Adenosine-induced cardiac arrest during intraoperative cerebral aneurysm rupture

1. Introduction 

Intraoperative rupture of the cerebral arterial aneurysm can have undesired consequences. Whether it has an effect on patient neurologic outcome remains to be determined. The most recent study suggests, however, that intraoperative aneurysm rupture does not influence patient outcome [1], [18]. Stable intraoperative blood pressure, careful microneurosurgical technique, and the application of temporary clips may minimize the risk of rupture of the aneurysm [2], [6], [9], [13]. In a case of an aneurysm rupture, adenosine, a short-acting drug with negative effect on sinoatrial and atrioventricular nodes, has been used successfully to induce transient cardiac arrest to stop the bleeding when suction fails to clear the operative field [10], [12], [15]. The relatively bloodless field may enable the surgeon to place temporary or permanent clip under visual control.

There are only 3 earlier single-patient case reports with successful use of adenosine in inducing a transient cardiac arrest to facilitate clipping of an aneurysm with or without a rupture [10], [12], [15]. We analyzed retrospectively the data of the patients who were administered adenosine during the intraoperative rupture of a cerebral arterial aneurysm.

2. Methods 

Patients with surgical clipping of an intracranial aneurysm were identified from the operative database and records of Turku and Helsinki University Hospitals over a period of 5.5 years (January 2003-May 2008). These 2 university hospitals serve southern and western Finland with a population of 3 million. Patients were included in the study if there was a rupture of an aneurysm during the surgery and if they had received adenosine after the rupture. As the study is of a retrospective nature, approval by the hospital ethics review committees was not required. The perioperative treatment protocols of patients with SAH, as well as of patients with nonruptured cerebral aneurysm, are similar in both university hospitals [17].

The clinical variables included in the analyses were age, comorbidities, GCS, Fischer scale, Hunt and Hess scale, presence of hydrocephalus, location of the aneurysm, hemodynamics before and after the adenosine, dose of adenosine, use of vasoactive drugs, number of delayed ischemic deficiencies, length of stay in the intensive care unit and in the hospital, patient state at discharge from the hospital, and GOS. Furthermore, the patients were grouped according to discharge from the hospital (dead or alive) and according to outcome (good outcome, GOS 4-5; poor outcome, GOS 1-3).

3. Results 

Altogether, 16 of 1014 patients (Helsinki, 825; Turku, 189) were identified with the use of adenosine during an intraoperative rupture of an intracranial aneurysm (Table 1). Fifteen of the patients were admitted to the hospital owing to a SAH, and one patient was scheduled for an elective clipping of a basilar aneurysm. Nine of the cerebral aneurysms were located in the anterior and 7 in the posterior cerebral circulation (Table 2). Seven of the patients were previously diagnosed to have hypertension, 2 with coronary artery disease, and 3 with universal atherosclerosis. The comorbidities associated with SAH are presented in Table 3.

Table 1. Demographics of the data, presented as numbers of patients and means ± SD

	Sex (male/female)	6/10 (37.5%/62.5%)
	Age	53.1 ± 15.5 y
	Height	76.0 ± 9.9 kg
	Weight	169.9 ± 7.9 cm
	SAH/Elective surgery	15/1

Table 2. Locations of the aneurysms

	Aneurysms	Numbers (%)
	Internal carotid artery	2 (12.5)
	Middle cerebral artery	4 (25)
	Anterior cerebral artery	1 (6.25)
	Anterior communicating artery	2 (12.5)
	Posterior cerebral artery	1 (6.25)
	Basilar artery	5 (31.25)
	Pericallosal artery	1 (6.25)

Table 3. Comorbidities associated with SAH

		Yes	No
	Hydrocephalus	5	11
	ECG Ischemia	4	12
	Neurogenic pulmonary edema	1	15
	DIND	2	13

ECG ischemia indicates myocardial ischemia seen on ECG; DIND, delayed ischemic neurologic deficiencies.

Fourteen patients had sinus rhythm preoperatively. In one patient, the preoperative ECG was not found. One patient with sinus rhythm had supraventricular extrasystolic beats. Ischemic ECG changes were observed in 4 patients preoperatively. The preoperative plasma potassium level was within normal range in all of the patients.

Anesthesia was maintained with propofol and remifentanil in all patients. Ten minutes before the aneurysm rupture and adenosine bolus, the mean systolic and diastolic blood pressure levels were 119 ± 14 and 59 ± 10 mm Hg, respectively, and the mean heart rate was 70 ± 13 per minute. After intraoperative aneurysm rupture, 12 patients received a single adenosine bolus, whereas 4 patients received repeated boluses of adenosine. The median (range) adenosine dose used for the single bolus was 12 (6-18) mg, whereas the median total dose for multiple boluses was 27 (18-89) mg.

As measured 10 minutes after the adenosine, the hemodynamics of the patients were stabilized. At this stage, the mean systolic and diastolic blood pressure levels were 113 ± 14 and 57 ± 9 mm Hg, respectively, and the mean heart rate was 74 ± 15 per minute. During the surgery, 13 patients needed an infusion of vasoactive drugs to maintain adequate blood pressure. Four patients were administered noradrenalin, 7 patients with phenylephrine, and one patient required both phenylephrine and dobutamine. All vasoactive drugs were commenced after the anesthesia induction and infused throughout the surgery. The mean duration of the surgery was 135 ± 27 minutes.

The mean stay in the intensive care unit was 6.3 ± 4.6 days and in the university hospital was 17.9 ± 11.7 days. The median (range) postoperative GCS was 9.5 (3-15). The number of patients discharged alive from the hospital was 12, and 4 died during the hospital stay. Four patients died later in other hospitals owing to complications related to SAH. Two patients experienced delayed ischemic neurologic deficiencies, and one of them died after discharge from the hospital. The median (range) GOS was 2 (1-5). Five patients were discharged with GOS of 5, 2 patients with GOS of 4, one with GOS of 3, and 8 patients with GOS of 1 (died). Table 4 presents the severity of SAH, administered doses of adenosine, and GOS.

Table 4. Severity of SAH and outcome of patients receiving adenosine

	Patient	GCS	Fischer	Hunt and Hess	Temporary clip	Occlusion time	Adenosine (mg)	GOS
	1	13	3	4	No		18	1
	2	15	3	2	No		6	5
	3	5	3	4	No		18	1
	4	6	4	5	Yes	6 min 28 s	9	4
	5	5	4	5	Yes	Not known	12	1
	6	10	4	4	No		16	1
	7	15	1	1	Yes	Not known	12	5
	8	3	4	5	Yes	19 min	87	1
	9	3	3	5	Yes	Not known	9	3
	10	7	4	5	Yes	Not known	12	1
	11	15	4	2	Yes	9 min 55 s	18	5
						3 min 22 s
	12	4	4	5	Yes	Not known	12	1
	13	15	Elective	Elective	No		9	5
	14	15	3	2	Yes	6 min 18 s	12	5
	15	3	4	5	Yes	Not known	36	1
	16	10	3	3	Yes	5 min	12	4

Glasgow Outcome Scale: 5 indicates good recovery; 4, moderate disability; 3, severely disabled; 2, vegetative state; 1, death.

In subgroup analysis, there was a significant difference in the median Hunt and Hess score between the patients discharged alive or dead from the hospital, 3.5 (0-5) and 5 (4-5) (P < .05), respectively. There was also a significant difference in the median pre- and postoperative GCS between the patients discharged alive or dead, 11.5 (3-15) and 4.5 (3-7) and 14 (4-14) and 4.5 (3-8) (P < .05), respectively. The Fischer scale, Hunt and Hess score, GCS on admittance or after the surgery, however, were similar in the good-outcome (GOS 4-5) and in the poor-outcome (GOS 1-3) groups. The total administered dose of adenosine or the hemodynamics were not different between any of these subgroups (P > .05).

4. Discussion 

In the present study, we analyzed the hospital records of 16 of 1014 patients who had an intraoperative rupture of a cerebral aneurysm with the short-term adenosine-induced circulatory arrest facilitating the clipping. The decision to give adenosine was made in cooperation with the neurosurgeon and the anesthesiologist. The final clipping of the aneurysm as well as the restoration of systemic circulation was successful in all cases. We did not observe any immediate or late adverse events related to the administration of adenosine.

Adenosine has a very short negative dromotropic and chronotropic effect on cardiac sinoatrial and atrioventricular nodes, and it is usually indicated in paroxysmal supraventricular tachyarrhythmia. The administration of adenosine in patients with normal sinus rhythm induces a rapidly reversible cardiac arrest. The intravascular half-life of adenosine at the physiologic level is less than a second. The mechanism of action of adenosine in cardiac muscle is hyperpolarization after its binding to A1 receptors and opening of potassium channels. Adenosine also decreases intracellular cyclic adenosine monophosphate, which inhibits calcium entry into the cell [3], [14], [16].

In the current study, the majority of the patients presented a cardiac arrest after a single dose of adenosine (median, 12 mg). This median dose is in accordance with the recommended doses of 6 to 12 mg for supraventricular tachyarrhythmias [7], [8]. However, 4 of 16 patients were administered adenosine more than once and the median cumulative dose was considerably higher, 27 mg. As assessed retrospectively, there may have been requirements for a prolonged cessation of circulation because of surgical reasons or the ineffectiveness of adenosine to induce cardiac arrest during normal sinus rhythm. Although none of the 16 patients had unstable hemodynamics nor abnormal arrhythmias after the restoration of spontaneous circulation, repeated doses of adenosine might be given only under extremely close collaboration between the surgeon and the anesthesiologist. For instance, Heppner et al [12] reported administration of a high dose of adenosine, that is, 36 mg, in one patient resulting in prolonged cardiac arrest up to 52 seconds. Adenosine has also been reported to induce ventricular tachycardia or torsades des pointes [5], [11]. Patients in our study received on average significantly smaller doses of adenosine, and cardiac standstills were shorter as well. The fact that most of our patients (n = 13/16) did not have coronary artery disease nor had ischemia in ECG (n = 12/15) preoperatively might have also favored the uneventful restoration of circulation after adenosine.

In the current study, 4 patients with SAH were treated perioperatively with intravenous calcium channel antagonist nimodipine to prevent vasospasm. Calcium channel antagonists and also dipyridamol may inhibit adenosine metabolism and reuptake to cell [11]. Although the adenosine-induced cardiac arrest of the 4 patients with SAH was comparable to that of the patients not on intravenous nimodipine, one should be aware of the possible interaction between nimodipine and adenosine: nimodipine might potentiate the effect of adenosine [4]. The possible interactions of adenosine with propofol, inhaled anesthetics, or opioids are unknown.

Five (31.25%) of 16 patients who were given adenosine underwent surgery of basilar artery aneurysm. This probably refers to the fact that these operations are technically the most challenging ones. This is also supported by other case reports. Groff et al [10] used 3 consequent doses of adenosine to facilitate the placement of a permanent clip to the nonruptured basilar artery aneurysm, whereas the report by Heppner et al [12] describes a case where 3 relatively high and consequent doses of adenosine were used to help the surgeon to place a permanent aneurysm clip on the basilar aneurysm, because the attempt to place a temporary clip had failed. Nussbaum et al [15] gave a single dose of adenosine to control the bleeding of a ruptured anterior communicating artery aneurysm.

The present report has limitations. As all the anesthetic records were hand written, and the study was retrospective, no details of the blood pressure or heart rate immediately after adenosine boluses could be identified. This may be related to the emergency situation with the intraoperative aneurysm rupture. However, we believe if there had been delayed restoration of spontaneous circulation or major hemodynamic instability requiring high doses of vasoactive agents, we could have been able to observe these adverse events in the individual patient's records. We also believe that circulatory arrest facilitated the clipping procedure enabling the neurosurgeon to place a temporary or final clip in a clear field to stop the bleeding, although we lack the neurosurgeon's specific grading of the benefit of the administration of adenosine in single patients. After initial clipping, the clips may be repositioned for optimal occlusion of the aneurysm.

According to our data, there were no differences in any of the measured scales (Hunt and Hess, GCS, Fisher's scale) as the patients were grouped according to good or poor outcome (GOS). However, both the preoperative Hunt and Hess scoring and GCS seemed to be good predictors of in-hospital survival when the patients were grouped at hospital discharge as dead or alive. As the dose of adenosine was comparable in these subgroups, the circulatory arrest induced by adenosine does not seem to have had a deleterious effect on patient outcome. We started to use adenosine soon after it was first introduced in this indication by Groff et al [10] in 1999. Since then, surgical techniques have also changed; especially, the use of temporary clips has become more frequent. Hence, comparison with older material may not be justified in evaluating the effect of adenosine on outcome.

We conclude that adenosine can be safely administered during surgery of a cerebral arterial aneurysm to patients who experience a sudden, uncontrolled bleeding without previous sinoatrial conduction abnormality. Good collaboration between the neurosurgeon and the anesthesiologist is mandatory. The indications of adenosine during intracranial aneurysm surgery are recommended to be discussed preoperatively with the neurosurgeon.