We thank Wu et al. for their thoughtful comments on our article, in which we proposed the novel concept of intraoperative use of transient receptor potential vanilloid 1 antagonists as a pharmacologic therapy for anesthesia-induced hypothermia.1  Wu et al. point out that as transient receptor potential vanilloid 1 may play a critical role in ischemia-reperfusion injury, perioperative blockade of transient receptor potential vanilloid 1 might have deleterious consequences. We believe this may not be a significant concern regarding our proposed use of intraoperative transient receptor potential vanilloid 1 antagonists for several reasons.

First, we are proposing the possibility of the use of transient receptor potential vanilloid 1 antagonists to “prevent” anesthesia-induced hypothermia to ensure normothermia, not to cause hyperthermia. Our data in preclinical models support this outcome. We realize that there are specific surgical cases where hypothermia may be beneficial (e.g., cardiac arrest). In these circumstances, transient receptor potential vanilloid 1 antagonists would simply be avoided as maintaining normothermia is not the desired medical outcome.

Second, whether hypothermia is beneficial as a protection strategy for organs such as the brain remains uncertain.2,3  Current guidelines recommend maintenance of normothermia in most surgical cases given the preponderance of evidence in favor of normothermia.4,5 

Third, the overall effect of transient receptor potential vanilloid 1 antagonism on various organ systems is likely complex and dependent on the particular preclinical model being studied. For example, while the articles cited by Wu et al. demonstrate a protective role of transient receptor potential vanilloid 1 agonism in postischemic recovery, others have shown that transient receptor potential vanilloid 1 antagonism may have protective role in ischemia-reperfusion in cardiac myocytes6  and in the brain,7  as well as in models of hemorrhagic shock, cardiac hypertrophy,8,9  and lung injury.10  These differences could be secondary to the relative lack of specificity of the antagonist studied (i.e., capsazepine) or unknown compensation in the global knockout phenotype. Notably, in our studies, we observed increased anesthesia-induced hypothermia in transient receptor potential vanilloid 1 knockout mice, and capsazepine had only modest efficacy in preventing anesthesia-induced hypothermia (Patwardhan et al., unpublished data). As is the case with any drug development, potential adverse effects on organ function can be monitored during clinical testing. Initial studies would be done in patients who are otherwise relatively young and healthy; later studies would be done in specific “at-risk” populations with careful monitoring.

Finally, preclinical literature has suggested a role for transient receptor potential vanilloid 1 in numerous, diverse biologic processes such as immune modulation, renal injury, anxiety, dementia, cognitive function, pancreatic function, airway reactiveness, pulmonary hypertension, and gastrointestinal transit, to name a few. Anticipation of all possible side effects of transient receptor potential vanilloid 1 antagonism is not possible. Like all pharmacologic therapies, risks will have to be weighed against benefits in specific patient populations and with use in specific circumstances. Importantly, however, multiple transient receptor potential vanilloid 1 antagonists have been advanced past phase I safety studies and evaluated further in clinical settings where the only reported outcomes were analgesia, decreased thermal sensation that is not a problem in the intraoperative setting, and hyperthermia. We look forward to clinical evaluation of transient receptor potential vanilloid 1 antagonists for perioperative use.

This research has been supported by a Foundation for Anesthesia Education and Research grant (to Dr. Patwardhan) and a University of Arizona, Tucson, Arizona, Career Development grant (to Dr. Patwardhan) and in part by the Research Fund of the Medical School, University of Pecs, Pecs, Hungary (grant No. KA-2016-15, to Dr. Garami) and the New National Excellence Program of the Hungarian Ministry of Human Capacities (grant No. UNKP-16-4-III, to Dr. Garami).

Drs. Patwardhan and Porreca declare a financial interest in Catalina Pharmaceuticals Inc. (Tucson, Arizona), which licenses the intellectual property involved in this research. This interest has been properly disclosed to the University of Arizona Institutional Review Committee, Tucson, Arizona, and is managed in accordance with its conflict of interest policies. Drs. Patwardhan, Porreca, and Romanovsky are founders of Catalina Pharmaceuticals Inc. and hold a provisional patent for the use of transient receptor potential vanilloid 1 antagonists in prevention of anesthesia-induced hypothermia. Dr. Romanovsky has consulted for Abbott Laboratories (Chicago, Illinois), AbbVie (Chicago, Illinois), Amgen Inc. (Thousand Oaks, California), Japan Tobacco Inc. (Tokyo, Japan), Teva Pharmaceutical Industries Ltd. (Petah Tikva, Israel), and other pharmaceutical companies, and his research has been supported by Abbott Laboratories, AbbVie, and Amgen Inc. The other authors declare no competing interests.

1.
Garami
A
,
Ibrahim
M
,
Gilbraith
K
,
Khanna
R
,
Pakai
E
,
Miko
A
,
Pinter
E
,
Romanovsky
AA
,
Porreca
F
,
Patwardhan
AM
:
Transient receptor potential vanilloid 1 antagonists prevent anesthesia-induced hypothermia and decrease postincisional opioid dose requirements in rodents.
Anesthesiology
2017
;
127
:
813
23
2.
Andrews
PJ
,
Sinclair
HL
,
Rodriguez
A
,
Harris
BA
,
Battison
CG
,
Rhodes
JK
,
Murray
GD
;
Eurotherm3235 Trial Collaborators
:
Hypothermia for intracranial hypertension after traumatic brain injury.
N Engl J Med
2015
;
373
:
2403
12
3.
Todd
MM
,
Hindman
BJ
,
Clarke
WR
,
Torner
JC
;
Intraoperative Hypothermia for Aneurysm Surgery Trial (IHAST) Investigators
:
Mild intraoperative hypothermia during surgery for intracranial aneurysm.
N Engl J Med
2005
;
352
:
135
45
4.
Hopf
HW
:
Perioperative temperature management: Time for a new standard of care?
Anesthesiology
2015
;
122
:
229
30
5.
American Society of Anesthesiologists Task Force on Postanesthetic C
:
Practice guidelines for postanesthetic care: A report by the American Society of Anesthesiologists Task Force on Postanesthetic Care.
Anesthesiology
2002
;
96
:
742
52
6.
Sun
Z
,
Han
J
,
Zhao
W
,
Zhang
Y
,
Wang
S
,
Ye
L
,
Liu
T
,
Zheng
L
:
TRPV1 activation exacerbates hypoxia/reoxygenation-induced apoptosis in H9C2 cells via calcium overload and mitochondrial dysfunction.
Int J Mol Sci
2014
;
15
:
18362
80
7.
Miyanohara
J
,
Shirakawa
H
,
Sanpei
K
,
Nakagawa
T
,
Kaneko
S
:
A pathophysiological role of TRPV1 in ischemic injury after transient focal cerebral ischemia in mice.
Biochem Biophys Res Commun
2015
;
467
:
478
83
8.
Akabori
H
,
Yamamoto
H
,
Tsuchihashi
H
,
Mori
T
,
Fujino
K
,
Shimizu
T
,
Endo
Y
,
Tani
T
:
Transient receptor potential vanilloid 1 antagonist, capsazepine, improves survival in a rat hemorrhagic shock model.
Ann Surg
2007
;
245
:
964
70
9.
Buckley
CL
,
Stokes
AJ
:
Mice lacking functional TRPV1 are protected from pressure overload cardiac hypertrophy.
Channels (Austin)
2011
;
5
:
367
74
10.
Thomas
KC
,
Roberts
JK
,
Deering-Rice
CE
,
Romero
EG
,
Dull
RO
,
Lee
J
,
Yost
GS
,
Reilly
CA
:
Contributions of TRPV1, endovanilloids, and endoplasmic reticulum stress in lung cell death in vitro and lung injury.
Am J Physiol Lung Cell Mol Physiol
2012
;
302
:
L111
9