Eur J Anaesthesiol 2014; 31:333–342

CORRESPONDENCE Do not know where to press? Cricoid pressure in the very young Laurin G. Allen, Thomas Engelhardt and Robbie A. Lendrum Correspondence to Laurin G. Allen, Department of Anaesthesia, Aberdeen Royal Infirmary, Foresterhill Road, Aberdeen AB25 2ZN, UK Tel: +44 1224 553142; e-mail: [email protected] Published online 16 October 2013

Editor, We would like to report on an observational study we recently undertook in our tertiary referral paediatric hospital in the North of Scotland, UK. Our aims were to assess the ability of anaesthetic personnel to locate the cricoid cartilage in preschool children and infants. Our local ethics committee (North of Scotland Research Ethics Committee) classified this study as an audit of clinical practice not requiring written patient or parental consent. However, information about the study was given preoperatively and verbal consent obtained. Patients aged 0 to 6 years requiring general anaesthesia for elective procedures were studied. Monitoring and induction of general anaesthesia were left to the discretion of the attending anaesthetist. An experienced anaesthetist or senior anaesthetic assistant was asked to identify the cricoid cartilage and mark its position in the midline with a washable marker pen. A linear ultrasound probe (Sonosite), SonoSite Ltd., London, UK, was used to determine the actual location of the cricoid cartilage, its maximum width and the distance from the middle of the cricoid cartilage to the skin mark in the midline. Data analysis was performed using the Mann–Whitney U-test and Pearson correlation. We collected data from 30 patients with a mean ( SD) age of 25.4 (15.6) months and a mean ( SD) weight of 12.3 (3.9) kg, with a sex ratio of 2 : 1 (male/female). Twenty-one (70%) of the identifications were performed by a senior anaesthetic assistant. The majority of identifications were made on the initial attempt (83%), with only five identifications requiring a second or third attempt. Comparing these identifications with the measurements made by ultrasound, the mean ( SD) width of cricoid cartilage was 2.5 (0.9) mm and the mean distance from the cricoid was 5.8 (2.9) mm for anaesthetists and 4.7 (3.8) mm for anaesthetic assistants (P U 0.22). The mean ( SD) width of the cricoid cartilage and mean measured distance by ultrasound for children aged

12 months or less was 2.5 (0.66) and 4.9 (3.28). For those children over 12 months old, the mean width was 2.6 (0.95) and 5.0 (3.81) (See Table 1). There were no statistically significant differences in the measured distances between the two age groups (P U 0.49). Our study demonstrates that correct identification of the cricoid cartilage in young children is difficult using surface landmarks only. In all but one patient, there was a measurable difference found between where the cricoid was thought to be, and where it was actually visualised using ultrasound. Despite these differences being small and in the majority of cases readily covered by the breadth of the fingertip used to apply cricoid pressure, the results of this study once again raise the question of the value of cricoid pressure in rapid sequence induction in young children. Interestingly, there were no age-dependent differences in these preschool children, with no statistically significant differences between those patients over and under 12 months of age. Our results indicate that the operating department practitioners and nurse anaesthetists were equally successful at identifying the cricoid cartilage as senior anaesthetists. Lack of exposure to performing cricoid pressure does not lead to less skill in identifying the cricoid cartilage correctly. The incorrect application of cricoid pressure has the potential to cause harm, by hindering laryngoscopy and causing difficulties with tracheal intubation. However, imaging the necks of children who are at risk of aspiration prior to general anaesthesia may not always be feasible. The potential aspiration risk in children appears to be very low and occurs despite the recorded application of cricoid pressure.1 Rapid sequence induction of anaesthesia in small children may lead to iatrogenic hypoxia, bradycardia and hypotension.2 Controlled bag-mask ventilation without application of cricoid pressure in children considered at risk of aspiration may be considered as a suitable alternative, to prevent such occurrences. The effectiveness of cricoid pressure during rapid sequence induction in children has long been questioned. However, it does have use as a landmark for emergency airway access. A large retrospective American study1 surveying over 60 000 paediatric patients undergoing general anaesthesia reported a 0.04% incidence of pulmonary aspiration. Seventeen out of the 24 patients who suffered aspiration were emergency cases and all had

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334 Correspondence

Table 1

Demographic description of patient population and results of cricoid cartilage measurements Age (months)

Weight (kg)

Cricoid width (mm)

Distance from mark (mm)

25.4 7.9 34.2

12.3 8.5 14.6

2.5 2.5 2.6

5.0 4.9 5.0

Overall Age 1 year Age >1 year

application of cricoid pressure. In a separate survey of paediatric anaesthetists, only 68% admitted using cricoid pressure when traditionally indicated.2 If indeed the use of cricoid pressure is deemed protective, then the second issue in this population relates to the accuracy of the localisation of the cricoid cartilage. The incorrect application of pressure on the cricoid, or other cartilaginous structures (in error) of the upper airway, could lead to structural damage as well as causing airway obstruction and difficulty at laryngoscopy.3 Accurately locating the cricoid cartilage in small children is difficult. Whether this has clinically significant consequences remains to be elucidated, but we believe that our study adds to the ongoing debate over the value of cricoid pressure in the paediatric population.

Acknowledgements relating to this article Assistance with the study: we would like to thank the theatre staff of the Royal Aberdeen Children’s Hospital for their assistance and cooperation with this study. Financial support and sponsorship: none. Conflicts of interest: none.

References 1 2


Warner MA, Warner ME, Warner DO, et al. Pulmonary aspiration in infants and children. Anesthesiology 1999; 90:66–71. Ahmed Z, Zestos M, Chidiac E, et al. A survey of cricoid pressure use among pediatric anesthesiologists. Pediatric Anesthesia 2004; 19:168–196. Landsman I. Cricoid pressure: indications and complications. Pediatr Anaesth 2004; 14:43–47. DOI:10.1097/EJA.0b013e328365cac0

Intrathecal baclofen toxicity An unusual cause of paediatric postoperative coma and respiratory depression Jason Stroud, Joseph Scattoloni, Melanie Blasingim and Olubukola O. Nafiu From the Section of Pediatric Anesthesiology, Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan, USA Correspondence to Dr Olubukola O. Nafiu, MD, FRCA, Room UH 1H247, 1500 East Medical Centre Drive, University of Michigan Health System, Ann Arbor, MI 48109-0048, USA Tel: +1 734 936 4280; fax: +1 734 936 9091; e-mail: [email protected] Published online 19 February 2014

Editor, Intrathecal baclofen (ITB) is increasingly being used in the management of spasticity and dystonia associated with cerebral palsy because of its high efficacy and few side-effects.1 This approach provides a targeted delivery of baclofen, which allows the achievement of high and consistent cerebrospinal fluid (CSF) baclofen levels with barely detectable plasma baclofen concentrations.2 With the rising prevalence of baclofen pumps in children with cerebral palsy who are undergoing anaesthesia and surgery, it is essential for anaesthesia caregivers to be aware of the possible perioperative complications associated with ITB pumps, as well as the clinical manifestations of baclofen toxicity. We present a case of severe postoperative respiratory depression and coma following ITB pump replacement in a child with spastic cerebral palsy. Institutional review board and parental approval were obtained prior to this report. A 17-year-old boy with 57 kg of weight and with American Society of Anesthesiologists II status and moderately severe spastic quadriplegia (due to cerebral palsy) was scheduled for an ITB pump change. His previous surgical procedures were uneventful. The operation was performed under general anaesthesia and it lasted 2.5 h. About 45 min after admission to the postanaesthesia care unit, the patient remained ‘very sleepy’, with small pupils, hypotension (87/39 mmHg) and significant bradypnoea (6 to 8 breaths min1). He was semi-comatose, with global hypotonia and hyporeflexia. His temperature was normal (36.88C), and heart rate was 54 bpm. He was given two doses of naloxone (0.1 mg intravenously each), with no appreciable response. Arterial blood gas (on supplemental oxygen) revealed mild respiratory acidosis, but was otherwise normal (pH 7.33, PaCO2 ¼ 7.46 kPa,

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pO2 ¼ 75.3 kPa, HCO3 25 mmol l1, Na 136 mmol l1, glucose ¼ 5.94 mmol l1, Ca2þ ¼ 1.23 mmol l1). Given the patient’s severely depressed conscious state and low respiratory rate, he was re-intubated. We considered (and excluded) several differential diagnoses such as opioid overdose, residual curarisation, hypothermia, hypoglycaemia, residual anaesthetic effect and possible intracranial vascular event. We then considered the possibility of inadvertent baclofen toxicity. We therefore administered an intravenous test dose of 1 mg physostigmine (0.02 mg kg1) and atropine 0.2 mg, to which the patient had a prompt, vigorous response. He became rousable, opened his eyes, his muscle tone increased and he began coughing and started to struggle to extubate himself. His heart rate increased to 94 bpm and his blood pressure to 123/56 mmHg. He was extubated, and remained fully conscious and communicative for about 40 min, after which he became increasingly somnolent, unresponsive, hypotensive and bradypnoeic again. We administered another 1 mg dose of physostigmine to which he only had a transient response. At this point, his ITB pump was switched off, he was re-intubated and transferred to the ICU. He remained intubated for about 8 h during which his muscle strength improved and he was again extubated. His condition continued to improve, and his ITB pump was recommenced at a dose 15% below the previous dose. He was discharged on the second postoperative day. This case highlights a potential perioperative complication associated with ITB pump change: inadvertent baclofen toxicity. There are very few reports of baclofen toxicity in the anaesthesia literature,3 making it likely that paediatric anaesthesiologists would have limited experience with recognising the symptoms. Baclofen is a gamma-aminobutyric acid (GABA) analogue that binds predominantly to GABAB receptors in the superficial layers of the spinal cord where it inhibits the release of excitatory neurotransmitters.1 Its clinical effect is muscle relaxation and it is especially effective for the treatment of spasticity associated with upper motor neuron lesions.1,2 ITB infusion has several advantages including drug delivery very close to its target site of action in the spinal cord, which allows for about a 1000-fold reduction in the dose required for therapeutic efficacy for spasticity reduction.1,2 Furthermore, there is very little transfer of baclofen from the CSF into the plasma and plasma baclofen concentrations are often undetectable in children with ITB infusion units.2 This substantially reduces systemic side-effects and therefore makes ITB infusion an increasingly popular therapeutic option for patients with significant spasticity and dystonia. Several complications have been reported in patients with ITB pumps, including device malfunction, catheter malfunction, programming error, and dose


calculation errors leading to inadvertent overdose or underdose.4 The majority of reported overdose states are directly related to refill procedures making it imperative that patients with ITB pumps are closely monitored whenever they undergo procedures that may directly or indirectly affect the ITB unit.5 Our patient’s baclofen toxicity occurred soon after a scheduled pump revision, which is consistent with many other reports. Our patient manifested several features of baclofen toxicity, including depressed sensorium, hypotonia, hyporeflexia, hypotension, bradycardia and bradypnoea.3,5 Unfortunately, many of these signs are seen with other conditions with which anaesthesiologists are more familiar such as opioid overdose, residual curarisation and residual anaesthetic. Management of ITB toxicity is largely supportive.5 After taking steps to maintain the airway, breathing and circulation, the next step is to stop further administration of baclofen by switching off the programmable infusion pump. This requires an ITB device-certified practitioner (usually the surgeon that implanted the device). In circumstances in which an ITB device-trained personnel is unavailable, it is recommended that the pump reservoir be aspirated until it is empty, a manoeuvre that will stall the pump and stop further drug infusion.6 Administration of intravenous or intramuscular physostigmine 0.02 mg kg1 up to a maximum of 2 mg is also recommended. Although not a specific antagonist to baclofen, physostigmine can antagonise many of the systemic side-effects.7 Physostigmine is a reversible anticholinesterase, although its mechanism of action in baclofen overdose remains unclear.7 The main drawback apart from the systemic cholinergic stimulation is its short duration of action. As in our patient, recurrence of sedation and respiratory depression is common following initial response to physostigmine. Finally, removal of a large volume of CSF (about 25 to 30 ml) is recommended.5 This reduces the concentration of baclofen in the CSF and the intrathecal concentration of baclofen decreases in a caudal to rostral direction. In summary, we report a case of postoperative coma and respiratory depression associated with ITB pump change. We suspect that this complication was because of an inadvertent baclofen overdose during the process of changing the ITB pump. We would suggest that patients who recently had baclofen pump manipulation be monitored in the postanaesthesia care unit for an extended period and be admitted to a monitored bed. Paediatric anaesthesiologists need to be aware of the potentially life-threatening complications of ITB therapy.

Acknowledgements relating to this article Assistance with the letter: the authors thank the parents of their patient for giving them permission to report this important adverse event.

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336 Correspondence

Financial support or sponsorship: none. Conflicts of interest: none.

References 1 2


4 5

6 7

Kolaski K, Logan LR. Intrathecal baclofen in cerebral palsy: a decade of treatment outcomes. J Pediatr Rehabil 2008; 1:3–32. Albright AL, Shultz BL. Plasma baclofen levels in children receiving continuous intrathecal baclofen infusion. J Child Neurol 1999; 14:408– 409. Anderson KJ, Farmer JP, Brown K. Reversible coma in children after improper baclofen pump insertion. Paediatr Anaesth 2002; 12:454– 460. Penn RD. Intrathecal baclofen therapy. Op Tech Neurosurg 2004; 7:124– 127. Delhaas EM, Brouwers JR. Intrathecal baclofen overdose: report of 7 events in 5 patients and review of the literature. Int J Clin Pharmacol Ther Toxicol 1991; 29:274–280. Yeh RN, Michele M, Nypaver MM, et al. Baclofen toxicity in an 8-year-old with an intrathecal baclofen pump. J Emerg Med 2004; 26:163–167. Mu¨ller-Schwefe G, Penn RD. Physostigmine in the treatment of intrathecal baclofen overdose. Report of three cases. J Neurosurg 1989; 71:273–275. DOI:10.1097/EJA.0000000000000055

Anaesthesia for orphan disease Management of an infant with Silver–Russell syndrome Roeland H.A. Passier, Edwin Verwijs and Jacques J. Driessen From the Department of Anaesthesia, University Medical Center St Radboud, Nijmegen, the Netherlands Correspondence to Roeland H.A. Passier, MD, Anaesthetist, Department of Anaesthesia, University Medical Center St Radboud, Geert Grooteplein-Zuid 10, Postbus 9101, 6500 HB Nijmegen, The Netherlands Tel: +31 243614406; e-mail: [email protected]

although in some patients, the syndrome seems to have a familial background.2,4 Literature on the anaesthetic implications of SRS is scant with a first case report published almost 20 years ago.8 Only a couple of cases have been published since, which are either dated, dealing with an older child and/or not readily accessible due to being in Japanese.9,10,11 We describe the anaesthetic management of a child with SRS in an attempt to increase awareness about anaesthesia in children with rare diseases and in particular, those with SRS. Consent was obtained from the parents to publish this report. A 3-year-old adopted child, weighing 9 kg, was admitted to our hospital for laparoscopic investigation of a nonscrotal testis and completion of the first stage of a Fowler-Stephens procedure. At the time of adoption about a year earlier, it was communicated that he had hypospadias and cryptorchidism, with an otherwise unremarkable past medical history, without any previous general anaesthetics. On medical examination in The Netherlands, ambiguous genitalia and severe growth retardation were noted. His psychomotor development and intelligence seemed normal for his age. He was diagnosed with SRS after genetic investigation. On preoperative assessment, it was found he had a short stature and craniofacial dysmorphy including a small mouth with limited opening and mandibular hypoplasia, predicting potential difficulty with airway management (Figure 1). There was no history of feeding difficulties or episodes of hypoglycaemia. Fig. 1

Published online 23 November 2013

Editor, Silver–Russell syndrome (SRS) is a heterogenous syndrome characterised by a variable combination of intrauterine growth retardation, postnatal dwarfism with relative macrocephaly and a typical facial appearance including a triangular shaped face, frontal bossing, downturned corners of the mouth with a small opening and micrognathia. Other features include limb and body asymmetry and fifth finger clinodactyly. Feeding difficulties are also seen in the majority of affected children.1–4 The syndrome derives its name from two doctors, Silver and Russell, who independently described children with this combination of clinical features in the 1950s.5,6 The incidence is around 1 per 100 000 live births.7 There are two main genetic subgroups of SRS children with limited phenotypical differences: methylation abnormalities of chromosome 11p15 and maternal uniparental disomy of chromosome 7 (mUPD7). In a significant number of patients, however, the molecular cause is not known.3 Most cases of SRS are sporadic,

The 3-year-old boy with Silver–Russell syndrome as described in this report.

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The child was premedicated on the ward with oral midazolam 4 mg and rectal paracetamol 240 mg. As a difficult airway and endotracheal intubation were anticipated, we planned to perform an inhalational induction of anaesthesia with sevoflurane and to maintain spontaneous respiration until tracheal intubation had been successfully achieved. A GlideScope (Blade 2; Verathon Inc., Bothell, Washington, USA) and paediatric fibreoptic bronchoscope (3.2 mm; Olympus Corporation, Tokyo, Japan) were immediately available in case direct laryngoscopy proved to be unsuccessful in securing the airway. The patient was positioned on a forced-air warming blanket to maintain normothermia and standard monitoring was applied including noninvasive blood pressure, ECG, pulse oximetry and capnograpy. Induction of anaesthesia was accomplished by inhalation of sevoflurane 6 to 8% in 100% oxygen by facemask, after which peripheral intravenous access was secured with a 24-gauge intravenous cannula. Mask ventilation was performed without difficulty by one person, without the need for an oropharyngeal or nasopharyngeal airway. Direct laryngoscopy was performed after intravenous administration of fentanyl titrated to a total of 20 mg and without the use of neuromuscular blocking agents in order to maintain spontaneous ventilation. The patient had a very small oral opening and an anterior larynx and only after significant external laryngeal manipulation and downward pressure was a Cormack and Lehane grade III view obtained. Tracheal intubation was performed using a 4.5 mm internal diameter cuffed endotracheal tube (Mallinckrodt Pharmaceuticals, Dublin, Ireland), which was passed easily on the first attempt. The cuff was left deflated, as there was no clinically significant air leak. We opted not to exchange the endotracheal tube for a size smaller as there was no resistance on passing the tube into the trachea and we wished to avoid multiple intubation attempts. The patient was artificially ventilated and maintenance of anaesthesia was achieved with sevoflurane (end-tidal concentration around 2.5%) in oxygen and air. A further 15 mg of fentanyl was administered intravenously during the case. Further anaesthetic management and surgery proceeded uneventfully. Local infiltration of the incisional wounds with 1.5 ml of bupivacaine 0.25% with adrenaline 1 : 200 000 was performed by the surgeon at the end of the case. The trachea was extubated with the child awake and only after return of airway reflexes. During the surgery, the child received a total of 140 ml of a combined glucose 3.3% and NaCl 0.3% infusion to compensate for fasting and maintenance requirements, followed postoperatively by a 50 ml h1 infusion of lactated Ringer’s solution until sufficient oral intake was restored. Postanaesthesia care was uneventful and the child was discharged to the ward later the same day. The complex genetic characteristics of children with SRS have been extensively reported.2 A cohort of 38 Dutch


children with a diagnosis of SRS proven by clinical and molecular means was recently published. It is noteworthy that a high proportion of these children were conceived as a result of assisted reproductive techniques.1 This child had a confirmed diagnosis of SRS as he was found to have a hypomethylation of the H19-gene on chromosome 11. This is the cause of SRS in the majority of cases. Methylation disorders on chromosome 11p15 contain a cluster of imprinted genes involved in fetal growth. This cluster is organised in two neighbouring imprinted domains, IGF2/H19 and the KCNQ1OT1/ CDKN1C. A less frequent cause of SRS is mUPD7, which is reported to cause a milder phenotype.3 Aberrant genomic imprinting of the 11p15 region is involved in both SRS and Beckwith–Wiedemann syndrome (BWS):2,12 hypomethylation at H19 causes the first, whereas hypermethylation at the same location causes the latter. SRS is characterised by growth retardation, whereas BWS is associated with pre and/or postnatal overgrowth. Anaesthetic considerations for SRS include airway management as a primary challenge: the facial dysmorphy with small mouth opening and mandibular hypoplasia may result in difficult mask ventilation, laryngoscopy and tracheal intubation. In addition, subglottic stenosis may be present. The child in our case had a Cormack and Lehane grade III view of the larynx on direct laryngoscopy. At present, we do not know whether this could worsen with the progression of the syndrome, although it is well recognised that the facial features of SRS tend to become less obvious with age. Children with SRS may also face other anaesthesiarelated problems due to the characteristic clinical features. In contrast to the case we presented, many SRS children suffer from various endocrinopathies, such as hypopituitarism and adrenal insufficiency. Hypoglycaemia is the most common associated problem. It occurs in a large percentage of neonates, but decreases in frequency by the age of 4 years.8,10 Children with SRS are prone to develop spontaneous hypoglycaemia, especially if they are not fed regularly, most likely due to accelerated starvation and/or growth hormone insufficiency.13 When anaesthetising these children, precautions should be taken to guard against hypoglycaemia, even in patients who are over the most susceptible age and who have not had any previous episodes of hypoglycaemia.14 In addition, SRS patients (especially infants) are prone to hypothermia due to the abnormally (relatively) large cranial size and the lack of muscle mass and subcutaneous fat.8,10 They may have feeding difficulties and gastrooesophageal reflux. The latter may cause additional problems in airway management, especially in emergency situations.3,15 Psychomotor retardation is present in around one-third of patients with SRS. Associated congenital anomalies including cleft palate, congenital heart disease, genital anomalies and limb defects are described

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338 Correspondence

in a minority of cases. Finally, SRS patients with mUPD7 abnormality are at an increased risk of developing dystonia and myoclonus.3 The current treatment of SRS consists of recombinant growth hormone administration for which the beneficial effects are dependent upon the early institution of the therapy. This treatment is effective in the short-term, although studies examining the long-term effects are lacking.4 In conclusion, SRS is a clinically recognisable syndrome, which has important implications for safe anaesthesia management, primarily due to possible difficulties in airway management. In addition, care should be taken to ensure glucose homeostasis and proper temperature management. Awareness of possible associated congenital anomalies, such as other endocrinopathies and congenital heart disease, will contribute to optimal anaesthetic care in children with this syndrome.

Acknowledgements relating to this article Assistance with the study: the authors would like to thank Professor Dr H. Brunner for his assistance with the report. Financial support and sponsorship: none. Conflicts of interest: none.

References 1

2 3 4 5



8 9 10 11 12

13 14


Lammers THM, van Haelst MM, Alders M, Cobben JM. The Silver-Russell syndrome in The Netherlands. Het Silver-Russell-syndroom in Nederland. Tijdschrift Kindergeneeskunde 2012; 80:86–91. Eggermann T. Russell-Silver syndrome. Am J Med Genet C Semin Med Genet 2010; 154C:355–364. Wakeling EL. Silver-Russell syndrome. Arch Dis Child 2011; 96:1156– 1161. Binder G, Begemann M, Eggermann T, et al. Silver-Russel syndrome. Best Pract Res Clin Endocrinol 2011; 25:153–160. Silver HK, Kiyasu W, George J, et al. Syndrome of congenital hemihypertrophy, shortness of stature and elevated urinary gonadotropins. Pediatrics 1953; 12:368–376. Russel A. A syndrome of intra-uterine dwarfism recognizable at birth with cranio-facial dysostosis, disproportionately short arms, and other anomalies (5 examples). Proc R Soc Med 1954; 47:1040–1044. Perkins RM, Hoang-Xuan MTA. The Russel-Silver syndrome: a case report and brief review of the literature. Pediatr Dermatol 2002; 19:546– 549. Dinner M, Goldin EZ, Ward R, et al. Russell-Silver syndrome: anesthetic implications. Anesth Analg 1994; 78:1197–1199. Imaizumi H, Namiki A, Kita H, et al. Anesthetic management of a patient with Russell-Silver syndrome. Masui 1986; 35:1569–1573. Scarlett MD, Tha MW. Russell-Silver syndrome: anaesthetic implications and management. West Indian Med J 2006; 55:127–129. Hara H, Matsunaga M. Anesthetic management of a child with RussellSilver syndrome. Masui 2006; 55:904–906. Demars J, Rossignol S, Netchine I, et al. New insights into the pathogenesis of Beckwith-Wiedemann and Silver-Russell syndromes: contribution of small copy number variations to 11p15 imprinting defects. Hum Mutat 2011; 32:1171–1182. Azcona C, Stanhope R. Hypoglycaemia and Russell-Silver syndrome. J Pediatr Endocrinol Metab 2005; 18:663–670. Tomiyama H, Ibuki T, Nakajima Y, et al. Late intraoperative hypoglycemia in a patient with Russell-Silver syndrome. J Clin Anesth 1999; 11:80– 82. Gangadhar P, Walia R, Bhansali A. Peripubertal hypoglycaemia: an unusual cause. J Pediatr Endocrinol Metab 2012; 25:199–201. DOI:10.1097/EJA.0000000000000013

Anaesthesia for orphan disease Haddad syndrome (Ondine–Hirschsprung disease) Johannes Prottengeier, Tino Mu¨nster, Philip Wintermeyer and Joachim Schmidt From the Department of Anaesthesia (JP, TM, JS) and the Department of Paediatrics (PW), Erlangen University Hospital, Erlangen, Germany Correspondence to Johannes Prottengeier, Department of Anaesthesia, Erlangen University Hospital, Krankenhausstrasse 12, 91054 Erlangen, Germany Tel: +49 9131 85 42332; fax: +49 9131 85 36147; e-mail: [email protected] Published online 24 February 2014

Editor, We report our anaesthetic management of a patient with Haddad syndrome, a rare phenotype comprising both congenital central hypoventilation syndrome (CCHS or Ondine’s curse) and Hirschsprung disease (aganglionosis). Written consent for this report was obtained prior to publication. In CCHS, mutations of the PHOX2B gene lead to a loss of function in the respiratory central pattern generator. Voluntary breathing is intact while awake. However, during sleep, there is no central control of ventilation, resulting in alveolar hypoventilation. Patients require lifelong artificial ventilation while asleep, and in severe cases, even during the daytime.1 Most patients are diagnosed at an early age, but there have been reports of clinically attenuated late-onset phenotypes as well.2 Additionally, disorders mimicking Ondine’s curse may be seen in patients with acquired severe brain damage. Diaphragmatic pacemakers may offer an alternative therapy for those requiring chronic ventilator support.3 Hirschsprung disease is a neurocristopathy of the hindgut caused by failed embryological migration of ganglion cells leading to functional bowel stenosis. It may be found in 20% of patients with CCHS.4 Treatment consists of surgical excision of aganglionic segments. Both disorders may be interpreted as extreme variants of a general autonomic nervous system dysfunction (ANSD).1 Accordingly, gastro-oesophageal motility, temperature regulation and glucose homeostasis may be impaired. Cardiac dysfunction can comprise arrhythmias and syncope as well as hypotension/hypertension. Chronic hypoxaemia may lead to pulmonary hypertension and right ventricular failure in CCHS.5 A 17-year-old boy underwent combined oesophagogastroscopy and sigmoidoscopy under general anaesthesia for histopathological diagnosis. For several years he had been complaining of being underweight (50 kg, BMI 18.4 kg m2), abdominal pains and diarrhoea. Extensive aganglionosis had led to a total colectomy. He had been diagnosed with Haddad syndrome as an infant and

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received non-invasive positive pressure ventilation during sleep. At evaluation, the boy presented without any limitations to daily life. Medical history revealed one episode of syncope, and an inconstant pattern of hypotension and hypertension indicating ANSD. Previous anaesthetic procedures had been uneventful except for one anaphylactic reaction to latex as an infant. To avoid central respiratory depressant effects, we prescribed no premedication. For the procedure we established routine monitoring and inserted one peripheral intravenous cannula. Because of the patient’s history of an anaphylactic reaction to latex, he received triple prophylaxis of prednisolone, clemastine and ranitidine. Sedating side-effects of antihistamines are common, but were accepted after weighing up the possible risks. All equipment inside the operating room was latex-free. The patient’s lungs were pre-oxygenated with 80% oxygen for 5 min via a face mask in order to avoid resorption atelectasis but still obtain a high oxygen load. For induction, remifentanil was administered at 0.5 mg kg1 min1 for 4 min. The throat was sprayed with lidocaine 40 mg. Lidocaine 40 mg and etomidate 0.4 mg kg1 were given intravenously and the trachea was intubated orally without any muscle relaxant. Anaesthesia was maintained using desflurane 7.3 to 8.5% and remifentanil 0.3 mg kg1 min1. Monitoring included bispectral index (BIS), which registered a range of 40 to 60 throughout the procedure. We used pressurecontrolled ventilation adjusted towards a normal endtidal carbon dioxide tension around 4.6 kPa. The inspired oxygen concentration was 40 to 50%. During anaesthesia we closely monitored the function of the autonomous nervous system. Measurements of blood glucose and lactate concentrations were performed every 30 min (via venous blood gas analysis) as global metabolic parameters. Body temperature was monitored using a nasal probe. A preheated operating room (278C), warming blanket and fluid warmers prevented cooling. Two episodes of hypotension following repositioning during endoscopy emphasised dysfunctional circulatory control, but were easily controlled by administration of the low-potency sympathomimetic cafedrine 20 mg and theodrenaline 1 mg. An alternative explanation may be hypovolaemia caused by irrigation with polyethylene glycol in preparation for the procedure; a low-serum ionised calcium concentration (1.06 mmol l1) on venous blood gas analysis would support such an explanation. At the end of the procedure, all anaesthetics were discontinued. Owing to the favourable kinetic profiles of remifentanil and desflurane there was rapid recovery of consciousness. Mandatory ventilation was maintained


until tracheal extubation because chemoreceptor changes in pH or carbon dioxide tension cannot trigger breathing in CCHS.1 End-tidal desflurane concentration was less than 0.6% within 2 min and after another 8 min, the patient woke up and immediately breathed spontaneously. Observation in our paediatric ICU was uneventful. For the remainder of the day the patient stayed alert and no hypoventilation was detected. Ventilation during the following night was without incident. A follow-up call 8 weeks after anaesthesia revealed no further problems. Short-acting anaesthetic agents are crucial in patients with CCHS. We decided to use remifentanil as an analgesic because of its reliably short context-sensitive half-line and we chose etomidate as the hypnotic because of its minimal haemodynamic effects, beneficial in a patient with suspected ADSN. Propofol was excluded because of prolonged complete atrioventricular block in a patient with CCHS.6 We also ruled out thiopental because of reports of bradycardia after induction in children.7 We decided not to use muscle relaxants because of their unwanted side-effects; nondepolarising blocking agents may cause respiratory depression through anticholinergic effects in the carotid body8 and succinylcholine is known to trigger bradyarrhythmias through vagolysis. Instead, we induced deep anaesthesia by using high doses of remifentanil and also reduced laryngeal reflexes by applying lidocaine both topically and intravenously. Oral intubation was easy, confirming reports that CCHS patients have no increased risk of a difficult airway.3 For maintenance of anaesthesia in CCHS, the literature provides conflicting recommendations. Some authors disapprove of volatile anaesthetics; they argue that sufficient ventilation is needed to ensure clearance at the end of anaesthesia.3 The pharmacokinetic properties of desflurane, with rapid and reliable washout after discontinuation, seem to make it a favourable choice of anaesthetic.

Acknowledgements relating to this article Assistance with the letter: none. Financial support and sponsorship: none. Conflicts of interest: none.

References 1


Weese-Mayer DE, Marazita ML, Berry-Kravis EM, Patwari PP. Congenital central hypoventilation syndrome. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong CT, Stephens K, editors. GeneReviews. Seattle (WA): University of Washington, Seattle; 1993–2013. NBK1427/. Mahfouz AKM, Rashid M, Khan MS, Reddy P. Late onset central hypoventilation syndrome after exposure to general anesthesia. Can J Anaesth 2011; 58:1105–1109.

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6 7


Niazi AU, Mocon A, Varadi RG, et al. Ondine’s curse: anesthesia for laparoscopic implantation of a diaphragm pacing stimulation system. Can J Anaesth 2011; 58:1034–1038. Ferna´ndez RM, Mathieu Y, Luzo´n-Toro B, et al. Contributions of PHOX2B in the pathogenesis of Hirschsprung disease. PLoS One 2013; 8:e54043. Movahed MR, Jalili M, Kiciman N. Cardiovascular abnormalities and arrhythmias in patients with Ondine’s curse (congenital central hypoventilation) syndrome. Pacing Clin Electrophysiol 2005; 28:1226– 1230. Sochala C, Deenen D, Ville A, Govaerts MJ. Heart block following propofol in a child. Paediatr Anaesth 1999; 9:349–351. Saarnivaara L, Hiller A, Oikkonen M. QT interval, heart rate and arterial pressures using propofol, thiopentone or methohexitone for induction of anaesthesia in children. Acta Anaesthesiol Scand 1993; 37:419–423. Jonsson M, Kim C, Yamamoto Y, et al. Atracurium and vecuronium block nicotine-induced carotid body chemoreceptor responses. Acta Anaesthesiol Scand 2002; 46:488–494. DOI:10.1097/EJA.0000000000000058

Anaesthesia for orphan disease Combined spinal-epidural anaesthesia in a patient with Friedreich’s ataxia Iva´n Huercio, Emilia Guasch, Nicolas Brogly and Fernando Gilsanz From the Hospital Universitario La Paz, Madrid, Spain Correspondence to Ivan Huercio, MD, Department of Anesthesiology and Intensive Care, Hospital Universitario La Paz, P8 de la Castellana, 261, 28043 Madrid, Spain Tel: 0034 653833852; e-mail: [email protected] Published online 21 January 2014

Editor, Friedreich’s ataxia is the most frequently inherited ataxia (1:29 000 cases in a white population). When patients affected by this disorder are scheduled for a surgical procedure, important anaesthetic issues have to be taken into account to optimise perioperative management. We report the case of a 35-year-old woman who was scheduled for elective correction of right cavus foot. Written consent was obtained from the patient to publish her clinical case. Other than the disorders associated with Friedreich’s ataxia diagnosed 13 years earlier, she had no significant medical history. Clinical examination revealed a thoracic scoliosis, pes cavus, ocular ataxia, hypoaesthesia with decreased sensation to vibration more obvious in the lower limbs and cerebellar syndrome (gait ataxia, dysmetria, dysdiadochokinesis, dysarthria and intention tremor). The EMG and somatory-evoked potentials did not show major alterations other than mild signs of denervation. No anomaly was visible on MRI. Genetic studies had identified two different known haplotypes of the Frataxin (FXN) gene associated with Friedreich’s ataxia. At preoperative assessment, the results of routine blood tests were normal. Right bundle branch block was present

on the ECG, but an echocardiogram and cardiac MRI were normal. Pulmonary function tests showed a mild restrictive pattern with no blood gas disturbance or chest radiograph anomalies other than the scoliosis. The intervention (triple arthrodesis with metatarsal osteotomies and Kirschner wire insertions) was performed with a tourniquet under combined spinalepidural (CSE) anaesthesia. With the patient in a sitting position, the epidural space was located using an 18G Tuohy needle at L4 to L5 with a loss of resistance to air technique. Intrathecal hyperbaric bupivacaine 13 mg and fentanyl 10 mg were administered through a 27G Whittacre spinal needle inserted through the Tuohy needle. A 21G multiperforated epidural catheter was then inserted (Perifix set; B-Braun). A sensory level to T8 was reached with no haemodynamic or respiratory disturbances. The intraoperative period, which lasted 90 min, was uneventful, and the patient was haemodynamically stable during the procedure. At the end of surgery, the patient was transferred to the postanaesthesia care unit. After 1 h, the motor block had recovered and the patient was discharged to the ward with a continuous epidural infusion of levobupivacaine 0.125% at 5 ml h1 for the treatment of postoperative pain, which was discontinued on day 3. The patient was discharged from hospital on day 3 with no respiratory or neurological complications. Friedreich’s ataxia is caused by hyperexpansion of trinucleotide GAA in the FXN gene located in chromosome 9, which provokes a deficiency of frataxin, a mitochondrial protein responsible for iron metabolism and oxidative status. This deficiency leads to iron overload and consequent mitochondrial dysfunction,1 which explains the neurological presentations of the disease, cardiomyopathy, alterations of glucose metabolism with hyperglycaemia and the scoliosis typically described in the disease. These patients are considered at high risk for anaesthesia, despite their young age (disease onset usually occurs before 25 years of age, with a median age of death of 35 years and a better prognosis for women). Concerns about the possible risk of worsening of neurological symptoms using central neuraxial blockade were discussed, but the safe use of spinal and epidural anaesthesia has been described in patients with Friedreich’s ataxia, usually for labour analgesia and caesarean section.2 In the present case, a CSE technique was chosen to allow the administration of top-up doses and to avoid general anaesthesia in case of a prolonged operation, and to provide postoperative analgesia. The duration of surgery was expected to be more than 90 min, but the patient did not present with cardiomyopathy or severe neuromuscular dysfunction, and a relatively large dose of bupivacaine was used to avoid the need for an intraoperative epidural top-up dose. The

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CSE technique can also be used to administer low doses of intrathecal local anaesthetic, with a lower incidence of sympathetic blockade, compensating for the shorter duration of the blockade by the administration of titrated top-up epidural doses if required. Despite the unpredictable risk of autonomic dysfunction in this case, we adopted a strategy with a higher dose of local anaesthetic because she did not present with any previous severe haemodynamic alterations.3 She required no analgesia other than the epidural infusion in the postoperative period and was haemodynamically stable throughout her hospital stay.

Conflict of interest: none.

General anaesthesia can jeopardise the outcome of patients with Friedreich’s ataxia due to intraoperative and postoperative respiratory disorders caused by thoracic kyphoscoliosis, associated with restrictive respiratory function. In addition, the use of nondepolarising muscle relaxants has been reported to have an unpredictable response, with cases of prolonged block leading to difficult weaning from the ventilator, longer recovery and a prolonged hospital stay.4 Reports of hyperkalaemia following administration of succinylcholine in patients with denervated muscle suggest that it would be preferable to avoid its use. If muscle relaxation is essential, a nondepolarising muscle relaxant can be used with care, with monitoring of the neuromuscular block.5


The mitochondrial dysfunction suggests that propofolbased total intravenous anaesthesia (TIVA) should not be used in these patients because of its depressant effects on mitochondrial metabolism, and its possible implication in propofol-infusion syndrome. These concerns make the use of regional anaesthesia preferable if general anaesthesia can be avoided.6 Glucose-containing solution with electrolytes should be used to ensure that the mitochondria receive enough glucose to fuel the respiratory chain without relying on fatty acid oxidation; the blood glucose concentration should thus be monitored to avoid hyperglycaemia due to the metabolic disturbance and impaired glucose metabolism associated with Friedreich’s syndrome. In conclusion, although CSE anaesthesia resulted in a satisfactory outcome, avoiding the complications of general anaesthesia, the use of a peripheral block would have been a very good alternative option in this case.7 Ultrasound-guided injection of local anaesthetic with insertion of a perineural catheter would have avoided the risks of a central block, but muscle degeneration can modify echogenicity and make the identification of neural structures more difficult, as has been found in Duchenne’s muscular dystrophy.

Acknowledgements relating to this article Assistance with the study: none. Financial support and sponsorship: none.


References 1 2

3 4 5 6

Delatycki MB, Corben LA. Clinical features of Friedreich ataxia. J Child Neurol 2012; 27:1133–1137. Wyatt S, Brighouse D. Anaesthetic management of vaginal delivery in a woman with Friedreich’s ataxia complicated by cardiomyopathy and scoliosis. Int J Obstet Anesth 1998; 7:185–188. Rawal N, Holmstrom B, Crowhurst JA, Van Zundert A. The combined spinalepidural technique. Anesthesiol Clin North America 2000; 18:267–295. Pancaro C, Renz D. Anesthetic management in Friedreich’s ataxia. Paediatr Anaesth 2005; 15:433–434. Levent K, Yavuz G, Kamil T. Anaesthesia for Friedreich’s ataxia. Case report. Minerva Anestesiol 2000; 66:657–660. Rivera-Cruz B. Mitochondrial diseases and anesthesia: a literature review of current opinions. AANA J 2013; 81:237–243. Barbary JB, Reme´rand F, Brilhault J, et al. Ultrasound-guided nerve blocks in the Charcot-Marie-Tooth disease and Friedreich’s ataxia. Br J Anaesth 2012; 108:1042–1043. DOI:10.1097/EJA.0000000000000041

Duchenne muscular dystrophy and malignant hyperthermia A genetic study of the ryanodine receptor in 47 patients Doris Rohde, Hubert J. Schmitt, Andreas Winterpacht and Tino Mu¨nster From the Department of Anesthesiology (DR, HJS, TM), and Department of Human Genetics (AW), University Hospital Erlangen, Erlangen, Germany Correspondence to Dr Tino Muenster, Department of Anesthesiology, University Hospital Erlangen, Krankenhausstrasse 12, 91054 Erlangen, Germany Tel: +49 9131 853 3680; fax: +49 9131 853 6147; e-mail: [email protected] Published online 19 February 2014

Editor, Duchenne muscular dystrophy (DMD) belongs to the heterogeneous group of progressive muscular diseases that vary in clinical manifestation and inheritance. DMD is characterised by early onset in childhood with rapid progression of muscular weakness leading to loss of walking ability in adolescence. Progressive respiratory failure and cardiac muscle involvement finally lead to death by the third decade of life. DMD is caused by a recessive mutation in the DMD gene located on locus Xp21 leading to complete loss of the muscle protein dystrophin.1 Due to X-chromosomal recessive inheritance, male patients are predominately affected by DMD with an incidence of approximately one in 3500 male births. Patients affected by DMD are susceptible to perioperative complications when undergoing general anaesthesia. A variety of critical events such as hyperkalaemia, hyperthermia, tachycardia, rhabdomyolysis and cardiac arrest have been reported previously in patients exposed to inhalational anaesthetic agents or depolarising muscle relaxants.2 In the past, these complications have been

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342 Correspondence

interpreted by some as indicators of malignant hyperthermia.3 In this study, we sequenced the ryanodine receptor 1 (RYR1) gene in 47 patients with DMD searching for malignant hyperthermia causative mutations in the skeletal muscle RYR1 gene. After approval of the local ethics committee (Ethical Committee No. 3636, Ethical Committee of Erlangen University Hospital, Erlangen, Germany, Chairperson Prof. Dr Peter Betz), and obtaining the patients’ informed consent, a sample of whole blood was taken. DNA was extracted from peripheral blood lymphocytes, amplified via PCR assay and sequenced in search of the most common malignant hyperthermia causative mutations in the RYR1 gene. In total, 28 of the most common causative mutations for malignant hyperthermia, as published by the European Malignant Hyperthermia Group,4 were analysed in 16 different exons of the RYR1 gene. We analysed all published mutations except the mutations located on exon 44, wherein we experienced technical difficulties and were not able to amplify the DNA to a level matching our quality standards. We did not find any tested malignant hyperthermia causative mutation in the RYR1 gene. Although the sample is small and a risk of malignant hyperthermia cannot be completely excluded by genetic testing,5 this finding supports the hypothesis that the perioperative metabolic complications in patients with DMD are probably not linked to the genetic disease malignant hyperthermia. From the genetic point of view, a link between the autosomal dominant inherited disease malignant hyperthermia and the recessive X-linked DMD is statistically quite unlikely. Despite the absence of changes in the RYR1 gene, studies in the mdx mouse (which carries a null mutation of the dystrophin gene and is used as a model of muscular dystrophy) indicate that the function of the ryanodine receptor may be altered indirectly as a result of abnormal calcium homeostasis caused by defective or absent dystrophin.6 Metabolic reactions could also be attributed to an abnormal fragility of the cell membrane, which is caused by the complete loss of the cytoskeletal protein dystrophin in skeletal muscle. Although clinical reports state that malignant hyperthermia like phenomena such as rhabdomyolysis, hyperkalaemia and hyperthermia in patients with DMD

occur in association with malignant hyperthermia triggering agents, the exact mechanism explaining the pathophysiology is still not clear. Most reports present cases during childhood at ages between 2 and 10 years. This may reflect the fact that with ongoing disease, muscle is replaced by fat and fibrosis.1 Another explanation may be that in older patients, the diagnosis of DMD is mostly known (the median age of diagnosis is 5 years)7 and inhalational anaesthetic agents or depolarising muscle relaxants have, therefore, not been used. Inhalational anaesthetics and depolarising muscle relaxants however, may trigger a variety of metabolic reactions through an interaction with, and disruption of, the defective cell membrane in dystrophin-deficient muscle cells. These metabolic reactions are triggered by the same agents triggering malignant hyperthermia, but via a different pathophysiology. Therefore, patients with DMD should be monitored carefully when undergoing general anaesthesia and the well known triggering substances should not be administered.

Acknowledgements relating to this article Assistance with the study: we are grateful to Dr Stephanie Meißner who worked on this project until she died in November 2010. Financial support and sponsorship: this work was supported by a research grant from the ‘Deutsche Gesellschaft fu¨r Muskelkranke, e.V’. Conflicts of interest: none.

References 1

2 3 4




Blake DJ, Weir A, Newey SE, Davies KE. Function and genetics of dystrophin and dystrophin-related proteins in muscle. Physiol Rev 2002; 82:291–329. Hayes J, Veyckemans F, Bissonnette B. Duchenne muscular dystrophy: an old anesthesia problem revisited. Paediatr Anaesth 2008; 18:100–106. Brownell AK. Malignant hyperthermia: relationship to other diseases. Br J Anaesth 1988; 60:303–308. European Malignant Hyperthermia Group. Causative mutations for malignant hyperthermia in ryanodine receptor RYR1. mutations-in-ryr1 [Accessed 10 January 2014]. Urwyler A, Deufel T, McCarthy T, West S. Guidelines for molecular genetic detection of susceptibility to malignant hyperthermia. Br J Anaesth 2001; 86:283–287. Bellinger AM, Reiken S, Carlson C, et al. Hypernitrosylated ryanodine receptor calcium release channels are leaky in dystrophic muscle. Nat Med 2009; 15:325–330. Muenster T, Mueller C, Forst J, et al. Anaesthetic management in patients with Duchenne muscular dystrophy undergoing orthopaedic surgery: a review of 232 cases. Eur J Anaesthesiol 2012; 29:489–494.


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Anaesthesia for orphan disease: Haddad syndrome (Ondine-Hirschsprung disease).

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