Clopidogrel Dosing

Clopidogrel Dosing

The usual dose for clopidogrel is 75mg once a day.

Start 5 days prior to the actual procedure because there is a 3–7 days latency period to full therapeutic effect.

LD: 300 mg PO, if there was no time to achieve therapeutic e ect over a course of days. A therapeutic effect can usually be achieved within 2 to 3 hours of LD.

Dosing Modifications

Renal impairment: Dose adjustment not necessary Hepatic impairment: Use caution; experience limited Dosing Considerations

CYP2C19 poor metabolizers associated with diminished antiplatelet response to clopidogrel; although higher-dose regimen (600 mg loading dose followed by 150 mg once daily) in poor metabolizers increases antiplatelet response, no appropriate dosing regimen for poor metabolizers has been established in clinical outcome trials Not recommended for pediatric use

Reduced Clopidogrel high on treatment platelet reactivity (CR) can lead to Clopidogrel underactivity (CU) causing acute thrombosis. However, the prevalence of CU among patients with acute symptomatic carotid artery disease remains unknown. Therefore, Honig et al. aimed to find the prevalence and identify the predictors for CU among patients with acutely symptomatic carotid stenosis.

Over the span of 14 months, CR was measured at the time of endovascular procedure in all patients undergoing angiography and stenting because of acute symptomatic carotid stenosis. Only patients treated per institutional protocol with a combination of Clopidogrel and Aspirin were included. CR was measured with P2Y12 reaction units (PRU) and CU was defined as PRU > 208. Patients with CU were compared to those without CU.

Thirty-five patients were included (mean age 71.3 ± 10, 76% men) and twelve (34.3%, mean age 71.8 ± 8.4, 58% men) had CU at the time of endovascular intervention. On univariate analysis more severe carotid stenosis was seen in CU patients (92.6 ± 6.5% vs 81.6 ± 13.6%, p = 0.013) and percent stenosis was independently associated with CU on multivariate analysis (p = 0.023).

Clopidogrel underactivity (CU) is present in 1 of every 3 patients with acutely symptomatic carotid artery disease. The current results suggest that platelet reactivity testing should become part of routine care in patients with acutely symptomatic carotid disease 1).


Honig A, Sacagiu T, Filioglo A, Simaan N, Kalish Y, Gomori JM, Horev A, Leker RR, Cohen JE. Clopidogrel underactivity is a common in patients with acute symptomatic severe carotid stenosis. J Neurol Sci. 2021 Apr 14;425:117450. doi: 10.1016/j.jns.2021.117450. Epub ahead of print. PMID: 33878658.

Bilateral inferior petrosal sinus sampling

Bilateral inferior petrosal sinus sampling

Inferior petrosal sinus sampling (IPSS) is an invasive procedure in which adrenocorticotropic hormone (ACTH) levels are sampled from the veins that drain the pituitary gland; these levels are then compared with the ACTH levels in the peripheral blood to determine whether a pituitary tumor (as opposed to an ectopic source of ACTH) is responsible for ACTH-dependent Cushing syndrome. IPSS can also be used to establish on which side of the pituitary gland the tumor is located.

Bilateral inferior petrosal sinus sampling (BIPSS) is considered the gold standard test for anatomical localization for Cushing’s disease where radiology has been inconclusive 1).

In a metaanalysis of 21 studies, the overall sensitivity and specificity of BIPSS were found to be 96% and 100% respectively 2).

Anatomical localization of pituitary adenoma can be challenging in adrenocorticotropic hormone (ACTH)-dependent Cushing’s syndrome, and bilateral inferior petrosal sinus sampling (BIPSS) is considered gold standard in this regard. Stimulation using corticotropin releasing hormone (CRH) improves the sensitivity of BIPSS.

In essence, it tests to see the source of the raised ACTH levels in a patient with diagnosed Cushing’s syndrome and high or normal serum ACTH levels. The inferior petrosal sinus is where the pituitary gland drains. Therefore, a sample from here showing raised ACTH compared to the periphery suggests that it is a pituitary cause of Cushing’s, i.e. Cushing’s disease. Equivocal levels of ACTH indicate ectopic or Paraneoplastic Cushing’s Syndrome. The sample is usually taken after administration of Corticotropin-releasing hormone or, more recently, DDAVP, which have been shown to increase ACTH production in active ACTH-producing pituitary tumors. Increasingly, it is known as a gold-standard method for diagnosing Cushing’s disease.

To increase the sensitivity, the sampling is repeated after peripheral administration of oCRH. Following this a peak central to peripheral plasma ACTH ratio of 3 or more occurring 3-5 minutes after oCRH stimulation is highly indicative of Cushing disease.

see Inferior petrosal sinus sampling with desmopressin.

Asymmetric inferior petrosal sinuses (IPS) are not infrequently encountered during bilateral IPS sampling. There is little data on whether IPS symmetry influences success in predicting the adenoma side in patients with ACTH-dependent Cushing’s syndrome (CS).

BIPSS was performed in 38 patients with a mean age of 45 ± 15 years. The overall technical success rate was 97% for bilateral cannulation. Asymmetric IPS were observed in 11 (39%) patients with Cushing’s disease (CD). A side-to-side ACTH ratio was not significantly different between patients with symmetric outflow and those with asymmetric outflow at baseline (8.6 ± 2.7 versus 16.4 ± 6.0; P = 0.45), but ratios were significantly different after ovine corticotropin-releasing hormone (oCRH) stimulation (6.0 ± 2.5 versus 35.7 ± 22.5; P = 0.03). BIPSS correctly predicted the side of the adenoma in 25 (96%) patients with CD. Prediction was better when the venous outflow was symmetric (100%) rather than asymmetric (93%), although the difference was not significant (P = 0.42). Remission from CS was achieved in 32 patients (87%), independent of the symmetry of IPS.

Bearing in mind the sample size of this audit, asymmetric IPS at least do not seem to diminish the accuracy of diagnosis of ACTH-dependent CS, nor do they influence the clinical outcome 3).


Most often, BIPSS is performed by sampling ACTH peripherally and from both IPSs before and after CRH (Acthrel; Ben Venue Laboratories, Ohio, USA) administration. In the US, CRH is typically given at a dose of 1 μg/kg, by slow intravenous push over 30 seconds; in other countries, a typical dose is 100 μg. Conscious sedation is preferred to allow for the monitoring of symptoms suggesting complications. A 6-French sheath is advanced into the right femoral vein, and a five-French sheath into the left femoral vein. The larger sheath allows for sampling from the common femoral vein, while a 5-French catheter is in place distally. Subsequently, 3,000–5,000 units of heparin are given to prevent cavernous sinus and other venous thrombosis.

Next, 5-French Davis catheters are advanced through each femoral vein sheath into the contralateral internal jugular vein, followed by 2.8-French microcatheters, directed medially at the C1–2 level to access the orifice of the IPS 4). without entering clival veins 5). Both catheters are positioned symmetrically.

Once catheter positions are confirmed, two baseline ACTH specimens are collected from the right femoral sheath (peripheral specimen) and both IPSs. CRH is then administered peripherally. Repeat ACTH sampling from the periphery and both IPSs is obtained 3 minutes, 5 minutes, 10 minutes, and 15 minutes after the injection of CRH. Samples are collected in tubes that are placed on ice before transport to the laboratory. Upon completion of sampling, both femoral sheaths are removed, and manual compression is used to obtain hemostasis before transferring patients to the recovery room for a rest of approximately 4 hours.

Case series

Pereira et al. evaluated all patients that undergone bilateral inferior petrosal sinus sampling in a tertiary center, between January 1995 and March 2018. The probable diagnosis of Cushing’s disease was made when the basal central/peripheral gradient was>2 and/or>3 after stimulation with a corticotrophin-releasing hormone. The localization was suggested when the inter-sinus gradient was>1.4. The results obtained were compared with the post-operatory results: compatible histology and positive immunohistochemistry to adrenocorticotrophic hormone and/or the presence of criteria of cure. Sensitivity, specificity and predictive positive value were calculated.

A total of 49 patients were evaluated (75.5% female; mean age 45.4±16.3 years old). Bilateral inferior petrosal sinus sampling was compatible with Cushing’s disease in 27 out of 28 confirmed cases in histology or by criteria of cure, and was compatible with ectopic secretion in the 2 cases confirmed as ectopic secretion of adrenocorticotrophic hormone (sensitivity 96.4%; specificity 100%). The lateralization calculated was concordant with the results after surgery in 17 out of 27 patients with Cushing’s disease – predictive positive value of 63%. Magnetic resonance had a higher predictive value to lateralization – 70.0%.

Bilateral inferior petrosal sinus sampling is a safe and reliable procedure to diagnose Cushing’s disease, with great sensitivity and specificity. Nevertheless, the capacity of this procedure to lateralize the lesion inside the pituitary is limited 6).



Lad SP, Patil CG, Laws ER Jr, Katznelson L. The role of inferior petrosal sinus sampling in the diagnostic localization of Cushing’s disease. Neurosurg Focus. 2007;23:E2.

Newell-Price J, Trainer P, Besser M, Grossman A. The diagnosis and differential diagnosis of Cushing’s syndrome and pseudo-Cushing’s states. Endocr Rev. 1998;19:647–72.

Andereggen L, Gralla J, Schroth G, Mordasini P, Andres RH, Widmer HR, Luedi MM, Kellner F, Beck J, Mariani L, Ozdoba C, Christ E. Influence of inferior petrosal sinus drainage symmetry on detection of adenomas in Cushing’s syndrome. J Neuroradiol. 2019 Jun 19. pii: S0150-9861(19)30233-0. doi: 10.1016/j.neurad.2019.05.004. [Epub ahead of print] PubMed PMID: 31228539.

Tomycz ND, Horowitz MB. Inferior petrosal sinus sampling in the diagnosis of sellar neuropathology. Neurosurg Clin N Am. 2009 Jul;20(3):361-7. doi: 10.1016/ Review. PubMed PMID: 19778704.

Doppman JL, Oldfield E, Krudy AG, Chrousos GP, Schulte HM, Schaaf M, Loriaux DL. Petrosal sinus sampling for Cushing syndrome: anatomical and technical considerations. Work in progress. Radiology. 1984 Jan;150(1):99-103. PubMed PMID: 6316418.

Pereira CA, Ferreira L, Amaral C, Alves V, Xavier J, Ribeiro I, Cardoso H. Diagnostic accuracy of Bilateral Inferior Petrosal Sinus Sampling: The Experience of a Tertiary Centre. Exp Clin Endocrinol Diabetes. 2019 Aug 19. doi: 10.1055/a-0981-5973. [Epub ahead of print] PubMed PMID: 31426111.


Thromboelastography (TEG)

Thromboelastography, is a method of testing the efficiency of blood coagulation. It is a test mainly utilized in surgery and anesthesiology, although few centers are capable of performing it. More common tests of blood coagulation include prothrombin time (PT,INR) and partial thromboplastin time (aPTT) which measure coagulation factor function, but TEG also can assess platelet function, clot strength, and fibrinolysis which these other tests cannot.

TEG may be a clinically sensitive test for identifying the underlying coagulopathyfollowing TBI. However, confirmation with conventional coagulation tests (CCTs) is recommended 1).

Platelet function testing with TEG altered a dual antiplatelet therapy (DAT) induction strategy in a significant number of cases.

Future studies should compare methods of platelet function testing and, possibly, no platelet function testing in neurovascular patients undergoing flow diversion and/or stent-assisted treatment of intracranial aneurysms 2).

Fulkerson et al. describe a 12-year-old female who experienced a number of complications after a craniopharyngioma surgery. The patient suffered multiple new intraventricular hemorrhages with removal of external ventricular drains. Standard coagulopathy tests did not reveal any abnormalities. However, an abnormal thromboelastography (TEG) value suggested primary hyperfibrinolysis, which led to a change in medical management. The patient did not suffer any further bleeding episodes after the change in treatment.

The authors discuss a case where TEG influenced patient management and identified a problem despite normal values of standard laboratorytests. Neurosurgeons should be aware of the potential benefits for TEG testing in pediatric patient3).



Albert V, Subramanian A, Pati HP, Agrawal D, Bhoi SK. Efficacy of Thromboelastography (TEG) in Predicting Acute Trauma-Induced Coagulopathy (ATIC) in Isolated Severe Traumatic Brain Injury (iSTBI). Indian J Hematol Blood Transfus. 2019 Apr;35(2):325-331. doi: 10.1007/s12288-018-1003-4. Epub 2018 Aug 11. PubMed PMID: 30988571; PubMed Central PMCID: PMC6439129.

McTaggart RA, Choudhri OA, Marcellus ML, Brennan T, Steinberg GK, Dodd RL, Do HM, Marks MP. Use of thromboelastography to tailor dual-antiplatelet therapy in patients undergoing treatment of intracranial aneurysms with the Pipeline embolization device. J Neurointerv Surg. 2015 Jun;7(6):425-30. doi: 10.1136/neurintsurg-2013-011089. Epub 2014 Apr 16. PubMed PMID: 24739599.

Fulkerson DH, Weyhenmeyer J, Archer JB, Shaikh KA, Walsh M. Thromboelastography-Guided Therapy of Hemorrhagic Complications after Craniopharyngioma Resection: Case-Based Update. Pediatr Neurosurg. 2019 Aug 7:1-8. doi: 10.1159/000501117. [Epub ahead of print] Review. PubMed PMID: 31390646.

Case of the Month Unilateral Hearing Loss

Unilateral Hearing Loss

History & Examination
30 y/o previously healthy female presents with a 1 year history of progressive left-sided hearing loss and tinnitus.
Her past medical history and surgical history are unremarkable.
Physical examination reveals difficulty with tandem gait and nystagmus, but no dysmetria.
A limited post-contrast study of the IAC and an audiogram are obtained.
Diagnostic Studies
Word recognition scores in the right ear is 100% at 55 dB and 84% at 75 dB
22 dB (air) and 18 dB (bone) –right
42 dB (air) and 32 dB (bone) – left
Summary -moderate to severe sensorineural hearing loss for the left ear

T1-Weighted with contrast



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