A systematic review of safety and adverse effects in the practice of therapeutic hypothermia
a b s t r a c t
Objective: To carry out a systematic review to estimate the rate and magnitude of adverse effects following ther- apeutic hypothermia (TH) procedure in patients resuscitated from out-of-hospital cardiac arrest (OHCA) and highlight the specific complications seen after the procedure.
Methods: A systematic review of currently published studies was performed following standard guidelines. On- line database searches were performed for controlled trials for the last twenty years. Papers were examined for Methodological soundness before being included. Data were independently extracted by two blinded re- viewers. Studies were also assessed for bias using the Cochrane criteria. The adverse effects attributed to TH in the literature were appraised critically.
Results: The initial data search yielded 78 potentially relevant studies; of these, 59 were excluded for some reason. The main reason for exclusion (n = 43, 55.8%) was that irrelevance to adverse effects of TH. Finally, 19 underwent full-text review. Studies were of high-to-moderate (n = 12, 63%) to low-to-very low (n = 7, 37%) quality. Five studies (27.7%) were found to have high risk of bias, while 8 (42.1%) had low risk of bias.
Interpretation: Although adverse effects related to the practice of TH have been studied extensively, there is sub- stantial heterogeneity between study populations and methodologies. There is a considerable incidence of side effects attributed to the procedure, e.g., from life-threatening ventricular arrhythmias to self-limited conse- quences. Most studies analyzed in this systematic review indicated that the procedure of TH has not caused se- vere adverse effects leading to significant alterations in the outcomes following resuscitation from OHCA. PROSPERO, registration number is: CRD42018075026.
(C) 2018
Introduction
Survival to discharge rate following resuscitation from out-of- hospital cardiac arrest (OHCA) with ventricular fibrillation (VF) was re- ported to be as high as 40% [1]. In the population-based 11-year study by Bunch et al., Survival to admission was found to be 72%, while 42% survived to discharge and 76% of those discharged patients survived for 5 years. neurologic injury is the most common cause of death in pa- tients with OHCA and contributes to the mortality of in-hospital cardiac arrest [2].
Out-of-hospital cardiac arrest (OHCA) is the most common way of dying and Therapeutic hypothermia is instituted to improve neuro- logical outcome after OHCA. “Therapeutic hypothermia,” is a general term to define intentional reduction of core body temperature, while it has evolved in decades into a more comprehensive control of a
* Corresponding author at: Dept. of Emergency Medicine, Istanbul Education and Research Hospital, Fatih, PK 34098 Istanbul, Turkey.
E-mail address: [email protected] (O. Karcioglu).
patient’s temperature profile, a strategy now referred to as “targeted temperature management” (TTM). Recent guidelines have recom- mended TTM for selected patients resuscitated successfully and are still unresponsive [3]. TH is practised mainly in the treatment of adult cardiac arrest and neonatal Hypoxic-ischemic encephalopathy.
Hypothermia has been historically classified into: mild (34.5-36.5
?C), moderate (34.5-32 ?C), marked (28-32 ?C) and profound hypo- thermia (b28 ?C) [4-6].
In the early 2000’s, researchers advocated the administration of ‘mild TH’ to improve neurological outcomes and to prevent severe brain damage after OHCA [5,6]. More recent evidence demonstrated that the core temperature should be maintained between 32 and 36
?C as the therapeutic range for TTM [3,7]. In this context, induced hypo- thermia is evaluated in three steps: induction, maintenance and rewarming, and each phase produces several changes in normal physiology.
In the post-resuscitative period, TH is thought to mitigate neurologic reperfusion injury by decreasing cerebral oxygen consumption and bio- chemical damage [5]. TH was postulated to offer an extended
https://doi.org/10.1016/j.ajem.2018.07.024
0735-6757/(C) 2018
therapeutic window to restore the integrity of circulation, with the brain maintained in a protective, hypometabolic state.
Hypothermia induction should be started without delay to minimize neurologic damage [7]. Infusing cold fluids, e.g., Ringer’s lactate N25 mL/kg at 4 ?C, can be seen as the easiest method for inducing hypo- thermia [8]. However, The Canadian Guidelines, pointed out that al- though high Level of evidence is lacking, most experts recommend to initiate TTM as soon as feasible after ROSC is achieved and to avoid cold IV fluids in the prehospital setting [7]. Mild cooling was shown to be beneficial without many of the feared side effects. Nonetheless, TH requires an intensive care unit setting with protocolized implementa- tion and Close monitoring [8,9]. It is likely that both survivors of arrest by itself and with the addition of TH procedure increase risk of compli- cations from the hypothermia [9,10].
Substantial amount of literature data on adverse or side effects of TTM are available although there is a need to culminate these in a sys- tematic and orderly fashion to guide monitoring the patients to avoid these in the procedure. This article reviews the current literature to pro- vide systematic data regarding adverse and untoward effects attributed to the procedure of TH in the emergency setting.
Side/adverse effects/complications attributed to TH
Decline in body temperature has an impact on all biological pro- cesses. Many important complications of hypothermia respond to stan- dard measures, while some may result in morbidity and mortality. MacLaren et al. compared the incidences of adverse events and predic- tors of good versus poor neurological recovery after TH in a review of medical records of 91 patients who received TH for >=6h [10,11]. They reported that common adverse events were hypoglycemia (99%), shiv- ering (84.6%), bradycardia (58.2%), electrolyte abnormalities (up to 91.2%), acute kidney injury (52.8%), infection (48.4%), and coagulopathy (40.7%).
TH performed in most scenarios was known as “Level 2 procedure”
which Australian Ministry of Health Guideline recommends “Allergy/ adverse reaction check” and to be advised/informed about the “Antici- pated critical events” attributed to the procedure [11]. In this context, there is also need to address safety of clinical trials and procedures pertaining to TH worldwide. Clinical trials must be conducted following established standards in order to protect the rights, safety and well- being of the subjects/participants [11,12].
To inform decision-making on the procedure of TH and attributable adverse effects, we performed a systematic review of the evidence on the probable side effects and specific subgroups predisposed to them. This article reviews the current literature to provide systematic data re- garding the following questions and determine evidence-based recommendations:
How safe is TH in patients resuscitated from OHCA?
A systematic review of currently published studies was carried out on the predefined subject via certain keywords. Online database searches were performed for randomized controlled trials published within twenty years before January 2018, on the comparison of the ad- verse and untoward effects of TH in adults and consequences in specific patient groups. Data were independently extracted by two blinded re- viewers. The discrepancies, on the other hand, were resolved by the pri- mary author.
Protocol and registration
This protocol is presented in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) guidelines [13]. The research protocol to answer these questions was
registered in PROSPERO, the International Prospective Register of System- atic Reviews (registration number is: CRD42018075026).
Search methodology
A literature search via the Cochrane Central Register of Controlled Trials, PubMed/Medline, ClinicalKey, EMBASE, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), and BIOSIS was carried out on the clinical trials conducted on adults published in all languages. Online searches were performed using the following search keywords and terms: ‘out of hospital cardiac arrest’ AND ‘therapeutic hypother- mia’ OR ‘targeted temperature management’ AND ‘adverse effects’. The reference lists of retrieved articles were used to generate more pa- pers related to the adverse effects attributed to the procedure.
Study selection, data screening and critical appraisal
The study included all clinical trials of any duration that examined adverse and untoward effects related to TH in humans, who underwent TTM (32-36 ?C), irrespective of the presenting rhythm exclusively in adults (aged N18 years). Reference lists of relevant systematic reviews and all included studies were checked to identify additional eligible ar- ticles. Conference abstracts and proceedings were not deemed eligible for inclusion in the review. Citation titles and abstracts were indepen- dently screened and assessed regarding the methodological quality by two reviewers (H.T. and O.D.). Any disagreements between the two re- viewers were then resolved by consensus or in consultation with a third reviewer (O.K.) if needed.
Assessment of quality and risk of bias
Eligible clinical studies were rated regarding the quality of evidence as per “Grading of Recommendations Assessment, Development and Evaluation” (GRADE) guidelines whICH Scores according to risk of bias, publication bias, consistency, directness and precision [14]. In accord with the GRADE, the studies were assigned to one of four groups: High (A), moderate (B), low (C) and very low (D) quality. Table 1 sum- marizes this evidence; grading and levels of evidence (Sackett’s original evidence based approach).
Studies that met the inclusion criteria for the review were assessed for bias using the risk of bias criteria developed by Cochrane’s EPOC group [15] which is based upon Cochrane’s Risk of Bias Tool [16]. Studies were assessed with regard to selection bias, performance bias, detection bias, attrition bias, reporting bias, and other sources of bias. Studies were rated as “low risk of bias (L)”, “high risk of bias (H),” or “unclear risk of bias (U)” on a general impression after evaluating all criteria (Table 2).
Table 1
Grading and levels of evidence (Sackett’s original evidence based approach).
Grading of evidence
A Supported by at least two level I studies
B Supported by only one level I study
C Supported by level II studies only
D Supported by at least one level III investigation
E Supported by level IV or level V evidence
Level of evidence
Level I Large, randomized trials with clear cut results Level II Small, randomized trials with uncertain results Level III Non-randomized, contemporaneous controls
Level IV Non-randomized, historical controls and expert opinion Level V Case series, uncontrolled studies and expert opinion
Main characteristics of the outstanding human studies evaluating the adverse effects of TH that were reviewed in the present study.
Investigator(s), title and
date, Ref.#
Sample size and population Quality of
evidence (GRADE)a
Risk of biasb
Objectives Findings Notes, conclusions
Pichon N, et al. 2007 [17]
Hammer L, et al. 2009 [18]
Kamarainen A, et al. 2009 [19]
Lyon RM, et al. 2014 [20]
Deye N, et al. 2015 [21]
Gagnon DJ, et al. 2015 [22]
40 patients in the ICU after OHCA underwent Mild induced hypothermia.
A total of 99patients; 22 treated with prehospital TH, and 77 patients treated with prehospital standard resuscitation served as controls.
44 cardiac arrest survivors (19 were analyzed in the treatment group and 18 in the control group).
13 patients with witnessed cardiac arrest and ROSC who have undergone Rhinochill device deployment
203 patients were randomized to the endovascular group and 197 to the external group
1240 comatose adult patients resuscitated from a CA treated with TTM at 32-34 ?C.
C H To evaluate the efficacy of and tolerance to mild TH achieved using an endovascular cooling system, and its ability to reach and maintain a target temperature of 33 ?C after CA.
U To evaluate the efficacy and safety of an immediate prehospital cooling procedure implemented just after the ROSC with a prehospital setting.
Post-rewarming ‘rebound hyperthermia‘, defined as a temperature of 38.5 ?C or greater, was observed in 25 patients (74%) during the first 24 h after cessation of mild TH. infectious complications were observed in 18 patients (45%), but no patient developed severe sepsis or septic shock. The biological changes that occurred during mild TH manifested principally as hypokalemia (b3.5 mmol/l; in 75% of patients).
The proportion of patients with complications like bleeding, pneumonia, sepsis, renal failure, seizures, or arrhythmia did not differ significantly between the 2 groups. Rapid Fluid loading was associated with a higher rate of bilateral Pulmonary infiltrates on the first chest x-ray (41% in the cooling group vs 16% in the control group; p = 0.02).
These x-ray abnormalities were not associated with hypoxemia, and the PO2/FIO2 ratio was
not different between the 2 groups.
There were no significant differences between the groups regarding safety or secondary outcome measures such as neurological outcome and mortality.
In all cases, the doctor and paramedic involved with the resuscitation reported that the Rhinochill was easy to set up and use during resuscitation and that it did not interfere with standard resuscitation practice.
Minor epistaxis was reported in two cases.
Minor side effects directly related to the cooling method were observed more frequently in the endovascular group, essentially minor bleedings not requiring transfusion and microbiological colonization of central venous catheters (p = 0.009), However, all 3 patients experiencing deep accidental per-procedural hypothermia (e.g., temperature b30 ?C occurring during the TTM phase) received external basic cooling.
Patients treated with Prophylactic antibiotics had less pneumonia (12.6% vs 54.9%, p b
0.001) and less sepsis (1.2 vs
5.7%, p b 0.001) compared to no-prophylactic antibiotics
patients. ICU length of stay (98 vs 100 h, p = 0.2) and incidence of a good functional outcome (41.1 vs 36.6%, p = 0.19) were similar between groups. Logistic regression demonstrated prophylactic antibiotics were associated with a lower incidence
The intravascular cooling system is effective, safe and allows a target temperature to be reached fairly rapidly and steadily over a period of 36 h.
In comatose survivors of CA, prehospital TH with infusion of large-volume, ice-cold intravenous saline is feasible and can be used safely by mobile emergency and ICUs.
Infusion of ice-cold fluid after ROSC was found to be well tolerated and effective.
Intranasal evaporative cooling using the Rhinochill system is feasible in an urban, prehospital, doctor/paramedic response unit.
The rates of usual side effects or complications described in
TH-treated CA patients, including shivering but excluding the procedural cooling-related complications, were globally similar between groups.
This large, retrospective study of CA survivors treated with TTM to 32-34 ?C identified that antibiotic prophylaxis was associated with a 4-fold decrease in the incidence of pneumonia, but not with improved functional outcome.
|
Investigator(s), Sample size and population title and date, Ref.# |
Quality of evidence (GRADE)a |
Risk of biasb |
Objectives |
Findings |
Notes, conclusions |
|
of pneumonia (OR 0.09, 95% |
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|
0.06-0.14, p b 0.001) and a |
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|
similar incidence of good |
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|
functional outcome. |
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|
Jacob M, et al. 171 patients were |
B |
U |
To investigate the effect of TTM at |
platelet counts were lower in the |
There was no evidence |
|
2015 [23] randomized to TTM at either |
33 or 36 ?C on various laboratory |
TTM33-group compared to |
supporting the assumption that |
||
|
33 or 36 ?C in the |
TTM36 (p = 0.009), but neither |
TTM at 33 ?C was associated with |
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|
postresuscitation phase. |
standard coagulation nor |
impaired hemostasis or increased |
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|
TEG-parameters showed any |
the frequency of adverse |
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|
difference between the groups. |
bleeding and thrombotic events |
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|
Thrombelastography revealed a |
compared to TTM at 36 ?C. |
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|
normocoagulable state in the |
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|
majority of patients, while |
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|
around 20% of the population |
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|
presented as hypercoagulable. |
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|
Adverse events included 38 |
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|
bleeding events, one stent |
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|
thrombosis, and one reinfarction, |
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|
with no significant difference |
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|
between the groups. |
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|
Kirkegaard H, 355 adult, unconscious |
A |
L |
To determine whether TTM at 33 |
The median length of ICU stay |
Adverse events were more |
|
et al. 2017 [24] patients with OHCA |
?C for 48 h results in better |
(151 vs 117 h; p b 0.001), but not |
common in the 48-hour TTM |
||
|
neurologic outcomes compared |
hospital stay (11 vs 12 days; p = |
group than in the 24-hour TTM |
|||
|
with currently recommended, |
0.50), was longer in the 48-hour |
group. |
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|
standard, 24-hour TTM. |
group than in the 24-hour group. |
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|
The proportion of patients with 1 |
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|
or more adverse events was |
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|
significantly higher in the |
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|
48-hour group (97%) than in the |
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|
24-hour group (91%) (difference, |
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|
5.6%; 95% CI, 0.6%-10.6%; relative |
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|
risk, 1.06; 95% CI, 1.01-1.12; p = |
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|
0.04). Significantly more patients |
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|
had hypotension in the 48-hour |
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|
group than in the 24-hour group |
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|
(62% vs 49%; p = 0.013). |
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|
severe bleeding was more |
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|
common in the 24-hour than in |
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|
the 48-hour group (4% vs 1%; p = |
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|
0.03). |
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|
Tiainen M, et al. 70 consecutive adult patients |
B |
L |
To evaluate the effects of TH of 33 |
The occurrence of premature |
The use of therapeutic HT of 33 ?C |
|
2009 [25] resuscitated from OHCA |
?C after OHCA on cardiac |
ventricular beats was increased in |
for 24 hours after CA was not |
||
|
(ventricular fibrillation) |
arrhythmias, heart rate |
the TH-treated group during the |
associated with an increase in |
||
|
variability (HRV), and their |
first two recordings, with no |
clinically significant arrhythmias. |
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|
prognostic value. |
difference in the number of |
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|
ventricular tachycardia or |
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|
ventricular fibrillation episodes. |
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|
All HRV values were significantly |
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|
higher during the TH (p b 0.01), |
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|
but no differences were observed |
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2 weeks later. In multivariate |
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|
analysis, only shorter delay to |
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restoration of spontaneous |
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circulation (p = 0.009) and the SD |
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of individual normal-to-normal |
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intervals N100 ms of the 24- |
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48-hour recording in the TH |
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group (p = 0.018) predicted good |
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|
outcome. |
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|
Oddo M, et al. 109 comatose patients with |
C |
H |
To evaluate whether TH could be |
In comparison with standard |
Infections and arrhythmias were |
|
2006 [26] OHCA due to ventricular |
effectively implemented in ICU |
resuscitation, TH was associated |
common and of comparable |
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|
fibrillation/asystole/pulseless |
practice and whether it would |
with higher plasma levels of |
frequency in both treatment |
||
|
electrical activity. |
improve the outcome of all |
myocardial creatine |
groups. |
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|
comatose patients with CA, |
phosphokinase. |
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|
including those with shock or |
The large majority of patients had |
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|
with CA due to nonventricular |
early-onset pneumonia |
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|
fibrillation rhythms. |
(i.e., occurring within 48-72 h |
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|
after tracheal intubation), except |
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|
three patients in the TH group |
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|
who had late-onset pneumonia. |
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|
Arrhythmias consisted of |
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|
unsustained ventricular tachy- |
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|
cardia and atrial fibrillation. |
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|
(continued on next page) |
Table 2 (continued)
Investigator(s), title and
date, Ref.#
Sample size and population Quality of
evidence (GRADE)a
Risk of biasb
Objectives Findings Notes, conclusions
Thomsen JH,
et al. 2016 [27]
Thomsen JH,
et al. 2016 [28]
Look X, et al. 2018 [29]
Thomsen JH,
et al. 2016 [30]
Lilja G et al. 2015 [31]
897 (96%) of the 939 comatose OHCA survivors from the TTM trial with heart rhythm data.
447 (TTM = 33 ?C) and 430
(TTM = 36 ?C) comatose OHCA patients with available heart rate data, randomly assigned in the TTM trial from 2010 to 2013.
23 patients were randomized to internal cooling and 22 patients to external cooling and 42 matched controls
58 patients were randomized to 33 ?C and 57 to 36 ?C.
278 OHCA-survivors and 119 STEMI-controls
A L To assess the prognostic implications of atrial fibrillation following OHCA, including relation to the level of TTM.
A L Bradycardia has been associated with favorable outcome following OHCA.
The aim is to confirm this finding in a large multicenter cohort of patients treated with TTM at 33
?C and explore the response to TTM targeting 36 ?C.
C U To evaluate survival-to-hospital discharge and neurological outcomes (Glasgow-Pittsburgh Score) of post-cardiac arrest patients undergoing internal cooling verses external cooling.
C H To assess the ventricular ectopic burden between patients treated with TTM at 33 ?C or 36 ?C for 24 h.
L To investigate anxiety and depression within a large cohort of OHCA-survivors.
Patients affected by atrial fibrillation had significantly higher 180-day mortality (atrial fibrillation: 66% vs no-atrial fibrillation: 43%; plog rank b 0.0001 and unadjusted hazard ratio, 1.75 (p b 0.0001).
Heart rates b 50 bpm and 50-59 bpm were recorded in 132 (30%)
and 131 (29%) of the 33 ?C group, respectively. Crude 180-day mortality increased with increasing minimum heart rate (b50 bpm = 32% 50-59 bpm = 43%, and >=60 bpm = 60%;
plog-rank b 0.0001). Bradycardia b 50 bpm was associated with lower 180-day mortality (hazard ratio adjusted = 0.50 [0.34-0.74; p b 0.001]) and lower odds of unFavorable neurologic outcome (odds ratio adjusted = 0.38 [0.21-0.68; p b 0.01]) in models adjusting for potential confounders including age, initial rhythm, time to ROSC, and lactate at admission. Independent associations of lower heart rates and favorable outcome were found in patients treated with TTM at 36 ?C.
No significant difference was seen between internal and external cooling in terms of survival, neurological outcomes and complications. However in the internal cooling arm, there was lower risk of developing overcooling (p = 0.01) and rebound hyperthermia (p = 0.02). Compared to normothermia, internal cooling had higher survival (OR = 3.36, 95% CI = (1.130, 10.412)), and lower risk of developing cardiac arrhythmias (OR = 0.18, 95% CI = (0.04, 0.63)).
The reduction in ventricular ectopic beats (VEB) per hour was significantly affected by target temperature (p interaction b 0.0001), with fewer VEB in the 36
?C-group. The total number of isolated, couplets and number of runs of VEB per hour showed similar results, with less VEBs in the 36 ?C-group (p interaction b 0.0001). Increasing numbers of pre-hospital defibrillations (log2) were associated with a 46% increase in VEBs (p b 0.01), adjusted for potential confounders.
24% of OHCA-survivors and 19% of the STEMI-controls reported symptoms of anxiety (OR 1.32; 95% CI (0.78-2.25), p = 0.30).
depressive symptoms were reported by 13% of
OHCA-survivors (equal in both intervention groups, p = 0.96) and 8% of STEMI-controls (OR
1.76; 95% CI (0.82-3.79), p =
0.15).
No difference was found between the groups of patients with AF following OHCA treated with TTM at 33 ?C and 36 ?C regarding outcomes.
This study confirms an independent association of bradycardia and lower mortality and favorable neurologic outcome in a large cohort of comatose OHCA patients treated by TTM at 33 ?C.
Internal cooling can potentially provide better
survival-to-hospital discharge outcomes and reduce cardiac arrhythmia complications in selected patients with OHCA as compared to normothermia.
Ventricular ectopic activity was reduced in comatose
OHCA-survivors treated with TTM at 36 ?C compared to 33 ?C. Higher numbers of Prehospital defibrillations were associated with higher incidence of ventricular ectopic activity.
One fourth of OHCA-survivors reported symptoms of anxiety and/or depression at 6 months which was similar to
STEMI-controls and previous normative data. The psychological outcomes were similar between the two temperature groups
(HADS-anxiety, p =
0.83/HADS-depression, p = 0.96) in survivors treated with TTM.
Investigator(s), title and
date, Ref.#
Sample size and population Quality of
evidence (GRADE)a
Risk of biasb
Objectives Findings Notes, conclusions
Tiainen M, et al. 2007 [32]
Lilja G, et al. 2015 [33]
Grejs AM, et al. 2016 [34]
Kim F, et al. 2014 [35]
A cohort of 70 consecutive adult patients resuscitated from OHCA (ventricular fibrillation).
652 CA survivors originally randomized and stratified for site to Temperature control at 33 ?C or 36 ?C within the TTM trial.
161 comatose OHCA patients were randomized to TTM for 24 h (n = 77) or 48 h (n = 84).
1359 adults with OHCA (583 with VF and 776 without VF) were randomized to TTM or Standard care
U To examine the effect of TH after OHCA on cognitive functioning and neurophysiological outcome.
No differences were found in any of the cognitive functions between the 2 groups. 67% of patients in TH and 44% patients in normothermia group were cognitively intact or had only very mild impairment. Severe cognitive deficits were found in 15% and 28% of patients, respectively. All EEG parameters were better in the TH-treated group, but the differences did not reach statistical significance.
Half of the OHCA survivors had cognitive impairment, which was mostly mild. Cognitive outcome did not differ (p N 0.30) between the 2 temperature groups (33
?C/36 ?C). Compared with Control subjects with
ST-segment-elevation myocardial infarction, attention/mental speed was more affected among OHCA patients, but results for memory and executive functioning were similar.
The results from the CK-MB analyses revealed a significantly lower CK-MB area under curve of 1829 mg/L/h (800-6799) in the 24-h group, compared with 2428 mg/L/h (1163-10,906) in the
48-hour group; p b 0.05 Survival to hospital discharge was similar among the intervention and control groups
among patients with VF (62.7%vs 64.3%, respectively; p = 0.69) and among patients without VF (19.2% vs 16.3%, respectively; p
= 0.30).
The intervention was not associated with improved neurological status of Full recovery or mild impairment at discharge for either patients with VF (57.5% of cases had full recovery or mild impairment vs 61.9%of controls; p = 0.69) or those without VF (14.4% of cases vs 13.4% of controls; p = 0.30). There is also an increased risk of rearrest after initial ROSC.
The use of TH was not associated with cognitive decline or neurophysiological deficits after OHCA.
Cognitive function was comparable in survivors of OHCA when a temperature of 33 ?C and 36 ?C was targeted. Cognitive impairment detected in CA survivors was also common in matched control subjects with ST-segment-elevation myocardial infarction not having had a CA.
It seems unlikely that the duration of TTM has a beneficial effect on the extent of myocardial injury after OHCA and may even have a worsening effect.
Prehospital TTM reduced core temperature by hospital arrival and reduced the time to reach a temperature of 34 ?C, it did not improve survival or neurological status among patients with or without VF.
TH group had significantly lower oxygenation, increased pulmonary edema on first chest x-ray, and greater use of diuretics during the first 12 h of hospitalization compared with the control group.
Abbreviations: return of spontaneous circulation: ROSC, cardiac arrest: CA; therapeutic hypothermia: TH; targeted temperature management: TTM.
a Quality of evidence and definitions (GRADE system) [14]: Grade A: High level of evidence (The true effect lies close to our estimate of the effect.); Grade B: Moderate level of evidence (The true effect is likely to be close to our estimate of the effect, but there is a possibility that it is substantially different.); Grade C: Low level of evidence (The true effect may be substan- tially different from our estimate of the effect.); Grade D: Very low level of evidence (Our estimate of the effect is just a guess, and it is very likely that the true effect is substantially different from our estimate of the effect.).
b Risk of bias: Studies were assessed for bias using the risk of bias criteria developed by Cochrane [15] which is based upon Cochrane’s Risk of Bias Tool [16]. Studies were assessed with regard to selection bias, performance bias, detection bias, attrition bias, reporting bias, and other sources of bias. Studies were rated as “low risk of bias (L)”, “high risk of bias (H),” or “un- clear risk of bias (U)” on a general impression after evaluating all criteria.
Endpoints
The primary endpoint was to find out the safety of and adverse ef- fects attributed to TH as defined within each study. The secondary end- points were to identify which specific untoward effects or complications are encountered in certain subgroups of patients receiving pre- or in- hospital TTM.
A flow chart displayed the phases of screening and selection of arti- cles, with reasons for exclusion (Fig. 1).
Results
The initial data search yielded 78 potentially relevant studies; of these, 59 were excluded for some reason. The main reason for exclusion
Records identified from electronic databases and other searchable sources
Records downloaded in full, screened and analysed (n=19)
Fig. 1. Flow diagram of study selection for systematic review of the adverse effects related to the procedure of Therapeutic hypothermia .
(n = 43, 55.1%) was that irrelevance to adverse effects of TH, followed by those totally irrelevant to TH (n = 9, 11.5%). and study protocols (n = 5, 6.4%). Finally, 19 researches underwent full-text review, and were analyzed for the study purposes (Fig. 1).
Data collected for the review of the 19 clinical studies included in the analysis of the side/adverse effects attributed to TH following OHCA were tabulated and summarized (Table 2). With respect to quality of evidence per GRADE guidelines, there were 7 (36.8%) high (A), 6 (31.5%) moderate quality (B) and 5 (26.3%) low quality
(C) and 1 (5.2%) very low quality evidence (D) derived from the studies.
Our GRADE assessment suggested that there was a high concern for risk of bias, particularly verification bias, and substantial inconsistency between studies in terms of their design. Specifically, methodologies of 5 studies (26.3%) were found to have high risk of bias, while 8 (42.1%) had low risk of bias and 6 (31.5%) had undefined risk of bias.
Findings derived from the analyzed articles
The present study culminated findings related to side/adverse ef- fects and/or complications attributed to TH following resuscitation from OHCA in a systematic fashion (Table 2).
Safety/effectivity: Most studies indicated the safety and efficient use of the procedure in patients resuscitated from OHCA. Pichon et al. pointed out that an intravascular cooling system can be an ef- fective and safe way to reach a target temperature [17]. Hammer et al. and Kamarainen et al. noted that prehospital infusion of large-volume, ice-cold saline can be used safely and effectively in pa- tients with OHCA [18,19]. On the other hand, intranasal evaporative
cooling using the Rhinochill system was reported to be feasible in an urban, prehospital, doctor/paramedic response unit by Lyon et al. [20].
General and miscellaneous side effects: Deye et al. put forth that endovascular and surface cooling yielded similar rates of side effects or complications in TH-treated patients following OHCA [21]. In an- other study, Gagnon et al. investigated the effect of antibiotic pro- phylaxis on survivors of OHCA who had undergone TTM (32-34
?C) and noted that it was associated with a substantial decline in the rate of pneumonia, although the treatment had no impact on outcome [22]. Jacob et al. focused to examine the effects of TH at 33 ?C on impaired hemostasis or increased frequency of bleeding and thrombotic events compared to TTM at 36 ?C and concluded that there was no such untoward outcome following the procedure [23]. In a more recent study, Kirkegaard et al. studied the impact of the time period of application of TH on adverse events and cited that the 48-hour TTM group was associated with more common ad- verse effects than the procedure lasting for only 24-h [24].
-Related to TH but irrelevant to adverse / untoward effects of TH (n=43)
-Totally irrelevant to TH (n=9)
-No details written in the article (n=1)
-Related to TH used in trauma (n=1)
Cardiac arrhythmias: Most researchers found that arrhythmias were common in patients undergoing TH following OHCA and of comparable frequency to those noted in patients treated without TH [25,26]. Thomsen et al. wrote that patients with AF treated with TTM at 33 ?C and 36 ?C had similar outcomes following OHCA [27]. On the other hand, bradycardia was associated with lower mor- tality and favorable neurologic outcome in comatose OHCA patients treated by TTM [28].
Furthermore, some researchers demonstrated that TH can provide better survival-to-hospital discharge outcomes and reduce cardiac arrhythmia in patients with OHCA as compared to normothermia [29].Ventricular ectopic activity was reduced in comatose OHCA- survivors treated with TTM at 36 ?C compared to 33 ?C [30].
Cognitive and/or neurophysiological consequences: Most re- searches cited that the outcomes were similar between STEMI and OHCA survivors treated with TTM and it was not associated with cognitive or neurophysiological deficits [31,32]. The data is clear that TTM improves Neurologically intact survival (both at 33 ?C and 36 ?C). Lilja et al. postulated that cognitive function was compa- rable in survivors of OHCA when a temperature of 33 ?C and 36 ?C had been targeted [33].
Studies with negative findings
One prominently negative interpretation was derived from the study by Grejs et al., in a recent study. They reported that the duration of TTM does not appear to have any beneficial effect on the extent of myocardial injury after OHCA and may even have a worsening effect [34]. This study focused on the myocardial injury associated with OHCA and its situation following TTM procedure. Another negative study was a population-based one from USA by Kim et al., which re- vealed that prehospital application of TTM helped to reduce the time to lower the temperature significantly, but it did not improve survival or neurological status among patients with or without VF [35]. This study also emphasized an increased risk of rearrest after initial ROSC.
The intervention (TH) group had significantly lower oxygenation, increased pulmonary edema on first chest x-ray, and greater use of di- uretics during the first 12 h of hospitalization compared with the con- trol group.
Table 3 summarizes the distribution of adverse effects and/or com- plications attributed to TH.
Discussion
Arrich et al. Published a Cochrane review based on randomized con- trolled trials in adults with OHCA comparing cooling in the field vs in-
Distribution of adverse effects and/or complications attributed to therapeutic hypothermia (TH).
Organ system Adverse effects Specific measures
Cardiovascular Sinus tachycardia Peripheral vasoconstriction Bradycardia
Increased contractility
‘Cold diuresis’
Prolonged action potential duration
J (Osborn) waves, prolonged PR, QRS, and QT intervals Hypertension
ventricular dysrhythmias coronary vasoconstriction
Pulmonary Neurologic pulmonary edema
Acute respiratory distress syndrome Pneumonia
Infections Suppression of the immune system Meningitis
Pneumonia Wound infections
Hematological low platelet count
Increased blood loss and transfusions with surgery Coagulopathy
Renal Diuresis
Renal tubular dysfunction Reduced creatinine clearance Depletion of electrolytes
Fluid boluses
bedside monitoring of the rhythm, right heart filling, vena cava inferior index etc. (via Swan-Ganz catheter)
Beware of fluid depletion
Dysrhythmias are typically managed conventionally
Pneumonia incidence is not increased if TH b48 h
Suctioning, head elevation, sedation breaks reduce ventilator associated pneumonia incidences
Cultures, prophylactic antibiotics, and removal of unnecessary catheters may decrease the Incidence of infection.
Extra caution must be exercised to prevent bedsores and monitor any catheter insertion sites closely
Close monitoring is warranted.
Analyses may be masked if performed after rewarming Returns to normal after rewarming
Fluid and Electrolyte disorders
Hypokalemia, hypomagnesemia, hypophosphatemia, hypo- and hyperglycemia
Frequent measurement and repletion of deficient serum magnesium and other electrolytes
Acid-base Increased serum lactate Ketonemia
Metabolic acidosis
Endocrine effects Hyperglycemia Hypoinsulinemia
Gastrointestinal Ileus
Delayed gastric emptying
Although still debated, tight control of blood glucose might be beneficial Early enteral nutrition is feasible in those without ileus
Liver function and drug metabolism
Reduced P450 activity
Reduced plasma clearance of drugs
Propofol, fentanyl, and acetaminophen are commonly associated with ADRs
Reversed after rewarming
Adding a bolus as opposed to increasing the drip rate is advised to achieve more sedation
Judicious use and close monitoring of drugs
Neurological Seizures
EEG abnormalities/malignant EEG
Decreased incidence with a target temperature of 32 ?C EEG monitoring to prevent seizures.
Others-miscellaneous Shivering Buspirone (PO) and/or meperidine (IV), skin warming work for treatment
hospital setting [36]. Adverse events were rare: based on four studies with 1713 adults pre-hospital induction of cooling may increase the risk of car- diac rearrests. 183 per 1000 persons in the in-hospital cooling group vs 225/1000 in the pre-hospital cooling group. The present study was not meant to perform a mortality analysis, therefore we’ll not compare rele- vant findings. This Cochrane review also noted that hyperglycemia was significantly more common in the in-hospital cooling group [odds ratio:
0.70 (0.55 to 0.89)] and therefore we can estimate that immediate cooling
could have exhibit a protective effect on glucose metabolism and blood glucose levels. Otherwise, there were not any significant differences be- tween the two groups in terms of timing of TTM initiation.
Another Cochrane review, assessed the influence of TTM after CA on neurological outcome, survival and adverse events [37]. Across all studies (1412 participants overall), the incidence of pneumonia (RR 1.15, 95% CI 1.02 to 1.30; two trials; 1205 participants) and hypokalemia (RR 1.38, 95% CI 1.03 to 1.84; two trials; 975 participants) was slightly increased among participants undergoing TTM, and no significant differences were noted regarding adverse events between hypothermia and control groups.
The present review also indicated that a number of side effects or ad- verse outcomes appear to be more frequent in those subjected to TTM. Nonetheless, the findings showed that the procedure - in the given range - has not caused severe consequences leading to significant wors- ening following resuscitation from OHCA.
Limitations
Limitations of this article are similar to all review articles: the depen- dence on previously published research and availability of references as
outlined in the present methodology. There is also a lack of published Level I and Level II studies specific to this topic in the world’s literature. Another limitation of the review is that some of the included studies are sub-studies of the Nielsen TTM trial (references [23,27,28,30,33]). Although all these sub-studies focused on analyses of complications, overrepresentation of information from one data set and/or population
is a vulnerable point for the article per se.
Conclusion
Studies included in the analysis disclosed the safety and feasibility data derived from the usage of TH. A great majority of studies favored practice of TH in the treatment of patients with OHCA, although differ- ent temperature ranges and durations of treatment are in clinical use. The findings of this systematic review indicated that the procedure of TH did not cause prominent untoward effects leading to significant al- terations in the outcomes of the patients following resuscitation from OHCA.
Authors’ contributions
OK, HT, contributed to refining the study question, outcomes and methods including search strategy and writing the first draft and final manuscript and generated the data extraction form. OK, HT, OD and OD contributed to the protocol methods and the final revision of the manuscript. OK, HT, OD and OD contributed to the development of search strategy and the critical revision of the final manuscript. OK, HT, OD and OD are the guarantor of this review, contributed to the
conception and design of the study, critical revision of the manuscript and final revision. All authors have read and approved the final version of the manuscript.
Declarations of interest
None.
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