A total of 179 patients underwent 290 anaesthetics. Eight of the reports present the anaesthetic experience of only a single patient, but six of these eight do report multiple episodes of anaesthetic care in the same patient [9-15]. Intraoperative complications were primarily cardiovascular with haemodynamic variability including episodes of hypotension, hypertension, bradycardia and dysrhythmias [6,7,9-13,16-19], complete heart block on one occasion  and three occurrences of cardiac arrest that were successfully treated [7,13]. Intraoperative oxyhaemoglobin desaturation was also reported on occasion . Postoperative complications included primarily cyclic vomiting and pulmonary complications such as pneumonia, atelectasis, excessive secretions and respiratory arrest requiring reintubation on two occasions [6,7,9,12,16,19-21]. Haemodynamic lability was reported in the postoperative period [6,7,9,12,16,19-21], but less frequently than in the intraoperative period [6,7,9-13,16-19]. One patient experienced a postoperative seizure  and one patient intraoperative confusion .
Perioperative management of these patients evolved with time, reportedly in an effort to mitigate these frequent complications. Early management strategies consisted primarily of premedication followed by various general anaesthetic techniques that consisted of nitrous oxide alone, nitrous oxide supplemented with various anaesthetic agents or anaesthetic agents alone [7,9-11,16]. In early reports, now obsolete anaesthetics such as tribromoethanol and the volatile agents ether, methoxyflurane and cyclopropane were used [7,9,16]. The two cardiac arrests reported by Kritchman and colleagues , developed during anaesthetics maintained by nitrous oxide, supplemented by thiopental sodium in one case and by tribromoethanol in the other case. The cardiac arrest reported by Kaufman and colleagues , was associated with the use of an unspecified volatile anaesthetic. McCaughey and colleagues  demonstrated that administration of methoxyflurane, ether or halothane resulted in hypotension and bradycardia, and haemodynamics were more stable with nitrous oxide alone. Postoperative care was not reported in these early series.
Beilin and colleagues  reported aggressive preoperative management including intravenous (i.v.) hydration with fresh frozen plasma; pulmonary optimization with chest physiotherapy, deep suctioning, antibiotics and tracheostomy in one patient; and administration of cimetidine. Anaesthesia was induced with a benzodiazepine and fentanyl and maintained with nitrous oxide with fentanyl supplementation and intraoperative haemodynamic perturbations were less frequent and milder than in the previous series . Postoperative care consisted of ventilation for several hours and there were no reported postoperative pulmonary complications . Axelrod and colleagues  reported preoperative care that consisted of i.v. hydration, anxiolysis and cimetidine. Initially, patients' tracheas were extubated in the recovery room and post-laparotomy atelectasis was reported as often as 57% . In the second part of their series, patients remained intubated for as long as 72 h after the procedure, received aggressive chest physiotherapy and broad spectrum antibiotics, and post-laparotomy atelectasis complicated only 12% of cases . However, the criteria used to make the diagnosis of atelectasis in the Axelrod series was not offered, introducing a degree of ambiguity. Dell'oste and colleagues  reported good outcomes with a ketamine anaesthetic technique. Challands and colleagues  reported reduced postoperative complications with placement of an epidural catheter for postoperative analgesia in patients undergoing Nissen fundoplications. Leiberman and colleagues  reported a successful caesarean section performed with only local infiltration of 1% lidocaine. Most recently, Wengrower and colleagues  reported successful management of endoscopic procedures under heavy sedation with i.v. midazolam and propofol. Patients were reported to respond normally to both depolarizing and non-depolarizing muscle relaxants [6,10,16-19,22]. Besides cimetidine used to neutralize gastric secretions and chlorpromazine used as a sedative, prophylactic anti-emetics were not reportedly administered.
Cardiovascular and haemodynamic effects
Patients with FD suffer derangements of several organ systems that present challenges to the anaesthesiologist. Haemodynamic instability is one of the hallmarks of the disorder. Orthostatic hypotension without compensatory tachycardia [24,25] is common. There is a congenital reduction in the number of peripheral sympathetic neurons in the sympathetic ganglia but further degeneration continues with age [26,27]. There is a lack of sympathetic innervation of blood vessels . The parasympathetic nervous system and the baroreflex are dysfunctional and this may explain the abnormal cardiac response to changes in blood pressure (BP) [25,29]. Patients are often chronically dehydrated with reduced intravascular volume which contributes to haemodynamic instability. Catecholamine metabolism is abnormal in FD . Plasma levels of the enzyme that converts dopamine to norepinephrine, dopamine β-hydroxylase, is reduced in these patients . Orthostatic hypotension can be particularly problematic, and patients are encouraged to maintain adequate hydration, a high salt diet and may be medicated with mineralocorticoids, such as fludrocortisone and midodrine . Patients experience paroxysmal dysautonomic crises, often triggered by emotional upset, characterized by vomiting, rash, sweating as well as hypertension . It has been hypothesized that the observed hypertension is secondary to an increased sensitivity of the vasculature to circulating catecholamines released during a crisis. Exaggerated response by skin vessels in patients with FD to norepinephrine has been observed . These patients also have a greater increase in BP in response to systemic administration of norepinephrine compared to healthy controls . General anaesthetics with volatile agents were noted to precipitate haemodynamic instability [9,12] and may be associated with cardiac arrest . Isoflurane was reported to be associated with haemodynamic instability . Efforts to supplement volatile anaesthetics with i.v. fentanyl or regional anaesthesia [6,18,19] or with i.v. anaesthetic techniques [22,23] seem to reduce these negative effects. It is difficult to elucidate retrospectively the primary role of inhalational anaesthetics such as ether, methoxyflurane etc., in the pathogenesis of some of the problems described with these patients. More specifically, at that time, four to five decades ago, lack of both contemporary monitoring and/or today's standards of airway management could had been a contributing factor. Several decades ago anaesthetic overdose and problems with ventilation were frequent causes of anaesthesia attributed perioperative morbidity and mortality in the general surgical population . Assessment of effects of an easily titratable volatile agent such as sevoflurane or desflurane has not been reported to date in dysautonomic patients.
State of hydration
Patients with FD may suffer from chronic dehydration secondary to dysphagia . Intraoperative hypotension in these patients was attributed to inadequate hydration or blood loss and as all patients favorably responded to infusion of blood or crystalloid and reduction of inhaled anaesthetic concentrations . In several reports, preoperative hydration was useful to optimize haemodynamics [6,18,20-23]. Some authors conducted preoperative hydration with fresh frozen plasma, but they did not provide rationale or evidence that plasma is superior over other safer alternative fluids such as crystalloids and colloids [18,20].
Pulmonary derangements are common secondary to frequent aspiration that predispose patients to pneumonia and bronchiectasis . The kyphosis frequently encountered in these patients can cause restrictive lung disease . Hypotonia  can diminish postoperative pulmonary cough strength. Furthermore, FD patients demonstrate an abnormal response to moderate hypoxia with development of hypoventilation, hypotension and bradycardia . Aggressive preoperative optimization of the pulmonary status is prudent if the patient shows signs of pulmonary congestion . Improved outcome with prolonged tracheal intubation following laparotomy has been demonstrated , but pulmonary complications were still described . Minimally invasive techniques such as laparoscopic or endoscopic surgery are associated with fewer postoperative pulmonary complications [21,23]. Postoperative epidural analgesia after open laparotomy was also shown to be beneficial .
Gastrointestinal manifestations of the syndrome include abnormal motility of the eosophagus resulting in gastroeosophageal reflux . Patients also suffer dysautonomic crises characterized by paroxysms of vomiting, hypertension, tachycardia and personality changes . Functional neuroimaging of FD patients revealed that dysautonomic crises are associated with abnormal cerebral perfusion in the temporal and frontal lobes, similar to abnormalities seen in patients with seizure activity . The observation that the administration of benzodiazepines is effective in treating dysautonomic crises further supports the hypothesis that these episodes arise from cerebral dysfunction. Clonidine has also been used in conjunction with benzodiazepines to control associated hypertension during crises. These manifestations may result in aspiration pneumonia, malnutrition, chronic dehydration and electrolyte abnormalities. Patients may be on proton pump inhibitors or H2-antagonists as management of gastroeosophageal reflux. Fundoplication has been demonstrated to mitigate many of these symptoms . Postoperative vomiting was frequently reported and treated with diazepam , promethazin  and dimenhydrinate . The effects of potent 5-HT3 antagonists on postoperative nausea and vomiting in FD have not been reported. Rapid sequence induction with application of cricoid pressure was recommended to reduce the risk of aspiration with endotracheal intubation . However, others did not perform rapid sequence induction , or secure the trachea [22,23] and did not encounter complications from pulmonary aspiration.
Neurologic and pain effects
Mental retardation can be present in patients with FD. Emotional upset can trigger a dysautonomic crisis characterized by hypertension, erythematous macular skin rash, excessive sweating and intractable vomiting, making preoperative anxiolysis an important priority. Attention must also be paid to protecting the eyes of FD patients as they suffer from lacrimal secretory disorders (alacrima) and corneal insensitivity . However, corneal abrasions were not reported in the reviewed cases. Hyposensitivity to pain is a feature of FD; however, opiate analgesics administration was reported in most reports, and regional anaesthetic techniques were associated with favorable outcomes . This is in contrast to the anaesthetic management of patients with other HSAN disorders who frequently do not require any perioperative analgesics and typically tolerate general anaesthetics without major complications . As with all HSAN disorders, temperature dysregulation can manifest in FD . Postoperative fever was reported, but it was unclear if this was secondary to more common causes of postoperative fevers such as infection or atelectasis, or due to primary temperature dysregulation. Of note, there is no association between malignant hyperthermia and FD, as the genetic mechanisms of precipitating hyperpyrexia in malignant hyperpyrexia and FD are fundamentally different.
In conclusion, FD has profound implications for general anaesthesia. While these patients were reported to have a relatively high rate of various perioperative complications, these reports date to the time of obsolete inhalational anaesthetics. The safety of newer volatile anaesthetic agents, such as sevoflurane and desflurane, has not been assessed in these patients. Use of minimally invasive surgical techniques, regional anaesthesia, and i.v. techniques appears to contribute to reduction of the complication rate. Correction of chronic dehydration with preoperative hydration seems to reduce intra-operative haemodynamic instability. Preoperative optimization of pulmonary status by treating underlying infections and aggressive respiratory therapy is also prudent. Aggressive postoperative pulmonary management can further decrease respiratory complications. I.v. fluid boluses often correct hypotension and vasopressors should be used with caution as patients may be hypersensitive to these agents. Vomiting often responds to benzodiazepines. The perioperative management of patients with FD requires full understanding of its pathophysiology in order to anticipate and prevent possible complications.
This work was entirely supported by the Department of Anesthesiology, Mayo Clinic, Rochester, MN, USA.
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Keywords:© 2007 European Society of Anaesthesiology
DYSAUTONOMIA FAMILIAL; HUMAN BEINGS; SURGICAL PROCEDURES; OPERATIVE; ANAESTHESIA GENERAL; SYSTEMATIC REVIEW; INTRAOPERATIVE COMPLICATIONS