Keywords
pregnancy, brain tumours, propofol, dexmedetomidine, remifentanil, anaesthetic
pregnancy, brain tumours, propofol, dexmedetomidine, remifentanil, anaesthetic
In response to the reviewers comments we adjusted the numbers of cases in our results and discussion sections to reflect the effect of anesthetics used during craniotomy in the pregnant patient only. We also performed some grammar and spelling changes.
We also corrected the order of references to make sure they are exactly corresponding to the text within the manuscript.
See the authors' detailed response to the review by Michael James Paech
See the authors' detailed response to the review by Carolyn Weiniger
See the authors' detailed response to the review by Hiroyuki Sumikura
Pregnancy may increase the growth of a previously existing intracranial tumour, and can even unmask a previously undiscovered tumour. A previous study that included 8 patients who had been diagnosed antenatally with a malignant brain tumour stated that all had severe neurological manifestations, and six of them had a severe neurological event that lead to premature termination of the pregnancy1. It was suggested that immunological tolerance and steroid mediated growth led to this exacerbation during pregnancy2.
In a population based study; Haas et al. reported that the number of meningiomas, acoustic neuromas, and primary malignant intracranial neoplasms diagnosed during pregnancy was less than expected with the ratio of observed/expected tumours associated with pregnancy to be 0.383.
In 1988, Simon4 postulated a theory to predict the prevalence of brain tumours in pregnant patients by using the intersection of the probability of being pregnant at any given time with the probability of having a brain tumour at a specific age and sex. Based on this theory the author calculated that in the USA there are about 89 pregnant women per year that also have brain tumours.
Brain tumours in pregnant patients impose a unique risk to both the foetus and mother. There are no previous studies that proposed any guidelines for the anaesthetic management of pregnant patients with brain tumours.
The aim of this case series is to characterize the current perioperative management of pregnant patients with brain tumours and to suggest guidelines for the proper anaesthetic management.
Information on pregnant patients diagnosed with brain tumours that underwent CS and/or brain tumour resection from May 2003 to June 2008 was obtained from the Department of General Anaesthesia and the Rose Ella Burkhardt Brain Tumour & Neuro-Oncology Centre (BBTC) IRB-approved databases at the Cleveland Clinic in OH, USA. Patients were managed by the Departments of Neurosurgery, Obstetrics and Gynaecology, Anaesthesiology and BBTC. We used the Anaesthesia Record Keeping System (ARKS) to obtain the electronic record of the anaesthetic management. Additional data from the patients’ electronic and paper charts were used to complete the pre- and post-operative patient information.
Five pregnant patients presented with brain tumours during their pregnancy. An additional two patients had their diagnosis of brain tumours made in the immediate postpartum period. Diagnoses (Table 1) included meningioma (1 patient) and glioma (6 patients). The mean age was 34.5 years (range 29–40 years) and parity was 0 (2 patients), 1 (1 patient), and >2 (4 patients). More than half of the patients (57%) underwent CS with craniotomy performed, on average, 45 days after the CS (range: 2–90 days). Two patients were diagnosed with a brain tumour during pregnancy and had a craniotomy (Table 2). All our patients were managed by general anaesthesia or monitored anaesthesia care (MAC). Inhalational anaesthetic agents (isoflurane and desflurane) were used under 1-minimal alveolar concentration for the maintenance of anaesthesia. Four drugs were used in our patients for both induction and maintenance of anaesthesia; propofol in 2 pregnant patients, remifentanil in 2 pregnant patients and alfentanil in one patient. Foetal heart rate monitoring was applied in one patient receiving MAC for an “awake” craniotomy. Rapid sequence induction was not universally applied. Four cases had general anaesthesia and used rocuronium as a muscle relaxant to facilitate endotracheal intubation. There were no major intraoperative events (Table 1 and Table 3). The neonatal outcomes of the six patients with elective or emergent delivery were six viable infants with normal Apgar scores. Pregnancy was terminated in the 7th patient. There was neither operative mortality nor significant sustained morbidity in this series. One patient suffered a pulmonary embolus in the postoperative period.
Brain tumours tend to increase in size during pregnancy due to several factors such as fluid retention, increased blood volume and hormonal changes and therefore may be diagnosed earlier5. The decision to proceed with neurosurgery during pregnancy depends on the site, size, type of tumour, neurological signs and symptoms, age of the foetus, and the patient’s wishes6,7.
There are no guidelines for the management of intracranial tumours in pregnant women. A possible algorithm to follow is shown in Figure 1 (modified from Tewari et al.1).
Corticosteroids have been recommended as they are safe in pregnancy, promote foetal lung maturity and reduce cerebral oedemas1.
During the first and early second trimesters, if the patient is stable, it is acceptable to permit pregnancy to proceed into the early second trimester and surgery can then be performed at this time. It is also possible to administer radiotherapy, radio-surgery and image guided surgery beyond the first trimester. If the patient is unstable, undergoing an urgent neurosurgery is recommended1.
At the end of the second trimester; in stable patients, proceed with pregnancy with close observation. But if the patient has a worsening neurological status; radiotherapy can be used to delay surgery. If the patient is unstable and shows symptoms of impending herniation, it is recommended to use general anaesthesia to deliver the baby by CS which is followed by surgical decompression1.
At term; in a stable patient, induction of vaginal delivery is permitted8. A shortened second stage can be achieved with epidural anaesthesia9. CS should only be performed for accepted indications as it has been shown that CS does not seem to provide any advantage over vaginal delivery in protecting against increased intracranial pressure. In unstable patients, perform, as above, CS under general anaesthesia, followed by surgical decompression1.
Mannitol and hypocapnia were avoided in our patients to prevent foetal dehydration and cerebral ischemia/hypoxia, respectively.
General anaesthesia can be safe in pregnant patients with intracranial tumours. Tracheal intubation is very important as it allows maternal hyperventilation thereby controlling raised intracranial pressure10. Patients should be pre-medicated with ranitidine 50 mg I.V. to protect the patient against possible vomiting and aspiration.
Propofol was used in 2 pregnant patients without producing any side effects. The main side effect is that it has a relaxing effect on the gravid uterus11. It is still controversial whether its use is safe with newborns. Bacon et al. did not report any adverse effects of propofol in newborns after emergency CS12 while another study reported seizure, ataxia, and hallucinations after prolonged propofol anaesthesia for more than 6 hours13.
Meanwhile, isoflurane is known to produce many adverse effects on the foetus4,5. It was used in one of our pregnant patients but our records did not show any adverse effects. Desflurane was used in one of our patients with no complications. But the neurotoxicity of desflurane and sevoflurane is still a controversial issue16.
Remifentanil was used in 2 pregnant patients without producing any adverse effects; this may be explained by the fact that it has a unique metabolism by plasma and tissue esterases and a context-sensitive half-life of 3 to 4 min, independent of the duration of infusion17. One concern is that the transfer of opioids, such as remifentanil, across the placenta may lead to neonatal depression. However, remifentanil can be metabolized and redistributed to both the mother and the foetus rapidly18. Remifentanil has opioid properties that allow both control of the intraoperative stress response and a more rapid recovery compared to other opioids. Because of its metabolism and short duration of action, remifentanil is therefore considered to be safe and effective for general anaesthesia for emergency CS in patients with neurological risk factors19.
Clinically relevant concentrations of remifentanil induce rapid, persistent increases in NMDA-induced ion currents. Since NMDA-receptor blockade during a critical stage in brain development leads to depression of neuronal activity and as such is known to initiate the apoptotic cell death cascade in immature neurons, we suggest that remifentanil may be safe for the developing brain. In addition, remifentanil is known to offer a neuron-protective effect in cases of opioid induced hyperalgesia or tolerance20. Dexmedetomidine use is recommended in pregnant patients21.
In the following paragraphs we will discuss drugs that were not used in our study but have been investigated before.
There are no human trials examining the effects of nitrous oxide on neuronal structure and neurocognitive performance in young children. Some case studies showed that the exposure of neonates to nitrous oxide in utero during the third trimester or during CS can result in transient neurological sequelae22.
Although sevoflurane is one of the most prevalent volatile anaesthetics, a recent study has suggested that it can cause epileptic seizure activity, neurotoxicity, and both acute and chronic impairment in synaptic plasticity in neonatal rats16.
Oxytocin has been used in patients with intracranial tumours without any adverse effects. Ergotamine can cause hypertensive responses, which may increase the intracranial cranial pressure and can lead to haemorrhage. It should be avoided in pregnant women with brain tumours3.
Dexamethasone has been traditionally used to reduce brain oedema. It may be safe to use it in an acute setting but its chronic use may be harmful to the foetus as it may cause hypoadrenalism. Weighting the risks and benefits for treating seizures with anticonvulsants; it is recommended to use them in this setting to avoid seizures that may lead to maternal and foetal hypoxia and acidosis23.
Several studies investigated the mechanism of anaesthesia-induced neurotoxicity. Previous reports suggested depression of neuronal activity due to anaesthesia induced GABA A receptor activation and NMDA receptor blockade during a critical stage in brain development20. Several adjuvants, such as estradiol, pilocarpine, melatonin and dexmedetomidine, have been identified in animal studies to ameliorate anaesthesia induced neurodegeneration24–26. It is still controversial whether etomidate is neurotoxic or not. There is evidence that the rarely used anaesthetic, xenon, in clinical doses does not have neurodegenerative effects and may be neuroprotective27.
A recent study showed that the administration of lithium significantly increased the activation of a neuroprotective pathway in the hippocampus. Further studies and human trials are necessary to fully investigate the beneficial effects of lithium in the anaesthetic management of pregnant patients with brain tumours28.
Management of brain tumours in pregnant women is mainly reliant on case reports and the doctor’s personal experience. Therefore, close communication between the neurosurgeon, neuroanaesthetist, obstetrician and the patient is crucial. Good knowledge of the variable anesthetic agents and their effects on the fetus is very important in managing those patients.
Alaa A Abd-Elsayed: designed, analyzed, interpreted data and wrote the manuscript. Jose Diaz Gomez: designed, analyzed and interpreted data. Gene H Barnett: designed the study and drafted the article. Andrea Kurz: interpreted data and drafted the article. Maria Inton-Santos: interpreted data and drafted the article. Sabri Barsoum: designed the study and drafted the article. Rafi Avistian: interpreted data and drafted the article. Zeyd Ebrahim: designed the study and drafted the article. Vesna J Todorovic: designed the study and drafted the article. Ehab Farag: substantial contribution to conception and design, acquisition, analysis and interpretation of data. All authors approved the final manuscript for publication.
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Competing Interests: No competing interests were disclosed.
Competing Interests: No competing interests were disclosed.
Competing Interests: No competing interests were disclosed.
Competing Interests: No competing interests were disclosed.
Competing Interests: No competing interests were disclosed.
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