Bortezomib for Glioblastoma

Bortezomib for Glioblastoma

Bortezomib is a boronic acid-based potent proteasome inhibitor that has been actively studied for its anti-tumour effects through inhibition of the proteasome. The proteasome is a key component of the ubiquitin-proteasome pathway that is critical for protein homeostasis, regulation of cellular growth, and apoptosis. Overexpression of polo-like kinase 4 (PLK4) is commonly reported in tumour cells and increases their invasive and metastatic abilities. In this study, we established a cell model of PLK4 knockdown and overexpression in LN-18, A172 and LN-229 cells and found that knockdown of PLK4 expression enhanced the anti-tumour effect of bortezomib. We further found that this effect may be mediated by the PTEN/PI3K/AKT/mTOR signalling pathway and that the apoptotic and oxidative stress processes were activated, while the expression of matrix metalloproteinases (MMPs) was down-regulated. Similar phenomenon was observed using in vitro experiments. Thus, we speculate that PLK4 inhibition may be a new therapeutic strategy for GBM 1).

The addition of bortezomib to current standard radiochemotherapy in newly diagnosed glioblastoma patients was tolerable. The PFS and OS rates appeared promising, with more benefit to MGMT methylated patients. Further clinical investigation is warranted in a larger cohort of patients 2).

Jane et al. investigated the sensitivity of a panel of glioma cell lines (U87, T98G, U373, A172, LN18, LN229, LNZ308, and LNZ428) to TRAIL alone and in combination with the proteasome inhibitor bortezomib. Analysis of these cell lines revealed marked differences in their sensitivity to these treatments, with two (LNZ308 and U373) of the eight cell lines revealing no significant induction of cell death in response to TRAIL alone. No correlation was found between sensitivity of cells to TRAIL and expression of TRAIL receptors DR4, DR5, and decoy receptor DcR1, caspase 8, apoptosis inhibitory proteins XIAP, survivin, Mcl-1, Bcl-2, Bcl-Xl, and cFLIP. However, TRAIL-resistant cell lines exhibited a high level of basal NF-κB activity. Bortezomib was capable of potentiating TRAIL-induced apoptosis in TRAIL-resistant cells in a caspase-dependent fashion. Bortezomib abolished p65/NF-κB DNA-binding activity, supporting the hypothesis that inhibition of the NF-κB pathway is critical for the enhancement of TRAIL sensitization in glioma cells. Moreover, knockdown of p65/NF-κB by shRNA also enhanced TRAIL-induced apoptosis, indicating that p65/NF-κB may be important in mediating TRAIL sensitivity and the effect of bortezomib in promoting TRAIL sensitization and apoptosis induction 3).

Premkumar et al. demonstrated that proteasome inhibitors, such as bortezomib, dramatically sensitized highly resistant glioma cells to apoptosis induction, suggesting that proteasomal inhibition may be a promising combination strategy for glioma therapeutics.

They examined whether bortezomib could enhance response to HDAC inhibition in glioma cells. Although primary cells from glioblastoma multiforme (GBM) patients and established glioma cell lines did not show significant induction of apoptosis with vorinostat treatment alone, the combination of vorinostat plus bortezomib significantly enhanced apoptosis. The enhanced efficacy was due to proapoptotic mitochondrial injury and increased generation of reactive oxygen species. Our results also revealed that combination of bortezomib with vorinostat enhanced apoptosis by increasing Mcl-1 cleavage, Noxa upregulation, Bak and Bax activation, and cytochrome c release. Further downregulation of Mcl-1 using shRNA enhanced cell killing by the bortezomib/vorinostat combination. Vorinostat induced a rapid and sustained phosphorylation of histone H2AX in primary GBM and T98G cells, and this effect was significantly enhanced by co-administration of bortezomib. Vorinostat/bortezomib combination also induced Rad51 downregulation, which plays an important role in the synergistic enhancement of DNA damage and apoptosis. The significantly enhanced antitumor activity that results from the combination of bortezomib and HDACIs offers promise as a novel treatment for glioma patients 4).

One resistance mechanism in malignant gliomas (MG) involves nuclear factor-κB (NF-κB) activation. Bortezomib prevents proteasomal degradation of NF-κB inhibitor α (NFKBIA), an endogenous regulator of NF-κB signaling, thereby limiting the effects of NF-κB on tumor survival and resistance. A presurgical phase II trial of bortezomib in recurrent MG was performed to determine drug concentration in tumor tissue and effects on NFKBIA. Patients were enrolled after signing an IRB approved informed consent. Treatment was bortezomib 1.7 mg/m(2) IV on days 1, 4 and 8 and then surgery on day 8 or 9. Post-operatively, treatment was Temozolomide (TMZ) 75 mg/m(2) PO on days 1-7 and 14-21 and bortezomib 1.7 mg/m(2) on days 7 and 21 [1 cycle was (1) month]. Ten patients were enrolled (8 M and 2 F) with 9 having surgery. Median age and KPS were 50 (42-64) and 90 % (70-100). The median cycles post-operatively was 2 (0-4). The trial was stopped as no patient had a PFS-6. All patients are deceased. Paired plasma and tumor bortezomib concentration measurements revealed higher drug concentrations in tumor than in plasma; NFKBIA protein levels were similar in drug-treated vs. drug-naïve tumor specimens. Nuclear 20S proteasome was less in postoperative samples. Postoperative treatment with TMZ and bortezomib did not show clinical activity. Bortezomib appears to sequester in tumor but pharmacological effects on NFKBIA were not seen, possibly obscured due to downregulation of NFKBIA during tumor progression. Changes in nuclear 20S could be marker of bortezomib effect on tumor 5).

McCracken et al. conducted a phase I trial of dose-escalating temozolomide with bevacizumab and the proteasome inhibitor bortezomib for patients with recurrent disease. Three groups of three patients were scheduled to receive daily doses of temozolomide at 25, 50, and 75 mg/m2. Fixed doses of bortezomib and bevacizumab were given at standard intervals. Patients were monitored for dose-limiting toxicities (DLT) to determine the maximum-tolerated dose (MTD) of temozolomide with this regimen. No DLT were seen in the first two groups (25 and 50 mg/m2 temozolomide). One patient in the 75 mg/m2 group experienced a grade 4 elevation of ALT and three more patients were accrued for a total of six patients at that dose level. No other DLT occurred, thus making 75 mg/m2 the MTD. Progression-free survival was 3.27 months for all patients and mean overall survival was 20.75 months. The MTD of temozolomide was 75 mg/m2 in combination with bevacizumab and bortezomib for recurrent glioblastoma. Only one patient experienced a severe (Grade 4) elevation of ALT. This study will provide the framework for further studies to elicit effectiveness and better determine a safety profile for this drug combination 6).

Oncolytic viruses, proteasome inhibitors, and natural killer (NK)-cell immunotherapy have all been studied extensively as monotherapies but have never been evaluated in combination. Synergetic treatment of oncolytic virus-infected glioblastomas with a proteasome inhibitor induces necroptotic cell death to enhance NK-cell immunotherapy, prolonging survival against human glioblastoma 7).

The proteasome inhibitor bortezomib is effective for a variety of tumors, but not for GBM. The authors’ goal was to demonstrate that bortezomib can be effective in the orthotopic GBM murine model if the appropriate method of drug delivery is used. In this study the Alzet mini-osmotic pump was used to bring the drug directly to the tumor in the brain, circumventing the blood-brain barrier; thus making bortezomib an effective treatment for GBM. METHODS The 2 human glioma cell lines, U87 and U251, were labeled with luciferase and used in the subcutaneous and intracranial in vivo tumor models. Glioma cells were implanted subcutaneously into the right flank, or intracranially into the frontal cortex of athymic nude mice. Mice bearing intracranial glioma tumors were implanted with an Alzet mini-osmotic pump containing different doses of bortezomib. The Alzet pumps were introduced directly into the tumor bed in the brain. Survival was documented for mice with intracranial tumors. RESULTS Glioma cells were sensitive to bortezomib at nanomolar quantities in vitro. In the subcutaneous in vivo xenograft tumor model, bortezomib given intravenously was effective in reducing tumor progression. However, in the intracranial glioma model, bortezomib given systemically did not affect survival. By sharp contrast, animals treated with bortezomib intracranially at the tumor site exhibited significantly increased survival. CONCLUSIONS Bypassing the blood-brain barrier by using the osmotic pump resulted in an increase in the efficacy of bortezomib for the treatment of intracranial tumors. Thus, the intratumoral administration of bortezomib into the cranial cavity is an effective approach for glioma therapy 8).



Wang J, Ren D, Sun Y, Xu C, Wang C, Cheng R, Wang L, Jia G, Ren J, Ma J, Tu Y, Ji H. Inhibition of PLK4 might enhance the anti-tumour effect of bortezomib on glioblastoma via PTEN/PI3K/AKT/mTOR signalling pathway. J Cell Mol Med. 2020 Mar 3. doi: 10.1111/jcmm.14996. [Epub ahead of print] PubMed PMID: 32126150.

Kong XT, Nguyen NT, Choi YJ, Zhang G, Nguyen HN, Filka E, Green S, Yong WH, Liau LM, Green RM, Kaprealian T, Pope WB, Nghiemphu PL, Cloughesy T, Lassman A, Lai A. Phase 2 Study of Bortezomib Combined With Temozolomide and Regional Radiation Therapy for Upfront Treatment of Patients With Newly Diagnosed Glioblastoma Multiforme: Safety and Efficacy Assessment. Int J Radiat Oncol Biol Phys. 2018 Apr 1;100(5):1195-1203. doi: 10.1016/j.ijrobp.2018.01.001. Epub 2018 Jan 6. PubMed PMID: 29722661.

Jane EP, Premkumar DR, Pollack IF. Bortezomib sensitizes malignant human glioma cells to TRAIL, mediated by inhibition of the NF-{kappa}B signaling pathway. Mol Cancer Ther. 2011 Jan;10(1):198-208. doi: 10.1158/1535-7163.MCT-10-0725. PubMed PMID: 21220502; PubMed Central PMCID: PMC3075591.

Premkumar DR, Jane EP, Agostino NR, DiDomenico JD, Pollack IF. Bortezomib-induced sensitization of malignant human glioma cells to vorinostat-induced apoptosis depends on reactive oxygen species production, mitochondrial dysfunction, Noxa upregulation, Mcl-1 cleavage, and DNA damage. Mol Carcinog. 2013 Feb;52(2):118-33. doi: 10.1002/mc.21835. Epub 2011 Nov 15. PubMed PMID: 22086447; PubMed Central PMCID: PMC4068609.

Raizer JJ, Chandler JP, Ferrarese R, Grimm SA, Levy RM, Muro K, Rosenow J, Helenowski I, Rademaker A, Paton M, Bredel M. A phase II trial evaluating the effects and intra-tumoral penetration of bortezomib in patients with recurrent malignant gliomas. J Neurooncol. 2016 Aug;129(1):139-46. doi: 10.1007/s11060-016-2156-3. Epub 2016 Jun 14. PubMed PMID: 27300524.

McCracken DJ, Celano EC, Voloschin AD, Read WL, Olson JJ. Phase I trial of dose-escalating metronomic temozolomide plus bevacizumab and bortezomib for patients with recurrent glioblastoma. J Neurooncol. 2016 Oct;130(1):193-201. Epub 2016 Aug 9. PubMed PMID: 27502784.

Suryadevara CM, Riccione KA, Sampson JH. Immunotherapy Gone Viral: Bortezomib and oHSV Enhance Antitumor NK-Cell Activity. Clin Cancer Res. 2016 Nov 1;22(21):5164-5166. Epub 2016 Aug 12. PubMed PMID: 27521450; PubMed Central PMCID: PMC5093093.

Wang W, Cho HY, Rosenstein-Sisson R, Marín Ramos NI, Price R, Hurth K, Schönthal AH, Hofman FM, Chen TC. Intratumoral delivery of bortezomib: impact on survival in an intracranial glioma tumor model. J Neurosurg. 2017 Apr 14:1-6. doi: 10.3171/2016.11.JNS161212. [Epub ahead of print] PubMed PMID: 28409734.



Nadroparin is an anticoagulant belonging to low molecular weight heparins. Nadroparin was developed by Sanofi-Synthélabo. Nadroparin is used in general and orthopedic surgery to prevent thromboembolic disorders, and as treatment for deep vein thrombosis.

Patients undergoing CPA tumour excision in the period between January 2014 and November 2015 received nadroparin as a single therapy. Patients treated since November 2015 received, in addition to this therapy, peri-operative compression stockings as venous thromboembolism (VTE) prophylaxis due to a change in protocol. VTE was defined as symptomatic deep vein thrombosis or pulmonary embolism and was confirmed via radiological imaging or autopsy.

A total of 146 consecutive patients were reviewed. Treatment groups were comparable with respect to demographics and risk factors. Six of the 60 patients (10.0%; 95% confidence interval [CI] 3.8-20.5) receiving nadroparin single therapy developed symptomatic VTE. One out of 86 patients (1.2%; 95% CI 0-6.3) treated with combination therapy developed VTE (p = 0.019) with a risk difference of 8.8% (95% CI 1.43-19.0). In comparison to combination therapy, nadroparin single therapy showed a relative risk of 8.6 (95% CI 1.1-69.6).

Adding compression stockings to peri-operative nadroparin, as a prophylactic strategy for thromboembolic complications in patients undergoing surgical intervention for CPA tumours, was associated with a significant reduction in the occurrence of VTE 1).

Medical records of 158 adult patients with an aSAH were retrospectively analyzed. Those patients treated endovascularly for their ruptured aneurysm were included in this study. They received either high-dose (twice daily 5700 AxaIE) or low-dose (once daily 2850 AxaIE) nadroparin treatment after occlusion of the aneurysm. Medical charts were reviewed and imaging was scored by 2 independent neuroradiologists. Data with respect to in-hospital complications, peri-procedural complications, discharge location, and mortality were collected.

Ninety-three patients had received high-dose nadroparin, and 65 patients prophylactic low-dose nadroparin. There was no significant difference in clinical DCI occurrence between patients treated with high-dose (34%) and low-dose (31%) nadroparin. More patients were discharged to home in patients who received high-dose nadroparin (40%) compared to low-dose (17%; odds ratio [OR] 3.13, 95% confidence interval [95% CI]: 1.36-7.24). Furthermore, mortality was lower in the high-dose group (5%) compared to the low-dose group (23%; OR 0.19, 95% CI: 0.07-0.55), also after adjusting for neurological status on admission (OR 0.21, 95% CI: 0.07-0.63).

Patients who were treated with high-dose nadroparin after endovascular treatment for aneurysmal SAH were more often discharged to home and showed lower mortality. High-dose nadroparin did not, however, show a decrease in the occurrence of clinical DCI after aSAH. A randomized controlled trial seems warranted 2).

The objective of a study was to prospectively analyze the rate of postoperative hemorrhage during a 3-year period of early postoperative administration of the low molecular weight heparin nadroparin (Fraxiparin) plus compression stockings in a large cohort of patients undergoing intracranial surgery.

A total of 2823 intracranial neurosurgical procedures, performed between June 1999 and 2002, were studied. Of these operations, 1319 (46.7%) were major intracranial surgical procedures (Group 1). Group 2 comprised 1504 operations (53.3%) considered to be minor surgical procedures (e.g., shunt procedures, biopsies). All patients except those with transnasal transsphenoidal removal of pituitary tumors underwent early postoperative imaging (computed tomography or magnetic resonance imaging) to determine postoperative hemorrhage. All significant postoperative hematomas (defined as those requiring surgical evacuation because of relevant space occupation and/or neurological deterioration) were treated surgically. Prophylaxis of venous thromboembolic events included early (<24 h) postoperative administration of 0.3 ml nadroparin subcutaneously plus intra- and postoperative compression stockings until discharge.

Forty-three major postoperative hemorrhages (1.5%) were observed after 2823 intracranial procedures (95% confidence interval, 1.1-2.05). Forty-two (3.2%) of 1319 postoperative hematomas occurred in patients undergoing major intracranial procedures (Group 1). There was only 1 (0.07%) significant hemorrhage after 1504 minor intracranial procedures (Group 2). A subgroup analysis of patients who needed preoperative anticoagulation because of medical comorbidity did not reveal an increased frequency of postoperative hematoma when anticoagulation was stopped 24 hours before surgery P = 0.1, chi(2) test; 95% confidence interval, 0.89-3.0).

This report describes the largest prospective study conducted to date to determine the hemorrhage rate after early postoperative anticoagulation. The results support the concept of postoperative pharmacological thromboembolic prophylaxis in patients undergoing intracranial surgery 3).

Nurmohamed et al. performed a multicentre, randomized, double-blind trial in neurosurgical patients to investigate the efficacy and safety of adding a low molecular weight heparin (LMWH), nadroparin, initiated postoperatively, to graduated compression stockings in the prevention of VTE. Deep-vein thrombosis was detected by mandatory venography. Bleeding was determined according to pre-defined objective criteria for major and minor episodes. An adequate bilateral venogram was obtained in 166 of 241 LMWH patients (68.9%) and 179 of 244 control patients (73.4%). A total of 31 of 166 LMWH patients (18.7%) and 47 of 179 controls patients (26.3) had VTE up to Day 10 postoperatively (p = 0.047). The relative risk reduction (RRR) was 28.9%. The rates for proximal deep-vein thrombosis/pulmonary embolism were 6.9% and 11.5% for the two groups, respectively (RRR: 40.2%; p = 0.065). Secondary analyses involved all VTE up to day 56 post-surgery which was detected in 33 patients of 241 in the LMWH group (13.7%) and 51 of 244 control patients (20.9%; RRR 34.5%; p = 0.018). The corresponding percentages for proximal deep-vein thrombosis/pulmonary embolism were 5.8% and 10.2% for the two groups, respectively, giving a RRR of 43.3%; p = 0.36. Major bleeding complications, during the treatment period, occurred in six low molecular weight heparin treated patients (2.5%) and in two control patients (0.8%); p = 0.87. A higher mortality was observed in the low molecular weight heparin group over the 56-day follow-up period (22 versus 10; p = 0.026). However, none of these deaths was judged by a blinded adjudication committee to be related to the study drug. In conclusion, this study demonstrates that the low molecular weight heparin, nadroparin, added to graduated compression stockings results in a clinically significant decrease in VTE without inducing any significant increase of major bleeding 4).



Koopmans RJ, Cannegieter SC, Koot RW, Vleggeert-Lankamp CLA. Nadroparin Plus Compression Stockings versus Nadroparin Alone for Prevention of Venous Thromboembolism in Cerebellopontine Angle Tumour Excisions: A Cohort Study. Thromb Haemost. 2020 Feb 6. doi: 10.1055/s-0039-3402732. [Epub ahead of print] PubMed PMID: 32028534.

Post R, Zijlstra IAJ, Berg RVD, Coert BA, Verbaan D, Vandertop WP. High-Dose Nadroparin Following Endovascular Aneurysm Treatment Benefits Outcome After Aneurysmal Subarachnoid Hemorrhage. Neurosurgery. 2018 Aug 1;83(2):281-287. doi: 10.1093/neuros/nyx381. PubMed PMID: 28945859.

Gerlach R, Scheuer T, Beck J, Woszczyk A, Seifert V, Raabe A. Risk of postoperative hemorrhage after intracranial surgery after early nadroparin administration: results of a prospective study. Neurosurgery. 2003 Nov;53(5):1028-34; discussion 1034-5. PubMed PMID: 14580268.

Nurmohamed MT, van Riel AM, Henkens CM, Koopman MM, Que GT, d’Azemar P, Büller HR, ten Cate JW, Hoek JA, van der Meer J, van der Heul C, Turpie AG, Haley S, Sicurella A, Gent M. Low molecular weight heparin and compression stockings in the prevention of venous thromboembolism in neurosurgery. Thromb Haemost. 1996 Feb;75(2):233-8. PubMed PMID: 8815566.

Triple H therapy

Triple H therapy

The combination of induced hypertensionhypervolemia, and hemodilution (triple-H therapy) is often utilized to prevent and treat cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH).

Although this paradigm has gained widespread acceptance since 1985, the efficacy of triple-H therapy and its precise role in the management of the acute phase of SAH remains uncertain. In addition, triple-H therapy may carry significant medical morbidity, including pulmonary edemamyocardial infarctionhyponatremia, renal medullary washout, indwelling catheter-related complications, cerebral hemorrhage, and cerebral edema 1).

This practice is based on low level evidence.

see Induced hypertension for vasospasm.

Many older treatment schemes for CVS included so-called “triple- H” therapy (for HypervolemiaHypertension, and Hemodilution2). This has given way to “hemodynamic augmentation” consisting of maintenance of euvolemia and induced arterial hypertension 3). While potentially confusing, this has now sometimes been referred to as Triple-H therapy 4).

Inducing HTN may be risky with an unclipped ruptured aneurysm. Once the aneurysm is treated, initiating therapy before CVS is apparent may minimize morbidity from CVS 5) 6).

Use fluids to maintain euvolemia.

Administer pressors to increase SBP in 15% increments until neurologically improved or SBP of 220 mm Hg is reached.

Agents include:

● dopamine

○ start at 2.5 mcg/kg/min (renal dose)

○ titrate up to 15–20 mcg/kg/min

● levophed

○ start at 1–2 mcg/min

○ titrate every 2–5 minutes: double the rate up to 64 mcg/min, then increase by 10 mcg/min

● neosynephrine (phenylephrine): does not exacerbate tachycardia

○ start at 5 mcg/min

○ titrate every 2–5 minutes: double the rate up to 64 mcg/min, then increase by 10 mcg/min up to a max of 10 mcg/kg

● dobutamine: positive inotrope

○ start at 5 mcg/kg/min

○ increase dose by 2.5 mcg/kg/min up to a maximum of 20 mcg/kg/min

Complications of hemodynamic augmentation:

● intracranial complications 7)

○ may exacerbate cerebral edema and increase ICP

○ may produce hemorrhagic infarction in an area of previous ischemia

● extracranial complications

○ pulmonary edema in 17%

○ 3 rebleeds (1 fatal)

○ MI in 2%

○ complications of PA catheter: 8)

– catheter related sepsis: 13%

– subclavian vein thrombosis: 1.3%

– pneumothorax: 1%

– hemothorax: may be promoted by coagulopathy from dextran 9).

Case series

In a study of Engquist et al. from UppsalaCBF was assessed by bedside xenon CT at days 0-3, 4-7, and 8-12, and the cerebral metabolic state by cerebral microdialysis (CMD), analyzing glucoselactatepyruvate, and glutamate hourly. At clinical suspicion of DCIHHH therapy was instituted for 5 days. Cerebral blood flow measurements and CMD data at baseline and during HHH therapy were required for study inclusion. Non-DCI patients with measurements in corresponding time windows were included as a reference group.

In DCI patients receiving HHH therapy (n = 12), global cortical CBF increased from 30.4 ml/100 g/min (IQR 25.1-33.8 ml/100 g/min) to 38.4 ml/100 g/min (IQR 34.2-46.1 ml/100 g/min; p = 0.006). The energy metabolic CMD parameters stayed statistically unchanged with a Lactate to Pyruvate Ratio of 26.9 (IQR 22.9-48.5) at baseline and 31.6 (IQR 22.4-35.7) during HHH. Categorized by energy metabolic patterns during HHH, no patient had severe ischemia, 8 showed derangement corresponding to mitochondrial dysfunction, and 4 were normal. The reference group of non-DCI patients (n = 11) had higher CBF and lower L/P ratios at baseline with no change over time, and the metabolic pattern was normal in all these patients.

Global and regional CBF improved and the cerebral energy metabolic CMD parameters stayed statistically unchanged during HHH therapy in DCI patients. None of the patients developed metabolic signs of severe ischemia, but a disturbed energy metabolic pattern was a common occurrence, possibly explained by mitochondrial dysfunction despite improved microcirculation 10).

An audit of the SAH patient charts was performed. A total of 508 fluid measurements were performed in 41 patients (6 with delayed cerebral ischaemia; DCI) during 14 days of observation.

Underestimating for intravenous drugs was the most frequent error (80.6%; 112), resulting in a false positive fluid balance in 2.4% of estimations. In 38.6% of the negative fluid balance cases, the physicians did not order additional fluids for the next 24h. In spite of that, the fluid intake was significantly increased after DCI diagnosis. The mean and median intake values were 3.5 and 3.8l/24h respectively, although 40% of the fluid balances were negative. The positive to negative fluid balance ratio was decreasing in the course of the 14 day observation.

This study revealed inconsistencies in the fluid orders as well as mistakes in the fluid monitoring, which illustrates the difficulties of fluid therapy and reinforces the need for strong evidence-based guidelines for hypervolemic therapy in SAH 11).



Lee KH, Lukovits T, Friedman JA. “Triple-H” therapy for cerebral vasospasm following subarachnoid hemorrhage. Neurocrit Care. 2006;4(1):68-76. Review. PubMed PMID: 16498198.

Origitano TC, Wascher TM, Reichman OH, et al. Sustained Increased Cerebral Blood Flow with Prophylactic Hypertensive Hypervolemic Hemodilution (“Triple-H” Therapy) After Subarachnoid Hemorrhage. Neurosurgery. 1990; 27:729–740

Dankbaar JW, Slooter AJ, Rinkel GJ, et al. Effect of different components of triple-H therapy on cerebral perfusion in patients with aneurysmal subarachnoid haemorrhage: a systematic review. Crit Care. 2010; 14. DOI: 10.1186/cc8886

Connolly ES,Jr, Rabinstein AA, Carhuapoma JR, et al. Guidelines for the management of aneurys- mal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/american Stroke Association. Stroke. 2012; 43:1711–1737

Solomon RA, Fink ME, Lennihan L. Prophylactic Volume Expansion Therapy for the Prevention of Delayed Cerebral Ischemia After Early Aneurysm Surgery. Arch Neurol. 1988; 45:325–332

Solomon RA, Fink ME, Lennihan L. Early Aneurysm Surgery and Prophylactic Hypervolemic Hypertensive Therapy for the Treatment of Aneurysmal Subarachnoid Hemorrhage. Neurosurgery. 1988; 23:699–704
7) , 9)

Shimoda M, Oda S, Tsugane R, et al. Intracranial Complications of Hypervolemic Therapy in Patients with a Delayed Ischemic Deficit Attributed to Vasospasm. J Neurosurg. 1993; 78: 423–429

Rosenwasser RH, Jallo JI, Getch CC, et al. Complications of Swan-Ganz Catheterization for Hemodynamic Monitoring in Patients with Subarachnoid Hemorrhage. Neurosurgery. 1995; 37:872–876

Engquist H, Lewén A, Hillered L, Ronne-Engström E, Nilsson P, Enblad P, Rostami E. CBF changes and cerebral energy metabolism during hypervolemia, hemodilution, and hypertension therapy in patients with poor-grade subarachnoid hemorrhage. J Neurosurg. 2020 Jan 10:1-10. doi: 10.3171/2019.11.JNS192759. [Epub ahead of print] PubMed PMID: 31923897.

Szmuda T, Waszak PM, Rydz C, Springer J, Budynko L, Szydlo A, Sloniewski P, Dzierżanowski J. The challenges of hypervolemic therapy in patients after subarachnoid haemorrhage. Neurol Neurochir Pol. 2014;48(5):328-36. doi: 10.1016/j.pjnns.2014.09.001. Epub 2014 Oct 13. PubMed PMID: 25440011.
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