Abrupt reduction in dopaminergic transmission in the hypothalamus alters the core temperature set point, leading to impaired thermoregulation in NMS [36]. Blockade of dopamine receptors in the corpus striatum causes muscular rigidity and secondary heat production. While fever is a defining symptom in NMS, many conditions in critically ill patients result in inflammation, tissue injury and a febrile reaction and it may be difficult to determine the etiology of a fever early in the clinical course. Leukocytosis, ranging from 10,000 to 40,000/μL, with or without a “left shift” is a consistent laboratory finding in NMS [37]. Obtaining appropriate cultures should not be avoided although approximately half of febrile patients in the intensive care unit (ICU) will have a non-infectious cause of fever, with most no greater than 38.9 °C (102 °F) [38]. A fever in excess of 38.9 °C (102 °F) is usually of an infectious etiology, though a transfusion reaction or a drug fever may also trigger temperatures exceeding 102 °F [39]. In patients with a temperature greater than 104 °F, however, NMS, SS, MH and SAH should always be considered. Hyperthermia should be aggressively treated with cooling blankets, ice packs and fans. The role of NSAIDs and acetaminophen in toxin-induced hyperthermia is not established but antipyretic agents can be helpful if an infection is a comorbid factor.

A reduced or fluctuating level of consciousness typically precedes systemic signs in patients with NMS [11] but the onset of symptoms may be underappreciated given the psychiatric comorbidity of susceptible patients. Altered mental status is multifactorial and may reflect hypothalamic and spinal dopamine receptor antagonism, hyperthermia effects on the CNS, or direct effects of other drugs [40]. Individuals may appear alert but dazed and unresponsive. Catatonic signs and mutism can be prominent and patients may evolve into profound encephalopathy and eventual coma [41]. Malignant or lethal catatonia, a condition similar to NMS that some argue is on the same spectrum [42], can be distinguished by a several-week prodrome of psychosis, agitation, and catatonic excitement [43, 44]. Hyperactivity and agitation are common to SS and CAS, in contrast to the catatonic stupor more prevalent in NMS [12].

Interference with nigrostriatal dopamine pathways contributes to muscle rigidity and tremor in NMS, classically characterized by “lead pipe rigidity” or stable resistance through all ranges of motion when passively moving the extremities [1, 2, 45, 46]. The motor symptoms of malignant catatonia display more positive phenomena (dystonic posturing and stereotyped repetitive movements) than what is seen in NMS while the presence of myoclonus, ataxia, shivering and hyperreflexia is more indicative of serotonin syndrome [33, 47] (Table 39.1). Patients with anticholinergic syndrome have few muscular abnormalities because skeletal muscle contraction is effected by nicotinic rather than muscarinic transmission. The muscle rigidity seen in malignant hyperthermia, however, is quite similar to NMS and must be distinguished by the clinical setting. Tremor is often associated with NMS, and dystonia, trismus, chorea, opisthotonus, and other dyskinesias are present less commonly [5, 48]. Patients can also have prominent dysarthria, sialorrhea, and dysphagia and prophylactic intubation may be required. Acute respiratory failure was the strongest independent predictor of mortality (p < 0.001) in the NIS database analysis [35]. Creatine kinase concentration may be elevated before the onset of muscle rigidity and higher levels are consistent with a poor prognosis [48–50]. Muscle damage and necrosis from the metabolic inequality between energy consumption and production can progress quickly to rhabdomyolysis, with associated hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia and lactemia. Aggressive fluid resuscitation to maintain adequate urine output is imperative in preventing progression to acute myoglobinuric renal failure, compartment syndrome, cardiac dysrhythmias from electrolyte abnormalities, and disseminated intravascular coagulopathy [51, 52]. Sodium bicarbonate to alkalinize the urine and prevent breakdown of myoglobin into nephrotoxic metabolites is often used though it has not been shown to be superior to saline alone, and bicarbonate may worsen hypocalcemia [51].

Dysautonomia in NMS is likely due to hypothalamic dopamine type-2 (D₂) receptor blockade. Removal of normal dopamine regulation of efferent sympathetic activity leads to autonomic activation while unregulated vasomotor and sudomotor activity causes labile blood pressure and heart rate [53]. Early clues of autonomic instability are urinary incontinence, pallor and profuse diaphoresis, with increased “insensible fluid losses.” Hypotension should be treated with generous isotonic crystalloid administration but vasopressors, antiarrhythmic agents or pacing may be required. Respiratory distress and tachypnea are common and result from hypermetabolism and subsequent metabolic acidosis. Chest wall restriction, autonomic dysfunction with loss of protective airway reflexes and aspiration pneumonia can lead to respiratory failure.

Benzodiazepines are the most widely used pharmacologic adjuncts in management of NMS because of their rapid onset of action and usefulness in reversing catatonic symptoms and agitation. Benzodiazepines facilitate GABA-mediated chloride transport, producing neuronal hyperpolarization which attenuates the sympathetic hyperactivity characterized by NMS [40]. Several clinical reports suggest that lorazepam and other benzodiazepines may reduce recovery time and improve outcome [19, 56, 57] and a few cases found benzodiazepines to be effective when other medications failed [58]. A trial of lorazepam, starting with 1–2 mg parenterally, is a reasonable first-line intervention for acute NMS with difficulty in assessing mental status as the primary disadvantage.

Because of its efficacy in reducing heat production, rigidity and oxygen consumption in anesthetic-induced malignant hyperthermia, dantrolene, a direct-acting skeletal muscle relaxant, has been used in the treatment of NMS. Dantrolene is believed to decrease skeletal muscle contraction by interfering with calcium ion release from the sarcoplasmic reticulum which uncouples the excitation-contraction process. In some meta-analyses, improvement of NMS occurred in approximately 80 % of patients treated with dantrolene monotherapy [59–61]. In contrast, a more recent meta-analysis of 271 published cases found that treatment of NMS with dantrolene as monotherapy was associated with a higher mortality, and complete time to remission was prolonged by combination therapy including dantrolene [54]. Dantrolene can be administered intravenously starting with an initial bolus dose of 1–2.5 mg/kg followed by 1 mg/kg every 6 h up to a maximum dose of 10 mg/kg/day [6, 60–63]. Effects are usually reported within minutes of administration. Due to a risk of hepatoxicity, dantrolene is typically discontinued once symptoms begin to resolve although some recommend continuing for 10 days followed by a slow taper with doses of oral dantrolene that range from 50 to 200 mg/d to minimize relapse [63].