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).

References

1)

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.
2)

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
3)

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
4)

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
5)

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
6)

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
8)

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
10)

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.
11)

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.

Linezolid

Linezolid

MRSA and MRSE (with MIC > 1 mcg/ml) or patient with vancomycin allergy Linezolid 600mg IV or PO q 12 hrs

Linezolid is an antibiotic used for the treatment of serious infections caused by Gram positive bacteria that are resistant to other antibiotics. Linezolid is active against most Gram-positive bacteria that cause disease, including streptococci, vancomycin-resistant enterococci (VRE), and methicillin resistant Staphylococcus aureus (MRSA).

The main uses are infections of the skin and pneumonia although it may be use for a variety of other infections.

When administered for short periods, linezolid is a relatively safe antibiotic. It can be used in people of all ages and in people with liver disease or poor kidney function. Common adverse effects of short-term use include headache, diarrhea, and nausea. Long-term use, however, has been associated with serious adverse effects such as bone marrow suppression and low platelet counts, particularly when used for more than two weeks. If used for longer periods still, it may cause sometimes irreversible chemotherapy-induced peripheral neuropathy and optic nerve damage, and lactic acidosis (a buildup of lactic acid in the body), all most likely due to mitochondrial toxicity.

As a protein synthesis inhibitor, it stops the growth of bacteria by disrupting their production of proteins, that is, it is a bacteriostatic agent, not bacteriocidal. Although many antibiotics work this way, the exact mechanism of action of linezolid appears to be unique in that it blocks the initiation of protein production, and not one of the later steps.

Bacterial resistance to linezolid has remained very low since it was first detected in 1999, although it may be increasing. It is a member of the oxazolidinone class of drugs.

Linezolid was discovered in the 1990s by a team at Pharmacia and Upjohn Company and first approved for use in 2000. It is on the World Health Organization’s List of Essential Medicines, the most important medications needed in a basic health system.

Linezolid costs approximately US$100 per tablet in the United States. Nonetheless, it appears to be more cost-effective than generic alternatives such as vancomycin, mostly because of the possibility of switching from intravenous to oral administration as soon as patients are stable enough, without the need for dose adjustments.


In animal studies of meningitis caused by Streptococcus pneumoniae, linezolid was found to penetrate well into cerebrospinal fluid, but its effectiveness was inferior to that of other antibiotics.

There does not appear to be enough high-quality evidence to support the routine use of linezolid to treat bacterial meningitis. Nonetheless, it has been used successfully in many cases of central nervous system infection—including meningitis—caused by susceptible bacteria, and has also been suggested as a reasonable choice for this indication when treatment options are limited or when other antibiotics have failed.

The guidelines of the Infectious Diseases Society of America recommend linezolid as the first-line drug of choice for VRE meningitis, and as an alternative to vancomycin for MRSA meningitis.

Linezolid appears superior to vancomycin in treating community-acquired MRSA infections of the central nervous system, although very few cases of such infections have been published (as of 2009).

Effectiveness in Neurosurgery

Evidence for the effectiveness of linezolid in neurosurgical infections (NSIs) is growing. The comfortable oral dosage and tolerance of linezolid opens the possibility for sequential antimicrobial treatment (SAT) in stable patients after a period of intravenous treatment 1).

Reviews

Relevant studies were identified through searches of the PubMed, Current Contents, and Cochrane databases (publications archived until October 2006).

Case reports, case series, prospective and retrospective studies, and randomized controlled trials were eligible for inclusion in our review if they evaluated the effectiveness and safety of linezolid for the treatment of patients with CNS infections.

In 18 (42.9%) of the 42 relevant cases identified, patients had undergone neurosurgical operations and/or had prosthetic devices. Meningitis was the most common CNS infection, accounting for 20 (47.6%) cases. Other CNS infections included brain abscesses (14; 33.3%), ventriculitis (5; 11.9%), and ventriculo-peritoneal shunt infection (3; 7.1%). In the 39 patients in whom the responsible pathogen was isolated, those predominantly responsible for the CNS infections were: penicillin-nonsusceptible Streptococcus pneumoniae (7; 17.9%), vancomycin-resistant enterococci (6; 15.4%), Nocardia spp. (5; 12.8%), methicillin-resistant Staphylococcus epidermidis (4; 10.3%), and methicillin-resistant Staphylococcus aureus (3; 7.7%). Of the 42 patients who received linezolid for the treatment of CNS infections, 38 (90.5%) were either cured or showed clinical improvement of the infection. The mean duration of follow-up was 7.2 months; no recurrent CNS infection was reported.

The limited published data suggest that linezolid may be considered for the treatment of patients with CNS infections in cases of failure of previously administered treatment or limited available options 2).

Case series

To evaluate the efficacy and safety of SAT with oral linezolid in patients with NSI and to analyse the cost implications, an observational, non-comparative, prospective cohort study was conducted on clinically stable consecutive adult patients at the Neurosurgical Service. Following intravenous treatment, patients were discharged with SAT with oral linezolid.

A total of 77 patients were included. The most common NSIs were: 41 surgical wound infections, 20 subdural empyemas, 18 epidural abscesses, and 16 brain abscesses. Forty-four percent of patients presented two or more concomitant NSIs. Aetiological agents commonly isolated were: Propionibacterium acnes (36 %), Staphylococcus aureus (23 %), Staphylococcus epidermidis (21 %) and Streptococcus spp. (13 %). The median duration of the SAT was 15 days (range, 3-42). The SAT was interrupted in five cases due to adverse events. The remainder of the patients were cured at the end of the SAT. A total of 1,163 days of hospitalisation were saved. An overall cost reduction of €516,188 was attributed to the SAT. Eight patients with device infections did not require removal of the device, with an additional cost reduction of €190,595. The mean cost saving per patient was €9,179.

SAT with linezolid was safe and effective for the treatment of NSI. SAT reduces hospitalisation times, which means significant savings of health and economic resources 3).

References

1)

Jahoda D, Nyc O, Pokorný D, Landor I, Sosna A. [Linezolid in the treatment of antibiotic-resistant gram-positive infections of the musculoskeletal system]. Acta Chir Orthop Traumatol Cech. 2006 Oct;73(5):329-33. Czech. PubMed PMID: 17140514.
2)

Ntziora F, Falagas ME. Linezolid for the treatment of patients with central nervous system infection. Ann Pharmacother. 2007 Feb;41(2):296-308. Epub 2007 Feb 6. Review. PubMed PMID: 17284501.
3)

Martín-Gandul C, Mayorga-Buiza MJ, Castillo-Ojeda E, Gómez-Gómez MJ, Rivero-Garvía M, Gil-Navarro MV, Márquez-Rivas FJ, Jiménez-Mejías ME. Sequential antimicrobial treatment with linezolid for neurosurgical infections: efficacy, safety and cost study. Acta Neurochir (Wien). 2016 Oct;158(10):1837-43. doi: 10.1007/s00701-016-2915-0. Epub 2016 Aug 13. PubMed PMID: 27520361.

Radiation necrosis treatment

Radiation necrosis treatment

Radiation necrosis (RN) will be increasingly encountered due to the widespread use of SRS. Symptomatic RN can cause significant morbidity and should be managed pro-actively. There is no single modality which can reliably distinguish RN from recurrent tumor, and a multi-modal approach is often required. For patients with symptomatic RN, oral corticosteroid therapy and bevacizumab are both effective. A minority of patients, with an unclear diagnosis, or refractory symptoms, will require surgical resection. As RN proves to be a challenging condition to diagnose and manage, risk factor mitigation becomes important in clinical decision making 1).


Using the internal database for pharmaceutical products, all patients who received BEV in the University of Munich were identified. Only patients who received BEV as symptomatic treatment for radiation necrosis were included. Patient characteristics, symptoms before, during, and after treatment, and the use of dexamethasone were evaluated using medical reports and systematic internal documentation. The symptoms were graded using CTCAE version 5.0 for general neurological symptoms. Symptoms were graded directly before each cycle and after the treatment (approximately 6 weeks). Additionally, the daily steroid dose was collected at these timepoints. Patients who either improved in symptoms, received less dexamethasone after treatment, or both were considered to have a benefit from the treatment.

Twenty-one patients who received BEV due to radiation necrosis were identified. For 10 patients (47.6%) symptoms improved and 11 patients (52.4%) remained clinically stable during the treatment. In 14 patients (66.7%) the dexamethasone dose could be reduced during therapy, 5 patients (23.8%) received the same dose of dexamethasone before and after the treatment, and 2 patients (9.5%) received a higher dose at the end of the treatment. According to this analysis, overall, 19 patients (90.5%) benefited from the treatment with BEV. No severe adverse effects were reported.

BEV might be an effective and safe therapeutic option for patients with radiation necrosis as a complication after cranial radiation therapy. Patients seem to benefit from this treatment by improving symptomatically or through reduction of dexamethasone 2).


Perez-Torres et al. validated the VEGF specificity by comparing the therapeutic efficacy of anti-VEGF with non-specific isotype control antibody. Additionally, they found that VEGF over-expression and radionecrosis developed simultaneously, which precludes preventative anti-VEGF treatment 3).

References

1)

Vellayappan B, Tan CL, Yong C, Khor LK, Koh WY, Yeo TT, Detsky J, Lo S, Sahgal A. Diagnosis and Management of Radiation Necrosis in Patients With Brain Metastases. Front Oncol. 2018 Sep 28;8:395. doi: 10.3389/fonc.2018.00395. eCollection 2018. Review. PubMed PMID: 30324090; PubMed Central PMCID: PMC6172328.
2)

Bodensohn R, Hadi I, Fleischmann DF, Corradini S, Thon N, Rauch J, Belka C, Niyazi M. Bevacizumab as a treatment option for radiation necrosis after cranial radiation therapy: a retrospective monocentric analysis. Strahlenther Onkol. 2019 Oct 4. doi: 10.1007/s00066-019-01521-x. [Epub ahead of print] PubMed PMID: 31586230.
3)

Perez-Torres CJ, Yuan L, Schmidt RE, Rich KM, Drzymala RE, Hallahan DE, Ackerman JJ, Garbow JR. Specificity of vascular endothelial growth factor treatment for radiation necrosis. Radiother Oncol. 2015 Sep 12. pii: S0167-8140(15)00462-4. doi: 10.1016/j.radonc.2015.09.004. [Epub ahead of print] PubMed PMID: 26376163.
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