|Year : 2020 | Volume
| Issue : 2 | Page : 23-27
Desmopressin in Critically Ill Neurosurgical Patients: An Overview
Angie Ching-Gonzalez1, Christian Meza-Valle1, Karen Muñoz-Báez1, Juan Medrano-Carreazo1, Amit Agrawal2, Rakesh Mishra3, Adesh Shrivastava2, Tariq Janjua4, Luis Rafael Moscote-Salazar5
1 Center of Biomedical Research, Faculty of Medicine, University of Cartagena, Cartagena, Colombia
2 Department of Neurosurgery, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India
3 Department of Neurology, National Institute of Mental Health and Neuro Sciences, Military Hospital Jabalpur, Madhya Pradesh, India
4 Regions Hospital, MN, USA
5 Center of Biomedical Research, Faculty of Medicine, University of Cartagena, Cartagena, Colombia; Department of Neurology, Paracelsus Medical University, Salzburg, Austria, Australia
|Date of Submission||22-Aug-2020|
|Date of Acceptance||24-Nov-2020|
|Date of Web Publication||31-Dec-2020|
Dr. Luis Rafael Moscote-Salazar
Paracelsus Medical University, Salzburg
Source of Support: None, Conflict of Interest: None
Severely ill neurosurgical patients are those who present with pathologies of the nervous system associated with either a high mortality or that which leaves significant sequelae in those who survive. Desmopressin is a synthetic analog of the antidiuretic hormone that is stored in neurohypophysis. Its function is to decrease urinary volume by increasing reabsorption of water in the convoluted tubules and nephron collectors, additionally increasing the expression of coagulation factor VII and the von Willebrand factor. For this reason, its usefulness in the management of various pathologies has been tested, from coagulopathies to posttraumatic and postsurgical diabetes insipidus. It contributes in improving hyponatremia and in maintaining the balance of fluids and electrolytes in traumatic brain injury and subarachnoid hemorrhage (SAH) patients. It has been additionally studied for its role in the risk of rebleeding in SAH patients and in those with coagulopathies, where its implicated mechanism of action is through platelet anti-aggregation.
Keywords: Desmopressin, neurosurgery, neurosurgical intensive care, neurosurgical patient
|How to cite this article:|
Ching-Gonzalez A, Meza-Valle C, Muñoz-Báez K, Medrano-Carreazo J, Agrawal A, Mishra R, Shrivastava A, Janjua T, Moscote-Salazar LR. Desmopressin in Critically Ill Neurosurgical Patients: An Overview. J Transl Crit Care Med 2020;2:23-7
|How to cite this URL:|
Ching-Gonzalez A, Meza-Valle C, Muñoz-Báez K, Medrano-Carreazo J, Agrawal A, Mishra R, Shrivastava A, Janjua T, Moscote-Salazar LR. Desmopressin in Critically Ill Neurosurgical Patients: An Overview. J Transl Crit Care Med [serial online] 2020 [cited 2022 Dec 3];2:23-7. Available from: http://www.tccmjournal.com/text.asp?2020/2/2/23/305789
| Introduction|| |
When we speak of a seriously ill neurosurgical patient, we refer to any person who has neuropathology associated with high mortality, whether traumatic or nontraumatic, which, if they survive, will have sequelae that will affect their quality of life. Examples of these pathologies are traumatic brain injury (TBI), aneurysmal or nonaneurysmal subarachnoid hemorrhage (SAH), and intracranial hemorrhage because of coagulopathies, among others. Multiple drugs have been investigated to decrease intracranial pressure (ICP) or to improve hemostatic function, however, in this article, we will focus on the different uses that have been attributed to desmopressin in neurosurgery.
| Overview of Desmopressin|| |
Desmopressin (1-desamino-8-D-arginine vasopressin) is a synthetic analog of the antidiuretic hormone (ADH) or vasopressin, produced in the supraoptic and paraventricular nuclei of the hypothalamus, stored in the neurohypophysis. This drug is widely used in primary nocturnal enuresis, von Willebrand disease, diabetes insipidus (DI), and hemophilia A, among others., It is a pure agonist of the V2 receptors, widely expressed in the collecting tubules and distal convoluted tubules of the nephron. There they bind to the receptors coupled to protein G which, after activating adenylate cyclase and increasing intracellular levels of cyclic adenosine monophosphate, increases the permeability of water. As a result, water is reabsorbed from the lumen of the tubule and it decreases urine volume. However, its functions are not only limited to the nephron, and desmopressin has been shown to also increase the expression of coagulation factor VII and von Willebrand factor by exocytosis.,, The most common routes of administration are intranasally, intravenously, subcutaneously, and innovatively, in sublingual tablets., The doses usually vary depending on the pathology. Dosage is between 120 and 300 μg, used every 12 or 24 h.,, It is considered a very safe drug with few adverse effects, but if they occur, they usually comprise hyponatremia, headache, tachycardia, and facial redness.
| Desmopressin in Severe Traumatic Brain Injury|| |
TBI is the major cause of death and disability secondary to trauma, with young patients being affected in large proportions, almost always secondary to traffic accidents. TBI is either the result of primary injuries because of the impact, or secondary ones, developed by various mechanisms such as increased reactive oxygen species. However, one of the fundamental problems when facing TBI is recognizing and managing signs of intracranial hypertension, and associated conditions such as hypernatremia, which results in increased mortality and morbidity. In the search of novel ways to manage TBI-associated hypernatremia that do not cause drastic changes in ICP, Harrois et al. conducted a retrospective, observational, and multicentric study in 2019, using desmopressin for the management of posttraumatic DI. The study included 262 patients, of whom 14.9% received desmopressin in daily doses between 0.125 and 10 μg (doses usually differ between different intensive care units). They further reported that the decreases in natremia did not exceed the recommended limits (>1 mmol/h), and the ICP variations during desmopressin therapy were not significant (<5 mmHg). In addition, there was no need to use osmotherapy. Based on these findings, the authors concluded that the use of desmopressin for posttraumatic DI in severe TBI is effective as well as safe. This was in contrast to the previous studies that showed uncertainty regarding the use of desmopressin to treat posttraumatic DI in severe TBI. However, one disadvantage of this study is the wide range of doses used between an intensive care unit and others. Currently, there is no recommended guideline for management, so further research is required to reach consensus in this regard. In addition, desmopressin is a widely acceptable therapy for the management of DI secondary to trauma.,
| Desmopressin in Subarachnoid Hemorrhage|| |
SAH is defined as the presence of blood in the subarachnoid space, which can be spontaneous or posttraumatic. As for spontaneous SAH, its main cause is undoubtedly aneurysmal, but it can also be secondary to a lesser extent to arteriovenous malformations or hemostasis disorders. The primary management is the occlusion of the vessel responsible for bleeding, however, the complications of this pathology, even with correction of the vascular defect, are usually devastating, such complications consist of hyponatremia, hydrocephalus, vasospasm, rebleeding, and intraparenchymal extension. The possible benefits of the use of desmopressin in aneurysmal SAH consist of ensuring a good balance of perioperative fluids and electrolytes, which is why a qualitative systematic review was carried out in Turkey in 2018 by Kararslan et al. The authors concluded that the use of desmopressin may be important to prevent the hyponatremia due to inappropriate antidiuretic secretion, in addition to improving secondary volume contraction and negative sodium balance. Another hypothesis arisen for desmopressin in SAH was that it could have some effect to prevent rebleeding in the initial days after bleeding.
It is worth noting that, within the small group of spontaneous SAH secondary to coagulopathies, there are case reports associated with hemophilia C. Although primary therapy in these cases is the replacement of coagulation factor XI, other medications such as desmopressin and antifibrinolytics such as tranexamic acid may have some benefits to reduce bleeding associated with surgery to correct the bleeding vessel. In an observational cohort study by Francoeur et al., desmopressin was associated with 45% reduction of risk of rebleeding. They studied the risk of rebleeding in 1639 patients, of which 12% received desmopressin along with antiplatelet therapy. The guidelines of Neurocritical Care Society and Critical Care Society suggest use of desmopressin in reversal of antithrombotics in intracerebral hemorrhage (ICH) and SAH. Desmopressin also finds its clinical application in DI in cases of anterior communicating artery aneurysms.
| Desmopressin in Patients Receiving Antiplatelet Aggregating Treatment|| |
Antiplatelet aggregation therapy is essential in the prevention of cardiovascular diseases, reducing the occurrence of myocardial infarction by 17% and ischemic stroke by 14%., An irreversible cyclooxygenase 1 inhibitor, acetylsalicylic acid (ASA), is the most widely used antiplatelet agent in the world, and it is estimated that more than a third of Americans over the age of 35 regularly consume it., Clopidogrel, an adenosine diphosphate receptor antagonist (ADP), is also widely used for this purpose, often with ASA.,, It is common that when performing surgical procedures in this group of patients bleeding occurs, therefore before deciding to perform them, their hemostatic competence and their risk of bleeding must be taken into account. When these require emergency neurosurgical procedures, maintaining homeostasis is crucial to get successful results, which poses a challenge for the neurosurgeon who must choose the options to prevent and treat possible intraoperative bleeding.
Antiplatelets in elderly population complicate the management of TBI. The treating neurosurgeon has to balance the risk of bleeding with prothrombotic risk. Studies with prognostic evidence Level I and therapeutic evidence Level II suggest that patients who are on clopidogrel before the injury have increased likelihood of progression of ICH and need for surgical intervention. Desmopressin is effective in reducing bleeding time, because of its ability to increase plasma levels of factor XIII and von Willebrand factor, and stimulating the expression of glycoprotein receptors on platelet surface.,, This has led to studying its ability to prevent bleeding in patients with antiplatelet aggregation treatment undergoing emergency neurosurgery, administered before and/or during it. Although it is rarely used in neurosurgery as the sole agent for this purpose, it is regularly used with platelet transfusion in patients medicated with ADP receptor inhibitors., There are few studies on ICH with limited size reporting conflicting results on the role of desmopressin in stabilizing platelet function., As a result, there is no convincing evidence that it prevents bleeding and improves platelet function in patients on antiplatelet therapy., Furay et al. studied platelet function in trauma patients by assessing platelet ADP inhibition using thromboelastography and found that desmopressin has similar result as platelet transfusion on platelet function. Naidech et al. reported on the use of desmopressin in 14 patients with ICH and found increased platelet activity after the administration of desmopressin. There was a reduction in the size of ICH in seven patients who received desmopressin within 12 h of the onset of ICH. Similarly, in a retrospective study of 202 trauma patients, the researchers found significant association between desmopressin use and decrease in hematoma expansion in patients receiving antiplatelets. There were no significant thrombotic events found with the use of desmopressin in these patients. Kapapa et al. reported in their study of 10 patients with ICH who were on aspirin that, platelet function returned to normal, but this effect was short lasting and depends on the frequency of drug intake in these patients. In a retrospective study by Kim et al. on TBI, ICH, and desmopressin use, no significant role of desmopressin was found on reducing hematoma. Feldman et al. reported in a retrospective study of 124 patients (55 received desmopressin) that desmopressin use resulted in 88% decreased risk of hematoma progression during the first 24 h and there were no significant thrombotic events. In contrast, Schmidt et al. reported no significant effect of desmopressin on hematoma reduction in a cohort of 71 patients. Similarly, Mengel et al. found no role of desmopressin in limiting the hematoma size or function outcome in a nonrandomized study of 140 patients.
For its helpful risk/benefit ratio, recent guidelines have recommended considering its administration in the management of intraoperative bleeding in regular users of ASA, as evidenced in small studies of patients with spontaneous and traumatic intracranial hemorrhage with abnormal platelet function. The Neurocritical Care Society recommends the use of a desmopressin dose of 0.4 μg/kg for the management of intracranial hemorrhage associated with the use of ASA and ADP receptor antagonists., In spite of limited evidence, guidelines also recommend the use of desmopressin in reducing bleeding after trauma and in patients with von Willebrand disease.,,
| Desmopressin in Diabetes Insipidus Management and Postsurgical Diabetes Insipidus|| |
Central-origin DI is an endocrine disorder characterized by ADH deficiency, characterized by causing polydipsia and polyuria with diluted urine emission, with consequent hypernatremia, and complications such as hypovolemia and hypotension. Its multiple causes include intracranial surgery, occurring more frequently in pituitary surgery, as a consequence of trauma caused by surgical manipulation or by a reduction in blood supply to the stalk and the posterior pituitary.
In general, in these cases, it manifests temporarily, starting 24–48 h after surgery and resolving in approximately 10 days with replacement of the water either orally or intravenously. Desmopressin treatment is reserved for patients with excessive polyuria or hypernatremia, at a single subcutaneous dose of 1–2 μg, with a possible second dose after 6–12 h if the urine output is 200–250 mL/h, the osmolality is <200 mOsm/kg, or urinary density is <1005. In cases presenting with DI, hypodipsia, or polydipsia, due to injury to the hypothalamic osmoreceptors that regulate thirst and vasopressin secretion (arginine vasopressin [AVP]), fixed doses of desmopressin are prescribed, accompanied by a high fluid intake (1.5 L/day) that will change based on daily weight measurements., Transient DI is a rare complication of pregnancy because of placental secretion of vasopressinase. Desmopressin is resistant to vasopressinase and is an thus effective treatment for transient DI of pregnancy as well.
| Transient Diabetes Insipidus after Vasopressin Use|| |
AVP is a second- or third-line medication in the vasopressor management of the neurosurgical patients to maintain cerebral perfusion pressure, especially in patients with sepsis. In 2016, a series of cases was reported in which patients who have had AVP management and subsequently presented transient DI, were believed to be of nephrogenic origin, secondary to the negative regulation of the vasopressin receptor (V2) in the renal distal convoluted tubule and collecting duct cells. For the prevention and treatment of this pathology, the use of desmopressin in a dose of 2 μg twice a day is indicated, which will act on the V2 receptors, thereby correcting the DI and the hydroelectrolyte imbalance. In case of resistance to this therapy, management with AVP is indicated.
| Conclusions|| |
Despite being a drug mostly used in the management of clinical and endocrine pathologies, the use of desmopressin constitutes a striking option for the management of bleeding in the neurosurgical patient, with multiple studies supporting its use associated with special situations such as coagulopathies and platelet anticoagulation therapy. As it is a widely safe drug, it can be used with relative ease in the management of postsurgical and posttraumatic DI, providing effectiveness even with a single-dose administered. Through this article, the potential of desmopressin has been revealed, contributing from the regulation of the hydroelectrolyte balance to the prevention of bleeding in specific cases.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Karaarslan N, Yilmaz I, Akgun FS, Caliskan T, Ozbek H, Ates O. Systematic evaluation of desmopressin applied to the patients with aneurysmal subarachnoid haemorrhage in the light of the literature. Turk Neurosurg 2018 Apr 9. doi: 10.5137/1019-5149.JTN.23064-18.1.
Bar-Natan M, Hymes KB. Management of intraoperative coagulopathy. Neurosurg Clin N Am 2018;29:557-65.
Richardson DW, Robinson AG. Desmopressin. Ann Intern Med 1985;103:228-39.
Cvetković RS, Plosker GL. Desmopressin: In adults with nocturia. Drugs 2005;65:99-107; discussion 108-9.
Stoof SC, Cnossen MH, de Maat MP, Leebeek FW, Kruip MJ. Side effects of desmopressin in patients with bleeding disorders. Haemophilia 2016;22:39-45.
Naidech AM, Maas MB, Levasseur-Franklin KE, Liotta EM, Guth JC, Berman M, et al.
Desmopressin improves platelet activity in acute intracerebral hemorrhage. Stroke 2014;45:2451-3.
Mannucci PM, Remuzzi G, Pusineri F, Lombardi R, Valsecchi C, Mecca G, et al.
Deamino-8-D-arginine vasopressin shortens the bleeding time in uremia. N Engl J Med 1983;308:8-12.
Cohn JA, Kowalik CG, Reynolds WS, Kaufman MR, Milam DF, Dmochowski RR, et al.
Desmopressin acetate nasal spray for adults with nocturia. Expert Rev Clin Pharmacol 2017;10:1281-93.
Cárdenas Chávez WP, Meza Valle C, Moscote Salazar LR. Neuro-rehabilitation in patients with neurological neurotrauma physical therapy in patients affected by traumatic brain injury. Monotemático Sobre Trauma Craneoencefálico 2018;17:110-5.
Harrois A, Anstey JR, Taccone FS, Udy AA, Citerio G, Duranteau J, et al
. Serum sodium and intracranial pressure changes after desmopressin therapy in severe traumatic brain injury patients: A multi-centre cohort study. Ann Intensive Care 2019;9:99.
Kalra S, Zargar AH, Jain SM, Sethi B, Chowdhury S, Singh AK, et al.
Diabetes insipidus: The other diabetes. Indian J Endocrinol Metab 2016;20:9-21.
Alharfi IM, Stewart TC, Foster J, Morrison GC, Fraser DD. Central diabetes insipidus in pediatric severe traumatic brain injury. Pediatr Crit Care Med 2013;14:203-9.
Alghamdi MA, Almubarak AO, Alsedrani N, Alshehri WM, Alturki AY. Pretruncal nonaneurysmal subarachnoid hemorrhage with underlying hemophilia C. World Neurosurg 2019;127:109-12.
Francoeur CL, Roh D, Schmidt JM, Mayer SA, Falo MC, Agarwal S, et al.
Desmopressin administration and rebleeding in subarachnoid hemorrhage: Analysis of an observational prospective database. J Neurosurg 2018 Jan 1;1-7. doi: 10.3171/2017.7.JNS17990.
Frontera JA, Lewin JJ 3rd,
Rabinstein AA, Aisiku IP, Alexandrov AW, Cook AM, et al.
Guideline for reversal of antithrombotics in intracranial hemorrhage: A statement for healthcare professionals from the Neurocritical Care Society and Society of Critical Care Medicine. Neurocrit Care 2016;24:6-46.
Nguyen BN, Yablon SA, Chen CY. Hypodipsic hypernatremia and diabetes insipidus following anterior communicating artery aneurysm clipping: diagnostic and therapeutic challenges in the amnestic rehabilitation patient. Brain Inj 2001;15:975-80.
Clappers N, Brouwer MA, Verheugt FW. Antiplatelet treatment for coronary heart disease. Heart 2007;93:258-65.
Bollati M, Gaita F, Anselmino M. Antiplatelet combinations for prevention of atherothrombotic events. Vasc Health Risk Manag 2011;7:23-30.
Borges JM, de Carvalho FO, Gomes IA, Rosa MB, Sousa AC. Antiplatelet agents in perioperative noncardiac surgeries: To maintain or to suspend? Ther Clin Risk Manag 2018;14:1887-95.
Bhatt DL, Scheiman J, Abraham NS, Antman EM, Chan FK, Furberg CD, et al.
ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: A report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. Circulation 2008;118:1894-909.
Foreman PM, Ilyas A, Mooney J, Schmalz PG, Walters BC, Griessenauer CJ. Antiplatelet medication reversal strategies in operative intracranial hemorrhage: A survey of practicing neurosurgeons. World Neurosurg 2018;116:e649-54.
Godier A, Garrigue D, Lasne D, Fontana P, Bonhomme F, Collet JP, et al.
Management of antiplatelet therapy for non-elective invasive procedures or bleeding complications: Proposals from the French Working Group on Perioperative Haemostasis (GIHP) and the French Study Group on Thrombosis and Haemostasis (GFHT), in collaboration with the French Society for Anaesthesia and Intensive Care (SFAR). Arch Cardiovasc Dis 2019;112:199-216.
Joseph B, Pandit V, Aziz H, Kulvatunyou N, Hashmi A, Tang A, et al
. Clinical outcomes in traumatic brain injury patients on preinjury clopidogrel: A prospective analysis. J Trauma Acute Care Surg 2014;76:817-20.
Tauer JT, Gneuss A, Lohse JE, Jürgens T, Knöfler R. Evaluation of desmopressin effect on primary haemostasis in pediatric patients with aspirin-like defect as hereditary thrombocytopathy. Klin Padiatr 2011;223:169-72.
Mappus JL, Fellows SE, Anand S, Gandhi MA. The use of desmopressin acetate in patients presenting with intracranial hemorrhage: A review. Trauma 2017;19:3-10.
Swieringa F, Lancé MD, Fuchs B, Feijge MA, Solecka BA, Verheijen LP, et al.
Desmopressin treatment improves platelet function under flow in patients with postoperative bleeding. J Thromb Haemost 2015;13:1503-13.
Wiegele M, Schöchl H, Haushofer A, Ortler M, Leitgeb J, Kwasny O, et al
. Diagnostic and therapeutic approach in adult patients with traumatic brain injury receiving oral anticoagulant therapy: An Austrian interdisciplinary consensus statement. Crit Care 2019;23:62.
Desborough MJ, Oakland KA, Landoni G, Crivellari M, Doree C, Estcourt LJ, et al.
Desmopressin for treatment of platelet dysfunction and reversal of antiplatelet agents: A systematic review and meta-analysis of randomized controlled trials. J Thromb Haemost 2017;15:263-72.
Furay EJ, Daley MJ, Satarasinghe P, Lara S, Aydelotte JD, Teixeira PG, et al
. Desmopressin is a transfusion sparing option to reverse platelet dysfunction in patients with severe traumatic brain injury. J Trauma Acute Care Surg 2020;88:80-6.
Barletta JF, Abdul-Rahman D, Hall ST, Mangram AJ, Dzandu JK, Frontera JA, et al.
The role of desmopressin on hematoma expansion in patients with mild traumatic brain injury prescribed pre-injury antiplatelet medications. Neurocrit Care 2020;33:405-13.
Kapapa T, Röhrer S, Struve S, Petscher M, König R, Wirtz CR, et al
. Desmopressin acetate in intracranial haemorrhage. Neurol Res Int 2014;2014:298767.
Kim DY, O'Leary M, Nguyen A, Kaji A, Bricker S, Neville A, et al
. The effect of platelet and desmopressin administration on early radiographic progression of traumatic intracranial hemorrhage. J Neurotrauma 2015;32:1815-21.
Feldman EA, Meola G, Zyck S, Miller CD, Krishnamurthy S, Cwikla GM, et al.
Retrospective assessment of desmopressin effectiveness and safety in patients with antiplatelet-associated intracranial hemorrhage. Crit Care Med 2019;47:1759-65.
Schmidt KJ, Sager B, Zachariah J, Raad BF, James EG, Fletcher JJ. Cohort analysis of desmopressin effect on hematoma expansion in patients with spontaneous intracerebral hemorrhage and documented pre-ictus antiplatelet use. J Clin Neurosci 2019;66:33-7.
Mengel A, Stefanou MI, Hadaschik KA, Wolf M, Stadler V, Poli K, et al
. Early administration of desmopressin and platelet transfusion for reducing hematoma expansion in patients with acute antiplatelet therapy associated intracerebral hemorrhage. Crit Care Med 2020;48:1009-17.
Rossaint R, Bouillon B, Cerny V, Coats TJ, Duranteau J, Fernández-Mondéjar E, et al.
The European guideline on management of major bleeding and coagulopathy following trauma: Fourth edition. Crit Care 2016;20:100.
Singleton T, Kruse-Jarres R, Leissinger C. Emergency department care for patients with hemophilia and von Willebrand disease. J Emerg Med 2010;39:158-65.
Prete A, Corsello SM, Salvatori R. Current best practice in the management of patients after pituitary surgery. Ther Adv Endocrinol Metab 2017;8:33-48.
Bsat SS, Chanbour H, Darwish H. Transient diabetes insipidus post endoscopic third ventriculostomy: Case report and literature review. Interdiscip Neurosurg Adv Tech Case Manag 2020;20:100676.
Hensen J, Henig A, Fahlbusch R, Meyer M, Boehnert M, Buchfelder M. Prevalence, predictors and patterns of postoperative polyuria and hyponatraemia in the immediate course after transsphenoidal surgery for pituitary adenomas. Clin Endocrinol (Oxf) 1999;50:431-9.
Dzeranova LK, Mikaylova DS, Pigarova EA, Mokrysheva NG, Rozhinskaya LY, Grigoriev AYu, et al
. Options for individualizing therapy for postoperative central diabetes insipidus. Obesity and metabolism. 2017;14(3):54-7. (In Russ.) https://doi.org/10.14341/omet2017354-57
Chanson P, Salenave S. Diabetes insipidus and pregnancy. Ann Endocrinol (Paris) 2016;77:135-8.
Bohl MA, Forseth J, Nakaji P. Transient diabetes insipidus after discontinuation of vasopressin in neurological intensive care unit patients: Case series and literature review. World Neurosurg 2017;97:479-88.