Update: Adenosine-induced cardiac standstill with hypotension

Several flow-arrest techniques have been introduced for the treatment of complex aneurysms that cannot be treated with conventional clipping or endovascular coil embolization. Adenosine-induced transient asystole is an alternative method of flow arrest.

Adenosine-induced flow arrest briefly reduces cerebral perfusion pressure and reduces the turgor of the aneurysm, thereby facilitating the clip ligation in complex aneurysms. Periods of flow arrest have to be carefully coordinated with the surgeon such that necessary working time is available for aneurysm dissection and clip placement. Adenosine-induced transient asystole is safe and efficacious when administered at an average of 0.3 to 0.4 mg/kg IBW in combination with remifentanil/low-dose volatile anesthetic with propofol. The adenosine dose will achieve approximately 45 seconds of controlled systemic hypotension and a bloodless surgical field. Adenosine offers the advantage of easy applicability in different situations without advanced preparation or complex logistical coordination with anesthesiology and cardiovascular surgery. This technique also allows the surgeon to have the maximum amount of space available to manipulate the aneurysm and place the clips, as no temporary clips are in the field of view. Also, temporary clips only decrease flow from the clipped inflow, whereas adenosine produces a more global hypotension and therefore often a better collapse of the aneurysm 1).
Adenosine-induced asystole for cerebral aneurysms surgery was first described by Groff et al. 2) in 1999 in posterior circulation aneurysms.
It is an easily applied technique in a variety of clinical situations. Its use requires minimal advanced preparation and no complex logistical coordination with other subspecialties. However, patient-specific dose-response relationships must be determined by exposure, so the relationship may not be known in an emergent situation. Persistent hypotension is a potentially major complication. Rapid ventricular pacing (RVP) has recently been reintroduced into cerebrovascular surgery. It is more predictable than adenosine in response time and, thus, can be used during unanticipated complications, such as aneurysmal rupture. It also induces a shorter period of hypotension compared with adenosine. However, RVP is more invasive and more complex from an anesthesia standpoint. Vascular neurosurgeons should be familiar with these techniques and know their applications and limitations 3).

Case series


The aim of a study is to report the experience in the use of adenosine in aneurysm clipping and arteriovenous malformation (AVM) resection and review the literature. The records of all patients who had adenosine-assisted clipping of intracranial aneurysms and AVM resections between November 2015 and December 2016 were extracted from prospectively maintained database. The following data were collected: patient demographics, comorbidities, size and location of the aneurysms or AVM, number of boluses and total dose of adenosine administered, duration of cardiac standstill and hypotension (systolic blood pressure < 60 mmHg), intraoperative and postoperative complications and outcome scores at discharge. Literature search on Embase and PubMed for the terms “adenosine and clipping”, “adenosine and aneurysm” and “adenosine and AVM” was performed. Eight aneurysms and two AVMs were identified. While both AVMs were elective procedures, half of the aneurysm clippings were on urgent basis.
Al-Mousa et al. used adenosine safely with spontaneous return of rhythm in all cases. Temporary clips to the parent artery were applied for brief periods in 2 patients who had pre-adenosine intraoperative rupture. They did not observe any immediate or late adverse events related to administration of adenosine.
In a review, a total of ten case series and four case reports were identified. There were no reports on the use of adenosine in AVM resection. Transient adenosine-induced asystole is a safe and effective technique in facilitating surgical treatment of complex aneurysms and AVMs. In addition, adenosine use reduces the need, duration, and associated complications of temporary clip applications to parent arteries 4).


A total of 22 aneurysms in 22 different patients that underwent adenosine-induced transient asystole during aneurismal neck clipping within the past 4 years were retrospectively reviewed. Adenosine was administrated intravenously in a test-incremental manner (starting with 6-12 mg and then giving additional doses as needed) in 11 patients and in an estimated manner (pre-calculated as 0.3-0.4 mg/kg) in 11 patients.
Overall, the study consisted of 18 unruptured saccular aneurysms, three ruptured saccular aneurysms, and a ruptured pseudoaneurysm. Adenosine-induced transient asystole was used in cases of temporary clipping inability, wide necked aneurysm, deep-seated aneurysm, or a thin aneurysm wall. The number of administrations, dose (mg/kg in ideal body weight) and duration of asystole were 1-4 (mean, 2.3) times, 0.08-1.27 (mean, 0.36) mg/kg and 0-30 (mean 13) seconds in the test-incremental manner and 1-2 (mean, 1.09) times, 0.24-0.42 (mean, 0.34) mg/kg and 13-41 (mean, 24) seconds in the estimated manner, respectively. There was a linear relationship between the dose and the duration of asystole. Twenty out of 22 aneurysms were clipped successfully with adenosine-induced transient asystole. However, in the other two cases, additional suction decompression was required for the final clipping. Adenosine-related cardiologic complications occurred in two cases of self-limited atrial fibrillation during restoration of the cardiac rhythm.
In our experience, adenosine-induced transient asystole was safe and helpful for satisfactory clipping of a complicated aneurysm. An estimated dose injection of adenosine was more convenient than the test-incremental method and did not result in serious cardiologic problems 5).


A report describes three children, aged eight to 11 years, with high-flow cerebral arteriovenous malformations who underwent interventional neuroradiological procedures involving glue (N-butyl cyanoacrylate) embolisation under general anaesthesia. The procedure was facilitated by relative hypotension induced by esmolol infusion and intravenous adenosine boluses. To allow controlled deposition of N-butyl cyanoacrylate into the arteriovenous malformations, glue injection was synchronised with the onset of adenosine-induced brief cardiac standstill. This resulted in satisfactory obliteration of the arteriovenous malformations nidus in all cases. The haemodynamic modulations, including the adenosine-induced brief cardiac standstill, was noted to not affect the BIS values in our patients. All patients had satisfactory obliteration of their arteriovenous malformations and had good neurological outcomes at one-year follow-up 6).

Britz GW. Adenosine-induced transient asystole. Methodist Debakey Cardiovasc J. 2014 Oct-Dec;10(4):220-3. doi: 10.14797/mdcj-10-4-220. Review. PubMed PMID: 25624976; PubMed Central PMCID: PMC4300060.

Groff MW, Adams DC, Kahn RA, Kumbar UM, Yang BY, Bederson JB. Adenosine-induced transient asystole for management of a basilar artery aneurysm. Case report. J Neurosurg. 1999 Oct;91(4):687-90. PubMed PMID: 10507394.

Rangel-Castilla L, Russin JJ, Britz GW, Spetzler RF. Update on transient cardiac standstill in cerebrovascular surgery. Neurosurg Rev. 2015 Oct;38(4):595-602. doi: 10.1007/s10143-015-0637-z. Epub 2015 May 1. PubMed PMID: 25931209.

Al-Mousa A, Bose G, Hunt K, Toma AK. Adenosine-assisted neurovascular surgery: initial case series and review of literature. Neurosurg Rev. 2017 Jul 22. doi: 10.1007/s10143-017-0883-3. [Epub ahead of print] Review. PubMed PMID: 28735438.

Lee SH, Kwun BD, Kim JU, Choi JH, Ahn JS, Park W, Yun JH. Adenosine-induced transient asystole during intracranial aneurysm surgery: indications, dosing, efficacy, and risks. Acta Neurochir (Wien). 2015 Nov;157(11):1879-86; discussion 1886. doi: 10.1007/s00701-015-2581-7. Epub 2015 Sep 18. PubMed PMID: 26385113.

Puri GD, Sen I, Bapuraj JR. Adenosine-induced cardiac standstill to facilitate endovascular embolisation of cerebral arteriovenous malformations in children. Anaesth Intensive Care. 2009 Jul;37(4):619-23. PubMed PMID: 19681422.

Update: Heparin induced thrombocytopenia in Neurosurgery

Heparin-induced thrombocytopenia (HIT) is a complication of heparin therapy.


There are two types of HIT. Type 1 HIT presents within the first 2 days after exposure to heparin, and the platelet count normalizes with continued heparin therapy. Type 1 HIT is a nonimmune disorder that results from the direct effect of heparin on platelet activation.
Type 2 HIT is an immune-mediated disorder that typically occurs 4-10 days after exposure to heparin and has life- and limb-threatening thrombotic complications. In general medical practice, the term HIT refers to type 2 HIT.
HIT must be suspected when a patient who is receiving heparin has a decrease in the platelet count, particularly if the fall is over 50% of the baseline count, even if the platelet count nadir remains above 150 x 109/L. Clinically, HIT may manifest as skin lesions at heparin injection sites or by acute systemic reactions (eg, chills, fever, dyspnea, chest pain) after administration of an intravenous bolus of heparin.
Unlike other forms of thrombocytopenia, HIT is generally not marked by bleeding; instead, venous thromboembolism (eg, deep venous thrombosis, pulmonary embolism) is the most common complication. Less often, arterial thrombosis (eg, myocardial infarction) may occur. For that reason, the disorder is sometimes termed heparin-induced thrombocytopenia and thrombosis (HITT).
Diagnosis of HIT is based on the combination of clinical findings, thrombocytopenia characteristics, and laboratory studies of HIT antibodies. Treatment of HIT begins with discontinuation of all heparin products (including heparin flushes of intravenous catheters). The patient should then be started on an alternative anticoagulant 1).

The incidence of heparin induced thrombocytopenia (HIT) in neurological patients continues to increase with expansion of indication for neurointerventional procedures. The pathophysiology of HIT is related to a hypersensitivity reaction against complex platelet factor 4. The diagnosis is mostly clinical and is often confirmed by laboratory testing. Patients with HIT have a higher rate of thromboembolic complications, both arterial and venous, and with worse neurological outcomes at the time of discharge. Early diagnosis and heparin cessation are essential in the management of those patients. Both immediate and prolonged alternative anticoagulation are necessary. Understanding of the mechanism of action, indication and drug interaction of the alternative anticoagulants (direct thrombin inhibitors, fondaparinux and danaparoid) and warfarin is essential during management of these patients 2).
Venous thromboembolism (VTE) is associated with heparin induced thrombocytopenia (HIT) infrequently (< 1%) in low molecular weight heparin (LMWH) treated patients, yet often (approximately one in eight cases) in unfractionated heparin-treated patients. Physicians should suspect the possibility of HIT if VTE develops during or soon after unfractionated heparin use; if thrombocytopenia is present, alternative anticoagulation should be used until HIT is excluded 3).
Heparin-induced thrombocytopenia type II correlates with a worse outcome and higher risk of thromboembolic complications in aneurysmal subarachnoid hemorrhage patients. In addition, HIT II was strongly associated with the number of angiographic procedures performed during the same hospitalization 4).
The presence of HIT in SAH has adverse consequences and is more likely in female patients who have undergone aneurysm clipping and require multiple endovascular vasospasm treatments 5).
SAH patients with isolated heparin induced thrombocytopenia and heparin induced thrombocytopenia with thrombotic syndrome did not differ in the incidence of new thromboses, incidence of hemorrhage, or hospice/death. Patients with isolated heparin induced thrombocytopenia had fewer “poor treatment-related effects” than heparin induced thrombocytopenia with thrombotic syndrome patients 6).

Studies reveal a high occurrence of overdiagnosis of heparin-induced thrombocytopenia in surgical patients with critical illness. The optimal criteria for diagnosis of heparin-induced thrombocytopenia remain unclear, contributing to unnecessary treatment.
Overtreatment of heparin-induced thrombocytopenia in the surgical ICU continues even with recent increased caution encouraging a higher antiplatelet factor 4/heparin enzyme-linked immunosorbent assay optical density threshold before initiating treatment. More stringent criteria should be used to determine when to order serologic testing and when the results of such testing should prompt a change in anticoagulant treatment. If antiplatelet factor 4/heparin enzyme-linked immunosorbent assay is used to consider immediate treatment, an optical density greater than or equal to 2.0 may be a more appropriate threshold 7).

Case series

During a 3.5-year period (January 2000-June 2003), 389 consecutive SAH patients were treated at our center. We retrospectively reviewed their laboratory data and medical records and used accepted clinical criteria for the diagnosis of HIT II to determine the incidence of HIT II, thrombotic complications, management, and outcome.
Fifty-nine patients (15%) met the clinical diagnostic criteria for HIT II. The average platelet count nadir in the HIT II patients was 68,600 +/- 25,300/microl (mean +/- standard deviation). Female patients and patients with Fisher Grade 3 were more likely to develop HIT II (P < 0.01). Thirty-six patients (61%) underwent a neuroendovascular procedure. The rate of systemic thrombotic complications in the HIT II patients was 37 versus 7% in SAH patients without HIT II (P < 0.001), and the rate of new hypodensities on head computed tomographic scans was 66% in the HIT II patients versus 40% in the SAH patients without HIT II (P < 0.001). Clinical outcomes were worse in the HIT II patients. The outcome was favorable for 38% in the HIT II patients versus 52% in all SAH patients (P < 0.05), and deaths were more common (29%) in the HIT II patients than in all SAH patients (12%, P < 0.001).
The incidence of HIT II in SAH patients at a single center was 15%. The SAH patients with HIT II had significantly higher rates of thrombotic complications, new hypodensities on head computed tomographic scans, more deaths, and significantly less favorable outcomes. This is the first report of the incidence of HIT II in a neurosurgical patient population 8).

Case reports


A 63-year-old man with HIT and multiple medical comorbidities underwent emergent coronary artery bypass grafting, postoperative imaging revealed plaque at the origin of the left internal carotid artery with 80%-99% stenosis and minimal contralateral internal carotid artery disease. During the patient’s evaluation to undergo CEA for symptomatic high-grade carotid stenosis, enzyme-linked immunosorbent assay revealed persistent platelet factor 4 antibodies.
The endarterectomy was successfully performed while the patient received argatroban, both as a continuous infusion and intermittent irrigation during dissection of the plaque. Postoperatively, the drip was continued for 24 hours, and the patient was discharged day 2 on a daily dose of 325 mg of aspirin. At the 6-month examination, Doppler ultrasound revealed normal anterograde velocities with no evidence of stenosis, and the patient noted no subsequent ischemic events.
Serrone et al., now recommend systemic intravenous and local argatroban irrigation to prevent thromboembolic complications in CEA cases with HIT and renal insufficiency. Bivalirudin for both systemic intravenous use and local irrigation may be safer in patients without renal insufficiency because of its shorter half-life 9).


Kruljac et al., report a case of an elderly female who received prophylactic fractionated heparin therapy due to sepsis, consequent rhabdomyolysis, and overt disseminated intravascular coagulation. On the seventh day of heparin therapy, she reported sudden vision loss, ptosis, diplopia, and severe headache. Severe thrombocytopenia and positive antibodies to the complex of platelet factor 4 and heparin confirmed heparin-induced thrombocytopenia type 2 (HIT). Magnetic resonance imaging disclosed a homogenous pituitary tumor mass with pronounced sphenoid sinus mucosa thickening and two hypointense zones within the tumor mass on contrast-enhanced images consistent with focal ischemic necrosis. The tumor was confirmed to be squamous cell carcinoma with no signs of necrosis. Ischemic necrosis was found within marginal pituitary tissue. This is the first reported case of ischemic PA associated with pituitary metastasis and the first case in which HIT triggered PA. Our case demonstrates that prothrombotic states such as HIT can precipitate ischemic PA. Pituitary metastasis can present with ischemic PA, but radiological features differ from those described in pituitary adenomas. Segregated low-signal intensity zones within the tumor mass on postcontrast images indicate partial infarction of the tumor, which could be a special feature of ischemic PA in pituitary metastasis and has never been described in pituitary adenomas. These are all novel findings and might enlighten the pathogenesis of PA 10).


A 58-year-old woman presented with right supplementary motor area glioblastoma multiforme and deep venous thrombosis in her legs. The tumor was resected after temporary inferior vena cava filter placement, considering that increased thrombosis during and after the operation would cause fatal pulmonary embolism. After anticoagulation with unfractionated heparin, thrombocytopenia was aggravated, and computed tomography showed filter catheter-related thrombosis in the inferior vena cava. The diagnosis was heparin-induced thrombocytopenia, and argatroban and urokinase were administered. Thrombolysis with urokinase was completed and the temporary inferior vena cava filter catheter was removed without complication 11).

A case of bifrontal intracerebral haemorrhage in a patient with heparin-induced thrombocytopenia type II (HIT II). HIT II was induced by treatment with low-molecular-weight heparin for recurrent deep vein thrombosis caused by essential thrombocytosis and accompanied by hepatic thromboembolism. This patient was treated with platelet substitution and neurosurgical haematoma evacuation. Anticoagulation with 2500 units danaparoid per day was sufficient for therapy of thrombosis and no rebleeding occurred 12).

A 61-year-old woman treated for cerebral venous thrombosis (CVT) leading to diagnosis of essential thrombocythemia (ET). During treatment with unfractionated heparin, after initial improvement of clinical state, signs of cerebral hypertension reappeared. Although the platelet count decreased, heparin-induced thrombocytopenia (HIT) was only suspected 2 days later when it dropped below the standard 150 × 10(9) L(-1) threshold. HIT diagnosis was confirmed by the presence of anti-PF4/heparin IgG. This late finding was the cause of the extension of CVT with worsening of cerebral hypertension necessitating decompressive craniectomy. Elevated basal platelet count due to ET can delay diagnosis and treatment of HIT. In this case, physicians should be more attentive to platelet count variations rather than thrombocytopenia threshold 13).


A patient with heparin-induced thrombocytopenia type II and pulmonary embolism who was anticoagulated with argatroban and, later, with fondaparinux. No intracranial bleeding was detected when anticoagulation was performed with argatroban and, later, fondaparinux 14).

A case of intratumor haemorrhage in the cavernous sinus 1 week after cardiac surgery. The pathogenesis may be venous thrombosis and haemorrhagic infarct caused by HIT following cardiopulmonary bypass surgery 15).


The development of cerebral sinus thrombosis as a complication of heparin-induced thrombocytopenia is very rare. A 59-year-old patient with cerebral sinus thrombosis secondary to type II heparin-induced thrombocytopenia 16).


Doty et al., report the clinical course of two patients who in the immediate postoperative period developed heparin-associated thrombocytopenia that resulted in significant morbidity. In these two cases, the origin of the heparin was in “flush” solutions used to maintain the patency of indwelling vascular catheters and was infused at a dose of 250 to 500 units/day. The minimal daily dose previously reported to result in thrombocytopenia is 9000 units/day administered in divided doses subcutaneously. The case reports indicate that heparin in “flush” solutions should be considered as a cause for unexpected thrombocytopenia and that platelet counts should be monitored in patients receiving heparin in any amount 17).

2) Alaraj A, Wallace A, Tesoro E, Ruland S, Amin-Hanjani S, Charbel FT, Aletich V. Heparin induced thrombocytopenia: diagnosis and management. J Neurointerv Surg. 2010 Dec;2(4):371-8. doi: 10.1136/jnis.2010.002840. Epub 2010 Jul 23. Review. PubMed PMID: 21990651.
3) Levine RL, McCollum D, Hursting MJ. How frequently is venous thromboembolism in heparin-treated patients associated with heparin-induced thrombocytopenia? Chest. 2006 Sep;130(3):681-7. PubMed PMID: 16963663.
4) Alaraj A, Wallace A, Mander N, Aletich V, Charbel FT, Amin-Hanjani S. Risk factors for heparin-induced thrombocytopenia type II in aneurysmal subarachnoid hemorrhage. Neurosurgery. 2011 Nov;69(5):1030-6. doi: 10.1227/NEU.0b013e3182284a81. PubMed PMID: 21670717.
5) Mehta BP, Sims JR, Baccin CE, Leslie-Mazwi TM, Ogilvy CS, Nogueira RG. Predictors and outcomes of suspected heparin-induced thrombocytopenia in subarachnoid hemorrhage patients. Interv Neurol. 2014 Aug;2(4):160-8. doi: 10.1159/000362189. PubMed PMID: 25337085; PubMed Central PMCID: PMC4188165.
6) Benken ST, Tesoro EP, Kim KS, Mucksavage JJ. Treatment outcomes of heparin-induced thrombocytopenia in subarachnoid hemorrhage patients: a 4-year, retrospective single-center review. Neurocrit Care. 2012 Oct;17(2):177-82. doi: 10.1007/s12028-012-9725-x. PubMed PMID: 22692920.
7) Harada MY, Hoang DM, Zaw AA, Murry JS, Volod O, Sun BJ, Nuño M, Mason R, Margulies DR, Ley EJ. Overtreatment of Heparin-Induced Thrombocytopenia in the Surgical ICU. Crit Care Med. 2016 Aug 4. [Epub ahead of print] PubMed PMID: 27513533.
8) Hoh BL, Aghi M, Pryor JC, Ogilvy CS. Heparin-induced thrombocytopenia Type II in subarachnoid hemorrhage patients: incidence and complications. Neurosurgery. 2005 Aug;57(2):243-8; discussion 243-8. PubMed PMID: 16094152.
9) Serrone JC, Andaluz N, Brink V, Zuccarello M, Ware SL. Systemic infusion and local irrigation with argatroban effective in preventing clot formation during carotid endarterectomy in a patient with heparin-induced thrombocytopenia. World Neurosurg. 2013 Jul-Aug;80(1-2):222.e15-8. doi: 10.1016/j.wneu.2013.01.037. Epub 2013 Jan 12. PubMed PMID: 23321376.
10) Kruljac I, Cerina V, Pećina HI, Pažanin L, Matić T, Božikov V, Vrkljan M. Pituitary metastasis presenting as ischemic pituitary apoplexy following heparin-induced thrombocytopenia. Endocr Pathol. 2012 Dec;23(4):264-7. doi: 10.1007/s12022-012-9224-9. PubMed PMID: 23129546.
11) Nitta N, Shitara S, Nozaki K. Heparin-induced thrombocytopenia in a glioblastoma multiforme patient with inferior vena cava filter placement for deep venous thrombosis. Neurol Med Chir (Tokyo). 2011;51(6):445-8. PubMed PMID: 21701111.
12) Hertle DN, Hähnel S, Richter GM, Unterberg A, Sakowitz OW, Kiening KL. The use of danaparoid to manage coagulopathy in a neurosurgical patient with heparin-induced thrombocytopenia type II and intracerebral haemorrhage. Br J Neurosurg. 2011 Feb;25(1):117-9. doi: 10.3109/02688697.2010.502266. Epub 2010 Aug 13. PubMed PMID: 20707682.
13) Richard S, Perrin J, Lavandier K, Lacour JC, Ducrocq X. Cerebral venous thrombosis due to essential thrombocythemia and worsened by heparin-induced thrombocytopenia and thrombosis. Platelets. 2011;22(2):157-9. doi: 10.3109/09537104.2010.527399. Epub 2010 Dec 8. PubMed PMID: 21142409.
14) Kerz T, Schinzel H. Anticoagulation in a Neurosurgical Patient with Heparin-Induced Thrombocytopenia Type II with Argatroban and Fondaparinux after Clipping of an Intracranial Aneurysm. Transfus Med Hemother. 2009;36(2):141-143. Epub 2009 Mar 13. PubMed PMID: 20823996; PubMed Central PMCID: PMC2928829.
15) Tsai HC, Yen HC, Hsu JC, Lin CL. Heparin-induced thrombocytopenia associated with intra-tumour haemorrhage in cavernous sinus after cardiac myxoma surgery. Br J Neurosurg. 2009 Feb;23(1):95-6. doi: 10.1080/02688690802272164. PubMed PMID: 19234918.
16) Fountas KN, Faircloth LR, Hope T, Grigorian AA. Spontaneous superior sagittal sinus thrombosis secondary to type II heparin-induced thrombocytopenia presenting as an acute subarachnoid hemorrhage. J Clin Neurosci. 2007 Sep;14(9):890-5. Epub 2007 Jun 19. PubMed PMID: 17582771.
17) Doty JR, Alving BM, McDonnell DE, Ondra SL. Heparin-associated thrombocytopenia in the neurosurgical patient. Neurosurgery. 1986 Jul;19(1):69-72. PubMed PMID: 3748340.
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