Hypertonic saline use in neurocritical care for treating cerebral edema: A review of optimal formulation, dosing, safety, administration and storage.

PURPOSE: Current Neurocritical Care Society guidelines on the management of cerebral edema recommend hypertonic saline (HTS) over mannitol in some scenarios, but practical questions remain regarding the appropriate administration method, concentration/dose, monitoring to ensure safe use, and storage. The aim of this article is to address these practical concerns based on the evidence currently available. SUMMARY: Many different hypertonic solutions have been studied to define the optimal hyperosmolar substance to relieve acute cerebral edema in patients with conditions such as acute ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage, and traumatic brain injury. Mannitol and HTS are the main hyperosmolar therapies in use in contemporary neurocritical care practice. Contemporary use of HTS has followed a circuitous path in regards to the practical aspects of dosing and formulation, with evidence mainly consisting of retrospective or observational data. The effectiveness of bolus doses of HTS to lower acutely elevated intracranial pressure is well accepted. Adverse events with use of HTS are often mild and non-clinically significant if appropriate monitoring of serum sodium and chloride concentrations is performed. Available evidence shows that peripheral administration of HTS is likely safe in certain circumstances. Timely utilization of HTS is complicated by regulatory requirements for safe storage, but with appropriate safeguards HTS can be stored in patient care areas. CONCLUSION: HTS formulations, methods of administration, infusion rate, and storage vary by institution, and no practice standards exist. Central intravenous administration may be preferred for HTS, but peripheral intravenous administration is safe provided measures are undertaken to detect and prevent phlebitis and extravasation. The safe use of HTS is possible with proper protocols, education, and institutional safeguards in place.

Use of intravenous cangrelor in the treatment of ruptured and unruptured cerebral aneurysms: an updated single-center analysis and pooled analysis of current studies.

BACKGROUND: Intracranial stent placement for the treatment of cerebral aneurysms is increasingly utilized in both ruptured and unruptured scenarios. Intravenous (IV) cangrelor is a relatively new antiplatelet agent that was initially approved for coronary interventions. In addition to our institution, five other centers have published their results using IV cangrelor in neurointerventional procedures. This article combines the aneurysm treatment data from all prior studies to provide insight into the safety and efficacy of cangrelor for intracranial aneurysm treatment. METHODS: A prospectively maintained database was reviewed to identify all cases of IV cangrelor administration during aneurysm embolization. 20 additional patients were identified who had not been previously published. In addition, a literature search was performed to identify prior publications regarding cangrelor in neurointervention. The data from these were combined with our institutional results in a pooled-analysis. RESULTS: Overall, 85 patients who received IV cangrelor during aneurysm embolization were identified, including 46 ruptured and 39 unruptured cases. The asymptomatic and symptomatic intracranial hemorrhage rates were 4% (2/46) for ruptured cases and 2.6% (1/39) for unruptured cases. The rate of retroperitoneal hematoma and gastrointestinal bleeding was 0%. There were no incidents of intraprocedural thromboembolic complication or intraprocedural in-stent thrombosis in either cohort. One subject suffered an ischemic stroke at 24 hours secondary to in-stent thrombosis in a ruptured case. CONCLUSIONS: IV cangrelor during aneurysm embolization appears to be safe, with a symptomatic intracranial hemorrhage rate of 4% in ruptured cases and 2.6% in unruptured cases. More research is needed to determine the ideal dosing regimen.

Characterization of antiplatelet response to low-dose cangrelor utilizing platelet function testing in neuroendovascular patients.

STUDY OBJECTIVES: The optimal antiplatelet therapy for emergent neuroendovascular stenting is uncertain. Cangrelor is an intravenous P2Y12 inhibitor that is an attractive option due its favorable pharmacokinetic profile and ease of measurability but optimal dosing remains unclear. The primary objective of this study is to characterize the dose response of low dose cangrelor (<2 mcg/kg/min) with the utilization of platelet function testing (PFT). DESIGN: A retrospective review of all patients treated with cangrelor for either procedural stenting or bridging was conducted between January 1st, 2019 and October 31st, 2020. Seventy-two patients met inclusion criteria. An in-depth analysis of dose response to low dose cangrelor based on PFT was performed. PATIENTS: Neuroendovascular patients treated with cangrelor. SETTING: Albany Medical Center Hospital. INTERVENTION AND MAIN RESULTS: Patients who underwent procedural stenting were given a bolus of 5 mcg/kg and an initial infusion rate of either 0.75 mcg/kg/min or 1 mcg/kg/min. Patients who were bridged with cangrelor were administered an initial infusion rate of 0.75 mcg/kg/min or 1 mcg/kg/min. Twelve patient's doses were titrated to achieve a platelet reactivity unit (PRU) between 50-150; three patient's doses were titrated multiple times. Based on initial PFT results, utilizing the 1 mcg/kg/min maintenance dose resulted in more patients being in the acceptable (10-180) and desired (50-150) PRU range than the 0.75 mcg/kg/min dose (47% vs 56% and 70% vs 80%, respectively). Final recorded PRU results showed that 64% of patients had PRUs in the optimal range (50-150) and 88% of patients had PRUs in the desire range (10-180). CONCLUSIONS: Utilizing low doses of cangrelor with platelet function testing is an option during emergent neuroendovascular stenting and bridging. Cangrelor demonstrates significant variability in response at low doses and exhibits a dose response relationship when PFT is utilized.

Cangrelor dose titration using platelet function testing during cerebrovascular stent placement.

BACKGROUND: Optimal antiplatelet inhibition is vital during cerebrovascular stenting procedures, yet no standardized recommendation exists for antithrombotic therapy in these scenarios. Cangrelor is an intravenous P2Y12 inhibitor with a favorable pharmacokinetic profile for use during neuroendovascular stenting. METHODS: A retrospective review of all neuroendovascular patients who underwent stenting between 1 January 2019 and 22 March 2020 and were treated with cangrelor was conducted. Thirty-seven patients met inclusion criteria. RESULTS: All patients were administered a bolus of 5 mcg/kg of cangrelor followed by a maintenance infusion. Antiplatelet effects of cangrelor were monitored using platelet reactivity units (PRU). Based on the initial PRU, seven patients' doses were adjusted with subsequent PRUs in or near the goal range of 50-150. One patient experienced an acute intraprocedural occlusion likely related to a subtherapeutic PRU which subsequently resolved with cangrelor dose adjustment and intra-arterial tirofiban administration, and one patient experienced a post-procedure stent occlusion which required a thrombectomy and intra-arterial tirofiban administration. No hemorrhagic complications occurred. DISCUSSION: Cangrelor utilization during neuroendovascular stenting with maintenance doses of <2 mcg/kg/min with dose adjustments based on platelet function testing has not been previously described. Cangrelor presents many advantages compared to standard therapy in patients undergoing stent placement related to its pharmacokinetic profile, rapid onset of action, ease of transition to oral P2Y12 antiplatelet agents, and measurability. CONCLUSION: Cangrelor is a promising alternative to currently available therapies, especially in patients with a high hemorrhagic risk.

Hypertonic saline buffered with sodium acetate for intracranial pressure management.

BACKGROUND: 3 % hypertonic saline (HS) is a hyperosmolar agent often used to treat elevated intracranial pressure (ICP). However, the resultant hyperchloremia is associated with adverse outcomes in certain patient populations. In this study, HS solution buffered with sodium acetate (HSwSA) is used as an alternative to standard 3 % formulations to reduce overall chloride exposure. Our objectives are to establish whether this alternative agent - with reduced chloride content - is similar to standard 3 % HS in maintaining hyperosmolarity and investigate its effects on hyperchloremia. METHODS: A retrospective chart review was conducted from August 1, 2014 to August 1, 2017 on patients receiving hypertonic therapies for ICP management. Patients were categorized into three groups, those that received: (1) 3 % HS for at least 72 h, (2) HSwSA for at least 72 h, or (3) were switched from 3 % HS within 72 h of initiating therapy to HSwSA for at least 72 h. RESULTS: The average increase in serum osmolality after 72 h of therapy was 21.1 moSm/kg for those only on 3 % HS and 20.3 mOsm/kg for those only on HSwSA. Serum chloride levels after 24 h decreased on average by 2.5 mEq/L after switching from 3% HS to HSwSA and stayed below baseline, whereas matched patients only receiving 3% HS on average had serum chloride levels increase 4.3 mEq/L after 24 h and continued to rise. CONCLUSIONS: Hyperchloremia has been associated with decreased renal perfusion, increasing the risk of acute kidney injury and hyperchloremic metabolic acidosis. Compared to standard 3% HS, our findings suggest an alternative hyperosmolar therapy with less chloride maintains similar hyperosmolarity while reducing overall chloride exposure.

A novel bone morphogenetic protein 2 mutant mouse, nBmp2NLS(tm), displays impaired intracellular Ca2+ handling in skeletal muscle.

We recently reported a novel form of BMP2, designated nBMP2, which is translated from an alternative downstream start codon and is localized to the nucleus rather than secreted from the cell. To examine the function of nBMP2 in the nucleus, we engineered a gene-targeted mutant mouse model (nBmp2NLS(tm)) in which nBMP2 cannot be translocated to the nucleus. Immunohistochemistry demonstrated the presence of nBMP2 staining in the myonuclei of wild type but not mutant skeletal muscle. The nBmp2NLS(tm) mouse exhibits altered function of skeletal muscle as demonstrated by a significant increase in the time required for relaxation following a stimulated twitch contraction. Force frequency analysis showed elevated force production in mutant muscles compared to controls from 10 to 60 Hz stimulation frequency, consistent with the mutant muscle's reduced ability to relax between rapidly stimulated contractions. Muscle relaxation after contraction is mediated by the active transport of Ca(2+) from the cytoplasm to the sarcoplasmic reticulum by sarco/endoplasmic reticulum Ca(2+) ATPase (SERCA), and enzyme activity assays revealed that SERCA activity in skeletal muscle from nBmp2NLS(tm) mice was reduced to approximately 80% of wild type. These results suggest that nBMP2 plays a role in the establishment or maintenance of intracellular Ca(2+) transport pathways in skeletal muscle.

The transcription factor Lc-Maf participates in Col27a1 regulation during chondrocyte maturation.

The transcription factor Lc-Maf, which is a splice variant of c-Maf, is expressed in cartilage undergoing endochondral ossification and participates in the regulation of type II collagen through a cartilage-specific Col2a1 enhancer element. Type XXVII and type XI collagens are also expressed in cartilage during endochondral ossification, and so enhancer/reporter assays were used to determine whether Lc-Maf could regulate cartilage-specific enhancers from the Col27a1 and Col11a2 genes. The Col27a1 enhancer was upregulated over 4-fold by Lc-Maf, while the Col11a2 enhancer was downregulated slightly. To confirm the results of these reporter assays, rat chondrosarcoma (RCS) cells were transiently transfected with an Lc-Maf expression plasmid, and quantitative RT-PCR was performed to measure the expression of endogenous Col27a1 and Col11a2 genes. Endogenous Col27a1 was upregulated 6-fold by Lc-Maf overexpression, while endogenous Col11a2 was unchanged. Finally, in situ hybridization and immunohistochemistry were performed in the radius and ulna of embryonic day 17 mouse forelimbs undergoing endochondral ossification. Results demonstrated that Lc-Maf and Col27a1 mRNAs are coexpressed in proliferating and prehypertrophic regions, as would be predicted if Lc-Maf regulates Col27a1 expression. Type XXVII collagen protein was also most abundant in prehypertrophic and proliferating chondrocytes. Others have shown that mice that are null for Lc-Maf and c-Maf have expanded hypertrophic regions with reduced ossification and delayed vascularization. Separate studies have indicated that Col27a1 may serve as a scaffold for ossification and vascularization. The work presented here suggests that Lc-Maf may affect the process of endochondral ossification by participating in the regulation of Col27a1 expression.