Intravenous Drug Use‐Associated Endocarditis Leads to Increased Intracranial Hemorrhage and Neurological Comorbidities

Abstract

Background

The United States is experiencing a rapidly increasing rate of opioid drug abuse. Intravenous drug use (IVDU)‐related endocarditis can lead to significant neurological complications with high morbidity and mortality. When patient care necessitates anticoagulation, the standards for radiographic screening and the risk for intracranial hemorrhage are not clearly elucidated.

Methods

We conducted a retrospective cohort study involving patients treated for infective endocarditis at a single institution from 2014 to 2018. Patients were grouped based in history of IVDU and their demographics and clinical predictors for intracranial hemorrhage were analyzed.

Results

A total of 351 patients met inclusion criteria for this study, of whom 170 patients (48%) had a history of IVDU‐associated endocarditis. IVDU was associated with an increased prevalence of intracranial hemorrhage (25.9% versus 13.9%; P=0.005), including intraparenchymal hemorrhage (12.4% versus 5.1%; P=0.012), subarachnoid hemorrhage (17.6 versus 4.4%; P=0.001), and cerebral microbleeds (14.1% versus 7.2%; P=0.022). IVDU was also associated with an increased incidence of infectious intracranial aneurysm (10.6% versus 1.8%; P=0.001) and brain abscesses (4.7% versus 1.1%; P=0.025). Multivariate analysis showed that the presence of intracranial septic emboli (odds ratio [OR], 18.47 [8.4–40.250]; P=0.001) and infectious intracranial aneurysm (OR, 12.38 [3.24–47.28]; P=0.001) as significant predictive factors for intracranial hemorrhage after presenting with endocarditis.

Conclusion

The opioid epidemic has increased the incidence of infective endocarditis and resultant neurovascular complications. IVDU‐associated endocarditis is associated with increased hemorrhagic stroke and more frequent neurodiagnostic imaging.

Nonstandard Abbreviations and Acronyms

ICH

intracerebral hemorrhage

IE

infective endocarditis

IIA

infectious intracranial aneurysm

IVDU

intravenous drug use

SAH

subarachnoid hemorrhage

Clinical Perspective

• The opioid epidemic has the incidence of infective endocarditis and resultant neurovascular complications.

• Intravenous drug use‐associated endocarditis is associated with increased hemorrhagic stroke and more frequent neurodiagnostic imaging.

• The presence of infectious intracranial aneurysms and septic emboli is a predictor of intracranial hemorrhage and symptomatic intraparenchymal hemorrhage after infective endocarditis.

The United States has been experiencing an increasing rate of opioid use disorders over the past 2 decades with the rate of drug overdose deaths tripling during this opioid epidemic. ¹ Mirroring this increase in death is an increase in hospitalization related to serious infections including infective endocarditis (IE) and its resultant neurological sequelae. ² IE is a major complication of intravenous drug use (IVDU) that results from valvular damage from repetitive bacterial/fungal infection introduced into the blood stream. ³ Neurological complications of septic emboli can result in stroke, brain abscesses, and infectious intracranial aneurysms (IIAs). These infections are associated with significant morbidity, mortality, and health care costs.

The need for anticoagulation during heart valve replacement presents a clinical dilemma with regard to risk factors for intracranial hemorrhage. There are limited data on IVDU‐associated IE with regards to risk for intracranial hemorrhage with a study showing an increase incidence of IIAs. ⁴ In these patients, there are limited data for recommendations on screening asymptomatic patients for intracranial hemorrhage and IIAs. ⁵ , ⁶ It is unknown whether a head computed tomography, computed tomography‐angiogram, or diagnostic cerebral angiogram are required to rule out intracranial pathology to facilitate risk management for valve replacement. ⁷ To date, there remains a lack of data on the neurological complications related to IVDU‐associated IE and the risk factors for intracranial hemorrhage in these patients.

Methods

This study was conducted after approval from our institutional review board. Patients presenting with initial admission with diagnosis of IE between January 2014 and July 2018 were retrospectively evaluated. These patients were identified from billing records using International Classification of Diseases, Tenth Revision (ICD–10) codes I33, I38, and B37.6 for IE with or without intracranial abscess, intracerebral hemorrhage, ischemic stroke, and mycotic aneurysm. Relevant demographic and clinical data were collected. Available radiographic data were assessed for the presence of subarachnoid hemorrhage (SAH), intracerebral hemorrhage, ischemic stroke, large vessel occlusion, hemorrhagic conversion, and mycotic aneurysm. Hemorrhagic stroke included intraparenchymal hemorrhage, SAH, and cerebral microhemorrhage seen on magnetic resonance imaging as sulcal susceptibility weighted imaging or gradient‐echo T2* lesions. ⁸ Septic emboli were identified on magnetic resonanceimaging diffusion weighted imaging and apparent diffusion coefficient map. Microbiology of the infectious disease was collected using relevant laboratory reports.

Statistical Analysis

Statistical analysis was performed with SPSS version 26 (Chicago, IL). Independent t test was used to evaluate differences between 2 independent groups with parametric data. The Pearson's chi‐square (X²) test was used to evaluate for intergroup differences, including demographic and nominal outcome variables. Two‐sided P values were reported, and a value <0.05 was considered to be statistically significant. In order to identify independent risk factors for intracranial hemorrhage, logistic regression analysis was used to analyze variables in a univariate model and then applied to a multivariate model, if the P value was ≤0.05. Odds ratios (ORs) were computed using logistic regression analysis including the independent predictors of intracranial hemorrhage and symptomatic intracranial hemorrhage.

Results

During the study period, 351 patients were identified who were admitted for treatment of IE. Among these patients, 170 patients (48%) had an associated history of IVDU.

Demographic data from this cohort showed significance differences between IVDU‐associated endocarditis and the non‐IVDU population (Table 1).

Table 1.

Patient Characteristic of Intravenous Drug Abuse–Associated Endocarditis

		IVDU	No IVDU	P value
No.		170	181	351
Male sex (%)		87 (51.2%)	116 (64.4%)	0.01
Mean age (std, y)		35.2 (±10.2)	56.6 (±15.8)	0.001
Race				0.19
	White	151 (88.8%)	150 (83.3%)
	Black	13 (7.6%)	24 (13.3%)
	Asian	0 (0%)	3 (1.7%)
	Other	6 (3.5%)	3 (1.7%)
HCV		94 (55.3%)	7 (3.9%)	0.001
HIV		1 (0.6%)	1 (0.6%)	0.96
Microbiology	MRSA	51 (30.0%)	23 (12.8%)	0.001
	MSSA	48 (28.2%)	24 (13.3%)	0.001
	Streptococcus sp.	24 (14.1%)	39 (21.8%)	0.53
	Candida/fungal	8 (4.7%)	6 (3.3%)	0.53
	Enterococcus sp.	19 (11.2%)	21 (11.7%)	0.83
	Staphylococcus epidermidis	1 (0.6%)	22 (12.2%)	0.001
	Serratia	11 (6.5%)	1 (0.6%)	0.003
	Pseudomonas	9 (5.3%)	2 (1.1%)	0.03
	Culture negative	7 (4.1%)	19 (10.6%)	0.02
	Other	9 (5.3%)	24 (13.4%)	0.008
Valve	Native	144 (84.7%)	124 (69.3%)	0.001
	AV	40 (23.5%)	78 (43.3%)	0.001
	MV	56 (32.9%)	59 (32.8%)	0.94
	TV	83 (48.8%)	29 (16.1%)	0.001

Values are expressed as absolute value (percentage, mean). AV indicates aortic valve; IVDU, intravenous drug use; HCV, hepatitis C virus; MRSA, methicillin‐resistant Staphylococcus aureus; MSSA, methicillin‐sensitive Staphylococcus aureus; MV, mitral valve; and TV, tricuspid valve.

Female sex contributed to a higher proportion of IVDU associated endocarditis (48.8%) compared with those in the non‐IVDU population (35.6%; P=0.012). IVDU‐associated endocarditis was associated with younger age 35.2 (±10.2) versus 56.6 (±15.8) years; P=0.001. No significant differences were observed regarding race. IVDU was associated with an increased incidence of concomitant hepatitis C infection, which was seen in 55.3% of IVDU patients (P=0.001).

Microbiological data identified different organisms associated with IVDU. An increasing incidence of methicillin‐resistant Staphylococcus aureus (30.9% versus 12.8%; P=0.001), methicillin‐sensitive Staphylococcus aureus (28.2% versus 13.3%; P=0.001), Serratia species, (6.5% versus 0.6%; P=0.003), and Pseudomonas species (5.3% versus 1.1%; P=0.027) were identified in IVDU‐associated endocarditis compared with the non‐IVDU cohort. Non‐IVDU endocarditis was associated with an increased incidence of Staphylococcus epidermidis (0.6% versus 12.2%; P=0.001) and culture‐negative endocarditis (5.3% versus 13.4%; P=0.019).

Native valve (84.7% versus 69.3%; P=0.001) and tricuspid valve endocarditis (48.8% versus 16.1%; P=0.001) were seen with greater frequency in IVDU‐associated endocarditis than in non‐IVDU patients.

The neurological manifestations related to IVDU‐associated endocarditis are displayed in Table 2. Upon admission, there was no difference in patient neurological presentation, which included headache, altered mental status, seizure, or focal neurological deficit. IVDU was associated with an increased incidence of overall intracranial hemorrhage (25.9% versus 13.9%; P= 0.01). This was observed as intraparenchymal hemorrhage (12.4% versus 5.1%; P=0.01), SAH (17.6% versus 4.4%; P=0.001), and cerebral microbleeds (14.1% versus 7.2%; P=0.02) seen on magnetic resonance susceptibility weighted imaging. Patients who had IVDU‐associated endocarditis were more likely to have symptomatic intracranial hemorrhage (12.4% versus 5.5%; P=0.02). IVDU was associated also with an increased incidence of IIAs (10.6% versus 1.8%; P=0.001) and brain abscesses (4.7% versus 1.1%; P=0.03). Patients with a history of IVDU were more likely to undergo frequent diagnostic imaging with more patients receiving head computed tomography (45.3% versus 35.0%; P=0.05), head computed tomography angiography (27.9% versus 15.5%; P=0.01), and cerebral digital subtraction angiography (10.6% versus 1.8%; P=0.001).

Table 2.

Comorbidities of Intravenous Drug Use–Associated Endocarditis in Central Ohio

		IVDU	No IVDU	P value
Neurological presentation		53 (31.3%)	43 (23.8%)	0.22
Hemorrhage		44 (25.9%)	25 (13.9%)	0.01
	SICH	21 (12.4%)	9 (5.1%)	0.01
	SAH	30 (17.6%)	8 (4.4%)	0.001
	CMB	25 (14.07%)	13 (7.2%)	0.02
Ischemic stroke	Septic emboli	58 (34.1%)	47 (26.1%)	0.1
	LVO	10 (5.9%)	13 (7.3%)	0.61
Osteomyelitis of spine		19 (11.2%)	14 (7.8%)	0.26
Intracranial mycotic aneurysm		18 (10.6%)	4 (1.8%)	0.001
	w/rupture	6 (33.3%)	3 (75.0%)	0.64
Brain abscess		8 (4.7%)	2 (1.1%)	0.03

Values are expressed as absolute value (percentage, mean). CMB indicates cerebral microbleed; DSA, digital subtraction angiography; ICH, intracerebral hemorrhage; IVDU indicates intravenous drug use; LVO, large vessel occlusion; SAH, subarachnoid hemorrhage; and SICH, symptomatic intracranial hemorrhage.

The risk of intracranial hemorrhage was assessed for patients with endocarditis. Table 3 lists possible predictors of all intracranial hemorrhage types, including asymptomatic SAH, intraparenchymal hemorrhage, or cerebral microbleeds.

Table 3.

Univariate and Multivariate Logistic Regression Analysis for Risk of Intracranial Hemorrhage Associated with Endocarditis

A. All hemorrhage (subarachnoid hemorrhage, intraparenchymal hemorrhage, and cerebral microbleeds)
Parameters		ß‐Coefficient	Odds ratios (95% CI)	P	ß‐Coefficient	Odds ratios (95% CI)	P value
		Univariate			Multivariate
Sex		0.28	1.280 (0.75–2.20)	0.37
HCV		0.64	1.9 (1.10–3.33)	0.02	0.75	2.11 (0.85–5.24)	0.11
HIV		1.39	4.03 (0.25–65.22)	0.33
IVDU		0.73	2.08 (1.22–3.57)	0.01	0.07	1.08 (0.45–2.61)	0.87
Native valve		0.31	0.94 (0.51–1.73)	0.84
Presence of intracranial septic emboli		2.7	14.86 (7.89–28.02)	0.001	2.92	18.47 (8.47–40.25)	0.001
Presence of large vessel occlusion		1.31	3.72 (1.55–8.92)	0.003	−0.47	.63 (0.22–1.80)	0.39
Presence of intracranial infectious aneurysm		2.8	16.36 (5.75–46.54)	0.001	2.52	12.38 (3.24–47.28)	0.001
Presence of brain abscess		1.64	5.18 (1.53–17.48)	0.008	−0.14	0.87 (0.21–3. 59)	0.85
Microbiology	MRSA	−0.19	0.82 (0.42–1.60)	0.56
	MSSA	−0.69	0.50 (0.24–1.07)	0.08
	Streptococcus sp.	0.23	1.26 (0.66–2.41)	0.49
	Candida	0.83	2.28 (0.74–7.04)	0.15
	Enterococcus sp.	0.46	1.58 (0.75–3.35)	0.23
	Staphylococcus epidermidis	0.38	0.57 (0.16–1.99)	0.38
	Serratia	−1.05	0.35 (0.04–2.75)	0.32
	Pseudomonas	−0.14	0.87 (0.18–4.13)	0.86
	Culture negative	0.65	1.91 (0.79–4.60)	0.15

B. Symptomatic intraparenchymal hemorrhage associated with endocarditis
Parameters		ß‐Coefficient	Odds ratios (95% CI)	P	ß‐Coefficient	Odds ratios (95% CI)	P
		Univariate			Multivariate
Sex		0.78	2.18 (0.95–5.01)	0.07
HCV		0.19	1.21 (0.55–2.66)	0.64
HIV		−18.89		0.99
IVDU		0.89	2.44 (1.12–5.35)	0.03	0.37	1.45 (0.53–3.96)	0.47
Native valve		0.27	1.31 (0.52–3.31)	0.57
Presence of intracranial septic emboli		2.32	10.20 (4.23–24.57)	0.001	2.02	7.54 (2.63–21.61)	0.001
Presence of large vessel occlusion		1.52	4.59 (1.64–12.81)	0.004	0.22	1.25 (0.34–4.52)	0.74
Presence of intracranial infectious aneurysm		3.33	27.97 (10.29–76.13)	0.001	2.74	15.41 (4.61–51.46)	0.001
Presence of brain abscess		0.03	1.03 (0.13–8.29)	0.98
Microbiology	MRSA	−0.97	0.38 (0.11–1.29)	0.57
	MSSA	−1.42	0.24 (0.056–1.04)	0.06
	Streptococcus sp.	0.65	1.92 (0.84–4.39)	0.12
	Candida	1.51	4.50 (1.32–15.32)	0.16
	Enterococcus sp.	0.42	1.53 (0.55–4.23)	0.42
	Staphylococcus epidermidis	−0.04	0.96 (0.22–4.31)	0.96
	Serratia	−0.09	0.91 (0.12–7.36)	0.94
	Pseudomonas	−0.14	0.87 (0.18–4.13)	0.86
	Culture negative	−0.15	0.86 (0.19–3.83)	0.84

HCV indicates hepatitis C virus; IVDU indicates intravenous drug use; MRSA, methicillin‐resistant Staphylococcus aureus; and MSSA, methicillin‐sensitive Staphylococcus aureus.

Univariate analysis showed hepatitis C infection, IVDU, and the presence of intracranial septic emboli, large vessel occlusion, IIA, and brain abscess as significant predictors. Multivariable analysis showed that only presence of intracranial septic emboli (OR, 18.47 [8.47–40.25]; P=0.001) and IIAs (OR, 12.38 [3.24–47.28]; P=0.001) was a significant predictive factor for intracranial hemorrhage after presenting with endocarditis. The presence of symptomatic intraparenchymal hemorrhage with corresponding neurological deficit was assessed in a subset of patients who presented with intracranial hemorrhage (Table 3). Multivariable analysis again showed that only the presence of intracranial septic emboli (OR, 7.54 [2.63–21.61]; P=0.01) and IIA (OR, 15.41 [4.61–51.45]; P=0.001) was a significant predictive factor for symptomatic intracranial hemorrhage after presenting with endocarditis.

Discussion

With the rise of the opioid epidemic, there has been an increased incidence of IVDU‐associated complications that frequently lead to neurological morbidity and mortality due to the increased incidence of ischemic stroke, intracranial hemorrhage, IIAs, and intracranial abscesses. ³

The incidence of stroke from IE ranges from 15% to 20% ⁹ and is a serious major complication contributing to disability and mortality, second behind congestive heart failure (27%–39%). Among these patients with stroke, ischemic stroke accounted for the majority (71.5%) of hospitalizations with hemorrhagic stroke accounting for 28.5%. ¹⁰ Within our cohort, higher rates of hemorrhagic stroke were observed in patients who had IVDU‐associated IE (25.9% versus 13.9%; P=0.005). Hemorrhagic stroke included intraparenchymal hemorrhage, SAH, and cerebral microhemorrhage seen on magnetic resonance imaging as sulcal susceptibility weighted imaging or gradient‐echo T2* lesions. There was no difference in incidence of ischemic stroke or large vessel occlusions between the cohorts. Fortunately, neurologic sequelae associated with IE are relatively infrequent but can incur significant morbidity. The incidence of intracranial mycotic aneurysm and intracranial abscess, however, is less frequent among neurological complications compared with stroke. The incidence of IIA was significantly higher in IVDU‐associated IE than in non‐IVDU patients with IE (10.6% versus 1.8%; P=0.001), a finding that has been identified in previous studies as well. ⁴ The increase in incidence of IIAs coincides with a difference in both methicillin‐resistant Staphylococcus aureus (30.9% versus 12.8%; P=0.001) and methicillin‐sensitive Staphylococcus aureus (28.2% versus 13.3%; P=0.001) infections between IVDU and non‐IVDU endocarditis cohorts. This is consistent with other studies that show that S. aureus account for 57%–91% of IIAs. ¹¹

We have found that patients with IVDU‐associated IE undergo more frequent diagnostic imaging than those with non‐IVDU IE. This lower threshold for imaging may reflect a small ascertainment bias by increasing the detection of stroke, intracranial hemorrhage, and IIAs. In looking at disease presentation, patients did present with symptomatic intracerebral hemorrhage among those with IVDU IE (12.4% versus 5.5%; P=0.02) that may lead to more intracranial imaging due to the acute neurological presentation.

We investigated whether the IVDU was a predictive variable for intracranial hemorrhage (Table 3). As a univariate variable, IVDU was a predictor of intracranial hemorrhage (OR, 2.08 [1.22–3.57]; P=0.01]. Within our multivariate analysis the only predictors of intracranial hemorrhage were the presence of intracranial infectious aneurysms and septic emboli. The presence of intracranial hemorrhage has been shown to be a significant predictor for in‐hospital mortality for mitral valve endocarditis. ¹² Within our cohort, there is a significant relationship with mycotic aneurysms and septic emboli and intracranial hemorrhage. Screening for patients with history of IVDU with noninvasive imaging may be important when care necessitates anticoagulation or when presenting with neurological deficit. Routine screening in patients with IVDU‐associated IE for IIAs and septic emboli may prevent morbidity and mortality.

Limitations of this study arise from the retrospective nature of this cohort. This single‐center cohort of patients also does not capture the whole breadth of patients presenting with IVDU complications, although it does capture a patient population at high risk, with elevated health care use and high interdisciplinary burden of a primary referral center for heart valve replacement in the heart of the opioid epidemic.

Conclusions

The opioid epidemic and the major complication of IVDU have a profound effect on the clinical practice of neurologists, cardiologist, neurosurgeons, cardiothoracic surgeons, and intensivists. The presence of IIAs and septic emboli is a predictor of intracranial hemorrhage and symptomatic intraparenchymal hemorrhage after IE.

Author Contributions

Alex N. Hoang, Ciaran J. Powers, Patrick P. Youssef, and Shahid M. Nimjee devised the project and the main conceptual ideas presented and planned and supervised the work. Alex N. Hoang, Varun Shah, Jessica Granger, and David Dornbos III performed data collection and data analysis. Alex N. Hoang and Varun Shah were involved in manuscript preparations. Louise D. McCullough and Omar Tanweer aided in interpreting the results and critical review of manuscript. All authors discussed the results and commented on the manuscript.

Sources of Funding

The authors did not receive any funding.

Disclosures

The authors have no conflicts of interest to declare.