Targeted Temperature

Management

Kyle Starkus, PharmD

PGY1 Resident
Ascension St. Vincent Evansville
Contact: Kyle.Starkus@Ascension.org
The speaker has no financial disclosures or conflicts
of interest as it relates to this presentation
Objectives

1. Identify the indication for targeted temperature management (TTM)

2. Describe the stages of TTM

3. Detail the pharmacotherapeutic management involved in TTM

4. Apply pharmacokinetic and pharmacodynamic principles in the context of

global hypothermia

2
What is Targeted Temperature Management?

● Targeted temperature management (TTM) is a management strategy post

cardiac arrest with the aim of decreasing mortality and improving neurological
outcomes

● Goal of therapy is to reduce and maintain the core body temperature in

comatose patients successfully resuscitated after cardiac arrest

● What does this have to do with pharmacists?

Peberdy, Mary Ann, et al. “Part 9: Post–Cardiac Arrest Care.”

Circulation, vol. 122, no. 18_suppl_3, 2010, 3
https://doi.org/10.1161/circulationaha.110.971002.
Arrhythmias
Asystole | Ventricular tachycardia | Ventricular fibrillation

(A)

(B)

(C)
Images: https://ecgwaves.com/lesson/arrhythmias-and-arrhythmology/
Cardiac Arrest Overview

● Cardiac arrest is defined by the sudden, unexpected loss of heart function,

breathing, and consciousness
○ 70% - 90% mortality rate in individuals with out-of-hospital cardiac arrest (OHCA)

● Treatment:
○ Advanced cardiac life support (ACLS) algorithm
■ Cardiopulmonary resuscitation (CPR)
■ Defibrillation*
■ Epinephrine
■ Amiodarone / lidocaine / treat reversible causes

“Algorithms.” Cpr.heart.org, https://cpr.heart.org/en/resuscitation-science/cpr-and-ecc-guidelines/algorithms.

5
Cardiac Arrest Infographic - Centers for Disease Control ...
https://www.cdc.gov/dhdsp/docs/cardiac-arrest-infographic.pdf.
Image: 6
https://www.ahajournals.org/doi/full/10.116
1/circulationaha.110.971002
 7
Image:
https://www.uncmedicalcenter.org/app/files/public/796fa281-cbe6-4d52-bfa
2-ed633c987dc2/pdf-medctr-alsprograms-2015ACLSUpdates-ROSC.pdf
Cerebral Anoxia

● Cardiac arrest results in cerebral anoxia, leading to adverse outcomes and

eventual death

● Within minutes of anoxia aerobic cellular respiration ceases

○ Loss of calcium hemostasis
○ Sustained and excess release of glutamate

● The cerebral metabolic rate decreases by 5-7% for every 1℃ decrease in body
temperature
Omairi, Ahmad M. “Targeted Hypothermia Temperature Management.”
StatPearls [Internet]., U.S. National Library of Medicine, 1 Jan. 2021, 8
https://www.ncbi.nlm.nih.gov/books/NBK556124/.
Reperfusion Injury

● Occurs over hours to days post return of spontaneous circulation (ROSC)

● Re-oxygenation results in increased reactive oxygen species and post- cardiac

arrest inflammatory cascade
○ Result in endothelial dysfunction and paradoxical tissue-level hypoxia

● Targeted temperature management is proposed to reduce the inflammatory

cascade, the release of excitatory amino acids and the amount of free radicals

Scirica MD, Benjamin M., et al. “Therapeutic Hypothermia after Cardiac

Arrest.” Circulation, 15 Jan. 2013,
9
https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.111.076851.
Mechanism of Anoxia Mediated Cell Death

Image: Mechanisms Contributing to Tissue ... - Researchgate.net.

https://researchgate.net/figure/Mechanisms-contributing-to-tissue-injury-in-is
chemia-reperfusion-I-R-Cellular_fig1_263291687.
Indication for Targeted Temperature Management
● A 2015 systematic review by the International Liaison Committee on Resuscitation
(ILCOR) found evidence to support TTM in adult patients with ROSC:

○ After OHCA with an initially shockable rhythm

■ (Strong recommendation, low-quality evidence)

○ After OHCA with an initially non shockable rhythm

■ (Weak recommendation, very low-quality evidence)

○ After in-hospital cardiac arrest (IHCA) with any initial rhythm

■ (Weak recommendation, very low-quality evidence)

Donnino, Michael W., et al. “Temperature Management after Cardiac

Arrest.” Circulation, 4 Oct. 2015,
11
https://www.ahajournals.org/doi/10.1161/CIR.0000000000000313.
Continued

ILCOR Recommendations
● Pre-hospital induction of mild hypothermia did not reduce poor neurological
outcomes or mortality
○ Based on 7 RCTs using rapid infusion of cold intravenous fluid
○ Increased risk of pulmonary edema

● No data that can be used to compare different durations of targeted

temperature management on outcomes
○ Recommend at least 24 hours based on two large RCTs (low quality evidence)

● Recommend target temperature of 32℃ - 36℃

○ Temperature target should be selected and maintained with minimal fluctuation
Donnino, Michael W., et al. “Temperature Management after Cardiac
Arrest.” Circulation, 4 Oct. 2015,
12
https://www.ahajournals.org/doi/10.1161/CIR.0000000000000313.
TTM Inclusion and Exclusion Criteria

● Inclusion:
○ Intubated and treatment initiated within 6 hours after cardiac arrest
○ Able to maintain a systolic blood pressure (BP) > 90 mmHg
○ In a coma at the time of cooling

● Exclusion
○ Intracranial hemorrhage
○ Severe hemorrhage leading to exsanguination
○ Hypotension refractory to multiple vasopressors
○ Severe sepsis
○ Pregnancy

Scirica MD, Benjamin M., et al. “Therapeutic Hypothermia after Cardiac

Arrest.” Circulation, 15 Jan. 2013,
13
https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.111.076851.
Updates Since 2015

● On November 9, 2021 the American College of Cardiology (ACC) published ‘A

Contemporary Update on Targeted Temperature Management’ analyzing more
recent randomized controlled trials (RCTs)

“A Contemporary Update on Targeted Temperature Management.” American

College of Cardiology, 14
https://www.acc.org/Latest-in-Cardiology/Articles/2021/11/09/13/16/A-Contempor
ary-Update-on-Targeted-Temperature-Management.
Authors N Design Year Population Intervention vs Primary Major Findings
Control Outcomes

Lopez et al. 150 RCT 2018 Witnessed OHCA with shockable TTM at 32, 33, Favorable No significant
(FROST-1 trial) rhythms and 34℃ neurological difference in
outcome at 90 primary outcome
days between study
groups

Lascarrour et al. 581 RCT 2019 OHCA and IHCA with non- shockable TTM at 33℃ vs Survival with a Significantly
(HYPERION trial) rhythms normothermia CPC of 1 or 2 at improved survival
90 days with a CPC of 1
or 2 in
hypothermia
group but no
difference in
overall mortality

Dankiewicz et al. 1861 RCT 2021 OHCA with a presumed cardiac TTM at 33℃ vs. Death from any No significant
(TTM2 trial) cause targeted cause at 6 difference
normothermia months between groups

Abbreviation: CPC - Cerebral Performance

“A Contemporary Update on Targeted Temperature Management.” American College of
Category Cardiology,
https://www.acc.org/Latest-in-Cardiology/Articles/2021/11/09/13/16/A-Contemporary-Update-on-Ta
rgeted-Temperature-Management.
The ACC’s Take
● The TTM2 trial failed to show mortality or neurological benefit to targeted
temperature management at 33℃ compared to normothermia (50% vs. 48%,
P= 0.37)
○ Largest related RCT at 1861 patients
○ Met 90% power
○ Higher risk of arrhythmia in hypothermia treated patients

● “Routine use of targeted hypothermia may no longer be necessary”

● Concerns?
○ 46% of patients received active cooling in the normothermia group
○ >90% of cardiac arrests were witnessed and ~80% received bystander CPR
○ Risk vs. benefit?
Question for the Audience

● Senario: You are a researcher for a pharmaceutical company that has just
developed a new chemotherapy medication to treat a previously untreatable
cancer that has no alternative therapies available
○ You are designing your phase III trial to have your medication approved for market
and have decided to set your alpha (risk of type I error) at 0.15 instead of the gold
standard 0.05

● Why would it be more acceptable to have a lenient alpha in this

particular study?

17
Phases of Targeted Temperature Management

Induction | Maintenance | Re-warming | Return to normothermia

Scirica MD, Benjamin M., et al.

“Therapeutic Hypothermia after Cardiac
Arrest.” Circulation, 15 Jan. 2013
Initiation
● Initiation should be started as soon as possible (but not pre-hospital) with a
target temperature of 32 - 36℃
○ ~20% increase in mortality for every hour of delay

● Methods of induction
○ Ice bags and cooling blankets
○ Temperature-regulated surface
○ Endovascular devices
○ Extracorporeal circulation (ECMO)

● Two methods of temperature measurement

○ Bladder | esophageal | rectal | groin | axillary
Scirica MD, Benjamin M., et al. “Therapeutic Hypothermia after
Cardiac Arrest.” Circulation, 15 Jan. 2013, 19
https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.1
11.076851.
Endovascular Device

Image: Dae, Michael W., et al. “Safety and Efficacy of Endovascular

Cooling and Rewarming for Induction and Reversal of Hypothermia
in Human-Sized Pigs.” Stroke, 13 Feb. 2003,
https://www.ahajournals.org/doi/full/10.1161/01.STR.0000057461.5
6040.FE.
Continued

Initiation - Shivering

● The result of core temperature being lower than the hypothalamic set point
○ Skin temperature contributes ~20% to the control of shivering

● Assess shivering regularly

○ Mild - facial tremors
○ Moderate - extremity tremors
○ Severe - full body tremors

● Non-pharmacological treatment?

“Shivering Treatments for Targeted Temperature Management: A ... : Journal of Neuroscience Nursing.” LWW,
https://journals.lww.com/jnnonline/fulltext/2018/04000/shivering_treatments_for_targeted_temperature.4.aspx.
21
Continued

Initiation - Shivering

● Magnesium sulfate
○ Reduced smooth muscle tone
○ Target levels of 3-4 mg/dL
● Analgesics
○ Hydromorphone
○ Fentanyl
○ Meperidine*
● Alpha-agonists
○ Dexmedetomidine
■ Challenges?

“Shivering Treatments for Targeted Temperature Management: A ... : Journal of Neuroscience Nursing.” LWW,
https://journals.lww.com/jnnonline/fulltext/2018/04000/shivering_treatments_for_targeted_temperature.4.aspx.
22
Continued

Shivering - Pharmacotherapeutics

● Anesthetics / Sedatives
○ Midazolam
○ Propofol
● Serotonin agonists
○ Buspirone
○ 30mg combination with low-dose meperidine (25 - 50mg)?
● Antipyretics
○ Acetaminophen, aspirin, NSAIDs
○ May block endogenous pyrogens through COX-mediated prostaglandin synthesis

“Shivering Treatments for Targeted Temperature Management: A ... : Journal of Neuroscience Nursing.” LWW,
https://journals.lww.com/jnnonline/fulltext/2018/04000/shivering_treatments_for_targeted_temperature.4.aspx.
23
Continued

Initiation - Shivering

● Neuromuscular blocking agents (NMBA)

○ Rocuronium | Nimbex | Vecuronium | Pancuronium
○ A prospective comparative study found rocuronium to have a faster onset of action
and faster spontaneous recovery rate compared to Nimbex
○ Small randomized double-blind study (n=30) found vecuronium to be better for
reduction of shivering than pancuronium
■ Pancuronium group had higher incidence of increase in heart rate (HR) and increase in
myocardial oxygen consumption

● NMBA use is associated with prolonged length of stay, prolonged mechanical

ventilation, and increased risk of ventilator-associated pneumonia

Adamus M;Belohlavek R;Koutna J;Vujcikova M;Janaskova E; “Cisatracurium vs. Rocuronium: A Prospective, Comparative, Randomized Study in Adult Patients under Total
Intravenous Anaesthesia.” Biomedical Papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia, U.S. National Library of Medicine,
https://pubmed.ncbi.nlm.nih.gov/17426802/.
24
Anesthesia, Department of. “Pancuronium or Vecuronium for Treatment of Shivering after... : Anesthesia & Analgesia.” LWW,
https://journals.lww.com/anesthesia-analgesia/Abstract/1994/09000/Pancuronium_or_Vecuronium_for_Treatment_of.12.aspx.
Continued

Shivering - Our Protocol

25
Richmond Agitation Sedation Scale -
Garden City Hospital.
https://www.gch.org/documents/rich
mond-agitation-sedation-scale.pdf.
Sedation / Ventilation - Our Protocol
Maintenance
● Recommended duration of at least 24 hours with the a targeted temperature
between 32 - 36℃

● Temperature fluctuations recommended to be minimized to <0.5℃

● Monitor heart rate

○ Only treat if associated with hemodynamic instability
○ Epinephrine | Norepinephrine
■ Norepinephrine preferred for being more alpha receptor selective

Scirica MD, Benjamin M., et al. “Therapeutic Hypothermia after Cardiac

Arrest.” Circulation, 15 Jan. 2013,
28
https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.111.076851.
Continued

Maintenance
● Monitor mean arterial pressure (MAP)
○ Goal of >90 mmHg | 65-100 mmHg have been studied
○ MAP = DP + ⅓(SP - DP)

● Central venous pressure

○ Goal 10 - 12 mmHg

● Oxygenation
○ Avoid hyper/hypoventilation
○ Goal saturation of 94-96%
○ Why not 100%?

Scirica MD, Benjamin M., et al. “Therapeutic Hypothermia after Cardiac

Arrest.” Circulation, 15 Jan. 2013,
29
https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.111.076851.
Continued

Maintenance - Electrolyte Repletion

● BMP should be drawn every 4 hours and replete abnormalities as appropriate

○ What relevant electrolyte is missing from a BMP?

● Potassium influx when cooling | Eflux when warming

○ Hold replacement 4 hours prior to warming

Scirica MD, Benjamin M., et al. “Therapeutic Hypothermia after Cardiac

Arrest.” Circulation, 15 Jan. 2013,
30
https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.111.076851.
Continued

Maintenance - Glucose Control

● Cooling decreases insulin secretion and increases insulin resistance

● Monitor every hour while cooling

○ Every 30 minutes if blood glucose (BG) < 80 mg/dL at any point

● Only start insulin infusion if BG > 200 mg/dL

○ Unless type 1 diabetic (T1DM)

Scirica MD, Benjamin M., et al. “Therapeutic Hypothermia after Cardiac

Arrest.” Circulation, 15 Jan. 2013,
31
https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.111.076851.
Continued

Maintenance - Infection

● Blood cultures should be drawn 12 hours after initiation

● More than two thirds of patients who receive TTM experienced some
infectious complication

● A retrospective review of 2803 patients demonstrated no mortality benefit

between those who received antibiotics within the first two days of TTM and
those who did not
Scirica MD, Benjamin M., et al. “Therapeutic Hypothermia after Cardiac Arrest.” Circulation, 15 Jan. 2013,
https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.111.076851
32
Tagami, Takashi, et al. “Early Antibiotics Administration during Targeted Temperature Management after out-of-Hospital
Cardiac Arrest: A Nationwide Database Study.” BMC Anesthesiology, BioMed Central, 7 Oct. 2016,
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5055699/.
Continued

Maintenance - Miscellaneous

● Seizure risk associated with lower goal temperatures

○ EEG after initiation of TTM
○ EEG STAT if any suspicion of seizure

● Skin care
○ Risk of burns depending on cooling method
○ Inspect skin every two hours

Scirica MD, Benjamin M., et al. “Therapeutic Hypothermia after Cardiac

Arrest.” Circulation, 15 Jan. 2013,
33
https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.111.076851.
Rewarming
● Begin 24 hours after the initiation of cooling

● Slow rewarming of 0.25℃ every hour until return to normothermia

○ 12 - 16 hours

● Maintain paralytic (if used) and sedation until threshold of 36℃

● Monitoring of hypotension, hyperkalemia, and hypoglycemia

○ Stop insulin infusion when glucose <200 mg/dL

● Maintain normothermia to avoid reflexive hyperthermia for at least 48 hours

○ Associated with worse neurological outcomes
Donnino, Michael W., et al. “Temperature Management after Cardiac Arrest.” Circulation, 4 Oct. 2015,
https://www.ahajournals.org/doi/10.1161/CIR.0000000000000313.
34
Scirica MD, Benjamin M., et al. “Therapeutic Hypothermia after Cardiac Arrest.” Circulation, 15 Jan. 2013,
https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.111.076851.
A Unique Pharmacotherapeutic Consideration

● TTM with goal temperatures recommended as low as 32℃ changes the

physiological landscape
○ Pharmacokinetic
○ Pharmacodynamic

35
Effects of Hypothermia on Drug Disposition, Metabolism,
and Response: A Focus of Hypothermia-mediated
Alterations on the Cytochrome P450 Enzyme System
● Systematic review to assess alterations in sedative and analgesic therapeutics
elimination, disposition and response

● Cytochrome P450 (CYP) enzymes are hepatic monooxygenases critical in the

activation and detoxification of many medications

● Animal studies have demonstrated that cytochrome P450 activity returns to

baseline rapidly after reaching normothermia
SM;, Tortorici MA;Kochanek PM;Poloyac. “Effects of Hypothermia on Drug Disposition,
Metabolism, and Response: A Focus of Hypothermia-Mediated Alterations on the
Cytochrome P450 Enzyme System.” Critical Care Medicine, U.S. National Library of
36
Medicine, https://pubmed.ncbi.nlm.nih.gov/17855837/.
SM;, Tortorici MA;Kochanek PM;Poloyac.
“Effects of Hypothermia on Drug
Disposition, Metabolism, and Response:
A Focus of Hypothermia-Mediated
Alterations on the Cytochrome P450
Enzyme System.” Critical Care Medicine,
U.S. National Library of Medicine,
https://pubmed.ncbi.nlm.nih.gov/1785583
7/.
SM;, Tortorici MA;Kochanek PM;Poloyac. “Effects of Hypothermia on Drug Disposition, Metabolism, and
Response: A Focus of Hypothermia-Mediated Alterations on the Cytochrome P450 Enzyme System.” Critical
Care Medicine, U.S. National Library of Medicine, https://pubmed.ncbi.nlm.nih.gov/17855837/.
Hypothermia Effect on Midazolam
● Benzodiazepine

● Exclusively metabolized by CYP3A4 and 3A5

○ Active metabolite?

● Five-fold increase in plasma concentrations in body temperatures <35℃

● Pharmacokinetic analysis showed >100-fold decrease in systemic clearance

● Likely due to depressed CYP3A4 and 3A5 activity

SM;, Tortorici MA;Kochanek PM;Poloyac. “Effects of Hypothermia on Drug Disposition,
Metabolism, and Response: A Focus of Hypothermia-Mediated Alterations on the
Cytochrome P450 Enzyme System.” Critical Care Medicine, U.S. National Library of
39
Medicine, https://pubmed.ncbi.nlm.nih.gov/17855837/.
Hypothermia Effect on Fentanyl
● Primarily metabolized by CPY3A4

● High clearance medication with a large Vd (4-6 L/kg)

○ Hepatic clearance of high clearance drugs is primarily dependent on hepatic blood flow

● Studies have found hypothermia of 32 - 34℃ dramatically inhibits fentanyl metabolism by CYP3A4 in
cardiac surgery patients

● Likely reduced portal vein perfusion from decreased cardiac output contributes to the increase in
serum concentration as well - elevated levels for 6 hours after rewarming

● Blunted sedative effect of narcotics during hypothermia due to decreased affinity for the Mu opioid
receptor
SM;, Tortorici MA;Kochanek PM;Poloyac. “Effects of Hypothermia on Drug Disposition,
Metabolism, and Response: A Focus of Hypothermia-Mediated Alterations on the
Cytochrome P450 Enzyme System.” Critical Care Medicine, U.S. National Library of
40
Medicine, https://pubmed.ncbi.nlm.nih.gov/17855837/.
Hypothermia Effect on Morphine

● Hepatic glucuronidation metabolism

● Decreased affinity to the Mu opioid receptor

● Six-fold increase in the dissociation constant at 30℃

● Hypothermia likely decreases metabolism through decreased portal vein

perfusion but also decreases the pharmacodynamic response

SM;, Tortorici MA;Kochanek PM;Poloyac. “Effects of Hypothermia on Drug Disposition,

Metabolism, and Response: A Focus of Hypothermia-Mediated Alterations on the
Cytochrome P450 Enzyme System.” Critical Care Medicine, U.S. National Library of
41
Medicine, https://pubmed.ncbi.nlm.nih.gov/17855837/.
Hypothermia Effect on Propofol

● CYP2B6 and glucuronidation metabolism

● Hypothermia shown to increase concentrations by ~30%

○ Indocyanine green was administered to assess hepatic blood flow at 34℃ which
demonstrated no effect yet a 28% increase in serum concentration was measured

● Predicted to decrease partitioning between the central and peripheral

compartments
○ Hypothermia alters the concentration of drug present at the effect site

SM;, Tortorici MA;Kochanek PM;Poloyac. “Effects of Hypothermia on Drug Disposition,

Metabolism, and Response: A Focus of Hypothermia-Mediated Alterations on the
Cytochrome P450 Enzyme System.” Critical Care Medicine, U.S. National Library of
42
Medicine, https://pubmed.ncbi.nlm.nih.gov/17855837/.
Hypothermia Effect on NMBAs

● Rocuronium
○ Bile elimination
○ Duration of action increased by 5 minutes for every 1℃ below normothermia
○ ~2-fold decrease in clearance

● Vecuronium
○ Eliminated via p-glycoprotein and P40-mediated metabolism
○ Three-fold increase in the duration of action in hypothermia
○ Hypothermia reduced plasma clearance by ~11% for every 1℃
○ Decreased rate constant for equilibration between plasma and nicotinic receptors

SM;, Tortorici MA;Kochanek PM;Poloyac. “Effects of Hypothermia on Drug Disposition,

Metabolism, and Response: A Focus of Hypothermia-Mediated Alterations on the
Cytochrome P450 Enzyme System.” Critical Care Medicine, U.S. National Library of
43
Medicine, https://pubmed.ncbi.nlm.nih.gov/17855837/.
Hypothermia Effect on Antibiotics

● Recall the previous slide that showed beta-lactams, aminoglycosides, and

glycopeptides are eliminated primarily via renal excretion

● Renal clearance is decreased in the context of hypothermia as a result of

reduced cardiac output

● One animal study found the half-life of gentamicin to be increased ~1.4 fold
during hypothermia

SM;, Tortorici MA;Kochanek PM;Poloyac. “Effects of Hypothermia on Drug Disposition,

Metabolism, and Response: A Focus of Hypothermia-Mediated Alterations on the
Cytochrome P450 Enzyme System.” Critical Care Medicine, U.S. National Library of
44
Medicine, https://pubmed.ncbi.nlm.nih.gov/17855837/.
The Future of TTM
● The ACC november publication suggesting the use of targeted hypothermia
may no longer be necessary
○ Will institutions modify treatment based on the new TTM-2 trial and the
recommendation made by the ACC?

● Has gained prevalence since the 2013 American Heart Association

therapeutic hypothermia guides
○ Possibility of meta-analyses looking at specific temperature goals with specific
rhythms with specific pre-hospital care

● Possibility of new novel treatments?

45
Targeted Temperature Management

Questions?

Contact: Kyle.Starkus@Ascension.org
Resources
Peberdy, Mary Ann, et al. “Part 9: Post–Cardiac Arrest Care.” Circulation, vol. 122, no. 18_suppl_3, 2010, https://doi.org/10.1161/circulationaha.110.971002.

“Algorithms.” Cpr.heart.org, https://cpr.heart.org/en/resuscitation-science/cpr-and-ecc-guidelines/algorithms.

Cardiac Arrest Infographic - Centers for Disease Control ... https://www.cdc.gov/dhdsp/docs/cardiac-arrest-infographic.pdf.

Omairi, Ahmad M. “Targeted Hypothermia Temperature Management.” StatPearls [Internet]., U.S. National Library of Medicine, 1 Jan. 2021, https://www.ncbi.nlm.nih.gov/books/NBK556124/.

Scirica MD, Benjamin M., et al. “Therapeutic Hypothermia after Cardiac Arrest.” Circulation, 15 Jan. 2013, https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.111.076851.

“A Contemporary Update on Targeted Temperature Management.” American College of Cardiology,

https://www.acc.org/Latest-in-Cardiology/Articles/2021/11/09/13/16/A-Contemporary-Update-on-Targeted-Temperature-Management.

“Shivering Treatments for Targeted Temperature Management: A ... : Journal of Neuroscience Nursing.” LWW, https://journals.lww.com/jnnonline/fulltext/2018/04000/shivering_treatments_for_targeted_temperature.4.aspx.

Adamus M;Belohlavek R;Koutna J;Vujcikova M;Janaskova E; “Cisatracurium vs. Rocuronium: A Prospective, Comparative, Randomized Study in Adult Patients under Total Intravenous Anaesthesia.” Biomedical Papers of
the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia, U.S. National Library of Medicine, https://pubmed.ncbi.nlm.nih.gov/17426802/.

Anesthesia, Department of. “Pancuronium or Vecuronium for Treatment of Shivering after... : Anesthesia & Analgesia.” LWW,
https://journals.lww.com/anesthesia-analgesia/Abstract/1994/09000/Pancuronium_or_Vecuronium_for_Treatment_of.12.aspx.

Tagami, Takashi, et al. “Early Antibiotics Administration during Targeted Temperature Management after out-of-Hospital Cardiac Arrest: A Nationwide Database Study.” BMC Anesthesiology, BioMed Central, 7 Oct. 2016,
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5055699/.

Donnino, Michael W., et al. “Temperature Management after Cardiac Arrest.” Circulation, 4 Oct. 2015, https://www.ahajournals.org/doi/10.1161/CIR.0000000000000313.

SM;, Tortorici MA;Kochanek PM;Poloyac. “Effects of Hypothermia on Drug Disposition, Metabolism, and Response: A Focus of Hypothermia-Mediated Alterations on the Cytochrome P450 Enzyme System.” Critical Care
Medicine, U.S. National Library of Medicine, https://pubmed.ncbi.nlm.nih.gov/17855837/.

47