, N.K., et al., Plasma and cerebrospinal fluid pharmacokinetic parameters
after single-dose administration of intravenous, oral, or rectal acetaminophen. Pain
Pract, 2012. 12(7): p. 523-32.
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Raffa, R.B., et al., Pharmacokinetics of Oral and Intravenous Paracetamol
(Acetaminophen) When Co-Administered with Intravenous Morphine in Healthy Adult
Subjects. Clin Drug Investig, 2018. 38(3): p. 259-268.
7.
Brett, C.N., S.G. Barnett, and J. Pearson, Postoperative plasma paracetamol
levels following oral or intravenous paracetamol administration: a double-blind
randomised controlled trial. Anaesth Intensive Care, 2012. 40(1): p. 166-71.
8.
Suzuki, S., et al., Paracetamol therapy and outcome of critically ill patients: a
multicenter retrospective observational study. Crit Care, 2015. 19(1): p. 162.
9.
Maxwell, E.N., et al., Intravenous Acetaminophen-Induced Hypotension: A
Review of the Current Literature. Ann Pharmacother, 2019. 53(10): p. 1033-1041.
10.
Schell-Chaple HM, Liu KD, Matthay MA, Sessler DI, Puntillo KA. Effects of
IV acetaminophen on core body temperature and hemodynamic responses in febrile
critically ill adults: a randomized controlled trial. Crit Care Med. 2017;45:1199-1207.
doi:10.1097/CCM.0000000000002340.
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