Handbook of COVID-19 Prevention and Treatment

Handbook of COVID-19 Prevention and Treatment

This handbook is currently available in Chinese, English, Italian, French, Spanish, Japanese, German, Persian and Bahasa Indonesia and will be translated to Arabic soon. Other language versions contributed by volunteers will also be continuously shared. The Resources Sharing Center will continue to launch more anti-epidemic resources and provide more practical suggestions and references for medical staff worldwide.

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Severe traumatic brain injury treatment

Severe traumatic brain injury treatment

There are currently no established treatments for the underlying pathophysiology in TBI and while neuro-rehabilitation efforts are promising, there are currently is a lack of consensus regarding rehabilitation following TBI of any severity 1).

see Severe traumatic brain injury guidelines.

see also Pediatric traumatic brain injury guidelines.

Severe traumatic brain injury (TBI) is currently managed in the intensive care unit with a combined medical-surgical approach. Treatment aims to prevent additional brain damage and to optimise conditions for brain recovery. TBI is typically considered and treated as one pathological entity, although in fact it is a syndrome comprising a range of lesions that can require different therapies and physiological goals. Owing to advances in monitoring and imaging, there is now the potential to identify specific mechanisms of brain damage and to better target treatment to individuals or subsets of patients. Targeted treatment is especially relevant for elderly people-who now represent an increasing proportion of patients with TBI-as preinjury comorbidities and their therapies demand tailored management strategies. Progress in monitoring and in understanding pathophysiological mechanisms of TBI could change current management in the intensive care unit, enabling targeted interventions that could ultimately improve outcomes 2).

Monitoring

see Intracranial pressure monitoring for severe traumatic brain injury.

Hormonal replacement

Hormonal analysis should be considered in patients with moderate-to-severe traumatic brain injury, so that appropriate hormonal replacement can be done to optimize the clinical outcome 3).

Case series

Data from 729 severe traumatic brain injury patients admitted between 1996 and 2016 were used. Treatment was guided by controlling intracranial pressure and cerebral perfusion pressure according to a local protocol.

Cerebral perfusion pressurepressure reactivity index curves were fitted automatically using a previously published curve-fitting heuristic from the relationship between pressure reactivity index and cerebral perfusion pressure. The cerebral perfusion pressure values at which this “U-shaped curve” crossed the fixed threshold from intact to impaired pressure reactivity (pressure reactivity index = 0.3) were denoted automatically the “lower” and “upper” cerebral perfusion pressure limits of reactivity, respectively. The percentage of time with cerebral perfusion pressure below (%cerebral perfusion pressure < lower limit of reactivity), above (%cerebral perfusion pressure > upper limit of reactivity), or within these reactivity limits (%cerebral perfusion pressure within limits of reactivity) was calculated for each patient and compared across dichotomized Glasgow Outcome Scores. After adjusting for age, initial Glasgow Coma Scale, and mean intracranial pressure, percentage of time with cerebral perfusion pressure less than lower limit of reactivity was associated with unfavorable outcome (odds ratio %cerebral perfusion pressure < lower limit of reactivity, 1.04; 95% CI, 1.02-1.06; p < 0.001) and mortality (odds ratio, 1.06; 95% CI, 1.04-1.08; p < 0.001).

Individualized autoregulation-guided cerebral perfusion pressure management may be a plausible alternative to fixed cerebral perfusion pressure threshold management in severe traumatic brain injury patients. Prospective randomized research will help define which autoregulation-guided method is beneficial, safe, and most practical 4).

Medicaments

Despite the incidence of these injuries and their substantial socioeconomic implications, no specific pharmacological intervention is available for clinical use.

see Progesterone for acute traumatic brain injury.

see 21-aminosteroids for severe traumatic brain injury.

Neuroprotection

see Neuroprotection in traumatic Brain Injury

see Decompressive craniectomy for severe traumatic brain injury.

Cell-based therapies

Cell-based therapies are currently being investigated in treating neurotrauma due to their ability to secrete neurotrophic factors and anti-inflammatory cytokines that can regulate the hostile milieu associated with chronic neuroinflammation found in TBI. In tandem, the stimulation and mobilization of endogenous stem/progenitor cells from the bone marrow through granulocyte colony stimulating factor (G-CSF) poses as an attractive therapeutic intervention for chronic TBI.

The potential of a combined therapy of human umbilical cord blood cells (hUCB) and G-CSF at the acute stage of TBI to counteract the progressive secondary effects of chronic TBI using the controlled cortical impact model.

Four different groups of adult Sprague Dawley rats were treated with saline alone, G-CSF+saline, hUCB+saline or hUCB+G-CSF, 7-days post CCI moderate TBI. Eight weeks after TBI, brains were harvested to analyze hippocampal cell loss, neuroinflammatory response, and neurogenesis by using immunohistochemical techniques. Results revealed that the rats exposed to TBI treated with saline exhibited widespread neuroinflammation, impaired endogenous neurogenesis in DG and SVZ, and severe hippocampal cell loss. hUCB monotherapy suppressed neuroinflammation, nearly normalized the neurogenesis, and reduced hippocampal cell loss compared to saline alone. G-CSF monotherapy produced partial and short-lived benefits characterized by low levels of neuroinflammation in striatum, DG, SVZ, and corpus callosum and fornix, a modest neurogenesis, and a moderate reduction of hippocampal cells loss. On the other hand, combined therapy of hUCB+G-CSF displayed synergistic effects that robustly dampened neuroinflammation, while enhancing endogenous neurogenesis and reducing hippocampal cell loss. Vigorous and long-lasting recovery of motor function accompanied the combined therapy, which was either moderately or short-lived in the monotherapy conditions. These results suggest that combined treatment rather than monotherapy appears optimal for abrogating histophalogical and motor impairments in chronic TBI 5).

Research

Research in traumatic brain injury (TBI) is challenging for several reasons; in particular, the heterogeneity between patients regarding causes, pathophysiology, treatment, and outcome. Advances in basic science have failed to translate into successful clinical treatments, and the evidence underpinning guideline recommendations is weak. Because clinical research has been hampered by non-standardised data collection, restricted multidisciplinary collaboration, and the lack of sensitivity of classification and efficacy analyses, multidisciplinary collaborations are now being fostered. Approaches to deal with heterogeneity have been developed by the IMPACT study group. These approaches can increase statistical power in clinical trials by up to 50% and are also relevant to other heterogeneous neurological diseases, such as stroke and subarachnoid haemorrhage. Rather than trying to limit heterogeneity, we might also be able to exploit it by analysing differences in treatment and outcome between countries and centres in comparative effectiveness research. This approach has great potential to advance care in patients with TBI 6).

Anticoagulation Resumption after traumatic brain injury

Anticoagulation Resumption after traumatic brain injury.

Thromboprophylaxis

The early administration of venous thromboembolism (VTE) chemoprophylaxis within 24 h after admission in patients with severe TBI did not increase the risk of intracranial bleeding progression 7).

Transcutaneous Vagus Nerve Stimulation for Severe Traumatic Brain Injury

see Transcutaneous Vagus Nerve Stimulation for Severe Traumatic Brain Injury.

References

1)

Marklund N, Bellander BM, Godbolt A, Levin H, McCrory P, Thelin EP. Treatments and rehabilitation in the acute and chronic state of traumatic brain injury. J Intern Med. 2019 Mar 18. doi: 10.1111/joim.12900. [Epub ahead of print] PubMed PMID: 30883980.
2)

Stocchetti N, Carbonara M, Citerio G, Ercole A, Skrifvars MB, Smielewski P, Zoerle T, Menon DK. Severe traumatic brain injury: targeted management in the intensive care unit. Lancet Neurol. 2017 Jun;16(6):452-464. doi: 10.1016/S1474-4422(17)30118-7. Review. PubMed PMID: 28504109.
3)

Prasanna KL, Mittal RS, Gandhi A. Neuroendocrine dysfunction in acute phase of moderate-to-severe traumatic brain injury: A prospective study. Brain Inj. 2015;29(3):336-342. PubMed PMID: 25671810.
4)

Donnelly J, Czosnyka M, Adams H, Robba C, Steiner LA, Cardim D, Cabella B, Liu X, Ercole A, Hutchinson PJ, Menon DK, Aries MJH, Smielewski P. Individualizing Thresholds of Cerebral Perfusion Pressure Using Estimated Limits of Autoregulation. Crit Care Med. 2017 Sep;45(9):1464-1471. doi: 10.1097/CCM.0000000000002575. PubMed PMID: 28816837.
5)

Acosta SA, Tajiri N, Shinozuka K, Ishikawa H, Sanberg PR, Sanchez-Ramos J, Song S, Kaneko Y, Borlongan CV. Combination therapy of human umbilical cord blood cells and granulocyte colony stimulating factor reduces histopathological and motor impairments in an experimental model of chronic traumatic brain injury. PLoS One. 2014 Mar 12;9(3):e90953. doi: 10.1371/journal.pone.0090953. eCollection 2014. PubMed PMID: 24621603.
6)

Maas AI, Murray GD, Roozenbeek B, Lingsma HF, Butcher I, McHugh GS, Weir J, Lu J, Steyerberg EW; International Mission on Prognosis Analysis of Clinical Trials in Traumatic Brain Injury (IMPACT) Study Group. Advancing care for traumatic brain injury: findings from the IMPACT studies and perspectives on future research. Lancet Neurol. 2013 Dec;12(12):1200-10. doi: 10.1016/S1474-4422(13)70234-5. Epub 2013 Oct 17. PubMed PMID: 24139680; PubMed Central PMCID: PMC3895622.
7)

Störmann P, Osinloye W, Freiman TM, Seifert V, Marzi I, Lustenberger T. Early Chemical Thromboprophylaxis Does not Increase the Risk of Intracranial Hematoma Progression in Patients with Isolated Severe Traumatic Brain Injury. World J Surg. 2019 Jul 2. doi: 10.1007/s00268-019-05072-1. [Epub ahead of print] PubMed PMID: 31267142.

Pediatric low-grade glioma treatment

Pediatric low grade glioma treatment

Low-grade gliomas (LGGs) constitute the largest, yet clinically and (molecular-) histologically heterogeneous group of pediatric brain tumors of WHO grades I and II occurring throughout all pediatric age groups and at all central nervous system (CNS) sites. The tumors are characterized by a slow growth rate and may show periods of growth arrest. Around 40% of all LGG patients can be cured by complete neurosurgical resection and are followed by close observation. In case of relapse, the second resection often is possible. Following incomplete resection, observation is recommended, as long as there is no radiologic tumor growth and the patient does not suffer from significant, tumor-related symptoms. This also applies to patients with a diagnosis of LGG on the basis of radiological criteria. By contrast, clinical worsening and/or radiologic progression are an indication of treatment with either chemo- or radiotherapyOverall survival is around 90%, and many patients survive with residual tumor, i. e. they suffer from chronic disease. All patients need comprehensive neuro-oncological care, the principles, and details of which are summarized in the current guidelines. These represent the standard of care for diagnostic work-up (including neuroimaging and neuropathology), and for therapeutic decisions (including the indications to non-surgical treatment) as well as concepts for neurosurgical intervention, chemotherapy, and radiotherapy as well as surveillance and rehabilitation. The current treatment algorithm was compiled by members of the LGG working group of the SIOP-E brain tumor group (SIOP-E-BTG) and is based upon the results of previous European LGG studies and international reports 1).


Within the multidisciplinary tumor board, all decisions concerning biopsy or resection at the time of diagnosis and progression must be carefully made weighing the potential risk of surgery vs. the therapeutic benefit of elucidating the histologic and molecular subtype of the tumor 2).

A treatment algorithm was compiled by members of the LGG working group of the SIOPE brain tumor group (SIOP-E-BTG) and is based upon the results of previous European LGG studies and international reports 3).

Since 2006 the German federal joint committee (G-BA, Gemeinsamer Bundesausschuss) has established that in line with all other pediatric hematological and oncological diseases – newly diagnosed low grade gliomas (LGG) patients must be treated within the current active society of pediatric oncology and hematology (Gesellschaft fuer paediatrische Onkologie und Haematologie, GPOH) trial or registry to ensure high quality standards of care and use of established referral systems 4).


Pediatric low grade gliomas (LGG) that are unresectable often require adjuvant chemotherapy such as carboplatin/vincristine. Small phase II studies have suggested equivalent efficacy of single agent 4-weekly carboplatin. A single-institution retrospective review captured all patients aged 0 to 18 years diagnosed with LGG between 1996 and 2013 and treated with carboplatin monotherapy. The response and survival according to tumor site was compared to published results for multi-agent chemotherapy. Of 268 children diagnosed with LGG diagnosed in this period, 117 received chemotherapy and 104 children received single agent carboplatin as first line chemotherapy. All patients received carboplatin at 560mg/m2 , four-weekly for a median of 12 courses. The mean age at diagnosis was 5.8 years (range 3m-16y) and 32% had neurofibromatosis type 1. With a mean followup of 54 months, 86% of patients achieved stabilisation or better (SD/PR/CR). 3-year progression free survival (PFS) 66% (95% C.I. 57% – 76%), and 5-year PFS was 51% (95% C.I. 41% – 63%). 5-year overall survival was 97%. Multivariate analysis showed poorer PFS for those with chiasmatic/hypothalamic tumors. In this retrospective analysis single agent carboplatin shows comparable efficacy to historical multiagent chemotherapy for the treatment of patients with unresectable LGG. Equivalent outcomes are achieved with less chemotherapy, reduced side effects and fewer hospital visits. Further research is required to establish the place of this simplified regimen in the up-front treatment of unresectable LGG 5).

Measures

Tumor measurement is important in unresectable pediatric low-grade gliomas (pLGGs) to determine either the need for treatment or assess response. Standard methods measure the product of the largest 2 lengths from transverse, anterior-posterior, and cranio-caudal dimensions (SM, cm). This single-institution study evaluated tumor volume measurements (VM, cm) in such pLGGs. Of 50 patients treated with chemotherapy for surgically inaccessible pLGG, 8 met the inclusion criteria of having 2 or more sequential MRI studies of T1-weighted Fast-Spoiled Gradient Recalled acquisition. SM and VM were performed by 2 independent neuroradiologists. Associations of measurement methods with defined therapeutic response criteria and patient clinical status were assessed. The mean tumor size at the first MRI scan was 20 cm and 398 cm according to SM and VM, respectively. VM results did not differ significantly from SM-derived spherical volume calculations (Pearson correlation, P<0.0001) with a high interrater reliability. Both methods were concordant in defining the tumor response according to the current criteria, although radiologic progressive disease was not associated with clinical status (SM: P=0.491, VM: P=0.208). In this limited experience, volumetric analysis of unresectable pLGGs did not seem superior to the standard linear measurements for defining tumor response 6).

References

1)

Gnekow AK, Kandels D, Tilburg CV, Azizi AA, Opocher E, Stokland T, Driever PH, Meeteren AYNS, Thomale UW, Schuhmann MU, Czech T, Goodden JR, Warmuth-Metz M, Bison B, Avula S, Kortmann RD, Timmermann B, Pietsch T, Witt O. SIOP-E-BTG and GPOH Guidelines for Diagnosis and Treatment of Children and Adolescents with Low Grade Glioma. Klin Padiatr. 2019 May;231(3):107-135. doi: 10.1055/a-0889-8256. Epub 2019 May 20. Erratum in: Klin Padiatr. 2019 May;231(3):e2. PubMed PMID: 31108561.
2)

PackerRJ,Pfister S,BouffetEetal.Pediatric low-grade gliomas: implications of the biologic era. Neuro-oncology 2017; 19: 750–761
3) , 4)

Gnekow AK, Kandels D, Tilburg CV, Azizi AA, Opocher E, Stokland T, Driever PH, Meeteren AYNSV, Thomale UW, Schuhmann MU, Czech T, Goodden JR, Warmuth-Metz M, Bison B, Avula S, Kortmann RD, Timmermann B, Pietsch T, Witt O. SIOP-E-BTG and GPOH Guidelines for Diagnosis and Treatment of Children and Adolescents with Low Grade Glioma. Klin Padiatr. 2019 May;231(3):107-135. doi: 10.1055/a-0889-8256. Epub 2019 May 20. PubMed PMID: 31108561.
5)

Dodgshun AJ, Maixner WJ, Heath JA, Sullivan MJ, Hansford JR. Single agent carboplatin for pediatric low-grade glioma: A retrospective analysis shows equivalent efficacy to multi-agent chemotherapy. Int J Cancer. 2015 Aug 1. doi: 10.1002/ijc.29711. [Epub ahead of print] PubMed PMID: 26235348.
6)

Kilday JP, Branson H, Rockel C, Laughlin S, Mabbott D, Bouffet E, Bartels U. Tumor volumetric measurements in surgically inaccessible pediatric low-grade glioma. J Pediatr Hematol Oncol. 2015 Jan;37(1):e31-6. doi: 10.1097/MPH.0000000000000168. PubMed PMID: 25517914.
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