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Adenosine-Induced Flow Arrest to Facilitate Intracranial Aneurysm Clip Ligation Does Not Worsen Neurologic Outcome

Bebawy, John F. MD; Zeeni, Carine MD; Sharma, Sonal MBBS, MD; Kim, Edina S. MD; DeWood, Mark S. BS; Hemmer, Laura B. MD; Ramaiah, Vijay K. MBBS, MD; Bendok, Bernard R. MD; Koht, Antoun MD; Gupta, Dhanesh K. MD

doi: 10.1213/ANE.0b013e3182a6d31b
Neuroscience in Anesthesiology and Perioperative Medicine: Research Report

BACKGROUND: When temporary arterial occlusion of the parent artery is difficult for anatomical reasons, or when inadvertent aneurysmal rupture occurs during surgical dissection, adenosine administration can be used to produce flow arrest and brief, profound systemic hypotension that can facilitate intracranial aneurysm clip ligation. There is a concern, however, that the flow arrest and profound hypotension produced by adenosine, although brief, may cause cerebral ischemia and therefore worsen neurologic outcome compared with other techniques to facilitate aneurysm clip ligation. Therefore, we performed a retrospective, case-control study to determine whether adenosine-induced flow arrest had negative effects on the neurologic outcome of our patients.

METHODS: We reviewed the perioperative records of all patients in our intracranial aneurysm surgery outcomes database between August 1, 2006, and June 15, 2012. The primary outcome was the presence or absence of a poor neurologic outcome 48 hours after surgery, with a modified Rankin scale score >2 being defined as a poor neurologic outcome. The neurologic outcome at the time of hospital discharge was a secondary outcome. Secondary outcomes related to cardiac morbidity included atrial or ventricular arrhythmia requiring treatment and elevated cardiac biomarkers consistent with ischemia (i.e., Troponin-I).

RESULTS: During the study period, adenosine-induced flow arrest was used in 72 of the 413 patients (17.4%) who underwent intracranial aneurysm clip ligation. The difference in the incidence of poor neurological outcome, with or without the use of adenosine, was no larger than 15.7% at 48 hours after surgery (P =0.524) or −12.7% at discharge (P = 0.741). In addition, the difference in the incidence of cardiac morbidity was no larger than −16.0% for persistent arrhythmia (P = 0.155) or −9.4% for biomarkers of myocardial ischemia (P = 0.898) in the initial 48 hours after surgery.

CONCLUSION: When used to facilitate intracranial aneurysm clip ligation, adenosine-induced flow arrest was associated with no more than a 15.7% increase or a 12.7% decrease in the incidence of a poor neurologic outcome at either 48 hours or at the time of hospital discharge. In addition, adenosine use was not associated with cardiac morbidity in the perioperative period (i.e., persistent arrhythmia or biomarkers of cardiac ischemia).

From the Department of Anesthesiology and Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Accepted for publication June 25, 2013.

Carine Zeeni, MD, is currently affiliated with Department of Anesthesiology, American University of Beirut, Beirut, Lebanon; Mark S. DeWood, BS, is currently affiliated with Department of Anesthesiology, University of Cincinnati College of Medicine, Cincinnati, Ohio; and Vijay K. Ramaiah, MBBS, MD, is currently affiliated with Department of Anesthesia, Stanford University School of Medicine, California.

Funding: Departmental support (Anesthesiology & Neurologic Surgery).

Edina S. Kim, MD, is currently affiliated with the University of Illinois, Chicago, IL.

The authors declare no conflicts of interest.

This report was previously presented, in part, at the SNACC & ASA 2012.

Reprints will not be available from the authors.

Address correspondence to Dhanesh K. Gupta, MD, Department of Anesthesiology and Neurological Surgery, Northwestern University Feinberg School of Medicine, Ward Memorial Building #13-179 303 East Chicago Ave., Chicago, IL 60611. Address e-mail to dhanesh-gupta@northwestern.edu.

For many surgically treated intracranial aneurysms, proximal temporary arterial occlusion is used to decrease the turgor of the aneurysm neck to facilitate clip ligation of the aneurysm. This is most commonly achieved by the placement of a temporary clip across the parent artery that supplies the aneurysm. For aneurysms of the internal carotid artery, it is often difficult, however, to find an anatomically suitable location for the placement of the temporary clip.1,2 There are alternative techniques to facilitate aneurysm clip ligation, such as endovascular balloon occlusion with suction decompression or deep hypothermic circulatory arrest, but they require significant logistical support and may be associated with significant morbidity.3–5

When temporary arterial occlusion of the parent artery is difficult for anatomical reasons, or when inadvertent aneurysmal rupture occurs during surgical dissection, adenosine administration can be used to produce flow arrest and brief, profound systemic hypotension that can facilitate aneurysm clip ligation.6–8 Adenosine, administered as a bolus, produces a dose-dependent decrease in atrial and ventricular electrical activity that results in bradycardia, atrioventricular nodal blockade, and sinus pauses. These negative chronotrophic effects produce a rapid and profound decrease in systemic and cerebral perfusion pressure, which decreases aneurysm neck turgor and facilitates clip ligation. In a population dose-response analysis, we determined that a dose of 0.3 to 0.4 mg·kg−1 (ideal body weight) reliably produced 45 seconds of profound hypotension (systolic blood pressure <60 mm Hg), which was the length of time required by our surgeons to place a permanent clip across the neck of the aneurysm.8

Although there was no clear association between immediate postoperative neurologic injury and adenosine administration in this small cohort of patients, there still remains a concern that the flow arrest and profound hypotension produced by adenosine, although brief, may cause cerebral ischemia and therefore worsen neurologic outcome compared with other techniques to facilitate aneurysm clip ligation. Unfortunately, it would be logistically difficult to perform a placebo-controlled, randomized controlled trial comparing the effects of adenosine-induced flow arrest on neurologic outcomes after aneurysm clip ligation. Therefore, we performed a retrospective, case-control study to determine whether adenosine-induced flow arrest had negative effects on the neurologic outcome of our patients.

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METHODS

Adhering to the STROBE (Strengthening the Reporting of Observational studies in Epidemiology) guidelines for reporting a case-control study, we reviewed the perioperative records of all patients who gave written informed consent to be included in our Northwestern University IRB-approved intracranial aneurysm surgery outcomes database between August 1, 2006, and June 15, 2012.9 The data from a subset of these patients (24 patients who received adenosine between August 1, 2006, and June 30, 2009, and 162 patients who underwent craniotomy for clip ligation without adenosine between August 1, 2006, and June 30, 2008) were included in our previous report detailing a population dose-response model for adenosine-induced flow arrest and a preliminary safety profile.8 The additional subjects used for this analysis were acquired between June 30, 2009, and June 15, 2012.

Variables collected included patient demographics, preoperative coexisting diseases, characteristics of the aneurysm(s) and any related subarachnoid hemorrhage, specific details related to the surgical procedure, and specific details related to postoperative neurologic outcome and cardiac morbidity and mortality.

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Statistics

The primary outcome was the presence or absence of a poor neurologic outcome 48 hours after surgery, with a modified Rankin scale (mRs) score >2 being defined as a poor neurologic outcome (i.e., at least a moderate disability, requiring some help, but able to walk without assistance).10,11 The neurologic outcome at the time of hospital discharge was a secondary outcome. Secondary outcomes related to cardiac morbidity included atrial or ventricular arrhythmia requiring treatment and elevated cardiac biomarkers consistent with ischemia (i.e., Troponin-I).

Univariate analysis was performed using StatsDirect statistical software (version 2.6.5, StatsDirect Ltd., Cheshire, United Kingdom). All of the data were tested for normality using the Shapiro-Wilk W-test. Normally distributed data were tested for equality of variance using Levene test.12 Normally distributed data are presented as the mean ± SD and the difference between the group means (99% confidence interval of the difference between the group means), and these data were compared between groups using either the unpaired t test for data with equal variances, or Satterthwaite approximate t test for data with unequal variances.13,14 Nonnormally distributed data are presented as median (range), and these data were compared between groups using the Mann-Whitney U test. Categorical data are presented as number (percent) and the difference between the group mean percentages (99% confidence interval of the difference between the mean group percentages), and these data were compared using Fisher exact test or χ2 test. A P < 0.05 was considered statistically significant.

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RESULTS

During the study period, adenosine-induced flow arrest was used in 72 of the 413 patients (17.4%) who underwent intracranial aneurysm clip ligation (Table 1). There were no patients who were not included in this analysis due to incomplete medical records pertaining to the major clinical variables and the primary outcome variable. The difference in the incidence of poor neurological outcome (defined as mRs score > 2), with or without the use of adenosine, was no larger than 15.7% at 48 hours after surgery (P = 0.524) or −12.7% at discharge (P = 0.741). In addition, the difference in the incidence of cardiac morbidity was no larger than −16.0% for persistent arrhythmia (P = 0.155) or −9.4% for biomarkers of myocardial ischemia (P = 0.898) in the initial 48 hours after surgery (Table 2).

Table 1

Table 1

Table 2

Table 2

Univariate analysis demonstrated that age, sex, aneurysm size, a history of coronary artery disease, a history of hypertension, Hunt Hess classification, Fisher Grade 4 subarachnoid hemorrhage, and the use of temporary arterial occlusion, but not the use of adenosine-induced flow arrest, were associated with a poor neurologic outcome (Table 3).

Table 3

Table 3

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DISCUSSION

When used to facilitate intracranial aneurysm clip ligation, adenosine-induced flow arrest was not associated with a poor neurologic outcome (defined as mRs score >2) at either 48 hours (difference no larger than 15.7%) or at the time of hospital discharge (difference no larger than −12.7%). In addition, adenosine use was not associated with cardiac morbidity in the perioperative period (i.e., persistent arrhythmia [difference no larger than −16.0%] or biomarkers of cardiac ischemia [difference no larger than −9.4%]). Increasingly, the technique of adenosine-induced flow arrest has been adopted at centers that perform clip ligation or clip reconstruction of complex or large intracranial aneurysms when the location of the aneurysm may make temporary arterial occlusion difficult, if not impossible. Small-to-moderate sized case series have reported that the technique is “safe.”8,15,16 However, to date, there have been no definitive data to demonstrate neurologic safety with approximately 45 seconds of adenosine-induced profound hypotension, in part due to the lack of practicality and/or difficulty in randomization. Therefore, epidemiologic techniques to analyze outcomes databases, which have been used to assess neurologic outcomes in other studies in this patient population, may provide the most practical method to determine whether adenosine-induced flow arrest is associated with poor neurologic outcomes.

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Limitations

One limitation of this study is the potential for selection bias in terms of which subjects did or did not receive adenosine. In our practice, the decision to use adenosine-induced flow arrest is based on anatomical aspects and the location of the aneurysm. Therefore, patients with proximal internal carotid artery aneurysms or complex posterior circulation aneurysms were more likely to receive adenosine in our study group. If surgery at either of these anatomic locations is related to neurologic outcome (basilar aneurysm surgery may be associated with higher mortality), this may have biased the results of this study.17 Another limitation of this study may be the perceived lack of “robust” reporting of neurologic outcomes. However, the mRs is commonly used in the clinical evaluation of neurologic outcomes in aneurysm and stroke patients. Not only does it possess a high degree of interobserver reliability, but it also strongly correlates with functional outcome, even when reduced to a dichotomous variable.10,11

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Risk Factors for Poor Neurologic Outcome After Aneurysm Surgery

Several preoperative factors were associated with a poor neurologic outcome 48 hours after surgery, such as female sex, advanced age, large aneurysm size, higher preoperative Hunt Hess classification, preexisting hypertension, preexisting coronary artery disease, and a Fisher Grade of 4 on presentation (Table 3). This is consistent with other studies that have confirmed that increasing age, giant aneurysms (>25 mm), worse initial World Federation of Neurosurgical Societies scores), larger size of hematoma on initial brain computed tomography scan, and previous diagnosis of hypertension or myocardial infarction are associated with worsened neurologic outcome after cerebral aneurysm surgery.18–21 Unfortunately, none of these factors is modifiable, and therefore, these findings serve the sole purpose of risk prediction, or stratification, and not risk modification.

The use of temporary arterial occlusion to assist in clip ligation or clip reconstruction of intracranial aneurysms has been used for decades and has been reported as a safe and acceptable technique.22,23 There are reports that temporary arterial occlusion, however, can be poorly tolerated under certain circumstances, such as in the presence of intraoperative aneurysm rupture or when the duration of temporary occlusion is >20 minutes.24 Other investigators have determined that 10 minutes of middle cerebral artery occlusion may be the safe upper limit of iatrogenic focal ischemia.25 Throughout planned temporary arterial occlusion, we routinely use propofol infusions to decrease the cerebral metabolic rate (i.e., electroencephalogram with a burst-suppression ratio of 0.7–0.8 or Bispectral Index 15–25) and potentially increase the tolerance to focal cerebral ischemia.26,27 When temporary arterial occlusion is expected to be very brief (i.e., < approximately 4 minutes, which is the duration of total hypotension achieved by adenosine in our previous study),8 coordinated use of adenosine-induced flow arrest may offer a possible alternative to this surgical technique.

As mentioned above, most of the factors that were associated with a worse postoperative neurologic outcome after aneurysm clip ligation (both in previous studies and in the current study) are nonmodifiable patient demographics (i.e., age, sex), preexisting medical conditions (i.e., hypertension, coronary artery disease), or characteristics of the aneurysm and related subarachnoid hemorrhage (i.e., aneurysm size, Hunt Hess classification). The only potentially modifiable factor that was associated with poor neurologic outcome was the use of temporary arterial occlusion to facilitate aneurysm clip ligation. Whether this is truly a modifiable factor, that is, can temporary arterial occlusion be avoided, less routinely used, or even replaced with coordinated adenosine-induced flow arrest when temporary arterial occlusion is expected to be very brief, is not clear. Further understanding of those discrete factors that influence the obligated use of temporary arterial occlusion versus the choice to use adenosine-induced flow arrest may help in better delineating whether this is truly a modifiable risk factor for poor neurologic outcome. Developing a multicenter database that has enough a priori defined variables to capture this level of detail might answer this question.

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Conclusion

In conclusion, our present case-control study provides evidence that adenosine-induced flow arrest is associated with between a 15.7% increase or a 12.7% decrease in the incidence of poor neurologic outcome and no cardiac morbidity and therefore may be safely used to facilitate aneurysm clip ligation. Outcomes databases will be invaluable for continued pharmacovigilance related to adenosine-induced flow arrest, especially as the technique is more widely adopted by other centers as an adjunct or alternative to temporary arterial occlusion. With pooling of detailed patient data, the benefits or risks of population dose-response models for adenosine for this indication, rather than exposure to multiple incremental doses to determine each individual’s appropriate adenosine dose, could be more closely examined.

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DISCLOSURES

Name: John F. Bebawy, MD.

Contribution: This author helped design and conduct the study, analyze the data, and write the manuscript.

Attestation: John F. Bebawy has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Carine Zeeni, MD.

Contribution: This author helped design and conduct the study, analyze the data, and write the manuscript.

Attestation: Carine Zeeni has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Sonal Sharma, MBBS, MD.

Contribution: This author helped design and conduct the study, analyze the data, and write the manuscript.

Attestation: Sonal Sharma has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Edina S. Kim, MD.

Contribution: This author helped design and conduct the study, analyze the data, and write the manuscript.

Attestation: Edina S. Kim has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Mark S. DeWood, BS.

Contribution: This author helped design and conduct the study, analyze the data, and write the manuscript.

Attestation: Mark S. DeWood has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Laura B. Hemmer, MD.

Contribution: This author helped design and conduct the study, analyze the data, and write the manuscript.

Attestation: Laura B. Hemmer has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Vijay K. Ramaiah, MBBS, MD.

Contribution: This author helped design and conduct the study, analyze the data, and write the manuscript.

Attestation: Vijay K. Ramaiah has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Bernard R. Bendok, MD.

Contribution: This author helped conduct the study and write the manuscript.

Attestation: Bernard R. Bendok has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Antoun Koht, MD.

Contribution: This author helped design and conduct the study, and write the manuscript.

Attestation: Antoun Koht has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Dhanesh K. Gupta, MD.

Contribution: This author helped design and conduct the study, analyze the data, and write the manuscript.

Attestation: Dhanesh K. Gupta has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.

This manuscript was handled by: Gregory J. Crosby, MD.

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