a b s t r a c t

Aim of the study: Targeted temperature management is a class I indication in comatose patients after a cardiac ar- rest. While the literature has primarily focused on innovative methods to achieve target temperatures, pharma- cologic therapy has received little attention. We sought to examine whether pharmacologic therapy using antipyretics is effective in maintaining normothermia in post cardiac arrest patients.

Materials and methods: Patients >=18 years who were resuscitated after an in-hospital or out-of-hospital cardiac arrest and admitted at our institution from January 2012 to September 2015 were retrospectively included. Pa- tients were divided into groups based on the method of Temperature control that was utilized. The primary out- come was temperature control <38 ?C during the first 48 h after the cardiac arrest.

Results: 671 patients were identified in Group 1 (no hypothermia), 647 in Group 2 (antipyretics), 44 in Group 3 (invasive hypothermia), and 51 in Group 4 (invasive hypothermia and antipyretics). Mean patient age was 59 (SD +-15.7) years with 40.6% being female. Using Group 1 as the control arm, 57.7% of patients maintained target temperature with antipyretics alone (p < 0.001), compared to 69.3% in the control group and 82.1% in the com- bined hypothermia groups 3&4 (p = 0.01). Patients receiving both invasive hypothermia and antipyretics (Group 4), had the greatest mean temperature decrease of 5.2 ?C.

Conclusions: Among patients undergoing targeted temperature management, relying solely on as needed use of antipyretics is not sufficient to maintain temperatures <38 ?C. However, antipyretics could be used as an initial strategy if given regularly and/or in conjunction with more aggressive cooling techniques.

(C) 2021 Published by Elsevier Inc.

1. Introduction

targeted temperature management has emerged as a critical aspect of post-arrest care in an effort to preserve neurological function. While moderate hypothermia was initially thought to be more optimal (32-34 ?C) [1-3], more recent trials have suggested that strict normo- thermia (34-36 ?C) can be just as effective [2,4,5]. While there is still de- bate in the field about what target temperature should be achieved post-arrest, avoidance of hyperthermia (<38 ?C) is consistently associ- ated with better outcomes [6]. Although sufficient supporting data for TTM has only included out-of-hospital cardiac arrest (OHCA) with

Abbreviations: IHCA, In-hospital cardiac arrest; OHCA, Out-of-hospital cardiac arrest; ROSC, Return of spontaneous circulation; TTM, Targeted temperature management.

* Corresponding author at: 6565 Fannin Street, #1901, Methodist Debakey Heart Center, Houston, TX 77030, United States of America.

E-mail address: [email protected] (T.S. Alnabelsi).

shockable initial rhythm, there has been no evidence to contraindicate TTM in the post-arrest care for in-hospital cardiac arrest and CA with non-shockable initial rhythms [6,7]. Recent guidelines have reflected the importance of TTM and have extended their recommenda- tions beyond the OHCA group to include IHCA and OHCA survivors re- gardless of initial rhythm [6,7]. It is now a Class I indication for all types of cardiac arrest.

Several non-pharmacologic measures to achieve targeted tempera- tures in the setting of CA have been extensively studied (i.e. cooling blankets, ice packs, cold saline, invasive cooling catheters); whereas pharmacologic therapy has received little to no attention in this popula- tion. pharmacologic interventions as adjunct therapy such as Coenzyme Q10 and erythropoietin have been studied in conjunction with TTM and have been shown improve Survival and neurological outcomes in post CA patients [8,9], but no studies evaluated pharmacotherapy as a sole means for TTM in post-arrest care. Pharmacologic temperature control has been examined in non-CA survivors. Multiple studies in several

https://doi.org/10.1016/j.ajem.2021.06.069 0735-6757/(C) 2021 Published by Elsevier Inc.

groups of patients have shown, on average, a decrease of 0.1-0.4 ?C with acetaminophen as an antipyretic agent [10-12]. If shown to be effective, pharmacologic therapy would substantially decrease costs to achieve TTM in post-CA patients.

It is possible that antipyretic agents such as acetaminophen and non- steroidal inflammatory drugs, could lower core body temperature, ei- ther in addition to, or independent of invasive cooling methods. Our hy- pothesis is that pharmacologic therapy is effective in maintaining normothermia in post cardiac arrest patients.

1. Methods

The retrospective cohort study was approved through the University of Kentucky Institutional Review Board and was performed at the Uni- versity of Kentucky Albert B. Chandler Medical Center (United States), a tertiary-care medical center with 945 beds. The study included all pa- tients who presented with a CA from January 1st 2012 to September 30th 2015. On January 1, 2012, a standardized invasive hypothermia protocol was instituted at the hospital, where all CA patients were eval- uated by the cardiology department for appropriateness of invasive therapeutic hypothermia. Additionally, all in-hospital cardiac arrests outside of the emergency room automatically had a Rapid Response team deployed, allowing for consistent documentation of IHCA. Our data range ends on September 30th 2015 when the transition from ICD-9 to ICD-10 medical classification occurred. This allowed us to use one set of codes to identify patients.

• 1. Study population

We reviewed all patient charts for potential cardiac arrests using a broad search matrix that includes: rapid response team notes; ICD-9 codes for cardiac arrest, ventricular fibrillation and ventricular tachycar- dia; individual code sheets from the entire hospital; cardiac arrest as an initial reason for admission; a prospective database of all patients who underwent invasive hypothermia; and all catheterization lab activa- tions with documented cardiac arrests. We included all adult patients suffering from an IHCA or OHCA of any origin given the most recent guidelines giving a Class I indication for TTM in all subtypes of cardiac arrest [6]. We excluded any patients who had an arrest after they were made Do Not Resuscitate , patients who had an arrhythmic arrest with a pre-existing ICD, and those patients who presented after a traumatic arrest.

• 1. Cohort definition

Patients were divided into one of four cohorts: patients receiving neither antipyretics nor invasive hypothermia (Group 1), patients re- ceiving antipyretics only (Group 2), patients receiving only invasive hy- pothermia (Group 3), and patients receiving both antipyretics and invasive hypothermia (Group 4). Given the lack of a protocol for sched- uled antipyretic medication administration during the study period, the medications were given at the discretion of the treating physician and likely in response to a persistent elevation in temperature > 38 degrees Celsius. Mean changes in temperature over the first 48 h was assessed in each group and then compared on a between group basis. Groups 3 and 4 were then combined to see the effectiveness of antipyretics versus in- vasive cooling in achieving guideline-directed temperature targets within the first 48 h.

• 1. Definition of interventions

Intervention with TTM for post CA care along with any antipyretics (acetaminophen, aspirin, ibuprofen, naproxen) administered within the first 48 h post CA were recorded. Combination medications were broken down into individual components and then medications were aggregated from all sources. Minimum daily dosage, maximum daily

dosage, and mean daily dosage for each antipyretic medication were calculated and reported. The timeframe of 48 h was used in keeping with the major TTM trials and our institutional protocol for invasive hypothermia. Patients were defined as receiving antipyretics if they received any of the above medications during that 48-h period. Temper- ature measurements were obtained primarily from a temperature sens- ing Foley catheter placed in the bladder. Alternatively, axillary or rectal temperatures were obtained.

During this time period, all decisions to initiate therapeutic hypo- thermia were made through the cardiology service, and hypothermia was initiated via an intravenous cooling catheter (Quattro Intravascular Heat Exchange Catheter, Zoll Medical, Chelmsford, MA). A prospective registry was maintained for all patients who underwent therapeutic hy- pothermia and all of these patients were managed in our Cardiovascular Intensive Care Unit. At the time of the care of these patients, the institu- tional policy was to initiate moderate therapeutic hypothermia (target temperature of 34 degrees Celsius) for the first 24 h with controlled rewarming to 36 degrees Celsius (and maintenance of temperature < 38 degrees Celsius) over the next 24 h

• 1. Outcome measures

Patient characteristics were extracted from the electronic health record system (Sunrise Clinical Manager system, Allscripts, United States). The extracted data included patients’ age, gender, comorbidi- ties, admission diagnosis, length of ICU/hospital-stay, TTM modalities used, Pharmaceutical interventions administered 48 h after CA, daily temperature recordings for 48 h after IHCA/OHCA, discharge disposi- tion, and survival to hospital discharge.

The primary outcome was normothermia (defined as temperature control <38 ?C) during the first 48 h after the cardiac arrest event. Given variations in the clinical trials, guidelines have not been specific and recommend at least 24 h of targeted-temperature control. While guidelines have recommended a target temperature of 32-36 ?C twenty-four hours post arrest, 38 ?C was chosen as the upper limit of normothermia to mimic the intervention arm in the TTM trial [2]. Using our institutional TTM protocol, a target temperature of <38 ?C was used for both the invasive and pharmacologic hypothermia arms. The secondary outcome was the difference in mean temperature in each group.

• 1. Statistical analysis

Patient characteristics were compared by treatment groups. For cat- egorical variables, frequencies and column percentages (%) were re- ported and p-values were calculated using ?2 and Fisher’s exact tests, as appropriate. Continuous variables were tested for normality using the Shapiro-Wilk normality test along with histograms. Normally dis- tributed continuous variables were reported using means and standard deviations (SD) and p-values were calculated using two-sample t-tests and One-way ANOVAs. Non-normally distributed variables were re- ported as medians and first/third quartiles, with p-values calculated using Mann-Whitney U and Kruskal-Wallis tests. Analysis was per- formed using SPSS v26 (IBM, Texas, USA), SAS 9.4 (SAS Institute Inc., Cary, NC, USA) and R (version 3.6.1).

1. Results

1561 patients met the inclusion criteria in this study. Of those pa- tients, temperature data within 48 h after the arrest was available for 1413 and those were included in the final analysis. 671 were identified in Group 1, 647 in Group 2, 44 in Group 3, and 51 in Group 4. Mean age for the total cohort was 59 (SD +-15.7) years of age, with 40.6% being fe- male (Table 1). The majority of patients had an initial Non-shockable rhythm (62.4%) and nearly 70% of patients had an in-hospital cardiac ar- rest. There were more OHCA patients in the hypothermia groups

Table 1

Baseline characteristics and cardiac arrest features in the four therapy groups

	Group 1 No hypothermia	Group 2 Antipyretics	Group 3 Invasive hypothermia	Group 4 Antipyretics & Invasive hypothermia	Total
Number of patients	671	647	44	51	1413
Age; mean (SD)	57.5 (16.1)	60.3 (15.1)	50.3 (15.8)	60.2 (11.7)	58.7 (15.7)
Female; N (%)	263 (39.2%)	271 (41.9%)	24 (54.6%)	16 (31.4%)	574 (40.6%)
clinical risk factors; N (%) Coronary artery disease	216 (32.2)	333 (51.5)	15 (34.1)	41 (80.4)	605 (42.8)
Chronic kidney disease	177 (26.4)	194 (30.0)	10 (22.7)	13 (25.5)	394 (27.9)
Hypertension	442 (65.9)	485 (75.0)	28 (63.6)	39 (76.5)	994 (70.4)
Chronic obstructive pulmonary disease	176 (26.2)	207 (32.0)	9 (20.5)	17 (33.3)	409 (29)
Diabetes	189 (28.2)	252 (39.0)	19 (43.2)	17 (33.3)	477 (33.8)

Cardiac arrest features Initial Rhythm

Pulseless electrical activity/Asystole	463 (69.0%)	390 (60.3%)	17 (38.6%)	12 (23.5%)	882 (62.4%)
Ventricular tachycardia/fibrillation	83 (12.4%)	134 (20.7%)	17 (38.6%)	29 (56.9%)	263 (18.6%)
Unknown	125 (18.6%)	123 (19.0%)	10 (22.7%)	10 (19.6%)	268 (19.0%)
Location of arrest
In-hospital	481 (71.7%)	477 (73.7%)	12 (27.3%)	14 (27.5%)	984 (69.6%)
Out of hospital	129 (19.2%)	86 (13.3%)	32 (72.7%)	34 (66.7%)	281 (19.9%)
Unknown	61 (9.1%)	84 (13.0%)	0 (0.0%)	3 (5.9%)	148 (10.5%)
Post-ROSC Minutes to ROSC, Median (Q1-Q3)	6 (1-11)	6 (2.5-9.5)	8 (3-13)	15 (2.5-27.5)	6 (3-9)
Glasgow coma score	9 (3-14)	14 (9-15)	3 (3-3)	3 (3-3.5)	14 (7-15)
Creatinine (mg/dL)	1.5 (1.0-2.6)	1.2 (0.9-2.1)	1.3 (1.1-1.5)	1.3 (1.0-1.6)	1.2 (0.9-1.9)
Lactate (mmol/L)	4.9 (1.9-9.5)	2.5 (1.4-6.2)	4.8 (3.3-8.4)	3.1 (1.8-7.3)	2.3 (1.2-5.6)
PH	7.2 (7.1-7.4)	7.3 (7.2-7.4)	7.3 (7.2-7.3)	7.2 (7.2-7.4)	7.3 (7.2-7.4)
Glucose (mg/dL)	148 (111-120)	137 (110-200)	213 (136-271)	202 (141-289)	132 (103-187)

(Groups 3 and 4) compared to Groups 1 and 2. The hypothermia groups included a higher percentage of patients with an Initial shockable rhythm compared to the other groups. Pharmacologic therapies used for TTM post ROSC included acetaminophen, aspirin, ibuprofen, and naproxen among others. Fig. 1 demonstrates the average dose per pa- tient, mapped against their body temperature.

• 1. Primary outcome

Our primary outcome of interest was maintenance of a temperature

< 38 ?C within 48 h post return of spontaneous circulation (ROSC). With Group 1 as the control arm compared to Group 2 (anti-pyretics only) and the hypothermia groups combined (Groups 3 and 4), 57.7% of pa- tients achieved target temperature with antipyretics alone (p < 0.001), compared to 69.3% in the control group and 82.1% in the com- bined hypothermia groups (p = 0.01) (Fig. 2).

• 1. Secondary outcome

Mean change in temperature was analyzed as a secondary outcome to evaluate its association with intervention of antipyretics and/or inva- sive hypothermia compared to the control arm (Fig. 3). Patients who were given antipyretics alone (Group 2) experienced a mean tempera- ture increase of 1.1 ?C. Patients who only received invasive hypothermia as an intervention had a mean decrease of 3.4 ?C. Patients receiving both invasive hypothermia and antipyretics (Group 4), had a mean tempera- ture decrease of 5.2 ?C.

1. Discussion
   1. Summary of major findings

Our study is one of the largest single-center series in recent years comparing the effectiveness of using antipyretics alone with the use of invasive hypothermia in maintaining a temperature less than 38 ?C within the first 48 h after ROSC. We report two important findings:

1. the reliance on a passive strategy of administering antipyretics (i.e in response to rising temperatures) showed no significant reduction in baseline mean temperature levels compared to invasive hypothermia,
2. the combination of antipyretics and invasive hypothermia demon- strated the largest decrease in body temperatures.

Mean daily drug dose (mg)

Fig. 1. Effect of medication and dosage on mean temperature.

Fig. 2. Percentage of patients who failed to maintain a target temperature of <38 ?C within 48-h post-ROSC.

Fig. 3. Secondary outcome demonstrating changes in temperature associated with the different treatment groups. (AP = anti-pyretics, HT = hypothermia).

• 1. Comparison with previous studies

Cardiac arrest has poor overall outcomes, and TTM is a strategy that has been demonstrated to improve favorable neurologic survival in car- diac arrest patients. However, the method of TTM (pharmacologic ver- sus invasive) has not been well studied, yet carries significant implications for developing and maintaining a comprehensive post- arrest care system. As need (PRN) use of antipyretics alone were not ef- fective in significantly reducing body temperatures, a finding in-line with findings in the stroke population [10-12]. More importantly, the group that received antipyretics alone were 2.5 times more likely to fail to maintain a temperature less than 38 ?C within the first 48 h, com- pared to the invasive hypothermia group. One component of this may be the lower daily dosages of the antipyretics used (~ 2 g per day of Acetaminophen). However, the temperature reduction seen in other studies with higher dosages was still minimal (<0.5 ?C), and likely is of limited clinical significance. At the very least, there needs to be a reg- ularly scheduled and aggressive dosing regimen given the minimal ex- pected effects and the short time period available to achieve the goal temperature. More aggressive pharmacotherapy regimens can be tested prospectively, but given these findings, PRN use of antipyretics alone are not adequate to achieve TTM in post-cardiac arrest patients. In fact, hos- pitals and Hospital systems that are interested in maintaining aggressive post-ROSC care that includes TTM will likely need to invest in other methods of temperature control.

Interestingly however, the combination of antipyretics and invasive hypothermia demonstrated the largest decrease in body temperatures with a mean decrease in temperatures of 1.8^o C more than the invasive hypothermia only group, suggesting that antipyretics have a significant effect in combined regimens for TTM. The apparent synergistic effect of antipyretics when combined with invasive hypothermia may be clini- cally helpful, and less invasive strategies for temperature control (cooling blankets, ice packs, cold saline, etc.) may be adequate despite their less consistent temperature control compared to invasive hypo- thermia [1,2]. The accessibility, cost and easy administration of antipy- retics make them appealing first line agents that may enhance the effect of temperature control achieved by other strategies. Further stud- ies should therefore aim to determine a more comprehensive tempera- ture control strategy, including aggressive pharmacological management followed by escalation to more active temperature control strategies.

• 1. Strengths and limitations

As one of the largest single-center reports on the differences in effi- cacy of invasive hypothermia and anti-pyretic medication we were able to demonstrate that while aggressive temperature control may be needed for a comprehensive TTM program, over 50% of those in the an- tipyretic arm were able to achieve targeted temperature even at these low to moderate dosages. Given rising Healthcare costs, a low cost, high value option such as this is still very appealing as an initial strategy particularly in low resource areas or facilities without advanced capabil- ities to provide aggressive cooling measures.

The study had several limitations. First and given the retrospective nature of the study, the effects of antipyretics across a wide dosing range was evaluated as opposed to maximally tolerated or regularly scheduled doses. For similar reasons, only one type of cooling technique (intravascular cooling) was assessed due to our institution’s current protocols. While temperature management is strictly indicated for co- matose patients, the ability to reliably assess this retrospectively was

limited, and some patients who may not have been comatose were in- cluded in the “control” group. However, given the overall survival in this cohort was similar overall to other studies, suggests that this may have been of minimal significance. Additionally, selection bias cannot be excluded given that cardiologist had the final say on which patients underwent invasive hypothermia. Finally, this study was underpowered to assess for differences in clinical endpoints, and therefore, the differ- ence in temperature has not been correlated in this study to survival or neurologic status on discharge.

1. Conclusion

This study showed that passive temperature control using as needed antipyretics alone are not sufficient to achieve TTM in all post-cardiac arrest patients and are inferior to more aggressive measures of temper- ature control. However, our results do suggest that there is a role for using antipyretics either as an initial strategy or more likely in conjunc- tion with aggressive cooling techniques in patients undergoing TTM. Larger prospective studies using scheduled antipyretic administration combined with protocols for adjuvant hypothermia measures will be necessary to determine exactly what role antipyretics play in maintain- ing normothermia in this patient population.

Declaration of Competing Interest

None.

Acknowledgements

None.

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