Subarachnoid hemorrhage rebleeding in the first 24 h is associated with external ventricular drain placement and higher grade on presentation: Cohort study

Abstract

Background:

Rebleeding after aneurysmal subarachnoid hemorrhage (aSAH) confers a poor prognosis; however, risk factors and differential outcomes associated with early rebleeding in the first 24 h after symptom presentation are incompletely understood.

Methods:

A retrospective cohort study of all aSAH presenting to our institution between 2001 and 2016 was performed. Early rebleeding events were defined as clinical neurologic decline with radiographically confirmed acute intracranial hemorrhage within 24 h after symptom presentation. Univariate and multivariate logistic regression analyses were used to assess clinical associations, with a specific focus on baseline Glasgow Coma Score (GCS), World Federation of Neurosurgical Societies (WFNS), and modified Fisher scores.

Results:

Of 471 aSAH cases, 33 (7%) experienced early rebleeding. Multivariate regression identified extraventricular drain (EVD) placement (OR = 2.16, P = 0.04) and WFNS 3–5 (OR = 2.69, P = 0.02) as significant predictors of early rebleeding. Good functional outcomes were observed in 8 patients with early rebleeding (24%), all of whom underwent aneurysm treatment. Higher SAH grade prior to rebleeding (WFNS 3–5) was significantly associated with increased odds of an unfavorable functional outcome (OR = 8.09, P < 0.01). Anticoagulation, aneurysm size and location were not significantly associated with either early rebleeding incidence or functional outcome.

Conclusions:

Early rebleeding in aSAH is associated with unfavorable functional outcomes. EVD placement and higher SAH grade on presentation appear to be significantly and independently associated with increased risk of rebleeding within first 24 h, as well as unfavorable long-term functional outcome; however, the clinical benefit of hyper-acute aneurysm treatment requires further investigation.

1. Introduction

Rebleeding is among the most feared and potentially devastating sequelae of aneurysmal subarachnoid hemorrhage (aSAH) [1,2]. With an estimated incidence of 6–22% throughout hospitalization, rebleeding after aSAH portends a grievous prognosis and is associated with a significant, independent increase in risk of death or long-term disability [3-9]. Although obliteration of the aneurysm via open clipping or endovascular intervention has been shown to markedly reduce the risk of rebleeding, factors contributing to individual risk profiles in the early post-hemorrhage period after symptoms arise are poorly understood [10,11].

Contemporary guidelines have recommended various thresholds for intervention ranging from 24 to 72 h, each of which has demonstrated a significant association with improved long-term outcomes [11,12]. In spite of this, a small but defined population of aSAH patients continue to experience early rebleeding prior to any intervention, defined as a repeated rupture of the aneurysm within 24 h of presentation. This population is of particular interest, given their heightened risk of preventable injury, as well as the associated increases in risk of other disease sequelae such as delayed cerebral ischemia (DCI) or radiographic infarct, and unfavourable long-term outcomes [13]. However to date, no study has attempted to interrogate and profile rebleed patients within the first 24 h of presentation alone. This could prove vital in terms of triaging immediate patient admission, vasospasm surveillance protocols and aggressiveness to intervene. Correspondingly, we performed a cohort study of all aSAH patients managed at our institution to identify risk and prognostic factors associated with early rebleeding within the first 24 h of presentation and ultimate functional outcomes.

2. Methods

2.1. Patient cohort

A prospectively maintained institutional registry was queried to identify all consecutive aSAH patients admitted to our institution during the study period, 2001–2016. Patients were categorized as either 1) Early rebleeding, defined as clinical and radiographic confirmation of an early rebleed event within 24 h of primary presentation prior to any intervention, or 2) No evidence of rebleeding during hospitalization. The timing of primary presentation was calculated based on patient history and time of admission. Patients without radiographic confirmation of an intracranial aneurysm as the SAH etiology were excluded, as were those individuals who experienced delayed rebleeding after 24 h of primary presentation, or post-treatment rebleeding.

2.2. Data collection

Demographic capture included age, sex, major medical comorbidities, and established aSAH risk factors (e.g. hypertension, smoking status, anti-platelet medications). Baseline disease parameters at initial presentation included Glasgow Coma Score (GCS), World Federation of Neurosurgical Societies (WFNS) score, and modified Fisher (mFisher) score. Other clinical variables abstracted were treatment modality (open and endovascular), EVD placement within 24 h of presentation (and prior to rebleeding, among patients with rebleeding events), ICU and hospital length-of-stay (LOS), total follow-up, and modified Rankin scale (mRS) at 3 months post-discharge or last clinical follow-up. Favorable outcome was defined as mRS 0–2 at last follow-up. All pertinent aspects of this study were reviewed and approved by our Institutional Review Board (17–010113), including a waiver-of-consent for retrospective chart review in a minimal risk study.

2.3. Outcomes

The primary outcome was incidence of early rebleeding, defined as a new pre-treatment clinical neurologic decline with confirmatory head CT demonstrating new acute intracranial hemorrhage. In the case of those patients initially presenting intubated and sedated, deterioration was implicated by changes in pupil size, shape and reactivity, as well as loss of brainstem reflexes. Additionally, respiratory and hemodynamic desaturation also mandated immediate clinical attention. The secondary outcome was functional outcome among patients with early rebleeding, defined by mRS score at last clinical follow-up within 6 months of ictus. For functional outcome analysis, the independent categorial variable was stratified as good (mRS = 0–2) or poor (mRS = 3–6).

2.4. Statistical analyses

Initial comparisons between demographic and clinical features of early rebleed versus control cohorts were conducted using the chi-square or Wilcoxon rank-sum tests for categorical and continuous data, respectively. Logistic regression analyses were then performed to identify possible predictors of early rebleeding events, as well as unfavorable functional outcome. Risk of incidence was presented as an odds ratio (OR). Univariate analysis was conducted to identify candidate predictors; variables demonstrating a significant between-groups test statistic were subsequently included in multivariate analysis with post-hoc Bonferroni correction. WFNS and GCS scores were considered, however due to collinearity concerns, GCS was excluded from any subsequent multivariate analysis. All analyses were conducted using STATA 14.1 (StataCorp, College Station, Texas); statistical tests were two-sided, and significance was defined using the uncorrected alpha threshold of 0.05.

3. Results

3.1. Descriptive analysis – study cohort overview

Four-hundred seventy-one aSAH cases met inclusion criteria, of which 438 (93%) experienced initial aneurysm rupture only, while 33 (7%) had a radiographically confirmed early rebleeding event within 24 h of presentation (Table 1). In the non-rebleed cohort, mean age was 55 years, 63% were female, 48% were smokers, and 51% had hypertension. Anticoagulant or antiplatelet medication use was reported in 3% and 13%, respectively. In the early rebleed cohort, mean age was 56 years, 73% were female, 36% were smokers, and 42% were hypertensive. Anticoagulant or antiplatelet medication use was documented in 6%.

Table 1.

Presentation features and outcomes in overall cohort.

Factor	Rebleed < 24 hrs (n = 33)		No rebleed (n = 438)		P
	n	%	n	%
Demographics and presentation
Age (yrs)*	56	52–61	55	54–57	0.61
Gender					0.24
Female	24	73%	274	63%
Male	9	27%	164	37%
Smoker	12	36%	210	48%	0.20
Hypertension	14	42%	225	51%	0.32
Anticoagulated	2	6%	13	3%	0.33
Antiplatelet medication	2	6%	54	13%	0.29
GCS at initial presentation					<0.01
3–12	19	58%	117	27%
13–15	14	42%	321	73%
Modified Fisher score at initial presentation					<0.01
1–2	2	6%	120	27%
3–4	31	94%	318	73%
WFNS score at initial presentation					<0.01
1–2	13	39%	311	71%
3–5	20	61%	127	29%
EVD placement	22	67%	201	46%	0.02
Aneurysm features
Location					0.18
ACom/ACA	10	33%	158	36%
ICA	5	17%	60	14%
MCA	7	23%	46	11%
PCoA	4	13%	80	18%
VB	4	13%	90	21%
Maximum dimension (mm)*	6.4	4.5–8.3	6.9	6.5–7.4	0.61
Clinical outcomes
Time to rebleed (hrs)*	8	6.3–9.7	.	.	.
Intervention required**	16	54%	420	93%	<0.01
VP shunt required	6	17%	82	18%	0.88
LOS, ICU (days)*	9.5	6.5–12.5	11.2	10.6–11.9	0.16
LOS, overall (days)*	15.1	8.7–21.5	19.4	17.3–21.7	0.28
Follow-up (mo)*	7.1	4.2–9.9	6.8	6.1–7.5	0.86
Functional status					<0.01
Good (Rankin 0–2)	8	24%	336	77%
Poor (Rankin 3–5)	6	18%	54	12%
Death (Rankin 6)	19	57%	48	11%

^*Mean and 95% CI respectively.

^**Rebleed preceded all intervention (endovascular or open).

GCS, Glasgow Coma Score; WFNS, World Federation of Neurosurgical Societies; ACoA/ACA, anterior communicating or anterior cerebral arteries; ICA, internal carotid artery; MCA, middle cerebral artery; PCoA, posterior communicating artery; VB, vertebrobasilar; EVD, extraventricular drain; LOS, length of stay; ICU, intensive care unit; VP, ventriculoperitoneal; CI, confidence interval.

When compared to aSAH patients without rebleeding, those individuals who experienced early rebleeding events were significantly more likely to have presented with higher grade hemorrhages, as assessed by GCS (P < 0.01), mFisher (P < 0.01), and WFNS (P < 0.01) scores. EVD placement was more commonly observed in patients with early rebleeding (67% vs 46%, P = 0.02). Aneurysm treatment by any technique (e.g. open or endovascular) was ultimately undertaken in 54% of patients with early rebleeding, as compared to 93% of those without rebleeding (P < 0.01).

Overall, poor or fatal functional outcomes were significantly more prevalent among patients with early rebleeding (24% vs 77%, P < 0.01). Among 33 patients with early rebleeding, 8 had good functional outcomes (24%), while 6 had a poor outcome (18%), and 19 were fatalities (57%). Of the 8 patients who ultimately achieved a good functional outcome after rebleeding, all 8 underwent aneurysm treatment by any technique (100%).

3.2. Predictive analysis – early rebleeding

Univariate analysis of patient parameters in the overall cohort (n = 471) was performed to identify possible predictors of early rebleeding (Table 2). GCS ≤ 12 (P < 0.01), mFisher 3–4 (P = 0.02), WFNS 3–5 (P < 0.01), and with EVD placement (P = 0.03) were all potentially independently associated with early rebleeding. Aneurysm treatment by any technique (e.g. open or endovascular) was significantly associated with a lower incidence of early rebleeding (P < 0.01). Statistically significant, independent predictors of early rebleeding confirmed on multivariate analysis included WFNS 3–5 (OR = 2.69, P = 0.02) and EVD placement (OR = 2.16, P = 0.04).

Table 2.

Univariate and multivariate regression analysis of parameters predicting rebleed < 24 h in overall cohort of those rebled < 24 h (n = 33) and those with no rebleed (n = 438). Reference variables are designated REF.

Factor	Univariate			Multivariate
	OR	95% CI	P	OR	95% CI	P
Demographics and presentation
Age (yrs)	1.00	0.98–1.03	0.80	.	.	.
Male gender	0.61	0.28–1.38	0.25	.	.	.
Smoker	0.63	0.30–1.30	0.24	.	.	.
Hypertension	0.83	0.40–1.74	0.62	.	.	.
Anticoagulated	2.33	0.50–10.9	0.28
Antiplatelet medication	0.24	0.03–1.79	0.16	.	.	.
GCS at initial presentation				.	.	.
3–12 (REF)	3.63	1.71–7.71	<0.01	N/P	.	.
13–15 (REF)	.	.	.	.	.	.
Modified Fisher score at initial presentation
1–2 (REF)	.	.	.	.	.	.
3–4	5.28	1.24–22.5	0.02	3.04	0.75–15.3	0.11
WFNS score at initial presentation
1–2 (REF)	.	.	.	.	.	.
3–5	8.80	3.02–25.7	<0.01	2.69	1.21–5.97	0.02
EVD placement	2.36	1.07–5.15	0.03	2.16	1.28–5.47	0.04
Aneurysm features and management
Location
ACom/ACA (REF)	.	.	.	.	.	.
ICA	1.17	0.39–3.52	0.77	.	.	.
MCA	2.37	0.90–6.21	0.08	.	.	.
PCoA	0.73	0.22–2.37	0.60	.	.	.
VB	0.68	0.20–2.12	0.48	.	.	.
Maximum diameter (mm)	0.98	0.88–1.10	0.71	.	.	.

OR, odds ratio; CI, confidence interval; GCS, Glasgow Coma Score; WFNS, World Federation of Neurosurgical Societies; ACoA/ACA, anterior communicating or anterior cerebral arteries; ICA, internal carotid artery; MCA, middle cerebral artery; PCoA, posterior communicating artery; VB, vertebrobasilar; EVD, extraventricular drain; N/P, not performed due to collinearity concerns with WFNS.

3.3. Predictive analysis – functional outcome

Univariate analyses of initial patient parameters within the early rebleeding cohort (n = 33) were performed to potentially identify risk factors for poor functional outcome (Table 3). Only initial GCS ≤ 12 (OR = 11.2, P < 0.01) and WFNS 3–5 (OR = 8.09, P < 0.01) were significantly associated with unfavorable functional outcomes; multivariate analysis was not conducted, due to colinearity between these variables. Clinical data on GCS and WFNS following rebleeding events was insufficiently reliable to allow for statistical comparison; however, anecdotal evidence suggested that a major neurologic decline in associated with rebleeding appears to be associated with an unfavorable outcome.

Table 3.

Univariate regression analysis of parameters and overall poor functional outcome (mRS 3–6) in those that rebleed < 24 h (n = 33). Reference variables are designated REF.

Factor	Univariate
	OR	95% CI	P
Demographics and presentation
Age (yrs)	1.04	0.98–1.11	0.18
Male gender	1.07	0.21–5.44	0.93
Smoker	0.42	0.09–1.92	0.27
Hypertension	1.34	0.32–5.63	0.68
Anticoagulated	Undefined	0	1.00
Antiplatelet medication	Undefined	0	1.00
GCS at initial presentation
3–12	11.2	2.11–59.2	<0.01
13–15 (REF)	.	.	.
Modified Fisher score at initial presentation
1–2 (REF)	.	.	.
3–4	Undefined	0	1.00
WFNS score at initial presentation
1–2 (REF)	.	.	.
3–5	8.09	1.38–57.5	<0.01
EVD placement	0.57	0.11–2.78	0.49
Aneurysm features
Location
ACom/ACA (REF)	.	.	.
ICA	7.46	0.63–88.8	0.11
MCA	1.57	0.30–8.34	0.60
PCoA	1.72	0.19–15.3	0.63
VB	4.12	0.31–54.9	0.28
Maximum diameter (mm)	1.00	0.80–1.24	0.99

OR, odds ratio; CI, confidence interval; SAH, subarachnoid haemorrhage; GCS, Glasgow Coma Score; WFNS, World Federation of Neurosurgical Societies; ACoA/ACA, anterior communicating or anterior cerebral arteries; ICA, internal carotid artery; MCA, middle cerebral artery; PCoA, posterior communicating artery; VB, vertebrobasilar; EVD, extraventricular drain; N/P, not performed due to collinearity concerns with WFNS.

4. Discussion

The goal of the current study was to identify risk factors for early rebleeding within the first 24 h from presentation among patients with aSAH, as well as parameters that might helpfully identify patients at increased risk of an unfavorable functional after early rebleeding. They represent a poorly defined subgroup of rebleed vulnerable patients that perhaps may warrant separate care should their clinical profile deviate sufficiently from that of “older” rebleed events 48 h, 72 h and later after presentation.

From a clinical perspective, our endpoints were defined with the ostensible goal of improving early post-SAH care by identifying those patients who might benefit from hyper-acute (<24 h) treatment, as well as those who, subsequent to the rebleeding event, would be least likely to mount a meaningful neurologic recovery. In keeping with much of the preceding aSAH literature, we found that early rebleeding is more common after more severe hemorrhages, and that hemorrhage grade predicts long-term functional outcome, independent of rebleeding status. The only potentially modifiable, independent predictor of early rebleeding was EVD placement within the first 24 h following onset of clinical symptoms.

The incidence of early rebleeding was 7% in the present study cohort, a figure that accords with previously reported observational series documenting early rebleeding in approximately 5–19% of aSAH patients [3,4,14-16]. As we have shown previously, patients experiencing rebleeding events at any point in their aSAH clinical trajectory are exposed to a significantly increased risk of poor functional outcomes, as compared to matched referent patients who did not have rebleeding events—a finding that was reproduced in the present analysis [13]. In this study, higher grade hemorrhage at time of presentation (WFNS 3–5) was independently associated with early rebleeding, which is also in agreement with preceding reports [8,9]. The pathophysiological explanation for this association remains poorly understood [17,18]. Notwithstanding, our results emphasize the possible role for early aneurysm treatment in high-risk patients, in particular those individuals who have both intermediate grade hemorrhages also an indication for early EVD placement.

The association between EVD placement and early rebleeding has been posited before, although not in the strictest sense within the first 24 h of presentation. Furthermore, no causal mechanism has been demonstrated, and the available data are largely inferential [8,15,19,20]. Pare et al. [20] suggested that EVD drainage establishes a transmural pressure across the aneurysm dome, predisposing it to rerupture in the early period following initial rupture, when the occlusive thrombus is thought to be most vulnerable. Kienzler et al. [4] noted in their series of patients with rebleeding that the primary indication for EVD placement was treatment or prevention of hydrocephalus. As such, they suggested that EVD placement was not itself the primary driver of rebleeding, but rather a surrogate marker for disease severity, akin to WFNS, GCS, or mFisher score.

Our observation that both EVD placement and unfavorable clinical status on presentation retained statistical significance on multivariate analysis suggests that there may be an independent contribution to the risk of rebleeding associated with EVD placement. What remains to be clarified moving forward is if and how different aspects of EVD management may predispose the reported risk of early rebleed. It was our practice to start with EVD system open without draining a specific volume before. Whether or not initial drain volume and speed influenced our findings requires prospective efforts in the future to ascertain. Notwithstanding, given the life-threatening nature of raised ICP in the setting of aSAH, we continue to recommend aggressive treatment of clinical hydrocephalus via EVD placement, with the caveat that these patients may benefit from rapidly progressing towards aneurysm obliteration, absent indications of a neurologically devastated patient.

An area of debate in predicting early rebleeding is the use of tranexamic acid (TXA), with a large degree of heterogeneity in the preceding literature [21]. There have been multiple randomized clinical trials that have provided conflicting results as to the risk reduction in rebleeding following aSAH via treatment with TXA over the course of hospitalization [22-24]. With this in mind, our analysis may provide a degree of additional insight into the possibility that any impact on aSAH rebleeding by TXA is time dependent, as our results indicated that its use does not impact the likelihood of early rebleeding at the least. Given the heterogeneous nature of clinical rebleeding phenomena and the associated aSAH, focused study of the interactions between anticoagulation rebleed risk should be the goal of carefully designed future trials, with particular attention to defining the clinically meaningful impact of TXA in terms of potential for early rebleeding risk reduction [21].

Although it has already been suggested that there is an increased risk of rebleeding earlier than later based on different timepoints within the first 72 h of presentation [25], our study is the first to demonstrate the predictors independently through single cohort multivariable analysis that does not suffer from the clinical heterogeneity of systematic reviews that pool studies with highly variable and independent definitions and procedures.

The relationship between timing of aneurysm treatment and reduction of rebleeding risk remains poorly discriminated; correspondingly, we recommend that treatment decisions be individualized to the patient, clinical context, and any other pertinent variables [2]. Based on the current study, we note that patients with higher grade hemorrhages appear to be at increased risk of early rebleeding, which is in turn associated with poor functional outcomes [10,11]. Further, the benefit of aneurysm treatment in patients with severe neurologic injuries is well known to be marginal with respect to functional outcomes, independent of early rebleeding, or aneurysm treatment [26]. By contrast, the current study does support the possibility that, among patients with intermediate grade aSAH, there may be a meaningful reduction of rebleeding risk associated with hyperacute treatment—particularly in those individuals requiring early EVD placement [27].

Interpretation of the current study is restricted by limitations. First, as a retrospective analysis, there are inevitable regarding selection bias, referral bias, and residual confounding, among other less common (but potentially applicable) sources of systematic error. Poor clinical grade is known to be a strong independent predictor of mortality, and therefore likely influenced the decision to withhold treatment in some of our patients—particularly following rebleeding events [28]. Second, the early rebleeding cohort was very limited in size, which decreases the statistical power of our models, and increases the risk of type II errors (false negatives) [18]. This is in part attributable to our methodological decision to specifically examine early rebleeding, rather than all rebleeding events occurring, or those that occurred after aneurysm obliteration. Although this feature of the study design sacrificed sample size, it was motivated by the intention to focus more rigorously on a specific clinical question: who among aSAH patients is at greatest risk of rebleeding prior to the commonly accepted 24 h from presentation threshold, and therefore may benefit from a more aggressive approach to treatment [18]. We acknowledge that guidelines advocate for treatment up to 72 h post-presentation, which other alike studies may have utilized, and may have underestimated more established predictors due to our more restrictive criteria of 24 h [11,12]. As such, direct comparability between this study and other studies that focused on rebleeding within 72 h is likely limited due to this and something we caution the reader against.

Finally, although we were able to reliably abstract key clinical variables at time of presentation, such as WFNS, the reliability and validity of the same variables was less reliable at later time points—in particular, following rebleeding. Correspondingly, we elected to limit out models to baseline parameters, which restricts our ability to comment on outcomes after rebleeding. These limitations emphasize the need for a large, well-designed, multi-center follow-up study to validate our conclusions in a more rigorous analysis, particularly given the low event rate and clinical heterogeneity observed in our single-institution study.

5. Conclusion

Although some patients may still reach a good functional outcome after early rebleeding, it is frequently a devastating sequela of aSAH. The current study identified patients with WFNS grade 3–5 as being the most susceptible to early rebleeding—particularly if an EVD has been placed. Appropriately selected patients presenting with intermediate grade aSAH and hydrocephalus may therefore benefit from hyper-acute treatment to reduce their risk of early rebleeding, which may in turn optimize their potential for good functional outcomes.