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Analgesia in labour: inhalational and parenteral
Obstetrics
Analgesia in labour: inhalational and parenteral
Inhalational analgesia Ether, chloroform, trichloroethylene and methoxyflurane have been used for labour pain in obstetrics. They all had drawbacks, including accumulation, maternal sedation and neonatal depression. More recent inhalational anaesthetic agents with low blood–gas partition coefficients have demonstrated increased analgesic efficacy for labour superior to Entonox, but with increased sedation. The main advantage of inhalational analgesia over systemic opioids is the reversibility of analgesia and sedation between contractions and the minimal products of metabolism affecting the fetus and neonate. Inhalational analgesia can also be self-administered and this forms a safety feedback loop, which parenteral analgesics lack.
Michael Wee
Abstract Inhalational analgesia and parenteral opioids are the most widely used analgesics for labour pain because of their availability, simplicity of administration, and cost. However, their analgesic efficacy is limited compared with regional analgesia. Nitrous oxide in oxygen (Entonox) provides moderate pain relief and is safe for use in labour. Low-dose isoflurane (e.g. 0.25%) with Entonox gives superior pain relief compared with Entonox alone. The more recently introduced inhalational agent, sevoflurane, at a concentration of 0.8% also seems to provide superior pain relief compared with Entonox. Sedation scores tend to be increased with inhalational analgesia. Pethidine is the most widely used opioid for labour despite its side effects and lack of analgesia. Diamorphine is being increasingly used in the UK. There is no good evidence to distinguish analgesic efficacy amongst the standard parenteral opioids and opioid partial agonists and antagonists. Fentanyl patient-controlled analgesia (PCA), with a bolus dose of 20 μg and lockout of 5 minutes, seems to be efficacious but accumulates over time. Close maternal, fetal and neonatal monitoring is required. Parenteral remifentanil PCA, at a dose of 0.25–0.5μg/kg with a lockout time of 1–2 minutes, has a rapid onset and offset without accumulative effects, which makes it ideal for use in labour with improved analgesic efficacy. However, more sophisticated modes of drug delivery and careful titration and monitoring of the parturient are required when sevoflurane and remifentanil are used.
Entonox Entonox (50% nitrous oxide, 50% oxygen) is the most widely available inhalational analgesic in the UK and is used by 60% of parturients. It has a long safety record as a self-administered inhalational analgesic for labour. With its low blood–gas partition coefficient (0.47) it equilibrates rapidly with arterial concentration. To achieve near maximum effect, about 10 breaths must be timed to coincide with peak contraction. Nitrous oxide may cause drowsiness and light-headedness as well as nausea. A systematic review1 of eleven randomized controlled trials of nitrous oxide use for labour analgesia concluded that while nitrous oxide is not a potent analgesic, it provides effective analgesia and is safe for labouring women and their babies. Isoflurane and desflurane When isoflurane 0.20–0.25% (blood–gas partition coefficient 1.4) is added to Entonox to improve its analgesic efficacy, pain relief scores and patient satisfaction are superior to Entonox alone. Desflurane has a low blood–gas partition coefficient (0.42) allowing rapid onset and offset of action. However, a significant proportion of women (23%) who received desflurane reported amnesia during use.
Keywords diamorphine; Entonox; inhalational analgesia; parenteral analgesia; PCA; pethidine; remifentanil; sevoflurane
Sevoflurane An open-labelled escalating dose study2 in 22 parturients concluded that the optimal sevoflurane inspired concentration for labour analgesia with acceptable sedation is 0.8%, resulting in significant pain relief. The blood–gas partition coefficient of sevoflurane is 0.69. A follow-up open-labelled sequential crossover study3 by the same research team confirmed that 0.8% sevoflurane gave significantly better pain relief scores compared with Entonox, but there was more sedation in women who used sevoflurane. Most women in these studies preferred sevoflurane to Entonox.
Inhalational and parenteral medications are the most commonly used form of analgesia in labour, despite being less efficacious than regional analgesia. Inhalational and parenteral analgesics are popular because they are readily available, simple to administer and can be used earlier in labour than regional analgesia, which may be contraindicated or not available. In most cases, inhalational and parenteral analgesics have the added advantage of not requiring anaesthetic input.
Parenteral opioids Pethidine (Meperidine or Demerol ) Pethidine is a synthetic opioid. It is a weakly basic phenyl piperidine derivative, related to fentanyl and sufentanil. Pethidine was made legally available to midwives for independent use in the UK in 1950. It remains the most widely available, used and investigated opioid in labour worldwide. The dose of pethidine commonly used by midwives is 1 mg/kg (up to 150 mg intramuscularly). The intramuscular route is not ideal because absorption may be variable. The UK National Birthday Trust
Michael Wee, FRCA, is Lead Consultant Anaesthetist in Obstetric Anaesthesia at Poole Hospital NHS Trust, Poole, Dorset. He qualified from Dundee University and trained in anaesthesia in Dundee, Copenhagen, Bristol and the South West of England. His interests include patient safety, obstetric anaesthesia, audit, research and information.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 8:7
276
Crown Copyright © 2007 Published by Elsevier Ltd. All rights reserved.
Obstetrics
(NBT) survey reported that only 16% of women who received pethidine rated it as ‘helpful’ and 25% rated it as ‘unhelpful’. Midwives rated pethidine much higher than parturients and may have confused sedation with analgesia.4
Morphine and diamorphine The analgesic efficacy of morphine for early labour pain has been questioned. High visual analogue scores were recorded in a prospective, double-blind, randomized study5 comparing intravenous morphine and pethidine. The authors concluded that neither drug is effective for pain relief. Morphine is rapidly cleared from the maternal circulation and metabolized to an inactive metabolite, morphine-3-glucuronide. In the NBT survey, midwives and parturients who used diamorphine graded it better than Entonox or pethidine. A small randomized clinical trial6 comparing intramuscular diamorphine with pethidine showed diamorphine provided better pain relief during labour. A UK national survey7 in 2006 showed that the use of diamorphine has increased from 3% to 34%.
Effects on the parturient include confusion, loss of control and sedation. Pethidine decreases gastric emptying by at least 5 hours in 70% of women and increases gastric volumes during labour. Maternal hypoxic episodes are also more common with pethidine than with epidural analgesia. The combination of Entonox and pethidine tends to exacerbate maternal oxygen desaturation. Effects on the fetus and neonate: pethidine is principally bound to α1-acid glycoprotein, but readily crosses the placenta by passive diffusion. The highest fetal concentrations are observed 2–3 hours after intramuscular administration. However, when given shortly before delivery (e.g. within 1 hour) the neonatal effects are minimal. As a weak base, pethidine is more ionized in the acidic environment of the fetal circulation, trapping pethidine in the fetal compartment. This effect is exaggerated in the compromised acidotic fetus. Changes in fetal heart rate variability may be reduced about 25 minutes after intravenous administration and 40 minutes after intramuscular administration of pethidine. The respiratory depressant effects of pethidine at a given blood concentration are more pronounced in the neonate. The neonatal effects of pethidine are compounded by the production of its active metabolite norpethidine. Norpethidine has limited analgesic efficacy and causes prolonged sedation and respiratory depression. It also has pro-convulsant properties. The half-life of norpethidine in the neonate is about 62 hours. The effects of pethidine and norpethidine can be reversed by an intramuscular dose of naloxone, 100 μg/kg. Naloxone should not be given to the neonate of an opioid-dependent parturient.
Fentanyl (Sublimaze) Fentanyl is a phenylpiperidine derivative and is highly proteinbound to albumin. It is about 50 times more lipid-soluble than morphine. It has a rapid onset of action but its terminal half-life of about 8 hours is longer than that of morphine or pethidine. Its advantages include rapid onset and lack of active metabolites. Fentanyl patient-controlled analgesia (PCA) has been used successfully for parturients with thrombocytopenia. A suggested regimen consists of a 50 μg loading dose, 20 μg bolus and a lockout period of 5 minutes. It may have a role as a substitute when epidural analgesia is contraindicated or refused, but the fetus and neonate require careful observation. Fentanyl PCA has been compared with alfentanil PCA. Parturients receiving fentanyl PCA were found to have significantly lower visual analogue pain scores. Remifentanil Remifentanil is a relatively new, ultrashort-acting opioid derivative of fentanyl. It is a pure mu agonist with rapid breakdown of the ester linkage by non-specific tissue and plasma esterases
Characteristics of opioid partial agonist/antagonists Opioid
Usual dose
Onset
Efficacy
Notes
Nalbuphine (Nubain)
10–20 mg i.m. every 4–6 hours; PCA dose 1–3 mg, 10 min lockout 100–150 mg i.m. every 2–4 hours
Within 15 min after intramuscular dose; and 2–3 min after intravenous dose
Similar to 100 mg pethidine i.m.
Kappa-mediated sedation. May cause dysphoria but less vomiting compared with pethidine
1/10 potency of morphine; similar to pethidine
Pentazocine (Talwin) Butorphanol (Stadol )
40 mg i.m. every 2–4 hours 1–2 mg i.m. or i.v.
Within 15–60 min after intramuscular dose
May cause dysphoric effects in high doses. Increased nausea and vomiting compared with pethidine May cause dysphoric effects, but less nausea compared with pethidine Ceiling effect of respiratory depression. Lack of active metabolites
Tramadol (Zydol )
50–100 mg i.m. or i.v.
Meptazinol (Meptid )
1/3 potency of morphine; similar potency to pethidine Five times more potent than morphine; 40 times more potent than pethidine Similar to pethidine and morphine
Fewer maternal side effects and neonatal respiratory depression compared with pethidine
i.m., intramuscularly; i.v., intravenously
Table 1
ANAESTHESIA AND INTENSIVE CARE MEDICINE 8:7
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Crown Copyright © 2007 Published by Elsevier Ltd. All rights reserved.
Obstetrics
into non-active metabolites. Its metabolism is independent of hepatic or renal function. A bolus dose of 0.25–0.5 μg/kg with a lockout period of 1–2 minutes has been suggested. Analgesia was effective when the parturient learned to anticipate the next contraction and administered a bolus dose. Reminfentanil can cause dose-dependent maternal sedation and respiratory depression. A small double-blind crossover study8 comparing intravenous remifentanil PCA and Entonox suggested that intravenous remifentanil PCA provided better pain relief.
3 Yeo ST, Holdcroft A, Yentis SM, et al. Sevoflurane compared with Entonox for labour analgesia. Br J Anaesth 2007; 98: 110–15. 4 Chamberlain G, Wraight A, Steer P, eds. Pain and its relief in childbirth: the results of a national survey conducted by the National Birthday Trust. Edinburgh: Churchill Livingstone, 1993. 5 Olofsson C, Ekblom A, Ekmann-Ordeberg G, et al. Lack of analgesic effect of systematically administered morphine or pethidine on labour pain. Br J Obstet Gynaecol 1996; 103: 968–72. 6 Fairlie FM, Marshall L, Walker JJ, Elbourne D. Intramuscular opioids for maternal pain relief in labour: a randomised controlled trail comparing pethidine with diamorphine. Br J Obstet Gynaecol 1999; 106: 1181–7. 7 Tuckey JP, Prout RE, Wee MYK. Prescribing habits of intra-muscular opioids for labour analgesia in consultant-led maternity units: a survey of UK practice. Int J Obstet Anaesth (in press). 8 Volmanen P, Akural E, Raudaskoski T, et al. Comparison of remifentanil and nitrous oxide in labour analgesia. Acta Anaesthesiol Scand 2005; 49: 453–8.
Other systemic drugs The Cochrane reviewers of 16 randomized clinical trials found no evidence of differences between the opioid partial agonists/ antagonists and pethidine in terms of pain relief. A summary of the characteristics of these opioid partial agonist/antagonists is given in Table 1. Sub-anaesthetic bolus doses of ketamine, 10–20 mg intravenously, have been used for analgesia during the second stage of labour. ◆
Further reading Bricker L, Lavender T. Parenteral opioids for pain relief: a systematic review. J Am Obstet Gynecol 2002; 186: S94–109. Campbell DC. Parenteral opioids for labor analgesia. Clin Obstet Gynecol 2003; 46: 616–22. Collis R, Plaat F, Urquhart J. Textbook of obstetric anaesthesia. London: Greenwich Medical Media, 2002. Russell R, Scrutton M, Porter J. Pain relief in labour. London: BMJ Publishing Group, 1997.
References 1 Rosen M. Nitrous oxide for pain relief of labor pain: a systematic review. Am J Obstet Gynecol 2002; 186: S110–26. 2 Yeo ST, Holdcroft A, Yentis SM, Stewart A. Analgesia with sevoflurane during labour 1: determination of the optimum concentration. Br J Anaesth 2007; 98: 105–9.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 8:7
278
Crown Copyright © 2007 Published by Elsevier Ltd. All rights reserved.
Analgesia in labour: inhalational and parenteral
Inhalational analgesia Ether, chloroform, trichloroethylene and methoxyflurane have been used for labour pain in obstetrics. They all had drawbacks, including accumulation, maternal sedation and neonatal depression. More recent inhalational anaesthetic agents with low blood–gas partition coefficients have demonstrated increased analgesic efficacy for labour superior to Entonox, but with increased sedation. The main advantage of inhalational analgesia over systemic opioids is the reversibility of analgesia and sedation between contractions and the minimal products of metabolism affecting the fetus and neonate. Inhalational analgesia can also be self-administered and this forms a safety feedback loop, which parenteral analgesics lack.
Michael Wee
Abstract Inhalational analgesia and parenteral opioids are the most widely used analgesics for labour pain because of their availability, simplicity of administration, and cost. However, their analgesic efficacy is limited compared with regional analgesia. Nitrous oxide in oxygen (Entonox) provides moderate pain relief and is safe for use in labour. Low-dose isoflurane (e.g. 0.25%) with Entonox gives superior pain relief compared with Entonox alone. The more recently introduced inhalational agent, sevoflurane, at a concentration of 0.8% also seems to provide superior pain relief compared with Entonox. Sedation scores tend to be increased with inhalational analgesia. Pethidine is the most widely used opioid for labour despite its side effects and lack of analgesia. Diamorphine is being increasingly used in the UK. There is no good evidence to distinguish analgesic efficacy amongst the standard parenteral opioids and opioid partial agonists and antagonists. Fentanyl patient-controlled analgesia (PCA), with a bolus dose of 20 μg and lockout of 5 minutes, seems to be efficacious but accumulates over time. Close maternal, fetal and neonatal monitoring is required. Parenteral remifentanil PCA, at a dose of 0.25–0.5μg/kg with a lockout time of 1–2 minutes, has a rapid onset and offset without accumulative effects, which makes it ideal for use in labour with improved analgesic efficacy. However, more sophisticated modes of drug delivery and careful titration and monitoring of the parturient are required when sevoflurane and remifentanil are used.
Entonox Entonox (50% nitrous oxide, 50% oxygen) is the most widely available inhalational analgesic in the UK and is used by 60% of parturients. It has a long safety record as a self-administered inhalational analgesic for labour. With its low blood–gas partition coefficient (0.47) it equilibrates rapidly with arterial concentration. To achieve near maximum effect, about 10 breaths must be timed to coincide with peak contraction. Nitrous oxide may cause drowsiness and light-headedness as well as nausea. A systematic review1 of eleven randomized controlled trials of nitrous oxide use for labour analgesia concluded that while nitrous oxide is not a potent analgesic, it provides effective analgesia and is safe for labouring women and their babies. Isoflurane and desflurane When isoflurane 0.20–0.25% (blood–gas partition coefficient 1.4) is added to Entonox to improve its analgesic efficacy, pain relief scores and patient satisfaction are superior to Entonox alone. Desflurane has a low blood–gas partition coefficient (0.42) allowing rapid onset and offset of action. However, a significant proportion of women (23%) who received desflurane reported amnesia during use.
Keywords diamorphine; Entonox; inhalational analgesia; parenteral analgesia; PCA; pethidine; remifentanil; sevoflurane
Sevoflurane An open-labelled escalating dose study2 in 22 parturients concluded that the optimal sevoflurane inspired concentration for labour analgesia with acceptable sedation is 0.8%, resulting in significant pain relief. The blood–gas partition coefficient of sevoflurane is 0.69. A follow-up open-labelled sequential crossover study3 by the same research team confirmed that 0.8% sevoflurane gave significantly better pain relief scores compared with Entonox, but there was more sedation in women who used sevoflurane. Most women in these studies preferred sevoflurane to Entonox.
Inhalational and parenteral medications are the most commonly used form of analgesia in labour, despite being less efficacious than regional analgesia. Inhalational and parenteral analgesics are popular because they are readily available, simple to administer and can be used earlier in labour than regional analgesia, which may be contraindicated or not available. In most cases, inhalational and parenteral analgesics have the added advantage of not requiring anaesthetic input.
Parenteral opioids Pethidine (Meperidine or Demerol ) Pethidine is a synthetic opioid. It is a weakly basic phenyl piperidine derivative, related to fentanyl and sufentanil. Pethidine was made legally available to midwives for independent use in the UK in 1950. It remains the most widely available, used and investigated opioid in labour worldwide. The dose of pethidine commonly used by midwives is 1 mg/kg (up to 150 mg intramuscularly). The intramuscular route is not ideal because absorption may be variable. The UK National Birthday Trust
Michael Wee, FRCA, is Lead Consultant Anaesthetist in Obstetric Anaesthesia at Poole Hospital NHS Trust, Poole, Dorset. He qualified from Dundee University and trained in anaesthesia in Dundee, Copenhagen, Bristol and the South West of England. His interests include patient safety, obstetric anaesthesia, audit, research and information.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 8:7
276
Crown Copyright © 2007 Published by Elsevier Ltd. All rights reserved.
Obstetrics
(NBT) survey reported that only 16% of women who received pethidine rated it as ‘helpful’ and 25% rated it as ‘unhelpful’. Midwives rated pethidine much higher than parturients and may have confused sedation with analgesia.4
Morphine and diamorphine The analgesic efficacy of morphine for early labour pain has been questioned. High visual analogue scores were recorded in a prospective, double-blind, randomized study5 comparing intravenous morphine and pethidine. The authors concluded that neither drug is effective for pain relief. Morphine is rapidly cleared from the maternal circulation and metabolized to an inactive metabolite, morphine-3-glucuronide. In the NBT survey, midwives and parturients who used diamorphine graded it better than Entonox or pethidine. A small randomized clinical trial6 comparing intramuscular diamorphine with pethidine showed diamorphine provided better pain relief during labour. A UK national survey7 in 2006 showed that the use of diamorphine has increased from 3% to 34%.
Effects on the parturient include confusion, loss of control and sedation. Pethidine decreases gastric emptying by at least 5 hours in 70% of women and increases gastric volumes during labour. Maternal hypoxic episodes are also more common with pethidine than with epidural analgesia. The combination of Entonox and pethidine tends to exacerbate maternal oxygen desaturation. Effects on the fetus and neonate: pethidine is principally bound to α1-acid glycoprotein, but readily crosses the placenta by passive diffusion. The highest fetal concentrations are observed 2–3 hours after intramuscular administration. However, when given shortly before delivery (e.g. within 1 hour) the neonatal effects are minimal. As a weak base, pethidine is more ionized in the acidic environment of the fetal circulation, trapping pethidine in the fetal compartment. This effect is exaggerated in the compromised acidotic fetus. Changes in fetal heart rate variability may be reduced about 25 minutes after intravenous administration and 40 minutes after intramuscular administration of pethidine. The respiratory depressant effects of pethidine at a given blood concentration are more pronounced in the neonate. The neonatal effects of pethidine are compounded by the production of its active metabolite norpethidine. Norpethidine has limited analgesic efficacy and causes prolonged sedation and respiratory depression. It also has pro-convulsant properties. The half-life of norpethidine in the neonate is about 62 hours. The effects of pethidine and norpethidine can be reversed by an intramuscular dose of naloxone, 100 μg/kg. Naloxone should not be given to the neonate of an opioid-dependent parturient.
Fentanyl (Sublimaze) Fentanyl is a phenylpiperidine derivative and is highly proteinbound to albumin. It is about 50 times more lipid-soluble than morphine. It has a rapid onset of action but its terminal half-life of about 8 hours is longer than that of morphine or pethidine. Its advantages include rapid onset and lack of active metabolites. Fentanyl patient-controlled analgesia (PCA) has been used successfully for parturients with thrombocytopenia. A suggested regimen consists of a 50 μg loading dose, 20 μg bolus and a lockout period of 5 minutes. It may have a role as a substitute when epidural analgesia is contraindicated or refused, but the fetus and neonate require careful observation. Fentanyl PCA has been compared with alfentanil PCA. Parturients receiving fentanyl PCA were found to have significantly lower visual analogue pain scores. Remifentanil Remifentanil is a relatively new, ultrashort-acting opioid derivative of fentanyl. It is a pure mu agonist with rapid breakdown of the ester linkage by non-specific tissue and plasma esterases
Characteristics of opioid partial agonist/antagonists Opioid
Usual dose
Onset
Efficacy
Notes
Nalbuphine (Nubain)
10–20 mg i.m. every 4–6 hours; PCA dose 1–3 mg, 10 min lockout 100–150 mg i.m. every 2–4 hours
Within 15 min after intramuscular dose; and 2–3 min after intravenous dose
Similar to 100 mg pethidine i.m.
Kappa-mediated sedation. May cause dysphoria but less vomiting compared with pethidine
1/10 potency of morphine; similar to pethidine
Pentazocine (Talwin) Butorphanol (Stadol )
40 mg i.m. every 2–4 hours 1–2 mg i.m. or i.v.
Within 15–60 min after intramuscular dose
May cause dysphoric effects in high doses. Increased nausea and vomiting compared with pethidine May cause dysphoric effects, but less nausea compared with pethidine Ceiling effect of respiratory depression. Lack of active metabolites
Tramadol (Zydol )
50–100 mg i.m. or i.v.
Meptazinol (Meptid )
1/3 potency of morphine; similar potency to pethidine Five times more potent than morphine; 40 times more potent than pethidine Similar to pethidine and morphine
Fewer maternal side effects and neonatal respiratory depression compared with pethidine
i.m., intramuscularly; i.v., intravenously
Table 1
ANAESTHESIA AND INTENSIVE CARE MEDICINE 8:7
277
Crown Copyright © 2007 Published by Elsevier Ltd. All rights reserved.
Obstetrics
into non-active metabolites. Its metabolism is independent of hepatic or renal function. A bolus dose of 0.25–0.5 μg/kg with a lockout period of 1–2 minutes has been suggested. Analgesia was effective when the parturient learned to anticipate the next contraction and administered a bolus dose. Reminfentanil can cause dose-dependent maternal sedation and respiratory depression. A small double-blind crossover study8 comparing intravenous remifentanil PCA and Entonox suggested that intravenous remifentanil PCA provided better pain relief.
3 Yeo ST, Holdcroft A, Yentis SM, et al. Sevoflurane compared with Entonox for labour analgesia. Br J Anaesth 2007; 98: 110–15. 4 Chamberlain G, Wraight A, Steer P, eds. Pain and its relief in childbirth: the results of a national survey conducted by the National Birthday Trust. Edinburgh: Churchill Livingstone, 1993. 5 Olofsson C, Ekblom A, Ekmann-Ordeberg G, et al. Lack of analgesic effect of systematically administered morphine or pethidine on labour pain. Br J Obstet Gynaecol 1996; 103: 968–72. 6 Fairlie FM, Marshall L, Walker JJ, Elbourne D. Intramuscular opioids for maternal pain relief in labour: a randomised controlled trail comparing pethidine with diamorphine. Br J Obstet Gynaecol 1999; 106: 1181–7. 7 Tuckey JP, Prout RE, Wee MYK. Prescribing habits of intra-muscular opioids for labour analgesia in consultant-led maternity units: a survey of UK practice. Int J Obstet Anaesth (in press). 8 Volmanen P, Akural E, Raudaskoski T, et al. Comparison of remifentanil and nitrous oxide in labour analgesia. Acta Anaesthesiol Scand 2005; 49: 453–8.
Other systemic drugs The Cochrane reviewers of 16 randomized clinical trials found no evidence of differences between the opioid partial agonists/ antagonists and pethidine in terms of pain relief. A summary of the characteristics of these opioid partial agonist/antagonists is given in Table 1. Sub-anaesthetic bolus doses of ketamine, 10–20 mg intravenously, have been used for analgesia during the second stage of labour. ◆
Further reading Bricker L, Lavender T. Parenteral opioids for pain relief: a systematic review. J Am Obstet Gynecol 2002; 186: S94–109. Campbell DC. Parenteral opioids for labor analgesia. Clin Obstet Gynecol 2003; 46: 616–22. Collis R, Plaat F, Urquhart J. Textbook of obstetric anaesthesia. London: Greenwich Medical Media, 2002. Russell R, Scrutton M, Porter J. Pain relief in labour. London: BMJ Publishing Group, 1997.
References 1 Rosen M. Nitrous oxide for pain relief of labor pain: a systematic review. Am J Obstet Gynecol 2002; 186: S110–26. 2 Yeo ST, Holdcroft A, Yentis SM, Stewart A. Analgesia with sevoflurane during labour 1: determination of the optimum concentration. Br J Anaesth 2007; 98: 105–9.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 8:7
278
Crown Copyright © 2007 Published by Elsevier Ltd. All rights reserved.