Download The use of uterotonic drugs during caesarean section

10 May 2013
No. 16
USE OF UTEROTONIC AGENTS AT
CAESAREAN DELIVERY
Onke Nqala
Commentator: P Gokal
Moderator: S Bechan
Descipline of Anaesthetics
CONTENTS
INTRODUCTION............................................................................................... 3
OXYTOCIN ....................................................................................................... 3
Mechanism of Action .................................................................................... 4
Pharmacokinetics ......................................................................................... 5
Physiological Effects .................................................................................... 5
Adverse effects ............................................................................................. 6
MECHANISMS TO OBTUND HAEMODYNAMIC EFFECTS OF OXYTOCIN 7
Use of Smaller Doses ................................................................................... 7
Bolus vs. Infusion ......................................................................................... 8
Effects of the Second Dose of Oxytocin .................................................... 8
Co-Administration of Oxytocin with Phenylephrine.................................. 8
ADMINISTRATION OF OXYTOCIN ................................................................. 9
Oxytocin Infusion .......................................................................................... 9
Infusion vs. Bolus & Infusion ...................................................................... 9
Timing and Route of Administration of Oxytocin .................................... 10
OXYTOCIN DOSES FOR DIFFERENT PATIENTS ....................................... 10
Elective C/S with No Risk Factors ............................................................. 10
Emergency C/S with Risk Factors for Uterine Atony .............................. 11
Patients with Pre Eclampsia ...................................................................... 12
Patients with Cardiac disease ................................................................... 12
CARBETOCIN ................................................................................................ 13
ALTERNATIVES TO OXYTOCIN................................................................... 13
Ergot alkaloids ............................................................................................ 13
Prostaglandins ............................................................................................ 14
SUMMARY ...................................................................................................... 15
RECOMMENDATIONS .................................................................................. 16
CONCLUSION ................................................................................................ 17
REFERENCES................................................................................................ 18
2
Use of Uterotonic Agents at Caesarean Delivery
INTRODUCTION
Clinicians performing obstetric anaesthesia require a good understanding of
the drugs used by obstetricians and the effects that these drugs have on the
parturient and the fetus. Uterotonic agents are mainly used post delivery and
during caesarean section for prevention and treatment of post partum
haemorrhage (PPH). They are also used during induction and augmentation
of labour.
In South Africa, during the period 2008-2010, there were 688 maternal
deaths as a result of obstetric hemorrhage, and it continues to be the most
common avoidable cause of maternal deaths.1,2
Obstetric hemorrhage
688
%
Bleeding after C/S
Abruption without HPT
Retained placenta
Ruptured uterus without previous C/S
Abruption with hypertension
Uterine atony
PPH not specified
150
63
62
61
47
44
103
21.8
9.2
9
8.9
6.8
6.4
15
Saving Mothers 2008-2010. The fifth report of the National Committee for Confidential Enquiry into
Maternal Deaths in South Africa.
The uterotonic agents available for use in South Africa are oxytocin,
alkaloid derivatives (ergometrine, syntometrine) , and prostaglandins.
OXYTOCIN
Oxytocin was discovered by Sir Henry Dale.3 It was the the first polypeptide
to be synthesized and this occurred in 1953. It is a polypeptide hormone
synthesized in the paraventricular nuclei of the hypothalamus and stored in
the posterior pituitary gland.3,4 Oxytocin is secreted mainly from the posterior
pituitary gland and other sites namely, the corpus luteum, Leydig cells,
pancreas, adrenal medulla and retina.
Oxytocin binds to oxytocin receptors, which are found in the uterus, breast,
central nervous system, heart and osteoblastic tissue. Oestrogen stimulates
an increase in oxytocin receptors after 20 weeks gestation.4
3
Mechanism of Action:
It binds to the G-protein coupled oxytocin receptor on the surface of the
myocyte, leading to the activation of phospholipase C, which cleaves
phosphatidyl-inositol bisphosphate to Diacylglycerol (DAG) and inositol
triphosphate (IP3). IP3 in turn stimulates release of calcium (Ca2+) from
endoplasmic reticulum, whereas DAG stimulates prostaglandin synthesis.
Ca2+ released from the endoplasmic reticulum binds to and activates
calmodulin, this calcium-calmodulin complex then binds to myosin light chain
kinase (MLCK), enabling the phospharylation of the short chain of myosin
and causing formation of adenosine triphosphate (ATP) and muscle
contraction.3,5
OXYTOCIN
OXYTOCIN RECEPTOR
Phospholipase C
DAG
IP3
PIP2
Release of Ca2+ from ER
PG Synthesis
UTERINE SMOOTH MUSCLE CONTRACTION
4
Oxytocin is administered via the parenteral route. It also is absorbed by the
buccal and nasal mucosa. When administered orally, oxytocin is rapidly
inactivated by trypsin, therefore parenteral route is preferred. It is then
distributed into the extracellular fluid and has no protein binding. A steadystate plasma concentration is reached in 20-30 minutes duration.
It has an onset of 1-2 minutes and half-life of 10-12 minutes. The metabolic
clearance rate in men and women (pregnant or non-pregnant) is 20-27
ml/kg/minute. This similarity of the metabolic clearance rate between men
and pregnant females is interesting, in view of the increase that occurs
during pregnancy suggesting a corresponding increase in factors
responsible for the degradation of oxytocin.
Pharmacokinetics5
The plasma concentration of oxytocin is similar during pregnancy and during
labor; however, there is a significant increase in the plasma concentration
during the last part of the second stage of labor. The highest concentration
however during labor is found in umbilical cord blood, indicating that there is
a significant production of oxytocin by the fetus during labor.
Physiological Effects 3,4,5
1. Uterine contraction followed by relaxation–pharmacological doses can
cause incomplete relaxation of uterine musculature
2. Contraction of myoepithelial cells in the breast causing milk ejection
3. Enhances sexual and maternal nurturing behaviour (love hormone)
4. Impairment of Memory and learning functions
5. Regulation of food and drink intake
5
6. Anti-inflammatory effects-modulation or decreasing cytokines
7. Transient relaxation of vascular smooth muscle causing hypotension
8. Protective role to the fetus  induces a switch from release of
excitatory to inhibitory neurotransmitter in the fetal brain, thereby
reducing its vulnerability to hypoxic damage during delivery.6
Adverse effects
Cardiovascular Effects:
a) Hypotension
This maybe due to transient relaxation of vascular smooth muscle cells via
calcium-dependant stimulation of the nitric oxide pathway or, the effect of its
preservative chlorbutanol on atrial myocytes in vitro which also causes the
release of Atrial Natriuretic Peptide and Brain Natriuretic Peptide.3 7Ola P.
Rosaeg and colleagues performed an in vitro study to investigate the effect
of pure oxytocin, chlorobutanol alone and commercial oxytocin solution
(containing chlorobutanol) on contractile force of human atria trabeculae.
The results showed that chlorobutanol, and oxytocin with chlorobutanol,
inhibit myocardial contractility. There was no difference between
chlorbutanol alone versus oxytocin with chlorbutanol in the magnitude of
negative ionotropic effect in the atrial preparation. Oxytocin didn’t cause
negative ionotropism.
The conclusion was that chlorobutanol exhibits negative ionotropic
properties in the human in vitro atria preparation, whereas Oxytocin alone
does not have a direct negative effect on the contractile force of human atrial
myocardium.7One limitation of this study was that they used right atrial tissue
samples from relatively old nonpregnant subjects.
b) Myocardial Ischaemia
A double-blind RCT compared the incidence of ST depression between 5 IU
and 10 IU Oxytocin in 103 healthy women, undergoing elective C/S under
spinal anaesthesia. It also compared the effect of these doses on chest
pains, BP, HR, Troponin I levels and blood loss. The results showed an
incidence of myocardial ischaemia of 21.6% in the 10 IU group and 7.7% in
the 5 IU group.
The average decrease in non-invasive mean blood pressure at 2 min after
oxytocin administration in the high dose group was 17mmHg versus 9mmHg
in the lower dose group. The decrease in MAP and ST depression were
comparable. There was no significant difference in chest pain, Troponin I
levels and blood loss.
6
The study concluded that the ST depression is possibly a consequence of
hypotension and that interventions to reduce hypotension may reduce the
occurrence of ST depression.8
Another RCT used invasive BP measurement and vector cardiography to
compare the occurrence of myocardial ischaemia in healthy patients given
either 10 IU bolus or 0.2 mg methylergometrine during C/S under spinal
anaesthesia and a control group consisting of non-gravid, not anaesthetised
women who also received 10 IU IV bolus.
Methylergometrine group had mild hypertension without significant ECG
changes. 10 IU oxytocin bolus induced chest pains, tachycardia,
hypotension and sings of MI on ECG. Conclusion these effects were solely
due to oxytocin administration rather than pregnancy, C/S or spinal induced
sympathetic blockade.9
c) Arrhythmias (tachycardia)3
d) Elevation of pulmonary artery pressures3
Other Adverse Effects:
a) Nausea3,12 (29%), vomiting3,12 (9%), headache and flushing3
b) Water retention (due to structural similarities with vasopressin) - causing
dilutional hyponatraemia, seizure and coma3,5
c) Death: Oxytocin has been a contributing factor to at least one of the
maternal deaths in both South African and UK based Confidential
Enquiry into Maternal Deaths.10,11 Thereafter the Food & Drug
Administration (FDA) has placed a black box warning restricting oxytocin
use to medical indications and the Institute for Safe Medication Practices
added oxytocin to a list of high alert medications.3
d) Fetal and neonatal adverse events: Decrease in SaO2 related to neonatal
seizures and uterine contraction frequency. Hyperbilirubinemia or retinal
hemorrhages are other effects of oxytocin on the neonate.3,6
MECHANISMS TO OBTUND HAEMODYNAMIC EFFECTS OF
OXYTOCIN
Use of Smaller Doses
Sartain and colleagues compared the hemodynamic and side effects in two
groups of patients administered either 5 IU or 2 IU of oxytocin followed by
oxytocin infusion of 10 IU/ hr. The 2 IU group showed less marked increase
in HR, and decrease MAP and had a decreased incidence of nausea and
vomiting compared to 5 U group. However there was no difference in uterine
tone, blood loss and the requirement for additional uterotonic agents.13
7
Bolus vs. Infusion
A single blinded study by Thomas et al compared the effects of the 5 IU of
oxytocin when given as an iv bolus or as an infusion over 5 min in 30 women
undergoing elective C/S. The study measured heart rate (HR), mean arterial
pressure (MAP) and estimated blood loss between the two groups. In the
bolus group HR increased by 17 beats/min compared to 10 beats/min in the
infusion group.
MAP decreased by 27mmHg in the bolus group and a steady decline by
8mmHg was noted in the infusion group. There was no difference in
estimated blood loss. The author recommended that bolus should be used
cautiously.14 The limitation of this study is that it is small study and single
blinded. Interestingly both groups used 12mg ephedrine.
Effects of the Second Dose of Oxytocin
Langesaeter et al studied the hemodynamic effects of second dose of
Oxytocin in 20 healthy women during spinal anaesthesia caesarean delivery.
They demonstrated that a second dose of oxytocin produced the same
hemodynamic effects but significantly smaller than the effects of the first
dose and suggests that these findings could be explained by oxytocin
induced desensitization phenomenon.15
Laboratory work collaborated those findings of oxytocin receptors loss during
oxytocin induced/ augmented labour. Concentration of oxytocin receptors
decreased more than 3 fold and oxytocin receptor mRNA concentration
decreased 60 fold (augmented) and 300 fold (induction of labour). Prior
exposure of rat myometrium to oxytocin suggests that efficacy falls as
concentration increases and this is independent of time3,16,17,18
Co-Administration of Oxytocin with Phenylephrine
Dyer’s DB - RCT randomized 20 patient to receive oxytocin or a mixture of
oxytocin and 80mcg phenylephrine. The primary outcome of the study was
to compare Cardiac Output (CO) changes between ephedrine and
phenylephrine. The results were as follows: The oxytocin group showed an
increase in stroke volume, heart rate and cardiac output whereas systemic
vascular resistance and mean arterial pressure decreased. The oxytocin +
phenylephrine group displayed a decrease in stroke volume, heart rate,
cardiac output and an increase in systemic vascular resistance and mean
arterial pressure.
The percentage change of HR and CO was lower in the group that received
phenylephrine & Oxytocin and SVR and MAP were significantly higher in
that group. Times to peak were also different in the two groups except for SV
and CO. In all these patients uterine contraction was assessed by
8
obstetrician as good. The study concluded that the hemodynamic response
to oxytocin were obtunded by phenylephrine but not abolished19
ADMINISTRATION OF OXYTOCIN
Oxytocin Infusion
There little evidence for the optimal rate of infusion following the initial bolus
of oxytocin. George et al investigated the ED90 of an oxytocin infusion for
adequate uterine contraction at 3 min after cord clamping, in 40 patients
undergoing elective Caesarean section using a biased coin sequential
allocation scheme.
Seven of the forty patients had uterine tone deemed unsatisfactory and
required additional uterotonics. The infusion range was between 0.1 -0.4 IU/
min.The study concluded that the ED90 was 0.29 IU/min (i.e. approximately
15 IU of Oxytocin in 1 L of fluid running over an hour) to prevent uterine
atony and PPH after elective Caesarean section.26Of note, however, after
that 1 hour, an infusion of 30 IU/1L oxytocin was administered at 150 ml/hr
while in PACU
Infusion vs. Bolus & Infusion
King et al. did a RCT on patients undergoing elective and emergency C/S
with at least one risk factor for PPH. One group received 5 IU oxytocin bolus
followed by continuous high dose oxytocin infusion, and the other group
received placebo followed by continuous high dose oxytocin infusion (40 IU
in 500ml of saline over 30 min). Initially there was better uterine tone in the
group that received the bolus.
There was no difference in the need for additional uterotonic agents in the
first 24 hours and there were no differences in blood loss and transfusion
requirements. They concluded that there was no benefit of oxytocin bolus
before an infusion even in women at high risk for PPH.27 The Elective C/S
Syntocinon Infusion Trial (ECSSIT) was a multi centre double blind placebo
controlled randomized trial involving 2000 women which set out to determine
the effects of adding an oxytocin infusion after a bolus of oxytocin during an
elective C/S.
The intervention group received 5 IU IV oxytocin over 1 min followed by 40
IU in 500ml N/S solution over 4hrs whilst the placebo group received the
same oxytocin bolus followed by a placebo infusion. The study found that the
addition of an oxytocin infusion after C/S significantly reduces the need for
additional uterotonic agents. It did not affect the overall occurrence of major
obstetric haemorrhage.28
9
McLeod et al. used routine standard monitors and thoracic bioimpedance
technology for haemodynamic measurements and found that an infusion of
30 IU oxytocin in 500ml Hartmann solution over 4 hours after initial bolus of
5 IU at elective C/S given over 3 min, did not adversely affect maternal
haemodynamics compared with a placebo infusion either during or after
surgery.
They suggested that even in haemodynamically unstable parturients
oxytocin as an infusion can be given safely.29 With regard to general vs
regional anaesthesia, there is no evidence that one has an advantage over
the other in terms of oxytocin dosing.
Timing and Route of Administration of Oxytocin
The timing of oxytocin administration remains debatable. Oxytocin can be
administered before placental separation or after expulsion. Optimal timing is
unclear. This has not been evaluated much in the literature. Most
randomized trials administered oxytocin before placental separation.30
There seems to be geographic variation: a survey of Canadian obstetricians
reported 52% give it before delivery of the placenta.31 In Texas, USA only
15% administer Oxytocin before delivery of the placenta.32 My practice is to
administer it before expulsion of the placenta. A RCT comparing the
different timing of administration did not find any difference between the
groups in terms of blood loss or retained placenta.33
Oxytocin maybe administered intravenously (IV), intramuscular (IM) or via
the umbilical vein. The IV route has been questioned because of
hemodynamic effects. The comparative efficacy of IM and IV has not be
studied in a randomized trial. However observational data and clinical
experience indicate that the IM route is an effective alternative to IV,
however the onset is slower.34 Injection into the umbilical vein has been
shown in a systemic review of RCTs to be ineffective for prevention of
PPH.34
OXYTOCIN DOSES FOR DIFFERENT PATIENTS
Elective C/S with No Risk Factors
A number of dose finding studies have been conducted to elucidate the
correct dose of oxytocin. Carvalho’s study in 2004 randomized 40 healthy
patients at term for elective C/S under regional anaesthesia20. Patients with
risk factors for uterine atony were excluded.
Three patients received 0 IU, 31 patients received 0.5IU and 6 patients
received 1IU of oxytocin according to the sequential allocation scheme.
10
They primarily looked at uterine response to initial intravenous bolus of
oxytocin, as rated by the obstetrician. There was no difference between 0.5
IU and 1 IU with respect to response time for adequate uterine tone. ED90
for oxytocin was found to be 0.35 IU. Therefore they concluded that
satisfactory uterine contraction can be achieved by IV dose not more than 1
IU.20
The search for the effective bolus dose during elective caesarean delivery to
produce adequate uterine tone continued. In 2010 Butwick et al randomly
selected patients to receive 0, 0.5 IU, 1 IU, 3 IU, and 5 IU over a 15 second
period following cord clamping21.
Nearly 50% of patients who received placebo required rescue oxytocin
during the study period. Hypotension was significant in the 5 IU group
compared to the 0 IU. There was no difference in the incidence of
hypotension in 0.5 IU to 3 IU groups, and no difference in estimated blood
loss. Other side effects rarely occurred.21
Authors concluded that routine use of 5 IU Oxytocin during elective C/S is no
longer recommended because adequate uterine contraction can be achieve
with lower doses i.e. 0.5 – 3 IU 21
Emergency C/S with Risk Factors for Uterine Atony
There have been no studies which specifically investigated the dose of
oxytocin in patients at high risk of uterine atony, such as those with multiple
pregnancies, grand multiparity and antepartum haermorrhage. The following
studies look at labour arrest as a risk factor for uterine atony. Balki’s group
set out to determine the minimum effective dose of oxytocin to produce
uterine contraction after C/S for labor arrest in women who had received
oxytocin during labour22.
Twenty patients were recruited who had labour epidural analgesia which
was topped up with 2% lignocaine for surgical anaesthesia. Oxytocin was
administered according to a biased coin up-and down sequential allocation
scheme. They used 0.5IU increments depending on the response from the
previous patient. A three minute interval was allowed to pass before the
next intervention, and then an infusion of 40mU/min (20 IU/L at the rate of
120ml/h) was started and continued at the same rate for up to 8 hours.
The outcomes which were assessed were uterine response to initial
intravenous bolus of oxytocin, and estimated blood loss. Side effects were
also recorded. Most patients had effective uterine contraction within 3 min
with 2-5 IU of initial oxytocin dose.
11
The study found the ED90 of oxytocin to be 2.99IU in patients with labour
arrest (approximately 9 times higher than for patients not in labour). The
conclusion was that Caesarean delivery for labour arrest requires a loading
dose of 3 IU oxytocin followed by 20IU/L @ 120ml/hr infusion.22
Patients with Pre Eclampsia
In an observational study using cardiac output monitoring, Dyer at el studied
the haemodynamic effects of spinal anaesthesia in 15 patients with severe
preeclampsia23. The study determined that cardiac output remained stable
during Caesarean delivery until the period of oxytocin administration.
Oxytocin (2.5IU) administration was associated with significant hypotension,
increase in heart rate, cardiac output and every little change in stroke
volume. This response was more pronounced compared to another study of
healthy parturients where they used 5 -10 IU as rapid bolus of Oxytocin.23
Langesaeter and colleagues investigated the haemodynamic effects of
oxytocin in women with severe pre-eclampsia24. All 18 patients who were
given 5 IU, demonstrated a decrease in systolic arterial pressure, systemic
vascular resistance, and an increase in heart rate. Six patients had a
decrease in CO due to a decrease in stroke volume.
This paradoxical effect could be explained by low plasma volume or
associated relative diastolic dysfunction in these patients. They concluded
that the haemodynamic effect in response to oxytocin is less
predictable.24Therefore, healthy parturients given the same dose have a
larger increase in CO, SV and HR compared to their counterparts with
severe preeclampsia.24
Patients with Cardiac disease
Use of oxytocin in this group is controversial. Some authors avoid oxytocin in
pregnant women with cardiac disease and others administer it as an
infusion. Langesaeter and colleagues looked at 103 patients with whole
range of cardiac diseases (cardiomyopathy, myocardiatis, valvular heart
diseases, intracardiac shunt disease, pulmonary hypertension, ischaemic
heart disease and severe arrthymias)25.
The study outcomes looked at mode of delivery, anaesthetic technique
during C/S, use of phenylephrine, use of oxytocin, Haemoglobin levels pre
and post delivery, bleeding, the need for transfusion and, maternal and fetal
outcomes at 6 months postpartum.
The results showed that with boluses of 0.05 – 0.5 IU IV, haemodynamic
changes were minor and transient. Cardiac symptoms were not aggravated.
Uterine tone was sufficient. In keeping with Carvalho and colleagues
12
findings, an ED95 of 0.35 IU in elective C/S and 3 IU in patients with prior
oxytocin stimulation was found.
No subsequent infusion is recommended as it may lead to volume overload.
However prophylactic B-lynch suture was offered in some patients. The
conclusion was that use of ultra-low doses of oxytocin (i.e. 0.05-0.5 IU)
administered extremely slowly is recommended in cardiac patients.25
CARBETOCIN
Carbetocin is a synthetic analogue of oxytocin. It has a similar mechanism of
action, and side effect profile, but the duration of action is 4-10 times longer.3
It produces titanic uterine contraction 2 minutes after an intravenous dose,
which lasts for 60 -120 seconds. It is contraindicated in preeclampsia, and is
licensed for use only with regional anaesthesia.40 Carbetocin is not available
in South Africa.
The dosage of Carbetocin is unclear. One RCT comparing carbetocin to
oxytocin during Caesarian Section suggests 100 mcg IV35. A double blinded
RCT compared the impact of carbetocin (100mcg) and oxytocin (5IU) on
maternal haemodynamic parameters for women undergoing elective C/S.
The authors concluded that both have similar hemodynamic effects and side
effect profile, but could not confirm reports that carbetocin has a slightly
better uterotonic effect.35
ALTERNATIVES TO OXYTOCIN
Ergot alkaloids
Fungus extract (Claviceps purpurea) was the first uterotonic agent used and
was originally known as ‘pulvis ad partum’ (powder of birth), but later came
to be known as “pulvis ad mortem’( powder of death) . Its use was reviewed
as it was associated with titanic and sustained uterine contraction, leading to
fetal asphyxia, stillbirth and uterine rupture. Today these agents are used in
the postpartum period, as prophylaxis for postpartum bleeding and treatment
for uterine atony.3
Ergometrine is a natural occurring alkaloid and methylergometrine is semisynthetic. Their mechanism of action is not clear, but they may act via
calcium channels or alpha adrenoceptors in the myometrium. Ergometrine is
also a partial agonist at alpha1 adrenoceptor, 5HT-1 and dopamine
receptors. It has been associated with a mean arterial pressure increase of
11%, increase in pulmonary arterial pressure of 30%, and a 46% incidence
of nausea and vomiting.3,5
13
Other side effects include CNS effects, psychosis, reversible cerebral
arteriopathy; cardiovascular effects - Hypertension, Coronary spasm and
myocardial infarction; and renal artery spasm. It has a half life of 120 min and
no desensitization phenomenon. RCOG guideline recommends an IV
injection of 0.5 mg slowly while WHO recommends 0.2mg IV/IM to be
repeated as necessary every 15 min to max of 1 mg.38,39
A systemic review comparing Oxytocin and Ergot alkaloids found no
significant difference in blood loss, but Oxytocin was associated with side
effects and manual removal of placenta.36 Syntometrine is a combination of 5
IU Oxytocin and 0.5mg Ergometrine.3
A systemic review comparing Syntometrine and Oxytocin alone showed a
small but statistically significant reduction in the risk of blood loss with the
syntometrine group but no difference in risk of PPH, however maternal side
effects such as hypertension, nausea and vomiting were higher with
syntometrine than Oxytocin group37
Prostaglandins
Prostaglandins have specific receptors that increase in concentration at the
beginning of labour. Their mechanism of action is activation of G-protein and
calcium channels which in turn increase intramyometrial calcium
concentration and enhanced uterine contraction. Prostaglandins can be
classified into 3 groups.
The first generation prostaglandin F2α (dinoprost) was described in 1976.
Second generation 15-methyl prostaglandin F2α (carboprost) was shown to
have an extended half-life, fewer GIT and vasopressor effects, good
uterotonic effects but, associated with bronchospasms, V/Q mismatch and
hypoxaemia. A recommended dosage of 500mcg may be administered
intramyometrially.
 There are two third generation prostaglandins:
Sulprostene synthetic prostaglandin E2 is associated with a marked
decrease in SVR and hypotension. The recommended dose is 250
mcg IM repeated every 15min to a maximum of 8 doses. Intravenous
dosing has been used: 500mcg in 50ml N/S, commence @ 10ml/hr
and increase every 15 min as necessary. Contraindications include
asthma, coronary artery disease, hypertension, heart failure,
glaucoma, epilepsy and uncontrolled DM
 Misoprostol E1 is cheap, widely available, does not require
refrigeration and is administered either orally, sublingually or rectally
for management of uterine atony.
14
Sublingual route has quicker time of onset, highest peak concentration
and greatest bioavailability of all routes of administration. Oral route
has the highest side effects whereas the rectal route has slower onset
of action, lower peak levels and fewer side effects. Other side effects
include fever, diarrhea, nausea and vomiting especially with oral
route. There is conflicting evidence. Small studies have concluded
that buccal misprostol may reduce the need for additional uterotonic
agent at C/S, while others concluded that oral misoprostol is as
effective as IV oxytocin in reducing intraoperative blood loss.42
However systemic review of its use to prevent PPH has been shown to be
less effective than oxytocin or ergometrine. A RCT has shown that
preoperative treatment with 400mcg of rectal misoprostol just prior to skin
preparation and draping for repeat elective C/S signicantly reduce intraoperative and postpartum blood loss41(29).
SUMMARY
Clinical Trials of Elective Caesarean Delivery
Author
Patient
No.
Study Design/
Methodology
Primary Outcome
Uterine
Massage
Saran
1997
Carvalho
2004
Sartain
2008
George
2010
Butwick
2010
40
5,10,15 or 20IU @ 1 IU/min
??
40
Biased coin up-down allocation: slow
bolus @ 0.5 IU/5/s
2 or 5 IU over 5- 10 sec
No difference in the
uterine tone
ED=0.35 IU
Change in HR 24 vs 32
b/min
ED90 = 0.29 IU/min
??
80
40
Biased coin up and down allocation;
infusion
0, 0.5,1,3 and 5 IU over 15 sec
75
No
signicant
difference in uterine
tone @ 2 min
no
If needed at 3
min
yes
Clinical Trials for Labouring Caesarean Section
Munn 2001
Balki 2006
Dyer 2008
0.33 vs 2.7 IU/min infusion
for laboring women
30
Biased
coin
up-down
allocation at 0.5 IU/5.s for
women with labour arrest,
Oxytocin augmentation and
epidural analgesia
Clinical Trials for Pre Eclampsia
15
2.5 IU in 10 ml of H2O over
30sec
Langesaeter 2010
321
18
5 IU bolus under invasive
monitoring
15
yes
ED90 = 2.99 IU
If needed at 3
min
Hemodynamic Effects
of SA in Preeclapmsia
and secondary effects
of
Oxytocin:
↓BP,↓SVR,↑HR
and
↑CO
but
SV
unchanged
↓MAP,↓SVR, ↑HR but
five had↓ CO due to
↓SV
??
??
RECOMMENDATIONS
Based upon current evidence
PROPHYLAXIS AGAINST UTERINE ATONY
1st
line
agents
2nd
line
agents
Healthy patient low
risk uterine atony
Pre-eclampsia
patient
Uncomplicated cases of
labour arrest
Oxytocin bolus 13IU over 30s with
phenylephrine 80µg
rescue dose within 3
min
Seldom needed
Oxytocin 3 IU slowly+
infusion slowly(fluid
overload)
Oxytocin 3 IU bolus slowly
“Rule of 3” remember
receptor down-regulation
Carbetocin and ergot
derivatives
are
contraindicated
Ergometrine 0.05-.0.5 IV
slowly/IMI
Preop Prostaglandin E1
400µg or
Prostaglandin F2α 250µg
intramyometrially
Cardiac
patient
esp. with
pulmonary HPT
Ultra small doses
oxytocin 0.1-0.5 IU
slowly. No infusionfluid overload
No suggestion
The use of uterotonic drugs during caesarean section
R.A. Dyer, D. van Dyk, A. Dresner
Department of Anaesthesia, University of Cape Town, South Africa
International Journal of Obstetric Anesthesia (2010) 19, 313–319
International Journal of Obstetric Anesthesia (2010) 19, 243–245
ESTABLISHED UTERINE ATONY AND PPH
1st line
2nd line in view of
oxytocin receptor
down regulation
Uncomplicated
Labour
arrest cases with PPH
3IU-5IU over 30sec followed
by 40IU/500ml @125ml/hr
over 4 hours
WHO 0.2 mg IV slowly
RCOG 0.5 mg IV slowly
Pre-eclampsia
Oxytocin 3IU slowly +
infusion
40IU/100ml@
25ml/hr
over 4 hrs to
minimize risk of fluid
overload
Misoprostol dose not clear
400µg
sublingually
or
1000µg PR
Or Prost E2 20mg PR 2
hourly
Misoprostol dose not clear
400µg
sublingually
or
1000µg PR
Or Prost E2 20mg PR 2
hourly
The use of uterotonic drugs during caesarean section
R.A. Dyer, D. van Dyk, A. Dresner
Department of Anaesthesia, University of Cape Town, South Africa
International Journal of Obstetric Anesthesia (2010) 19, 313–319
SA Perinatal Practice Guideline: Chapter 102a Syntocinon®: prophylaxis for third stage of labour and pph management
review 17 July 2012
16
CONCLUSION
Uterotonic agents after Caesarean delivery are an important medical
intervention to prevent and treat PPH. In patients undergoing an elective
C/S, a ‘ceiling effect’ of oxytocin 3 IU is seen, beyond which, no further
improvement in uterine tone and blood loss is observed.
A small dose of oxytocin (ED 90 = 0.35IU) has been determined to be
sufficient in producing adequate uterine contraction during elective
Caesarean delivery in patients not in labour. However a similar low loading
dose (ED90=2.99 IU) is required in parturient in labour, followed by infusion
10 IU in 1L of fluid over 4-6 hours during and after the C/S .The
phenomenon of receptor desensitization is a reality so other uterotonic
agents with different mechanism of action to oxytocin should be considered.
Issues which have not been covered in this review include:
Oxytocin dosing in normal vaginal delivery vs C/S
Oxytocin dosing in stenotic vs regurgitant heart lesions
Oxytocin dosing in regional vs. general anaesthesia
Objective measure of uterine contractility or tone
17
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