Incidence of Myocardial Injury and Cardiac Dysfunction Following Adult Traumatic Brain Injury: A Systematic Review and Meta-Analysis

Abstract

Myocardial injury and cardiac dysfunction following traumatic brain injury (TBI) have been reported in observational studies, but there is no robust estimate of their incidences. We conducted a systematic review and meta-analysis to estimate the pooled incidence of myocardial injury and cardiac dysfunction among adult TBI patients. A literature search was conducted using MEDLINE and EMBASE databases from inception to November 2022. Observational studies were included if they reported at least one of abnormal ECG findings, elevated cardiac troponin level, or echocardiographic evaluation of systolic function or left ventricular wall motion in adult TBI patients. Myocardial injury was defined as elevated cardiac troponin level according to the original studies and cardiac dysfunction was defined as presence of left ventricular ejection fraction < 50% or regional wall motion abnormalities assessed by echocardiography. The meta-analysis of the pooled incidence of myocardial injury and cardiac dysfunction was performed using random-effects models. The pooled estimated incidence of myocardial injury following TBI (17 studies, 3,773 participants) was 33% (95% CI 27% - 39%, I², 93%) and the pooled estimated incidence of cardiac dysfunction following TBI (9 studies, 557 participants) was 16.% (95% CI 9% - 25.%, I² = 84%). Although there was significant heterogeneity between studies and potential over-estimation of the incidence of myocardial injury and cardiac dysfunction, our findings suggest that myocardial injury occurs in approximately one-third of adults following TBI and cardiac dysfunction occurs in approximately one-sixth of TBI patients.

INTRODUCTION

Traumatic brain injury (TBI) poses a significant burden of morbidity and mortality globally¹. Although cranial/neuronal injury is the primary insult, patients with TBI can also develop multi-organ dysfunction^2–4. Patients with severe TBI often develop hypotension following injury, which can reduce cerebral perfusion, contribute to secondary brain injury, and increase mortality risk.

Electrocardiographic (ECG) changes following non-traumatic brain injury, including subarachnoid hemorrhage and stroke, have been described for decades^5–7. More recently, awareness of myocardial injury and cardiac dysfunction following TBI has increased due to evaluation with biomarkers of myocardial injury and echocardiography. Additionally, observational studies suggest that brain-heart interactions may play a pivotal role in the pathophysiology of hemodynamic instability following TBI^8,9, though a causal relationship has not been clearly established.

While observational studies have contributed to the understanding of TBI-related cardiac abnormalities, estimates of the incidence of myocardial injury and cardiac dysfunction following TBI are limited due to studies with small sample sizes and heterogeneous definitions. To address this, we conducted a systematic review and meta-analysis to estimate the pooled incidence of myocardial injury and cardiac dysfunction among adult patients with TBI.

METHODS

This review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses standards (PRISMA) 2020 statement ^10,11 and used the methodological guidance for systematic review of prevalence and incidence by a working group of the Joanna Briggs Institute¹². The protocol was pre-registered in the International Prospective Register of Systematic Reviews (CRD42020179315). A literature search was conducted to identify studies that examined cardiac abnormalities in adult patients with TBI. We performed an electronic search using MEDLINE and EMBASE databases from inception to November 2022, as well as article reference lists. The search strategy included the use of text words and Medical Subject Headings (MeSH) related to “traumatic brain injury”, “echocardiography”, “troponin”, “myocardial injury”, or “cardiac function”. Full search terms for both databases are listed in Supplemental Digital Content 1. The inclusion was not limited by sample size or language used. No ethical approvals were sought for this systematic review and meta-analysis of previously published data.

Selection criteria

Observational study designs, including case-control, cross-sectional, and cohort studies, were eligible for this systematic review. We included studies in which the population included patients who were diagnosed with TBI, regardless of gender, injury severity, or presence of associated injuries. Studies published only in abstract form, case reports, editorials, opinion articles, and letters were excluded. We also excluded studies reporting cardiac dysfunction in the pediatric TBI patients (age < 16 years), and studies in patients with brain death. The included studies must report at least one of the following indicators for myocardial injury or cardiac dysfunction: 1) abnormal ECG findings, including arrhythmias, QT prolongation, and ST-T changes, 2) elevated cardiac troponin level, or 3) echocardiographic evaluation of systolic function or left ventricular wall motions at any time point within the same admission following TBI.

Two independent investigators (NC and TK) ran the electronic search according to the protocols. After removal of any duplicates, the titles and abstracts of the studies were screened and independently evaluated for eligibility (NC and TK). Any differences in the determination of the eligibility of a study were resolved by a third investigator (VK). To avoid double counting, only one set of results was selected when data from the same cohort/database was utilized in multiple publications.

Data extraction and outcomes

Two investigators (NC and TK) independently extracted data from each study using a structured information collection form in an excel spreadsheet. Data extracted from the eligible studies included the title of the study, first author last name, published journal, year of publication, year (s) the study was conducted, the country where the study was conducted, the type of the study, study population (case and control), the method used to recruit/identify myocardial injury and cardiac dysfunction, the definition of cardiac dysfunction used by echocardiographic evaluation, types and cut-off point for troponin elevation reported in each study, the number of TBIs, and demographic/clinical data of TBI with/without myocardial injury and cardiac dysfunction (gender, age, polytrauma, injury severity). Cardiac indices of interest were: 1) left ventricular ejection fraction (LVEF), 2) fractional shortening (FS), 3) fractional area change (FAC), 4) presence of regional wall motion abnormalities (RWMA), 5) echocardiographic strain abnormalities, and 6) troponin level. There were no restrictions on the types of troponin assays used. It is challenging to compare the cut-off value of different troponin assays; therefore, we defined troponin elevation according to that used in the original studies. Due to variations in the definitions of cardiac dysfunction, we also extracted definitions of cardiac dysfunction as reported in individual studies.

The primary outcomes were the incidence of myocardial injury and cardiac dysfunction in adult patients with TBI. Myocardial injury was defined as elevated cardiac troponin level compared to reference values in the original manuscript and cardiac dysfunction was defined as the presence of either impaired left ventricular systolic function assessed using echocardiography and as defined using criteria according to the original studies, or the presence of RWMA assessed using echocardiography. We did not include patients with abnormal ECG patterns in the meta-analysis because ECG changes are less specific to myocardial injury or cardiac dysfunction than elevated troponin or abnormal echocardiographic findings.

Risk of bias assessment

Two reviewers (NC and TK) independently assessed the risk of bias of the individual studies using The Joanna Briggs Institute Critical Appraisal Checklist for studies reporting prevalence data¹². The appraisal checklist consisted of nine questions which could be divided into three categories: participants (questions 1,2,4, and 9), outcome measurement (questions 6 and 7), and statistical analysis (question 3, 5, and 8). Question 5 was excluded as it was redeemed irrelevant to the included studies. Therefore, a total of eight questions were assessed by the two reviewers. Any disagreement was resolved by the third investigator (VK). Since conventional funnel plots are inaccurate for assessing potential publication bias in meta-analyses of proportion studies¹³, we used the Doi plot and Luis Furuya-Kanamori asymmetry index (LFK index)¹⁴ to examine the publication bias. The Doi plot represents normal quantile against effect size to improve the visual precision for detecting asymmetry. The LFK index is used to quantify asymmetry of the overall study effects. A LFK index of within ± 1, within ± 1 to ± 2 interval, and beyond ± 2 interval indicate no asymmetry, minor asymmetry, and major asymmetry, respectively.

Statistical analysis

The pooled incidence of myocardial injury (elevated troponin levels) and cardiac dysfunction (LVEF < 50% or presence of RWMA) following TBI across studies was calculated as the proportion and confidence intervals (CIs)¹⁵. The meta-analysis of both the pooled incidence of myocardial injury and the pooled incidence of cardiac dysfunction was performed using random-effects models, assuming that all studies did not yield the same results because they were observational studies that included different populations. The pooled incidence of subsets according to types of TBI (isolated versus non-isolated, mild versus moderate-severe) was also explored. For secondary analysis of the outcomes of myocardial injury/cardiac dysfunction, the pooled effect estimates of mortality were calculated by combining the effect estimates of each eligible study using generic inverse variance method and presented as odds ratio (OR) with 95% CIs. We used a random-effects model due to the heterogeneity of the studies.

The magnitude of heterogeneity between studies was evaluated with the Q test and I² statistics¹⁶. A range of I² 0 – 25%, 26 – 50%, 51 – 75%, and > 75% represent insignificant, low, moderate, and high heterogeneity, respectively¹⁷. We also calculated the 95% prediction intervals for the pooled incidence and the pooled ORs in order to provide an estimate of the expected effects if future studies might be conducted ^18,19. Sensitivity analyses were performed to test the robustness of the overall estimates and to explore the potential causes of heterogeneity based on included the population, timing of evaluation, study design, and risk of bias. We used MetaXL v 5.3 (EpiGear International, Sunrise Beach, Queensland, Australia) in Microsoft Excel for Windows (https://www.epigear.com/index_files/metaxl.html) to perform the analyses of incidence, the Doi plot, and LFK index. Review Manager (RevMan [Computer program], Version 5.4, The Cochrane Collaboration, 2020) was used for the meta-analysis of mortality.

RESULTS

The search identified 22,435 articles of which 3,080 duplicates were removed. Following exclusion of a further 19,210 articles based on title, 145 abstracts were accessed for eligibility from which 64 articles were identified for full-text review. Four studies in the pediatric population, eight studies in patients with brain death, and three that did not report the number of patients with TBI were excluded. We also excluded eight studies because the primary outcome was not reported, and twelve studies which reported only ECG abnormalities or creatine kinase. Additionally, six studies that used overlapping datasets were also excluded. One study²⁰ reported used FS < 25% as a definition for cardiac dysfunction, and was excluded. Finally, 22 eligible studies were included in the meta-analysis^21–42 (Figure 1).

Figure 1. Flowchart of study selection.

Summary of the studies reporting myocardial injury and cardiac dysfunction following TBI

A total of 22 studies reporting troponin elevation or abnormal echocardiography involving 4,066 participants with TBI from 12 countries were included in the meta-analysis^21–42. The characteristics of the studies and reported incidence of myocardial injury and cardiac dysfunction are shown in Table 1. The methods used to evaluate myocardial injury and cardiac dysfunction following TBI and the timing of evaluation varied among studies. Eleven studies reported only elevated troponin ^{21–23,26–28,30,32,34,37,38}, six reported abnormal echocardiographic findings^{20,24,25,36,40,41}, while six studies evaluated both troponin and echocardiography after TBI^{29,31,33,35,39,42}. The troponin assays used and cut-off points also varied among the studies that reported troponin elevation. Fourteen studies used troponin I^{21–23,26,27,29–31,33–35,37–39} (threshold ranged between 0.056 ng/mL and 0.4 ng/mL), while three studies used troponin T^28,32,42, two of which^28,32 used high sensitivity troponin T with threshold of > 99^th percentile. For timing of troponin evaluation, one study²⁹ did not mention when serum troponin samples were obtained. Serum troponin data were available on admission in seven studies^{21,22,26,30,33,34,38}, and within 24 h of admission in eight studies^{23,26–28,31,32,37,38}. Serial serum troponin was obtained in only six studies^{21,26,30,31,38,39}, of which three studies followed troponin levels until day 3 ^26,30,31 and one study until day 4³⁹. Moreover, one study followed troponin levels until day 5 and reported that serum troponin reached a peak on day 3 and reduced thereafter²¹.

Table 1.

Summary of the studies reporting incidence of troponin elevation and abnormal echocardiography in patients with traumatic brain injury

Author/Year	Country	Study design	Time of evaluation	Definitions of myocardial injury/ cardiac dysfunction	Total TBI (n)	Prevalence n (%)
Troponin studies (11 studies)
Baffoun et al. 201120	Tunisia	Prospective	On admission, D3, D5	Elevated Troponin I	35	12 (34%)
Bender et al. 202021	Germany	Retrospective	On admission	Troponin I > 0.05 mcg/L	288	59 (20%)
Cai et al. 201622	USA	Retrospective	Within 24 hours	Troponin I ≥ 0.06 ng/mL	580	179 (31%)
Dixit et al. 200025	USA	Prospective	On admission, D1, D2, D3	Troponin I ≥ 0.4 mcg/L	34	6 (18%)
Dou et al. 202226	China	Retrospective	Within 24 hours	Troponin I ≥ 0.04 ng/mL	67	30 (45%)
El-Menyar et al. 201927	Qatar	Retrospective	Within 24 hours	High-sensitivity troponin T > 14 ng/L	1471	647 (44%)
Hamdi et al. 201229	Egypt	Prospective	On admission, D3	Troponin I > 0.2 mcg/L	32	14 (44%)
Krishnamoorthy et al. 202232	USA	Prospective multicenter	Within 4 h	High sensitivity troponin > 99th percentile	133	26 (20%)
Lippi et al. 201634	Italy	Retrospective	On admission	Troponin I > 99th percentile (> 40 ng/L)	145	99 (68%) (>10 ng/L) 31 (21%) (> 40 ng/L)
Rimaz et al. 201937	Iran	Prospective	Within 24 h	Troponin I ≥ 0.06 ng/mL	166	87 (52%)
Salim et al. 200838	USA	Retrospective	On admission, 24 to 48 hours	Troponin I > 0.3 ng/mL	420	125 (29%) (on admission) 173 (41%) (during hospitalization)
Echocardiographic studies (6 studies)
Chaikitisilpa et al. 201923	USA	Prospective	Within 24 hours	TTE (LVEF < 50%)	15	2 (13%)
Cuisinier et al. 201624	France	Prospective	Within 24 hours	TTE (LVEF < 50%)	20	0 (0%)
Krishnamoorthy et al. 201731*	USA	Prospective	D1, D2–4, D7–9	TTE (FS < 25%)	64	7 (11%)
Stewart et al. 200741	USA	Prospective	Within 24 h	TTE (LVEF < 40%) or diastolic dysfunction	28	15 (54%)
Praveen et al. 202136	India	Prospective	Pre- and postoperatively within 48 h	TTE (LVEF < 50% or RWMA)	60	8 (13%)
Srinivasaiah et al. 202240	India	Prospective	Within 48 hours (pre & postoperative D1)	TTE (LVEF < 50% or RWMA)	110	13 (12%)
Studies using both troponin and echocardiography (6 studies)
Gibbons et al. 201928	USA	Retrospective analysis of prospective cohort	Not mentioned	Troponin I ≥ 0.04 ng/mL,	114	60 (53%)
				TTE (LVEF < 50% or RWMA)	72	23 (32%)
Hasanin et al. 201630*	Egypt	Prospective	D1, 3	Troponin I > 0.056 ng/mL	50	27 (54%)
			Within 12 h, D3, D5, D7	TTE (LVEF < 55% or RWMA)	50	14 (28%)
Lee et al. 201633	Korea	Prospective	On admission (Troponin) Within 1 week (TTE)	Abnormal TTE (reduced LVEF or RWMA), ECG changes, and elevated troponin I > 0.4 ng/mL	64	4 (6%)
Prathep et al. 201435	USA	Retrospective	Within 14 days	Troponin I > 0.4 ng/mL	107	24 (22%)
				TTE (LVEF < 50% or RWMA)	139	31(22%)
Serri et al. 201639	Canada	Prospective	Daily the first 4 days	Troponin I > 0.1 mcg/L	43	15 (35%)
			Within 4 days	TTE (LVEF < 50% or RWMA)	49	4 (8%)
Venkata et al. 201842*	USA	Prospective	Anytime	Troponin T ≥ 0.04 ng/mL	24	6 (25%)
			Within 48 h	TTE (LVEF < 55% or RWMA)	46	6 (13%)

^*3 studies were excluded from the meta-analysis of the incidence of cardiac dysfunction due to the definitions used for cardiac dysfunction

FS, fractional shortening; LVEF, left ventricular ejection fraction; RWMA, regional wall motion abnormality; TBI, traumatic brain injury; TTE, transthoracic echocardiogram

In the 12 studies that included echocardiographic results^{20,24,25,29,31,33,35,36,39–42}, impaired left ventricular (LV) systolic function was reported in all studies. Low LVEF was used to identify patients with cardiac dysfunction in 11 studies; LVEF < 50% in seven studies^{24,25,29,35,36,39,40}, < 55% in two studies^31,42, < 40% in one study⁴¹, and not defined in one study³³. Fractional shortening < 25% was used in one study²⁰. We excluded studies using LVEF < 55% and FS < 25% as criteria for cardiac dysfunction from the final analysis to remain consistency of the definition. Therefore, a total of 9 studies examining cardiac dysfunction were included in the final meta-analysis. The presence of RWMA was examined in seven studies^{29,33,35,36,39,40,42}; however, most did not report any details about RWMA. Only five studies^{20,25,36,39,41} explored echocardiographic LV diastolic function abnormality but did not provide the definition for diastolic dysfunction; therefore, we could not perform meta-analysis of the incidence of diastolic dysfunction. For timing of echocardiographic evaluation, echocardiography was performed within 24–48 h in seven studies^{20,24,25,31,40–42}. Two studies^20,31 provided data on serial echocardiography throughout the first week, but only one²⁰ reported echocardiography trajectory change in which cardiac dysfunction occurred within the first 24 h and then recovered.

The characteristics of the included patients also varied between studies (Supplemental digital content 2: Table showing patient characteristics). Sixteen studies included only patients with TBI, three studies included acute trauma patients^27,34,41, and three included patients with other acute neurologic events^21,26,33. Among the included studies, 13 (2,161 participants, 53%)^{21–25,31,32,34–38,40} reported myocardial injury/cardiac dysfunction in patients with isolated TBI. The severity of TBI was reported in 15 studies (2,219 participants)^{20–25,29,31,32,35–40,42}, and most included patients with moderate-severe TBI (1,877 participants, 46%).

Quality of evidence

The quality of the 22 studies was assessed using The Joanna Briggs Institute Critical Appraisal Checklist for studies reporting prevalence data¹². The risk of bias assessment (yes, no, unclear or not applicable) is shown in supplemental digital content 3 and details of how each of the domains were scored are explained in supplement digital content 4. Overall, the risk of bias was considered moderate, but all of the included studies had limitations in at least one of the three domains (participants, outcome measurement, and statistical analysis). Inappropriate sample frame and insufficient sample size were the main risks of bias in most of the studies. Only two studies ^39,42 included our target population (adult patients with moderate-severe TBI with and without polytrauma), while 12 studies^{21–25,32,34–38,40} included only patients with isolated TBI. Concerning outcome measurement, studies described how serum troponin samples were obtained and reported cut-off values, except for one study²¹. Details of the echocardiogram performed, and timing of the evaluation were clearly described in most studies, though two^29,35 did not mention the timing of the evaluation. Though most studies performed appropriate statistical analyses, the sample size was considered adequate in only 10 studies^{22,23,28,29,32,34,35,37,38,40}.

Meta-analysis of the incidence of myocardial injury following TBI

The pooled incidence of myocardial injury (elevated troponin) after TBI (reported in 17 studies ^{21–23,26–35,37–39,42}, 3,773 participants) was 33% (95% CI 27% - 39%, 95% prediction interval 21 % - 48%, I² = 93%) (Figure 2). For subgroup analysis, 1,924 patients with isolated TBI were identified from 9 studies^{21–23,31,32,34,35,37,38}. The pooled incidence of myocardial injury among patients with isolated TBI was 32% (95% CI 24% - 40%, 95% prediction interval 19% - 49%, I² = 92%). The pooled incidence of myocardial injury among patients with moderate-severe TBI (10 studies^{21–23,29,32,35,37–39,42}, 1,601 participants) was 37% (95%CI 30% - 44%, 95% prediction interval 25% - 51%, I² = 85%).

Figure 2. Forest plots of the 17 studies reporting the incidence of myocardial injury (elevated troponin) following traumatic brain injury.

The diamond represents the pooled incidence from each of the included studies (squares) and 95% confidence interval.

Meta-analysis of the incidence of cardiac dysfunction following TBI

The pooled incidence of cardiac dysfunction (LVEF < 50% or RWMA) after TBI (reported in 9 studies ^{24,25,29,33,35,36,39–41}, 557 participants) was 16% (95% CI 9% - 25%, 95% prediction interval 7% - 34%, I² = 84%) (Figure 3). 344 patients with isolated TBI were identified from 5 studies^{24,25,35,36,40}. The pooled incidence of cardiac dysfunction in patients with isolated TBI was 13% (95% CI 6% - 21%; 95% prediction interval 5% - 31%, I² = 69%). The pooled incidence of cardiac dysfunction in patients with moderate-severe TBI (7 studies^{24,25,29,35,36,39,40}, 375 participants) was 15% (95%CI 8% - 23%, 95% prediction interval 7% - 31%, I² = 74%).

Figure 3. Forest plot of the 9 studies reporting incidence of cardiac dysfunction (left ventricular ejection fraction < 50% or regional wall motion abnormality from echocardiography) after traumatic brain injury.

The diamond represents the pooled incidence from each of the included studies (squares) and 95% confidence interval.

Mortality among TBI patients with myocardial injury and cardiac dysfunction

In-hospital mortality among patients with and without myocardial injury after TBI was reported in 6 studies^{21–23,28,37,38}, including 1,803 participants. A meta-analysis performed to determine the association between myocardial injury and mortality after TBI found that myocardial injury was associated with a higher risk of in-hospital mortality (OR 3.98, 95% CI 2.70 – 5.86, 95% prediction interval 1.19 – 13.31, p < 0.0001, I² = 70%) (Figure 4A).

Figure 4. Forest plot of the included studies reporting pooled estimated odds ratios for mortality in patients with myocardial injury and cardiac dysfunction after traumatic brain injury.

A. Myocardial injuryB. Cardiac dysfunctionThe diamond represents the pooled incidence from each of the included studies (squares) and 95% confidence interval.

Among the included studies reporting cardiac dysfunction from echocardiographic evaluation, 6 studies^{24,25,35,36,39,40} (314 participants) also reported in-hospital mortality. In one study, none of the patients in the study died; therefore, this study was not included in the meta-analysis³⁶. Compared with patients without cardiac dysfunction, the pooled OR for mortality in patients with cardiac dysfunction was 4.65 (95% CI 0.98 – 21.99, 95% prediction interval 0.05 – 390.59, p = 0.05, I² = 44%) (Figure 4B).

Sensitivity analysis

Due to the significant heterogeneity, we performed a sensitivity analysis to test for data consistency between studies (Supplemental digital content 5: Table showing sensitivity analysis). Myocardial injury was observed more frequently when troponin samples were obtained several times during admission. The pooled incidence of myocardial injury when troponin levels were obtained on admission was 25% (95%CI 15% - 36%, I² = 92%). Studies in which a single troponin sample was obtained tended to have lower incidence than those in which serial troponin samples were obtained (30% and 38%, respectively).

The incidence of cardiac dysfunction was similar when comparing studies evaluating single versus serial echocardiography assessments (Supplemental digital content 5: Table showing sensitivity analysis). When analyzing only the prospective studies which include echocardiography assessments, the incidence of cardiac dysfunction tended to be lower than that reported in the retrospective studies (13% and 26%, respectively).

ECG abnormalities

The incidence of ECG abnormalities were reported in nine studies including 689 participants (Supplemental digital content 6: Table showing the incidence of ECG abnormalities)^{21,29,31,33,36,39,42–44}. Two studies^43,44 reported only ECG abnormalities without troponin or echocardiographic evaluation and were excluded from the meta-analysis. Five studies^{29,31,33,39,42} reported ECG abnormalities with both troponin and echocardiographic evaluation, one study²¹ reported ECG and only troponin, and one study reported ECG and only echocardiography³⁶. The reported criteria for ECG abnormalities varied greatly among studies. Only four studies ^29,36,43,44 pre-specified the definition of ECG abnormalities. ST segment abnormality were used in six studies ^{33,36,39,42–44}, T wave inversion was used in six studies ^{29,33,36,39,43,44}, and abnormal QT interval was used in eight studies ^{29,31,33,36,39,42–44}. Arrhythmia was reported in five studies ^{21,31,36,43,44}. Since there was heterogeneity in the definition of ECG abnormalities and timing of ECG tests among studies, the incidence of ECG abnormalities following TBI varied between 37% - 88%. Moreover, ECG abnormalities are less specific for myocardial injury. Therefore, we did not include ECG abnormalities in the meta-analysis of the incidence of cardiac dysfunction.

Publication bias

The risk of publication bias was visualized across the 17 studies reporting myocardial injury after TBI. The Doi plot analysis and LFK index of the incidence of myocardial injury and cardiac dysfunction estimates are shown in supplemental digital content 7.

The Doi plot for myocardial injury demonstrated major asymmetry (LFK index, −3.08). For subgroup analysis, the Doi plot for the studies which included only patients with isolated TBI demonstrated no asymmetry (LFK index, 0.73) while the Doi plot for the studies among patients with moderate-severe TBI demonstrated major asymmetry (LFK index, −3.06). The risk of publication bias for the 9 studies reporting cardiac dysfunction using echocardiographic evaluation showed no asymmetry (LFK index, 0.22). For subgroup analysis, both the Doi plots for the studies which included only patients with isolated TBI and patients with moderate-severe TBI demonstrated minor asymmetry (LFK index, −1.45 and −1.28, respectively).

DISCUSSION

This systematic review and meta-analysis found that myocardial injury (elevated cardiac troponin level) occurred in approximately one-third of the patients and cardiac dysfunction (LVEF < 50% or RWMA on echocardiogram) occurred in about 16% of patients following moderate-severe TBI. Myocardial injury was associated with increased mortality. Given the high presence of myocardial injury and cardiac dysfunction in TBI patients and possible impact on poor patient outcomes, further research is needed to optimize the recognition and management strategies of patients with cardiac complications following moderate-severe TBI.

Traumatic brain injury is associated with single- and multi-organ dysfunction, which may be related to autonomic dysfunction following widespread catecholamine release via the hypothalamic-pituitary-adrenal axis and activation of the sympathetic nervous system^45–47. Initially adaptive, persistent sympathetic activation becomes maladaptive, resulting in multi-organ dysfunction. Specific to the cardiovascular system, high sympathetic tone and excess catecholamine levels result in vasoconstriction and increase in cardiac afterload and myocardial workload, and, subsequently, to increased myocardial oxygen demand. Due to simultaneous coronary vasoconstriction, a mismatch in cardiac oxygen delivery may lead to cardiac injury⁴⁸ which presents as contraction band necrosis under light microscopy⁴⁹. The resulting myocardial injury may be ascertained clinically through elevated cardiac troponin levels and may potentially lead to the development of cardiac dysfunction presenting as low LVEF or RWMAs. In addition to autonomic dysfunction, the robust dysregulated inflammatory cascade following TBI may also have a role in organ remodeling and subsequent dysfunction⁵⁰.

Given the high estimates of myocardial injury and cardiac dysfunction in moderate-severe TBI and its association with poorer immediate^23,29,31 and long-term outcomes^38,40, there may be a need for early cardiac monitoring in TBI patients. From this systematic review, seven studies reported troponin elevation on admission with a pooled incidence of myocardial injury of 25%, suggesting that cardiac injury may occur early after TBI. Meanwhile, the pooled incidence of myocardial injury was higher (38%) when serial troponin levels were obtained, indicating that more patients with moderate-severe TBI developed myocardial injury later during their hospital admission. Hence, continuous cardiac monitoring might be considered. However, the higher incidence of myocardial injury when serial troponin levels were obtained could be due to other factors such as sepsis⁵¹, renal failure⁵², or surgery⁵¹ which complicated TBI during the hospital course.

High heterogeneity among the available studies was observed, including in TBI severity, presence of associated injury, and timing of the cardiac evaluations. Therefore, it was not possible to rigorously examine the characteristics of those patients at risk for development of myocardial injury. Most of the studies were conducted in patients with moderate-severe TBI; therefore, the identified incidence of myocardial injury in patients with moderate-severe TBI was similar to the overall incidence. There may be specific patient subgroups who may benefit from increased cardiovascular monitoring, including patients with pre-existing cardiovascular comorbidities, and older patients who are at risk for hemodynamic instability, poorer outcomes and greater mortality, which should be further investigated. Currently, the guidelines for managing TBI patients recommend maintenance of systolic blood pressure above 100mmHg (50–69 years of age) and 110mmHg (others) to reduce mortality and improve outcomes⁵³ as a component the cardiovascular recommendations, without regard to the status of cardiac function.

In this analysis, cardiac monitoring was mainly conducted using serum cardiac troponin levels or echocardiography. Cardiac troponin was elevated in more patients (32%) compared to echocardiogram findings of reduced LVEF or RMWA (16%). However, it is important to interpret elevated troponin levels with respect to the sensitivity and specificity of the particular troponin assays used. There are no specific criteria for diagnosis of myocardial injury in patients with TBI or other neurologic injury. In this review, both troponin I and high-sensitivity troponin T were included and the cut-off points for troponin elevation based on the original studies were used, which may have resulted in the heterogeneity of the pooled incidence. Overestimation of the incidence of myocardial injury using elevated troponin level compared to cardiac dysfunction evidenced by echocardiographic evaluation may occur for the following reasons. First, the lower cut-off for elevated troponin may potentially create a false-positive result and lead to an over-estimation of myocardial injury^54,55. In the study by Lippi et al ³⁴, two detection limits (10 ng/L vs. 40 ng/L or 99^th percentile) were used and troponin elevation was reported in 68% and 21%, respectively. Second, troponin elevation reported in some of the studies may have been due to polytrauma since troponin elevation has been observed in trauma patients without TBI ^56,57.Moreover, the presence of low serum troponin concentration in healthy individuals has also been reported⁵⁸. Therefore, careful interpretation of troponin as a biomarker for myocardial injury following TBI should be made in the context of other cardiac parameters, in clinical practice or future research.

Nine studies^{21,22,26,29,31,33,39,42} included using ECG as part of the overall cardiac monitoring parameters assessed. However, ECG abnormalities do not necessarily correlate with troponin elevation^21,26 or abnormal echocardiography findings^31,33. Since ECG abnormalities are less specific for the diagnosis of cardiac dysfunction, we did not include ECG abnormality in this meta-analysis. Various factors other than injury to the myocytes may also cause ECG abnormalities in TBI patients, including pain, electrolyte abnormalities, and hypotension. Moreover, it is difficult to determine whether the ECG abnormalities were newly developed or pre-existing. Therefore, ECG abnormalities should be interpreted in conjunction with either troponin or cardiac imaging for the diagnosis of TBI-related cardiac dysfunction.

Although heterogeneity between studies was observed, our secondary analysis suggested an association between myocardial injury and in-hospital mortality following TBI. Elevated cardiac troponin levels have been reported in other neurological diseases, such as subarachnoid hemorrhage and stroke, and have been demonstrated to be associated with increased mortality regardless of the presence of coronary artery disease. Since cardiac troponin is a sensitive biomarker for cardiac injury and has a prognostic benefit for mortality, guidelines recommend routine assessment of serum troponin in patients with acute stroke⁵⁹. A meta-analysis El-Menyar et al.⁶⁰ also reported an association between elevated cardiac troponin and mortality in both TBI and non-TBI brain injury. Although patients with TBI generally carry lower risk of cardiovascular disease, serum troponin may potentially be a biomarker for cardiac injury after TBI.

While enhanced cardiac evaluation in TBI patients may improve clinical management, there remain significant areas for future research. Our analysis found various methods used and different timing for the initiation of cardiac evaluation. Therefore, the optimal timing for initiation and duration for monitoring troponin and echocardiography following TBI is unknown. Although there has been increased recognition of myocardial injury following TBI in recent years, few studies have evaluated the hemodynamic consequences and its relationship to cardiac dysfunction. In this analysis, the pooled incidence of myocardial injury was higher than the incidence of cardiac dysfunction. Although myocardial injury was associated with increased mortality, it was challenging to demonstrate whether death was related to cardiovascular impairment. In this analysis, six studies reported both troponin elevation and cardiac dysfunction using echocardiography, but none reported a relationship between troponin elevation and clinical or subclinical cardiac dysfunction. Future studies should examine the effects of myocardial injury to the patients, the association between troponin elevation and cardiac dysfunction, and how the recognition of cardiac dysfunction may modify hemodynamic management to optimize cerebral perfusion following TBI, in order to improve outcomes.

There are some limitations to this study. First, different troponin assays were used among the included studies with variations in threshold for troponin elevation; this created heterogeneity of the results. Troponin elevation can also occur due to reasons other than TBI, especially if troponin > 99^th reference value is used as the threshold. Cardiac troponins may be falsely elevated due to known cross-reactivities with alkaline phosphatase or rheumatoid factor⁵⁵. Moreover, troponin elevation has also been reported in trauma patients without TBI so troponin elevation in some of the studies may have been the result of polytrauma. This may explain the difference between the incidence of myocardial injury measured by cardiac troponin and the incidence of cardiac dysfunction assessed by echocardiography and have overestimated the incidence of myocardial injury. Second, it is impractical to have baseline troponin and echocardiographic evaluations before TBI, and developing a suitable control group for TBI patients may be challenging. Third, there are methodological confounders in the included studies. There was inconsistent timing of troponin and echocardiography assessments amongst studies. Given the potentially transient nature of cardiac dysfunction, LVEF and RWMA abnormalities may not be comparable if the echocardiogram is not conducted in the same timeframe (e.g., within 24 h of admission). Some studies also included ECGs, though many used them differently. For example, one study²¹ used T-wave changes in ECG as screening criteria, while another³⁹ measured ECG as part of cardiac monitoring. These methodological differences across these studies limit their overall comparability. Fourth, some studies conducted echocardiograms after vasopressor infusion despite the potential of vasopressors to mask reduced LVEF or RWMAs. Of note, in one study²⁹, echocardiograms were only undertaken when clinically indicated (rather than all patients), resulting in selection bias. Moreover, we focused echocardiographic-defined cardiac dysfunction primarily on LV systolic function and, hence, failed to include patients who might have had abnormal diastolic function or impaired right ventricular function. Finally, the analysis may be susceptible to publication bias, as the Doi plot showed asymmetry, since only studies with positive results were more likely to be published.

CONCLUSION

Despite significant variation in patient selection, methods, and timing of cardiac evaluation between studies, which may result in bias and over-estimation, this meta-analysis found that myocardial injury occurred in about one-third and cardiac dysfunction in approximately one-sixth of adult patients following moderate-severe TBI. The association between myocardial injury and cardiac dysfunction after TBI remains unclear and should be further investigated. However, myocardial injury was associated with increased mortality.

Supplementary Material

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Table showing search terms and results for MEDLINE and EMBASE

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Table showing patient characteristics of the included studies.

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Table summarizing the Joanna Briggs Institute Critical Appraisal Checklist for studies reporting prevalence data.

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Table showing criteria used for risk of bias grading of each domain of the Joanna Briggs Institute Critical Appraisal Checklist.

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Table showing sensitivity analysis.

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Table showing studies reporting the incidence of ECG abnormalities in patients with traumatic brain injury.

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Figure showing Doi plot analysis and LFK index of the incidence of myocardial injury and cardiac dysfunction estimates.