NEUROGENIC SHOCK IN SPINE AND SPINAL CORD INJURY. A LITERATURE REVIEW Lebedeva M.N., Ivanova A.A., Palmash A.V., Boyko N.S.
Tsyvyan Novosibirsk Research Institute of Traumatology and Orthopedics, Novosibirsk, Russia
EPIDEMIOLOGY OF SPINE AND SPINAL CORD INJURY AND NEUROGENIC SHOCK
Neurogenic shock (NS) is the integral part of spine and spinal cord injury (SSCI). On the basis of 87 literature sources relating to issues of etiology and clinical epidemiology of SSCI, I.N. Novoselova demonstrates some data on incidence of SSCI in various countries of the world. So, in USA, the incidence was 54 cases per 1 million n 2018, in Great Britain − 10-15 cases per 1 million. More than 8 thousand people receive SSCI in Russia each year [27]. Lumbar spine injuries prevail in the structure of SSCI − 40-48 %. Cervical spine injuries are rarer (28-38 %). Particularly, such injuries were identified in 45 % of patients in Europe. Post-injury tetraplegia occurs in 53 % of cases, paraplegia − in 42 % [6, 14, 31]. NS is considered as a common complication of this injury. Other causes of NS are rare, namely, acute spinal cord infarct or cases with NS as consequence of spinal surgery [23, 48].
Information on incidence of NS in SSCI is variable. According to J.T. Mallek et al., NS is observed in 7-10 % of patients with spinal cord injury [22]. A review article (2020) reports that incidence of NS in single injury to the spinal cord (SC) is 14.2 %. A review of another database showed that incidence of NS in cervical spine injuries was 19.3 % and 7 % in thoracic spine injuries [7].
There are some interesting results of a retrospective study which was conducted in Vancouver (Canada) in 2016. This study include 84 patients with SSCI including 38 (45 %) patients with single injury to SC [32]. Using the various combinations of hemodynamic criteria of NS, the authors of the study researched the incidence of NS development within 30 days from injury and compared the results in literature. Since hypovolemia and NS are not mutually exclusive, persons with signs of moderate hypovolemia (the criterion of hypovolemia was Hb level) were not excluded to receive more objective data. However, presence of NS was estimated only after correction of hypovolemia. The calculated incidence of NS with the used criteria of systolic arterial pressure (AP) < 100 mm Hg and heart rate (HR) < 80 beats per minute for cervical spinal cord injuries were 29.1 %, for thoracic part − 19 %. According to their opinion, these values give the most adequate reflection of true incidence of NS in SSCI since significant limitations for inclusion criteria were absent. The value of this study is also associated with terms of follow-up, considering the fact that NS can occur with delay at the background of edema and increasing ischemia of SC [4]. Although there are some findings that clinical sings of NS were registered already two hours after injury in most patients (87 %) [39].
Also were studied the incidence of NS in cervical spinal cord injury (ASIA A). To estimate severity of SC injury, we used the classification from ASIA (American Spinal Injury Association) [43]. The study included 27 patients who received injuries not more than 3 days ago. The information was recorded at the moment of admission to the admission unit. NS was registered in 11 (84.6 %) patients admitted within the first eight hours after injury and in 8 (57 %) who were admitted after 8 hours from injury. The high incidence of NS was probably determined by some limitations in inclusion criteria − SC injury, type ASIA A [36].
Therefore, the presented differences in incidence of NS were rather determined by multiple determinations of condition of NS and by various clinical situations where they are used [22]. This circumstance shows the necessity for development of consensus criteria for identification of NS that is important for clinical course and has the critical importance for distribution of healthcare resources [32].
PATHOPHYSIOLOGY OF NEUROGENIC SHOCK
It is known that neurons and axons of sympathetic nervous system are located in the region of SC. Any SC injury interrupts sympathetic innervation, whereas function of parasympathetic nervous system is preserved [25. 42]. Traumatic SC injury is associated with immediate death of nervous cells and corresponds to primary phase of an injury. However, after local destruction of nervous tissue, the chain of subsequent pathophysiological responses occurs which are responsible for secondary injury to nervous structures. It explains the variability of time of beginning, severity and duration of course of NS [18, 37, 44].
Acute sympathetic response to SC injury is observed due to release of noradrenaline and adrenaline from medullar layer of suprarenal glands − increasing systemic AP, bradycardia or tachyarrhythmia. However after 3-4 minutes, influence of parasympathetic nervous system prevails [6, 31].
In SSC, induced disbalance between sympathetic and parasympathetic nervous system leads to disorder of regulation of cardiovascular system function and vasoplegia, resulting in arterial hypotonia and disorder of atrioventricular conductance [25, 42]. As response to decreasing pressure, HR and cardiac output (CO) do not increase, and variability of cardiac rhythm decreases [10, 11, 29]. Severity of clinical manifestations correlates with injury level and SC injury severity (full or partial injury) [1].
These changes in cardiovascular system present 40 % of cases of death in patients within the first 4 days after trauma. Continuous sinus bradycardia, ventricular bradyarrhythmia and supraventricular tachyarrhythmia were described. According to some American studies, bradycardia was in 100 % and systolic hypotension in 60 % in SC injury of ASIA A. For SC injury of ASIA C and D, bradycardia was in 35-70 % of cases, and hypotonia was rare. The identified frequency of bradycardia allowed conclude that it presents less significant clinical criterion for SC injury below Th6. It is determined by the circumstance that sympathetic heart innervation remains under brain control that determines higher balance of mechanisms of vegetative innervation [16, 31].
DETERMINATION OF NEUROGENIC SHOCK CONDITION
NS is the hemodynamic consequence of SC injury. NS manifests itself as hypotonia due to vasodilatation and high perfusion of lower extremities. Therefore, NS is also known as "warm shock". In cases of cervical SC injury, hypotonia can be accompanied by paradoxical bradycardia [25].
Classic neurogenic shock presents the triad: hypotonia, bradycardia and vegetative dysreflexia [31, 33]. However, up to the present time, the hemodynamics parameters as criteria of NS condition are not generally accepted [25]. There are some multiple terms of NS and high heterogeneity of their use [22].
Which terms of NS condition did we find in analysis of scientific data?
According to some researchers, NS is the form of distributive shock, which occurs as result of SC injury in Th6 and higher [9, 32]. Some authors determine NS as circulatory shock of neurogenic origin, which is characterized by insufficiency of blood circulation due to hypotonia and inadequacy of cardiac response − absence of possibility for compensatory tachycardia [25, 29, 39]. In comparison with other types of circulatory insufficiency, this type of shock is rarer. Untimely recognition of and correction of NS leads to life threatening condition with risk of death that quite corresponds to the notion of circulatory shock from European Society of Intensive Therapy, considering it as life threatening syndrome, which leads to multiple organ failure and high mortality [5].
Mentioning the clinical criteria of NS in single SC injury, most authors determine it as condition with decreasing systolic AP < 100 mm Hg and HR < 80 beats per minute. Selection of hemodynamic criteria is historical and is based on expected response of cardiovascular system to hypotonia. Other researchers consider the hemodynamic criteria of NS as decreasing mean AP < 70 mm Hg or systolic AP < 90 mm Hg and HR < 50 per min. Some authors relate isolated bradycardia or isolated hypotonia to NS [4, 22, 38, 42]. In our original study, the criteria of NS were mean AP < 85 mm Hg and HR < 65 per minute [36].
According to modern views, shock is a life threatening condition, which is determined by acute insufficiency of blood circulation when oxygen is not delivered to tissues to required degree, resulting in increasing anaerobic metabolism and increasing lactate formation. In this sense, NS does not contradict to modern determination of shock condition. However, the authors of some publications note that hyperlactatemia, increasing C-reactive protein and procalcitonin are significant for NS diagnosis as AP and HR [4, 42]. The results of a Chinese experimental study suppose that the level of atrial natriuretic peptide (ANP) > 500 pg/ml can serve as the potential objective indicator of NS [50].
The joined committee of American Association of Spinal Injuries and International Society of Spinal Cord offered consideration of NS as extensive dysfunction of vegetative nervous system which includes such symptoms as orthostatic hypotension, vegetative dysreflexia and temperature dysregulation. Presence of focal neurological deficiency is not necessary condition for diagnosis of neurogenic shock [7].
Therefore, there are not any uniform hemodynamic criteria of NS at the present time, but most researchers relate this condition to hypotonia and bradycardia with systolic AP < 100 mm Hg and HR < 80 beats per minute [7, 16, 31, 39, 42].
INFLUENCE OF NEUROGENIC SHOCK ON THE COURSE OF ACUTE PERIOD OF SPINAL CORD INJURY
It is known that that SC injury caused by cervical spine injury leads to multiple multi-system complications, especially in acute phase of injury [24, 34]. In its turn, NS can significantly complicate the course of short term period owing to occurrence of dangerous disorders of cardiac rhythm, myocardial infarction and even death [3, 11, 28].
It is known that hemodynamic disorders in NS consist of two components which are characterized by vessel dilatation and cardiac changes. Higher level of an injury is associated with higher vascular dilatation and more intense hypotonia. Some ECG abnormalities are described, particularly, changes in RR interval within the first 72 hours after trauma [29].
An important study with systemic analysis was conducted in a level 1 trauma center in USA. The study was conducted according to the protocol confirmed by the Board of Directors of University Center of Mississippi [38]. Patients with isolated acute SC injury with clinical signs of NS were selected. AP, HR and CO were measured. Impedance cardiography was used for measurement of CO. This technique is generally accepted and can be easily used at early stages of management − before initiation of intensive care. Total peripheral vascular resistance (TPVR), period before left ventricle output (cardiac PEP) and left ventricle ejection time (LVET) were measured. The analysis of hemodynamic variables was performed with use of the unique analytic methodology using the systemic approach to evaluation of hemodynamic profiles of patients with NS. Calculation methodology was based on the computer model of human physiology (Gyton-Coulman-Sammers' model) which can describe integral physiological functioning of the virtual object and can be used as the platform for theoretical analysis of shock conditions. As result of the study, it was found that clinical course of NS determined by decreasing TPVR was registered in 3 cases (33 %; 95 % CI, 12 % - 65 %), loss of vascular volume − in two cases (22 %; 95 % CI, 6 % - 65 %) or their combination − in three cases (33 %; 95 % CI, 12 % - 65 %). In one case, NS was exclusively cardiac according to origin (11 %; 95 % CI, 3 % - 48 %). PEP and LVET did not correlate with one of analyzed elements of hemodynamic profiles of patients. Also it was noted that decreasing HR below 60 per minute is specific for NS of cardiac origin. Realization of the study concluded that determination of condition of NS as specific physiology, which occurs as result of the single cause and presents the potential spectrum of hemodynamic disorders, which cause hypotonia and can require for various ways of control.
According to literature data, time of initiation of NS is unclear. Manifestation of NS can be observed within several hours or days after injury and lasts for 1-5 weeks [37]. There is an interesting 3-year cohort study, which was carried out in a big trauma center at university clinic in Great Britain (University Hospital Coventry and Warwickshire, UK). The objective of the study was researching of identification of NS [39]. Among 3,096 analyzed cases in acute period of severe trauma, only 33 patients with SSCI were included into the study. Moreover, only 15 (45 %) patients corresponded to the criteria of screening of classical NS: systolic AP ≤ 100 mm Hg, HR ≤ 80 beats per minute. Selection of quite high value of HR as the criterion of NS can be explained by the fact that such approach allowed exclusion of clear hemorrhagic shock, which is always accompanied by increasing HR. A significant advantage of this study is the fact that the authors properly studied prehospital data. It was found that NS developed within two hours after trauma in 87 % of cases, on average after 34 ± 17 minutes (n = 28). 80 % of patients had AP ≤ 100 mm Hg and only 66 % of patients had HR ≤ 80 beats per minute. Intense bradycardia was not registered. The authors of the study concluded that bradycardia develops with delay and presents less sensitive criterion of NS as compared to AP. The authors also researched the influence of SC injury level on incidence of NS development. They showed that high amount of patients had injuries higher than Th6 (p = 0.009). It was found that higher amount of patients with NS had complete injury to SC (p = 0.039), although there are not any uniform opinion on influence of severity of SC injury on a degree of decrease in AP [46].
NS can develop immediately after injury or after several weeks. 50-90 % of patients with NS needed for procedures of intensive care with use of infusion therapy and vasoactive agents to maintain mean AP at the level of 85-90 mm Hg. As a rule, higher level of an injury is associated with more complete, severe and refractory NS [37].
Unstable hemodynamics usually decreases within the first 14 days since vegetative nervous system adapts to trauma. The various data of duration of NS course, symptoms of which can be registered within 4-5 weeks and more, are given [7]. There is a case of long term course of NS caused by continuous sympathetic blockade. NS was not corrected within 13 weeks after an injury in a bicyclist (age of 71) that required for vasoactive agents for long period [20].
The authors of a multi-center prospective study, combining 11 Northern American university medical centers with 801 patients with SC injuries, note various complications in 502 (63 %) patients. Totally, 203 acute complications developed: respiratory − 442 (19.2 %), hematologic − 402 (17.5 %), cardiovascular − 335 (14.5 %), gastrointestinal and urinary − 220 (9.6 %), trophic changes − 178 (7.7 %), mental neurological disorders − 149 (6.5 %). All complications were determined as acute undesirable events of SC injury which can significantly influence on long term neurological and functional outcomes. The study identified some factors which predispose to the mentioned complications: high level of cervical injury, complete injury to SC, older age, previous cardiopulmonary pathology. The authors do not report the amount of patients with registered NS. Mean AP of 85-90 mm Hg within the first 7 days was recommended for all clinical cases. However, the authors note that this position is disputable due to weak evidences [17]. Other scientific publications also show that NS can significantly influence on long term neurological and functional results [32].
INTENSIVE THERAPY OF NEUROGENIC SHOCK
Development of NS is variable and non-predictable. Severe degree of arterial hypotonia leads to secondary injury to SC, decreasing the probability of recovery of neurological functions. Therefore, each physician should master the screening techniques for NS diagnosis on the basis of X-ray imaging, clinical examination and hemodynamics monitoring and should perform appropriate actions for improvement in treatment outcomes. Urgent procedures of intensive care should be initiated before final diagnosis of SSCI to decrease a secondary injury, which can significantly influence on severity of injury treatment [7, 13, 19, 39].
The hemodynamic model of NS is unique due to specific pathophysiology, which is characterized by various types of hemodynamic disorders with absence of a possibility for compensatory narrowing of blood vessels and increasing CO in presence of hypovolemia [2, 13]. Therefore, the use of non-invasive hemodynamic monitoring allows determination of correct direction of medical procedures [36, 38].
Some authors determine the neurogenic shock as circulatory shock of neurogenic origin [25, 29, 39]. One should note that 2015 European Society of Intensive Care presented the revised consensus of intensive care of circulatory shock which determines the main directions of diagnosis, treatment and monitoring of shock. The presented consensus includes 44 well-known positions. However, it also includes some new important notions: about individualization of targeted values of arterial pressure; about estimation of sensitivity to volemic load; about use of echocardiography and hemodynamic monitoring [5]. The revised consensus of intensive care of circulatory shock should present the basis of intensive care of NS. However, it does not consider some specific features of the course of SSCI and NS.
So, according to systematic review of literature, in presence of SC compression, realization of early decompressive interventions is appropriate and safe surgical strategy [8]. The similar conclusions of favorable influence of SC surgical decompression within the first 24 hours after trauma were made according to results of the first large-scale international prospective cohort study STASCIS [40]. The similar conclusions were made as result of a metaanalysis, which was published in 2016 [21].
The earliest initiation of intensive care procedures for NS is oriented to provision of normoxaemia, normocapnia, normovolemia, normothermia with use of standardized approach [24, 25].
The priority task of intensive care for NS is stabilization of hemodynamics by means of intravenous infusion of fluid (the first line therapy). If hypotonia persists despite of normovolemia, vasopressors and inotropic agents are used which present the second line of therapy. Particularly, American Association of Neurosurgeons recommend using the vasoactive agents and maintaining the mean AP at 85-90 mm Hg within the first 7 days, but with caution, owing to the risk of worsening SC ischemia at the background of narrowed vessels [15, 19, 30, 33, 45]. Within the first 7 days, adequate blood flow is considered as necessary for removal of cytokines and their metabolites from the nervous tissue injury site. Since the neuroinflammatory process may continue after this 7-day period, it is possible that longer hemodynamic support is required [26]. It is also supported by the data from I.A. Ruiz et al. which report that decreasing AP as observed in almost all patients due to arrest of vasopressor therapy after 7 days [32]. Our previous study showed that 40.7 % of patients needed for hemodynamic support, which was conducted from the perspective of individual approach in each individual case [36].
Some authors note that the use of vasopressors is low efficient for increasing perfusion of SC since their pharmacological effect is the result of increase in narrowing of vessels. Therefore, it is not surprising that aggressive regulation of arterial pressure with use of alfa-agonists caused serious neurological disorders [9, 49].
As the authors of one of the studies note, estimation of adequacy of perfusion pressure at the injury site requires for control of intraspinal pressure [32]. Other researchers also report on necessity for control of perfusion pressure by means of direct measurement of intraspinal pressure [41, 45].
There are some data on the use of pseudoephedrine as the measure for completion of intravenous introduction of vasopressors and/or atropine. The efficiency of its use was shown in 31 (82 %) patients with NS from September, 2005, to October, 2012 [47, 49]. However, the authors of the study concluded that future studies are required for prove of efficiency.
There is a case of successful use of alfa-1-agonist of midodrine hydrochloride in a patient with severe SC injury with long term NS at the background continuous sympathetic blockade [20].
In 2018, S. Gray and B. Dieudonne reported on the first case of endovascular ballon occlusion of aorta for maintenance of cardiac and cerebral perfusion as addition to infusion therapy and the use of vasopressors in a patient with refractory hypotonia at the background of polytrauma with SC injury (C5 level) and NS. However, the authors note that the question of safety of this technique is disputable and requires for further research [12].
The reviewed aspects of intensive care present only the measures for improvement in prognosis of acute SC injury, whereas no pathogenetically substantiated methods for recovery of lost function exist at the present time. The perspective direction is development of new treatment methods of regenerative medicine, particularly, cellular therapy, for recovery of injured nervous structures [35].
CONCLUSION
The analysis of science sources shows that NS is associated not only with loss of vasomotor tone, as well as it has its own mechanism of development with combination of elements of hypovolemic, distributive and cardiogenic shock. It determines existence of various variants of hemodynamic disorders in NS which require for various approaches to their management. Moreover, the authors of most publications note that the criteria of NS condition are not generally accepted. This circumstance determine the necessity of development within the limits of a large-scale prospective multicenter study with protocol including clear hemodynamic and laboratory criteria of NS.
Information on financing and conflict of interests
The study was conducted without sponsorship. The authors declare the absence of any clear or potential conflicts of interests relating to publication of this article.