Dear Dr. Biswas,
In their recent article ‘Anaplastic astrocytoma during pregnancy: the importance of an effective multidisciplinary approach’, Filippi and colleagues described the therapeutic strategy for a pregnant patient whose left parietal glioma was discovered after a new-onset generalized seizure [1]. Following the multidisciplinary conference, they planned to attain a full-term pregnancy with staged tumor resection. First, the mass reduction was performed with neuronavigation and fluorescence-guided surgery using 5-aminolevulinic acid (5-ALA) under general anesthesia. Then awake craniotomy was planned for the residual tumor removal after delivery. Although the authors have provided excellent perioperative care for this complicated case, we have some reservations about the therapeutic strategy for malignant glioma in a pregnant patient.
The guidelines for the diagnosis and treatment of gliomas, released by the European Association for Neuro-Oncology, present the following management options for newly diagnosed malignant glioma: resection or biopsy, followed by radiotherapy or chemotherapy (or combined modality treatment) [2]. In pregnant patients, the neurosurgical intervention for a malignant tumor is recommended regardless of gestational age, although the 32 week gestation point is generally used as the cutoff [3]. The extent of glioma resection is a decisive prognosis factor irrespective of tumor subtype [4]. In view of the absence of information on the long-term effects on newborns of mothers that received anticonvulsants, chemotherapeutics, or radiation during pregnancy [5], the fact that the patient could be safely monitored without the need for adjuvant therapies is commendable [4].
The surgical strategy for eloquent malignant glioma in a pregnant patient offers two options. One is the two-staged strategy, as Filippi and colleagues presented, and the other is a single-stage operation with awake craniotomy in order to achieve maximum tumor resection with minimum postoperative neurological deficits. While awake craniotomy in pregnant patients is still challenging, several reports show that extensive resection with neurological monitoring is the best way to preserve the patient's motor and speech function [6-7]. Compared with the tumor removal under general anesthesia, awake craniotomy has some advantages on fetal-maternal wellbeing. The higher reliability of functional reservation is considered the most significant benefit of awake craniotomy. Especially among pregnant patients, electrophysiological monitoring and functional mapping should be minimized to reduce the risk of seizure occurrence and subsequent fetal hypoxia. As our previous case shows, the patient's subjective movement is a substitute for motor-evoked potential monitoring [7]. Maternal use of 5-ALA can be avoided in cases of awake craniotomy. In the last two decades, 5-ALA-induced fluorescence was introduced as a valuable technique for intraoperative visualization and improved resection of malignant gliomas [8]. However, its use during pregnancy is still prohibited in the European Public Assessment Report released by European Medicines Agency [9]. Fluorescence-guided surgery using 5-ALA is helpful for the identification of residual malignant glioma intraoperatively, but in the case presented by the authors, cortical or subcortical stimulation is truly informative to determine the resectable edge from the eloquent area. Considering the possible adverse reaction of 5-ALA to both the patient and fetus, fluorescence-guided surgery cannot be considered the best approach. The last concern is the detrimental effects of general anesthetics. Propofol, the most common sedative in neuroanesthesia, caused maternal mild metabolic acidosis after prolonged infusion [10]. On the other hand, volatile anesthetics have a significant tocolytic effect. Thus, awake craniotomy can reduce these unfavorable effects of general anesthesia on the patient and the fetus.
Due to the limited evidence on the use of adjuvant therapy during pregnancy, tumors causing neurological symptoms and seizures must be treated to stabilize the maternal condition and enable a safe birth. As far as the extent of tumor resection in malignant glioma is a decisive prognosis factor, the single-stage strategy with awake craniotomy should be considered an alternative. The multidisciplinary discussion should take place within the decision-making process, and careful perioperative preparation is mandatory.

References
1. Filippi V, Leu SM, Marengo L, et al. Anaplastic astrocytoma during pregnancy: the importance of an effective multidisciplinary approach. BMJ Case Rep 2021;14:e242135.
2. Weller M, van den Bent M, Hopkins K, et al. EANO guideline for the diagnosis and treatment of anaplastic gliomas and glioblastoma. Lancet Oncol 2014;15:e395-403.
3. Lynch JC, Gouvêa F, Emmerich JC, et al. Management strategy for brain tumour diagnosed during pregnancy. Br J Neurosurg 2011;25:225-30.
4. Nitta M, Muragaki Y, Maruyama T, et al. Proposed therapeutic strategy for adult low-grade glioma based on aggressive tumor resection. Neurosurg Focus 2015;38:E7.
5. Zwinkels H, Dörr J, Kloet F, et al. Pregnancy in women with gliomas: a case-series and review of the literature. J Neurooncol 2013;115:293-301.
6. Al-Mashani AM, Ali A, Chatterjee N, et al. Awake craniotomy during pregnancy. J Neurosurg Anesthesiol 2018;30:372-3..
7. Kamata K, Fukushima R, Nomura M, et al. A case of left frontal high-grade glioma diagnosed during pregnancy. JA Clin Rep 2017;3:18.
8. Stummer W, Pichlmeier U, Meinel T, et al. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomized controlled multicentre phase Ⅲ trial. Lancet Oncol 2006;7:392-401.
9. European Public Assessment Report (EPAR) GLIOLAN. Available at: https://www.ema.europa.eu/en/documents/overview/gliolan-epar-summary-pub.... Accessed 20 April 2021.
10. Sethuraman M, Neema PK, Rathod RC. Prolonged propofol infusion in pregnant neurosurgical patients. J Neurosurg Anesthesiol 2007;19:67-8.

The authors implicate caffeine as the causative agent of the cardiomyopathy in this case, caffeine being the main active ingredient within energy drinks. They ask that we enquire about energy drinks within our social histories; consumption of caffeinated products indeed not part of a standard cardiovascular history (1).

It is therefore conspicuous that within the article there are no calls to enquire about other, more widely used caffeine containing products, specifically tea and coffee. Dare I say, we would be unlikely to baulk at the idea of a patient drinking three or four coffees in a day. In fact, on the wards we offer patients tea or coffee eight times a day, yet think little of the caffeine burden we are imposing upon them. This almost tacit caffeine consumption is unlikely to make it into the medical notes, yet these patients would potentially be consuming levels of caffeine far in excess of the quantity consumed in this case report.

We seem to apply different value judgements to different drinks, assuming those drinking excess caffeine from expensive coffee machines are doing so knowingly, and as part of a healthy lifestyle. Yet we don’t afford those choosing to consume energy drinks with the same level of ability to make an informed choice. We medicalise the consumption of such drinks, assuming those using them must be doing so for sinister reasons.

We should treat all caffeinated products equally, given there is no pharmacological difference between them. Indeed, the caffeine found in energy drinks is extracted from coffee; a by-product of decaffeinated coffee production.

Further, I feel it unfair to suggest manufactures should provide warnings on cans, given that they already do – displaying both caffeine content, and warnings about its excessive consumption in certain groups. Indeed, these warnings and caffeine contents are absent from the sides of tea and coffee packaging, therein further preventing us from quantifying caffeine consumption.

That said, it is undeniable that the caffeine content of these drinks has increased over time, and it is not an unreasonable assumption that caffeine is to blame for the symptoms described in this case. Twenty years ago, the humble initial offerings of these drinks were a 250ml can with 75mg of caffeine. Today the bar has shifted to 200mg of caffeine in one can, and the market trend of increasing caffeine shows no signs of abating. This could be problematic, and lead to unwitting excess consumption as in this case report.

Direct regulation of these markets is often a wise solution. Rather than posting unheeded warnings of sugar content on the side of cans, the tax on sugar forced the hand of the market to adapt and reduce the sugar content within energy drinks, often to nil, and therein obviating the detrimental effects of sugar outright (2).

The same could be done for caffeine content; a cap of 20mg/100ml, or an overall cap of 100mg in any one drink would seem appropriate, though admittedly little can be done to stop people drinking multiple cans as in this case.

Like them or loathe them, these products do at least appeal to an ideal of activity, which should be celebrated in our overly sedentary society.

(1) Innes, J.A. et al., 2018. Macleod's Clinical Examination, Elsevier, pp.39-74
(2) Pell, D., Mytton, O., Penney, T.L., Briggs, A., Cummins, S., Penn-Jones, C., Rayner, M., Rutter, H., Scarborough, P., Sharp, S.J., Smith, R.D., White, M., Adams, J., 2021. Changes in soft drinks purchased by British households associated with the UK soft drinks industry levy: Controlled interrupted time series analysis. The BMJ 372. https://doi.org/10.1136/bmj.n254

We thank Dr Yap and colleagues for describing clearly the successful management of an unexpectedly challenging airway.1 We agree that the index case highlights the need for vigilance in all patients requiring airway management, particularly where an atypical presentation of a respiratory condition may indicate occult airway pathology.2 However, the case raises a number of important issues for airway assessment, intubation-related laryngeal pathology and the management of ‘can’t intubate, can’t ventilate’ scenarios which warrant further discussion, considered below.

Airway assessment can be encapsulated by the quote, “Hindsight is a wonderful thing but foresight is better, especially when it comes to saving life,” attributed the 19th Century English poet William Blake. Whilst subtle, there were a number of clues in the described case report that could, and perhaps should, have prompted a more thorough evaluation of the airway. It is surprising that the patient did not report their extreme prematurity at birth, or the fact that they spent the first year of their life in hospital. This would have almost certainly have involved prolonged ventilation and sequelae into childhood. Respiratory and airway complications are well recognised in premature neonates and may coexist.3 The authors highlight the Difficult Airway Society’s airway algorithms and the fact that any clinician managing an airway should prepare for failure.4-6 This should involve an examination of the front of the neck, in case an emergency surgical airway is required. This may have revealed the tracheostomy scar, noted during the evolving airway crisis. Although we recognise that these scars often heal very well after childhood tracheostomy and may not always be visible.

Any previous intubation of the trachea is associated with a risk of laryngeal injury and dysfunction occurring even after a short general anaesthetic.7 Clinical symptoms of hoarseness, breathiness (audible breathing), stridor, vocal fatigue or even ‘shortness of breath’ may indicate significant occult laryngeal pathology, including arytenoid fibrosis or dislocation, vocal cord paralysis or (sub)glottic stenosis.8 Even without the full disclosure of the preterm birth and likely prolonged intubation/ventilation, the history of intensive care unit admission in childhood is potentially significant, particularly when combined with the ongoing symptoms.

Lastly, the international language around what constitutes a “can’t intubate, can’t ventilate” scenario and, more importantly, what to do about it is well established. Dr Yap and colleagues describe appropriate initial actions following a failure to intubate the trachea: the patient could be ventilated and therefore oxygenated throughout via the use of a supraglottic airway device. Whilst we commend the authors for highlighting a stepwise approach to managing an evolving airway crisis, two important points need clarification. Repeated laryngoscopy and attempted intubation of the trachea (five in this case) are: increasingly likely to fail; will lead to trauma, bleeding and oedema; and risk provoking catastrophic airway obstruction and subsequent failure of ventilation and oxygenation.9 Furthermore, should a ‘can’t intubate, can’t ventilate’ scenario become apparent, the most appropriate course of action is an immediate cricothyroidotomy, not a tracheostomy which takes significantly longer and requires considerable surgical expertise which may not be immediately available.10 Therefore, we are concerned that the take home message from this report is potentially confusing. The authors rightly point out that different approaches to emergency cricothyroidotomy are debated, but we strongly recommend that the final learning point from their report is that a ‘can’t intubate, can’t ventilate’ scenario should be dealt with immediately, by whoever is managing the airway, by performing emergency scalpel-bougie cricothyroidotomy.10 Waiting for an ENT surgeon, who may not be immediately available, to attend may cause life threatening delay. Reinforcing this message consistently and supporting airway practitioners with appropriate training should reduce the potentially catastrophic outcomes associated with difficult and failed airway management.

 
References

1. Yap T, Quick M, Moore P. Emergency tracheostomy for failed intubation due to glottic stenosis. BMJ Case Rep 2021;14(2) doi: 10.1136/bcr-2020-239806 [published Online First: 2021/02/28]
2. Garini G, Fecci L, Giacosa R, et al. Adult idiopathic subglottic stenosis: a diagnostic and therapeutic challenge. Ann Ital Med Int 2004;19(1):54-7. [published Online First: 2004/06/05]
3. Jones M. Effect of preterm birth on airway function and lung growth. Paediatr Respir Rev 2009;10 Suppl 1:9-11. doi: 10.1016/S1526-0542(09)70005-3 [published Online First: 2009/08/11]
4. Higgs A, Cook TM, McGrath BA. Airway management in the critically ill: the same, but different. British journal of anaesthesia 2016;117 Suppl 1:i5-i9. doi: 10.1093/bja/aew055
5. Higgs A, McGrath BA, Goddard C, et al. Guidelines for the management of tracheal intubation in critically ill adults. British journal of anaesthesia 2018;120(2):323-52. doi: 10.1016/j.bja.2017.10.021
6. Frerk C, Mitchell VS, McNarry AF, et al. Difficult Airway Society 2015 guidelines for management of unanticipated difficult intubation in adults. British journal of anaesthesia 2015;115(6):827-48. doi: 10.1093/bja/aev371
7. Mota L, de Cavalho G, Brito V. Laryngeal Complications by Orotracheal Intubation: Literature Review. International archives of otorhinolaryngology 2012;16(2):236-45. doi: 10.7162/S1809-97772012000200014
8. Ponfick M, Linden R, Nowak D. Dysphagia--a Common, Transient Symptom in Critical Illness Polyneuropathy: A Fiberoptic Endoscopic Evaluation of Swallowing Study. Critical care medicine 2015;43(2):365-72. doi: 10.1097/CCM.0000000000000705
9. Mort TC. Emergency Tracheal Intubation: Complications Associated with Repeated Laryngoscopic Attempts. 2004
10. Pracy JP, Brennan L, Cook TM, et al. Surgical intervention during a Can't intubate Can't Oxygenate (CICO) Event: Emergency Front-of-neck Airway (FONA)? British journal of anaesthesia 2016;117(4):426-28. doi: 10.1093/bja/aew221 [published Online First: 2016/09/21]