ReviewNeuroleptic malignant syndrome in trauma patient
Introduction
The neuroleptic malignant syndrome (NMS) is a potentially fatal syndrome associated primarily with the use of neuroleptic agents that are in turn associated with dopaminergic receptor blockade in the basal ganglia and hypothalamus, and sympathetic dysregulation [1]. It is an uncommon and potentially fatal syndrome that occurs in association with the use of neuroleptic medications.
Although NMS has been historically linked to haloperidol, a variety of other antipsychotic medications and related drugs can produce the syndrome. Star et al. [2] in a case series reported suspected antipsychotic medicines for 20 cases and found that use of olanzapine, risperidone, haloperidol, paliperidone, quetiapine, clozapine, cyamemazine, aripiprazole and also the use of metoclopramide was involved in the rhabdomyolysis.
Psychiatric patients may experience episodes of delusions and hallucinations, which result in self-inflicted injuries and suicide attempts, with a large numbers of trauma mechanisms, mainly burns that are commonly treated with antipsychotic agents. These drugs are either typical or atypical. Atypical agents as clozapine, risperidone, olanzapine and quetiapine fumarate were reserved for patients who failed to respond to or were intolerant to typical agents as well as reducing side effects. They are now often chosen as first-line agents in schizophrenia and they are increasingly a common treatment option for other psychiatric and neurological conditions [3].
It is a rare syndrome with incidence estimated of 0.01–0.02% of patients treated with antipsychotics [4]. Signs and symptoms of NMS are similar to those of malignant hyperthermia (MH), including severe hyperthermia, autonomic instability, muscular rigidity, and a depressed level of consciousness [3].
Followed a neuroleptic drug administration, death can occur as a result of complications such as rhabdomyolysis or cardiovascular collapse [5], aspiration pneumonia, pulmonary embolus, or disseminated intravascular coagulation [3] that determine an estimated mortality rate about 10%[6].
There is some important differential diagnosis that can be considered in a patient with NMS symptoms, such as infection (meningitis, encephalitis and sepsis), psychiatric or neurological (malignant catatonia and delirium), toxic (malignant hyperthermia, serotonin syndrome, amphetamine abuse and hallucinogens substances), endocrine (thyrotoxicosis and pheochromocytoma) and environmental (sunstroke) [6]. Although the NMS cannot be prevented, early diagnosis is critical, since effective therapy would be available for a better prognosis.
Laboratory findings include leukocytosis with or without deviation, elevation of transaminases, lactate dehydrogenase and alkaline phosphatase. It was also described elevation of amylase and lipase in the setting of this syndrome [5]. Robb et al. [8] have described elevation of creatinine phosphokinase levels [7] (CPK) and white blood cells (WBC), electrolyte abnormalities and myoglobinuria.
Rebecca et al. [9] have reported previously, a dramatic drop in serum iron levels and concluded that this finding is consistently associated with NMS, and is a key feature of the acute phase response. Subsequent studies have repeated this finding [10] and the patients had their serum iron levels at the lowest limit of normal and returned to a high-normal range with clinical recovery.
On a clinical level, the acute phase response involves a host of systemic responses to cytokines and acute phase proteins [11]. Although the acute phase response would be generally understood to serve a homeostatic function [12], there are several conditions in which it becomes dysregulated and over expressed, leading to severe illness, such as sepsis [13]. We could understand that a fulminant acute phase response may account for the clinical and biochemical features of NMS related to other clinical conditions.
The abnormal results of laboratory testing that are characteristic of neuroleptic malignant syndrome are typical changes seen during the acute phase response. These results are consistent with activation of the acute phase response, having a temporal profile of acute phase reactants paralleled with changes in temperature, creatine phosphokinase levels and the clinical course of the syndrome, suggesting that the acute phase response may have been directly involved in the pathophysiology of neuroleptic malignant syndrome in that particular patient [14].
Usually, patients that developed NSM have presented with some risk factors, including pre-existing medical conditions, electrolyte imbalances, dehydration, poorer nutritional status, organic brain syndromes and agitation, all of which are common in the elderly and confer vulnerability to this patient group. Other risk group is patient with mental disorder in a postoperative condition, which can present, initially, agitation, and important symptom for differential diagnosis with hipóxia and hemorrhagic shock. Other mechanisms for the induction, such as autoantibody production, virus–drug interaction, heat stress, muscle breakdown and psychological stress are also involved in the generation of the NMS.
Other reported risk factors including a prior history of NMS, hot weather and exhaustion [15]. High doses, rapid increase in dosage and intramuscular injection of neuroleptic medications have also been implicated [16].
The pathogenesis of the NMS is unclear but appears to be a disorder of central dopaminergic neurotransmission. Levenson [17] and Lazarus et al. [18] have set forth diagnostic criteria, but the one published in 1994 by the American Psychiatric Association [19] is the most widely accepted.
Prager et al. [20] and Lavie et al. [21] reported the difficulty of diagnosing NMS [5], [20], [21]. Symptoms and signs can vary depending on the patient condition and the drug used. Shalev and Munitz [22] have found that the time of onset of symptoms varied from 45 min to 65 days after administration of an antipsychotic (phenothiazine). This significant overlap exists in the early signs and symptoms of NMS and the pathophysiologic manifestations of a burn. Velamoor et al. [23] reviewed case reports previously published and found that about 70% of patients presented with the sequence of mental status changes, muscle rigidity, hyperthermia, and autonomic dysfunction; in more than 80% of the patients that they have reviewed, the initial manifestation was either mental status change or muscular rigidity.
In a primary care perspective of the NMS [24], there is agreement that occurs high temperature (greater than or equal to 40 °C, or 104 °F); extrapyramidal symptoms, particularly lead-pipe rigidity; and autonomic instability (elevated or labile blood pressure, tachycardia, profuse diaphoresis, incontinence, and pallor) are considered cardinal features of NMS. Other findings that may help support the early diagnosis are consciousness altered, tremor, mutism, leukocytosis, and elevated creatine phosphokinase (CPK) levels. It is important that other general medical conditions, as well as psychiatric disorders such as catatonia, must have been excluded prior to making the diagnosis of NMS. The rarity of this entity in the burn unit is reflected by the sparse literature regarding NMS and the burned patient [5].
Cardiorespiratory stability, mechanical ventilation, antiarrhythmic agents, or pacemakers may be required [25]. Use of intravenous fluids for normovolemic state may be necessary. High volume of intravenous fluids with urine alkalinization may help prevent or mitigate renal failure from rhabdomyolysis if CPK is very elevated [26].
Use of cooling blankets for lower fever and more aggressive physical measures may be required: ice packs in the axilla and ice water for gastric lavage. Not well established, the use of acetaminophen or aspirin may have a role in reducing temperature in NMS, but still there is controversy. Clonidine is effective in this setting [27]. Sodium nitroprusside may have advantages by also facilitating cooling through cutaneous vasodilation [28].
Besides cessation of neuroleptic medication, supportive measures in NMS are essential and non controversial [29]. Corrections of the hyperpyrexia and electrolyte abnormalities are necessary and the administration of dantrolene and bromocriptine are the standard treatment for NMS [15]. Nachreiner et al. [5] includes amantadine that is used as an alternative to bromocriptine.
The effectiveness of dantrolene in the treatment of NMS is based on case reports. The maximum recommended intravenous dose is 10 mg/kg given in 2 mg/kg boluses every 10 min. It can be given orally for several more days to prevent relapse. Administration is guided by resolution of symptoms, including metabolic acidosis and hyperkalemia. In higher doses (10 mg/kg) dantrolene can be hepatotoxic, ranging from slightly elevated transaminases to fulminant liver failure. It is recommended that liver function test should be made during the administration of dantrolene [5].
The use of any of these medications is controversial and largely non-supported [30]. A retrospective analysis of published cases indicates that the use of bromocriptine and/or dantrolene appeared to hasten clinical response [31]. While evidence supporting the use of these agents is limited, they are frequently used because of anecdotal evidence of efficacy, lack of other proven treatments, and high morbidity and mortality of the disorder.
Section snippets
Criteria for selection of the articles
Searches were conducted in the PubMed database. Articles published between 1977 and 2014, 37 years, which could be accessed in PubMed and written only in English language were included.
All original articles indexed in the period between January 1, 1977 and April 3rd, 2014 that published use of antipsychotic associated to a trauma patient and NMS were selected. Case reports about antipsychotic use or NMS without associated trauma were excluded, resulting at the end only 16 articles selected.
Discussion
Neuroleptic malignant syndrome is rare and particularly important because of the association with rhabdomyolysis and renal failure in a patient burn or trauma. Besides of the actual relevant contribution for elucidating the pattern of the NMS, there is a lack of consistent studies in the trauma and mainly in the burned patient, that makes the diagnosis difficult though some related cases have ever been described similar clinical and laboratory manifestations that were confirmed by the present
Conflicts of interest
There are no conflicts of interest or the existence of any economic relationship.
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