 |
|
||||
| Home | Login | |||||
| About | Editorial board | Articles
|
NSI Publications
|
Search | Instructions | Online Submission | Subscribe | Videos | Etcetera | Contact |
|
||||||||||||||||||||
|
|
|
Understanding and Managing Autonomic Disorders in the Neurocritical Care Unit: A Comprehensive review
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.344657
Keywords: Autonomic dysfunction, autonomic storm, neurocritical care
The autonomic nervous system (ANS) is the part of the central nervous system that is responsible for modulating the body's internal responses to changes in the internal and external environment. As these responses must be instantaneous and require modification “on the run,” they need to be automatic and therefore beyond voluntary control. And yet, there is an overriding emotional and higher central component that modifies these automatic responses.[1] The executive arm of the ANS consists of two broad divisions: sympathetic and parasympathetic. The sympathetic system has a cervical (C1–C6) and thoracolumbar (T1–T12 and L1–L4) outflow. The parasympathetic system has a craniosacral outflow. The two arms of the ANS generally tend to produce opposite effects and act in tandem. In the resting state, optimum function of an organ system is ensured by the presence of an innate sympathetic and parasympathetic tone that results in a steady state of reciprocal stimulation of the two systems. Depending on the changes in circumstance, one system takes over from the other to produce the necessary modifications in function.[2] The ANS is also exquisitely linked in its responses to the neuroendocrine axes. Sympathetic stimulation results in the activation of the adrenal medulla to release copious amounts of noradrenaline and adrenaline into the blood, causing an amplification of the sympathetic response in these situations. This unique coordination is brought about predominantly through the hypothalamus, which is the great junction for the neural and endocrine responses.[3] In the brainstem, the main integrating nucleus is the nucleus tractus solitarious (NTS), which receives afferents via the 9th and 10th cranial nerves. Various subnuclei in the NTS are sensitive to visceral or chemical receptors from the heart, great blood vessels, and respiratory and gastrointestinal systems. The caudal NTS integrates these various stimuli and projects circuits to the hypothalamus, amygdala, insula, cingulate gyrus, and frontal cortices, receiving in turn a rich reciprocal innervation from these areas. Projections to the respiratory nuclei in the medulla integrate respiratory function. There are also to-and-fro projections to various subnuclei in the periaqueductal area and around the third ventricle. Therefore, the hypothalamus is the key coordinating center that integrates impulses from the limbic cortex, the neuroendocrine system, and other areas. The projections from here to the NTS determine the fine-tuned ANS output. What is important to understand in the context of acute autonomic derangement in a critical-care setting is the vital role that higher cortical centers and certain critical brain stem nuclei play in integrating the ANS output. In general, the higher cortical centers play an inhibitory role on the brain stem nuclei to dampen the ANS output. It is when there is a disconnection from these inhibitory impulses that the lower centers fire without control to produce an autonomic storm.
A major cause of an autonomic storm is a decapitation of the ANS from the higher inhibitory centers. The paroxysmal autonomic instability with dystonia (PAID) syndrome can be best explained by this mechanism. As the NTS is the primary integrator of the ANS, any direct injury to the NTS, as in brain stem stroke, encephalitis, demyelination, or bilateral deafferentation of the center from the NTS, leads to a loss of incoming stimuli and can cause derangement of autonomic function. This is what best explains the syndrome of acute baroreceptor failure. High cervical cord lesions—traumatic, infarcts, or demyelinating lesions—can also cause decapitation of the peripheral ANS. This initially results in spinal shock where there is total motor paralysis, areflexia, and dysautonomia. Later, the innate spinal reflex arcs take over, restoring a certain degree of function. However, the system will not be able to respond appropriately to changes of blood volume or temperature and therefore be susceptible to wild swings of pulse, blood pressure, and temperature, including gastrointestinal and bladder dysfunction. Acute involvement of the peripheral nerves, like in an autoimmune demyelination or toxic exposure, can lead to an acute ANS derangement if these nerves are also affected. This usually happens in pathological processes where small fibers are involved. There is a 20%–30% acute autonomic involvement in Guillain–Barre syndrome (GBS). Occasionally, the autonomic nerves may be primarily targeted in the syndrome of pan-dysautonomia, which may acutely occur as a post-viral condition or as an autoimmune phenomenon. Generally, in neuromuscular pathologies, such as myasthenia gravis, only the skeletal neuromuscular junctions get involved and the autonomic system is spared. However, autonomic derangement can be a predominant and accompanying phenomenon in botulism and in the Lambert–Eaten syndrome. Finally, the autonomic neurotransmitters can be rendered ineffective by certain drugs or toxins. This can be by a blockade or by overstimulation of the receptors. Cocaine overdose can produce sympathetic overdrive. Overdose of tricyclic anti-depressants can cause cardiac arrhythmias due to their anti-cholinergic effects. Organophosphorus poisoning produces an excess of acetylcholine at the neuromuscular junction (due to choline esterase inhibition), causing parasympathetic overactivity. Mushroom poisoning can produce similar effects.
Formal and systematic bedside testing of autonomic function and its various components can only be done in a stable, conscious patient. This is not possible in an acutely and seriously ill patient, who is often unconscious. Therefore, ANS dysfunction must be surmised from a constellation of symptoms in an appropriate setting. The symptom complex suggesting an ANS involvement can be unexplained tachycardia or bradycardia, severe hyper or hypotension, bizarre ECG changes without acute myocardial infarction, irregular breathing patterns with hyper or hypothermia, diaphoresis, or dystonic posturing. These can be episodic, continuous spontaneous, or triggered by minor stimuli such as touch, turning, light, sound, or suctioning. More recently, Baguley et al.[4] attempted to simplify the nomenclature and diagnostic criteria for such dysautonomic features in the critical care setting. They proposed the use of the paroxysmal sympathetic hyperactivity-assessment measure (PSH-AM) scale to assess the diagnostic likelihood of autonomic dysfunction. This scale utilizes a combination of clinical features scale (CFS), including heart rate, respiratory rate, systolic blood pressure, sweating, temperature, and posturing during episodes, with a diagnostic likelihood tool (DLT). A combination of CFS and DLT gives a PSH diagnostic likelihood measure. However, this scale has been tested only on patients with moderate to severe traumatic brain injury. Further studies are needed to validate its use in autonomic storms in other nontraumatic clinical settings. Mimics of ANS derangement should always be considered in the differential diagnosis. This can occur with an acute rise of intracranial tension (ICT), neuroleptic malignant syndrome (NMS), malignant hyperthermia, serotonergic syndrome, or a thyroid storm. PSH or PAID syndrome PAID is a syndrome of paroxysmal autonomic hyperactivity characterized by increased heart rate, respiratory rate, blood pressure changes, temperature variation, and sweating, associated with dystonia.[5] It results from a cerebral lesion, which may be due to trauma, infection, hemorrhage, infarction, brain tumor, cerebral hypoxia, or degeneration. There are various theories postulated regarding the pathophysiology of PAID, but the best explanation is the dysfunction of autonomic centers in the diencephalon (thalamus or hypothalamus) or their connections to cortical, subcortical, and brainstem loci that mediate autonomic function.[5] Bullard suggested a release phenomenon in which loss of cortical and subcortical control of vegetative functions occur, including regulation of blood pressure and temperature.[6] Boeve et al.[7] expanded this concept by speculating that the mechanism likely involves activation (or disinhibition) of central sympatho-excitatory regions such as the paraventricular hypothalamic nucleus, lateral periaqueductal grey substance, lateral parabrachial nucleus, or rostral medulla. Cortically provoked release of adrenomedullary catecholamines during PAID episodes may contribute to the rise in blood pressure as well as tachycardia and tachypnoea.[8] Thermoregulatory dysfunction may be produced by hypothalamic dysfunction.[9] Rigidity and decerebrate posturing are seen experimentally and clinically with lesions in the midbrain, blocking normal inhibitory signals to pontine and vestibular nuclei.[10] This allows these nuclei to become tonically active, transmitting facilitatory signals to the spinal cord control circuits. Spinal reflexes become hyperexcitable, evoked by sensory input signals that are usually below the threshold for excitation of a motor response. The excitatory to inhibitory ratio (EIR) model is used to describe the pathophysiology of this paroxysmal sympathetic overactivity. In the model, the motor and sympathetic overactivity are explained by two parameters acting at the spinal cord level with additional modulation from higher centers: (i) the extent and the rate of increase in the ratio between excitatory and inhibitory influences modulating spinal afferents (EIR) and (ii) the individual's tendency to develop an overreaction to nonnoxious stimuli in response to this change (termed as allodynic tendency).[11],[12] Baguley et al.[4] also moved to standardize the nomenclature of the PAID syndrome, also previously called hypothalamic dysregulation syndrome, diencephalic autonomic epilepsy, or dysautonomia. They proposed the use of the term PSH. A more recent paper by Scott et al.[13] suggested that PSH is more likely to be seen in patients with diffuse, multifocal cerebral injuries and in young comatose patients. Though traditionally described as a complication of acquired brain injury, the dominant cause of PSH is traumatic brain injury.[12] The most recent consensus for the diagnosis of PSH requires it to be a diagnosis of exclusion in the background of an acquired brain injury. There must be paroxysmal sympathetic overactivity to normally nonpainful stimuli. Clinical features as defined by the CFS described above are to be present for 3 or more consecutive days with 2 or more episodes daily with these features persisting for at least 2 weeks after acquired brain injury.[4] The commonly used drugs for treatment of PAID are morphine sulfate, bromocriptine mesylate, propranolol hydrochloride, clonidine hydrochloride, lorazepam, and dantrolene sodium. Supportive therapy includes Botox injection, splints, intrathecal baclofen, and prevention of noxious stimuli.[5] Prevention of external stimuli such as lower temperature, appropriate fluid and calorie supplementation, and hyperbaric oxygen therapy can help improve prognosis.[12] [Figure 1] is a simplified flowchart representation of the management process devised from the currently available literature.
Autonomic storms in autoimmune encephalitis Autoimmune encephalitis (AIE) is now a leading cause of encephalitis. In the California encephalitis project, NMDA receptor encephalitis and other autoimmune causes have far surpassed infectious causes of encephalitis.[14] With improvements in diagnostic technology, far more cases of AIE are now diagnosed in India as well. Most AIEs cause limbic encephalitis with seizures, psychosis, and amnesia. However, NMDAR encephalitis (NMDARE) is a prototypical AIE that results in autonomic storms. The autonomic stage is characterized by a “storm” that comprises thermoregulatory disturbances (hyperthermia or hypothermia), central neurogenic hypoventilation, volatile blood pressures, volatile heart rates, or Takotsubo cardiomyopathy. Other manifestations include hypersalivation, urinary incontinence, and erectile dysfunction. Cardiac disturbances may be severe enough to cause asystole and may require a pacemaker.[15] NMDA receptors are primarily distributed in the autonomic and limbic circuits of the brain. Hence, NMDARE results in an acute imbalance of the central autonomic network (CAN) and perturbations in the parasympathetic–sympathetic impulses to the cardia. The amygdala and insula probably play a central role in the CAN regulation of the cardiovascular system. Whereas the amygdala serves as an activator in the limbic circuit, the insular cortices play a central role in the efferent limb of the circuit.[16] The sympathetic output seems to be predominantly located in the right insular cortex and the parasympathetic output in the left insular cortex. Experimental studies of stimulation of the left insular cortex have shown sinus node dysfunction resulting in parasympathetic responses such as bradycardia, asystole, or heart blocks. Contrarily, stimulation of the right side results in sympathetic activation with hypertension and tachycardia. Respiratory disturbances are also common. Central neurogenic hypoventilation (CNHo) or hyperventilation (CNHe) can be observed. CNH is more common and often results in the need for prolonged mechanical ventilation.[17] Central neurogenic hyperventilation causes persistent hyperventilation that persists during sleep. Patients have hypocarbia, high arterial PaO2, and respiratory alkalosis in the absence of drug-induced, infectious, epileptic, or metabolic causes. NMDAR antibodies bind to neuronal surface NMDA receptors and result in glutamine–GABA imbalance. There is overactivation of the glutaminergic pathways and inhibition of GABA, resulting in motor cortex hyperexcitability.[18] This functional neurotransmitter imbalance may predispose patients to hypo or hyperventilation syndromes. CNHe may require infusions of propofol and midazolam for control. Hypersalivation is another troublesome symptom in NMDARE. This can be managed by botulinum toxin injections.[19] Most of these dysautonomias must be managed by a multidisciplinary team. However, immunomodulatory treatment remains the mainstay of treatment of NMDARE. Some cases are paraneoplastic and are associated with an ovarian teratoma. In such cases, removal of the underlying teratoma is also necessary. Autonomic dysfunction in GBS GBS is the most common and most severe acute paralytic neuropathy, with approximately 100,000 people developing the disorder every year worldwide. Acute autonomic dysfunction rivals respiratory failure and thromboembolism as an important cause of death in patients with this disorder.[20] Autonomic disturbance is reported to occur in 65% of patients with GBS. The most common autonomic manifestations of GBS to be looked for include the following:
The mainstay of treatment modalities in GBS includes intravenous immunoglobulin injection (IVIg) and plasmapheresis. IVIg has shown better outcomes in terms of overall cost and repeated hospital admissions.[23] Acute baroreceptor failure This is one of the most dramatic, though rare conditions, that can produce an autonomic storm in a critical care setting. The baroreceptors are essentially stretch sensitive receptors in the carotid sinus, heart, and great vessels that provide input information to the central ANS nuclei to prevent surges of blood pressure. They act through the glossopharyngeal and vagal nerves (afferent and efferent), the output being modulated mainly by the NTS.[24] When these impulses are impaired, it results in wide swings of heart rate and blood pressure along with palpitations and sweating. In a case of selective baroreceptor failure, only the afferent parasympathetic is affected relative to the efferent. In such a situation, exceedingly high tachycardia and severe hypertension can occur during times of excitement and sympathetic overdrive. This is accompanied by periods of severe bradycardia and hypotension, even asystole, during times of sleep or sedation. This is due to the malignant vagotonia that is seen in selective baroreceptor failure. In nonselective baroreceptor failure, both the afferent and efferent parasympathetic systems are affected while the sympathetic efferent is spared. This leads to surges of tachycardia and hypertension from uninhibited sympathetic overdrive during times of excitation. However, episodes of severe bradycardia and hypotension do not occur here as the parasympathetic efferent is also blocked.[25] Acute baroreceptor failure can occur after carotid stenting or endarterectomy, neck surgery or radiation, brain stem strokes with glossopharyngeal and vagal involvement, and in the autonomic variants of GBS.[26] The commonest differential diagnosis in this context is pheochromocytoma, thyroid storm, pure autonomic failure, or drugs such as opiates. Only when an adrenal or extra-adrenal pheochromocytoma is ruled out, should one consider baroreceptor failure as a differential.[27] Both produce extremely high levels of norepinephrine and epinephrine in the supine position. The treatment of choice in a hypertensive crisis of baroreceptor failure is clonidine.[28] This is a selective alpha 2 agonist that acts pre-synaptically to prevent the release of noradrenaline. In cases of selective baroreceptor failure, malignant vagotonia can produce severe bradycardia and hypotension; this can be treated with fludrocortisone along with increased intake of salt and fluid. In severe cases, malignant vagotonia in sleep or sedation can even produce critical bradycardia or asystole that may require a cardiac pacemaker. Autonomic disturbances in other conditions High cervical cord lesions secondary to trauma, demyelination, or autoimmune phenomenon can produce derangements of autonomic function, as already discussed before. Drug intoxication secondary to an overdose of amphetamines, cocaine, tricyclic antidepressants, or organo-phosphorous poisoning can knock out autonomic function and should be considered in the appropriate setting. Opiate withdrawal can also mimic an autonomic storm. Autonomic dysfunction is also a part of the now well-described condition, critical illness neuropathy (CIP)/myopathy (CIM). CIP and CIM share the major clinical sign of symmetric and flaccid weakness of muscles and the absence of deep tendon reflexes. It is seen most often in the setting of sepsis or septic shock. Autonomic dysregulation plays a significant role in the acute phase of severe sepsis as it is characterized by high concentrations of circulating catecholamines in the presence of impaired sympathetic modulation of the heart and vessels, thus contributing to circulatory failure in severe sepsis.[29],[30] Skin biopsy is a safe, minimally invasive, and painless method for the diagnosis of CIP.
Acute autonomic dysfunction can occur in a variety of situations in the critical care setting. Paramount among these are severe head injury, hypoxic encephalopathy, NMDA or viral encephalitis, and GBS. Though a diagnostic likelihood scale has been proposed for PSH, its utility outside of traumatic brain injury remains to be seen. Identifying an autonomic storm or derangement early can help treat this critical condition aggressively and appropriately. Tiding over this crisis, whatever the etiology, helps improve the chances of a good outcome. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
[Figure 1]
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||
