In a review of the safety and risks associated with the use of nitrous oxide labour analgesia (N2O), a weak anaesthetic at high dose as well as an analgesic and anxiolytic at high dose, the researcher not only investigated the effect that it has on the birthing process, the mother, the foetus and the neonate, but also how it affected breastfeeding and maternal-infant bonding.
The review was written by Judith P Rooks and published in The Journal of Midwifery & Women’s Health, a bi-monthly peer reviewed healthcare journal and the official journal of the American College of Nurse-Midwives.
The study was initiated after concerns were raised about apoptotic brain damage suffered young mammals that were exposed to high doses of N2O during late gestation. In addition, the possibility of cardiovascular risks from hyperthomocysteinemia caused by N2O and the hypothesis that children exposed to N2O during birth are more likely to become addicted to amphetamine drugs as adults, were also cause for concern.
N2O belongs to a large category of drugs that decrease the excitability of brain cells. Its analgesic effectiveness is thought to result from increases in the release of endogenous endorphins, dopamine and other natural opioids in the brain as well as neuromodulators in the spinal cord. In addition, it increases the release of prolactin and decreases the release of cortisol, effectively reducing the hormonal response to stress.
One of the main advantages of using N2O /oxygen (O2) labour analgesia is that it enters and is eliminated from the body through the lungs. Less than 1% is metabolised, while the rest is exhaled unchanged. Other advantages include that the patient can control dosage by how they inhale and how long they use it.
The effect of N2O varies from woman to woman. For the majority of women it helps them to relax, gives them a sense of control and reduces their perception of pain, even though they may still be aware that pain is present. Negative effects on consciousness may include detachment, dizziness, euphoria, fatigue, hallucinations, hazy memory of events, headache, nightmares, pleasure, relaxation, sedation and a sense of warmth.
It is strongly recommended that N2O is administered with O2 and that its concentration does not exceed 50%, it is self-administered and that the patient holds the mask or mouthpiece in place without assistance and that the N2O/O2 delivery equipment uses a demand valve to stop the supply when the patient is no longer inhaling. In addition, scavenging equipment has to be used to capture exhaled N2O.
Rooks based her review on the two international reviews of the biologic and toxicological effects of N2O that integrated findings from laboratory, clinical and epidemiological studies and that emphasised the use of N2O for anaesthesia and the effects of high dose as well as a review of the biologic mechanisms involved in the anaesthetic, analgesic and anxiolytic actions of N2O /O2 ,reviews of the safety of 50% N2O /O2 for conscious analgesia administered by professionals primarily in healthcare settings other than labour, a review by Rosen of 50% N2O labour analgesia, an authoritative text on risks related to maternal use of drugs during pregnancy and lactation as well as documents produced by the US National Institute for Occupational Safety and Health and the Occupational Safety and Health Agency.
In addition, Rooks looked at separate literature on the physiology of normal labour, birth, breastfeeding, mother-child bonding, effects on the mother, foetus and neonate as well as the occupational risks for healthcare workers. In terms of the latter, Rooks found that occupational exposure to N2O has been significantly reduced over the past 25 year as a result of scavenging – N2O /O2 equipment also provides constant negative pressure to capture her exhalations and suck them of the room and ultimately out of the hospital – and good ventilation.
Effects ofN2O when delivered in anaesthetic doses
Adverse effects include nausea, vomiting, neuro-apoptosis bone-marrow depression, macrocytic anaemia and neuropsychiatric disorders, caused by the inactivation of cobalamin. The good news is that these effects are reversed with time, except when the dose is so high that it causes cell death, which has been seen in animal models.
Complications can also arise in patients with conditions that reduce cobalamin function such as Crohn or celiac disease, gluten intolerance, long-term recreational abuse of N2O, chronic malnutrition or in those adhering to a struck vegan diet. Surgical patients who received N2O anaesthesia for greater than six hours are also at risk.
Hyperhomocysteinemia and the risk of cardiovascular disease
Chronic hyperhomocysteinemia increases the risk of developing cardiovascular disease. The use of N2O anaesthesia during surgery increases the incidence of postoperative hyperhomocysteinemia as well as subclinical myocardial ischaemia for as long as two days after carotid endarterectomy surgery. This can be prevented if the patient is treated with vitamin B complex before surgery.
Studies comparing the short-term effects of providing anaesthesia with and without N2O for long surgeries and the risk of developing cardiovascular diseases and to determine whether patients, who underwent N2O anaesthesia, stayed in hospital longer than those who received intravenous anaesthesia and breathed 80% O2 during surgery, showed that there was no difference in the median duration of hospitalisation. They also reported a statistically insignificant higher rate of myocardial infarctions and preoperative deaths in the group that breathed 70% N2O during surgery.
Despite the association between N2O anaesthesia doses and hperhomocysteinemia and between hyperhomocysteinemia and cardiovascular risk, Rooks concluded that there is no clear evidence that N2O /O2 increases patients' risk of dying during or after surgery.
Effects ofN2O /O2 used in analgesic doses
In a review conducted by Collado et al which included 140 studies of adverse events associated with approximately 48 000 administrations of 50% N2O/O2, the researchers identified 27 serious adverse events reported by 23 patients. Nine adverse events - two incidents of vomiting and one case each of consciousness disorder, bradycardia, vertigo, headache, sweating and somnolence - had a ‘reasonable’ causal relationship with the N2O/O2 administration. Rooks cautioned that only a few of the studies included in the review adhered to European standards for good clinical research.
Exposure to various drugs that inhibit transmission of excitatory stimuli during synaptogenesis have been shown in animal models to cause damage similar to foetal alcohol syndrome. However, Rook concluded that N2O by itself does not cause apoptosis in neonate rat brains at concentrations less than or equal to 75%.
Neurtotoxic effects are thought to be caused by damage to the myelin sheath that protects neural axons. Both vitamin B12 deficiency and long-term N2O abuse can result in neurotoxic symptoms including parenthesis, peripheral neuropathy, neuropsychiatric problems, irritability, mild memory impairment, dementia, depression and psychosis. Vitamin B12 deficiency can be treated with high doses of B vitamins.
Nausea, vomiting and inner-ear pressure
Nausea and vomiting are the commonest side-effects of N2O /O2 labour analgesia, ranging from 5% to 36%, followed by changes in consciousness. In addition, N2O can cause emesis in part by pressure changes in the middle ear, which are caused by diffusions of N2O if there is an obstruction or compromise in the Eustachian tube.
Upper respiratory infection, allergic rhinitis and severe sinusitis are common in some woman. These conditions should be taken into consideration when the patient ops for the use of N2O during labour. In addition, recent ear surgery should be considered a contraindication.
Hyperventilation and oxygen desaturation
Because the foetus depends on maternal oxygenation, any reduction in O2 in a labouring woman’s blood is concerning. Normal saturation (SPO2) for pregnant women is 98%. All pharmacological methods of labour analgesia can cause O2 desaturation. Two concerns have been raised about SPO2 between contraction during N2O /O2 labour analgesia; namely that many women hyperventilate during contractions, which can reduce the carbon dioxide in their blood flow to below the level needed to stimulate breathing after contractions, and secondly a theoretical concerns that N2O /O2 labour analgesia can cause ‘diffusion hypoxia’ between contractions. Rook concluded that oxygen desaturation should not be a concern for women using N2O /O2 without opioids.
Effects in labour, on the mother, foetus and neonate
Several studies have confirmed the efficacy of N2O /O2 in labour. The reason why N2O /O2 are so effective is because it does not reduce the release or effectiveness of endogenous oxycotin and has no effects on uterine contractions during labour. It has also been shown to shorten the active phases of labour (152 versus 187 minutes) and fewer caesarean sections (11,6% versus 19.3%).
The greatest maternal risk of any inhaled anaesthetic or analgesic is aspiration of stomach contests caused by the loss of the protective laryngeal reflexes during unconsciousness. Loss of consciousness was reported during the early period when N2O /O2 concentrations used during labour ranged between 75% and 100%. Rare instances of unconsciousness have occurred with 50% N2O /O2 if someone other than the patient held the mask.
The use of N2O /O2 has been shown to have no effect on the foetal heart rate. In addition, it does not depress respiration because it is eliminated quickly form the body. Studies have consistently found no negative effects on Agpar or neonatal neurobehavioural scores in neonates exposed to N2O during birth.
Risk of addiction in later years
The Karolinska Institute published a study in 1987 that found that there was a dose-dependent association between amphetamine addiction and intrapartum exposure to N2O. They found that the relative risk of amphetamine addiction did increased with duration of the mothers' intermittent use of 100% N2O during labour, reaching 5.6 for children whose mothers had inhaled high concentrations of N2O during labour for 4.5 hours or more compared to 25 minutes or less. The researchers explained their findings as a possible effect of neurological 'imprinting'. The same results were shown in opioids and opiate addiction.
Rooks recommended that in addition to women who have had recent ear surgery and women who have any condition that puts them at increased risk of vitamin B12 deficiency should not use N2O during labour until their vitamin B12 deficiency levels are within normal range.
She concluded by saying that N2O has many benefits for ameliorating the pain and anxiety of labour, including quick action and quick exit from the body. In addition, it does not cause complications or adverse outcomes for the mother, foetus or neonate. As a result, labouring women who use it do not need routine intravenous access, continuous electronic foetal monitoring or other procedures that are intrusive and restrict the mother’s freedom of movement during labour.
Registered as medicines
Gas giant Afrox provides a full range of pure medical gases in high-pressure gaseous cylinders and in low- and high-pressure liquid cylinders. N2O supplied by Afrox — and indeed all its medical gases — are registered as Schedule 4 medicines.
References available on request.
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Date: 13 June 2013