Adam Weinstein
Journal Club
4/11/14
 Recent
attention in the literature
 1:3 first time mothers develop fever (core
temp >37.5 C) with CLE
 Maternal
-
Consequences:
Increased HR, CO, O2 consumption
Rigors, shaking
Antibiotic exposure
Change in obstetric plans
Segal, Scott MD, MHCM. Labor Epidural Analgesia and Maternal Fever. Anesthesia & Analgesia. 2010 Dec. Vol
111.6.1467-1475
 Some
have even found a link to uterine
rupture:

-
Fetal Consequences:
Neonatal sepsis evaluations 3x
CBC, electrolytes, LFTs, urine, CSF, imaging
-
Antibiotic exposure
Low fetal tone
Neonatal seizures
Fetal hyperthermia
Question of lower APGAR scores
Increased neonatal encephalopathy
-
Meyer et al., Previc et al., Snyder-Keller et al., claim a
link between autism, schizophrenia, and even
Parkinson’s with maternal fever
Lieberman E, Lang JM, Frigoletto F Jr, Richardson DK, Ringer SA, Cohen A. Epidural analgesia,
intrapartum fever, and neo-natal sepsis evaluation. Pediatrics 1997;99:415–9
Fever is associated with decreased
dopamine levels, decreased dopamine
levels may stunt neonatal brain
development
 1.13%
 1.58%
 0.12%
incidence in febrile mothers
incidence in the acidotic fetus
with neither acidosis or febrile
mothers
 Much
effort is taken to reduce acidosis: fetal
monitoring, oxytocin protocols, increased
rates of C-sections, drug selection
 NOT
MUCH effort is taken to reduce a nonchorio maternal fever
Impey LW, Greenwood CE, Black RS,Yeh PS, Sheil O, Doyle P. The relationship between intrapartum maternal fever and
neonatal acidosis as risk factors for neonatal encephalopathy. Am J Obstet Gynecol 2008;198:49.e1–6
Goetzl L, Korte JE. Interaction between intrapartum maternal fever and fetal acidosis increases risk for neonatal
 Effort
has not been focused on reducing
fever because the mechanism remains
unclear…
 Epidurals
for C-sections and surgery result
in hypothermia due to vasodilation and
dissipation of heat – not increased temp
 However, epidurals
in laboring women can
result in hyperthermia
1 degree Celsius increase per 7 hours
Others report 0.1 degrees Celsius per hour
Segal, Scott MD, MHCM. Labor Epidural Analgesia and Maternal Fever. Anesthesia & Analgesia. 2010 Dec. Vol 111.6.1467-1475
 Imbalance
between heat production and
dissipation, increased VO2 with contractions
 Opioids
modestly attenuate the increase in
temperature of CLE, specifically systemic IV
fentanyl
 Maternal
Inflammation: (many theories no
clear answer) placental inflammation, CLE
may enhance an underlying inflammatory
process, spinal instrumentation
Negishi C, Lenhardt R, Ozaki M, Ettinger K, Bastanmehr H, Bjorksten AR, Sessler DI. Opioids inhibit febrile responses in
humans, whereas epidural analgesia does not: an explanation for hyperthermia during epidural analgesia. Anesthesiology
2001;94:218–22
Goetzl L, Evans T, Rivers J, Suresh MS, Lieberman E. Elevated maternal and fetal serum interleukin-6 levels are associated
with epidural fever. Am J Obstet Gynecol 2002;187:834–8
“If intrapartum infection is one of the
causes of maternal fever during epidural
analgesia, then prophylactic administration
of antibiotics might reduce the occurrence
of such infection related fever attributed to
epidural analgesia”
 Randomized, double
blind, placebo-
controlled
 University
of Texas SW Medical Center at
Dallas
 June
2002 – December 2005
Selected Population:
Healthy nulliparous women presenting at
4-6 cm cervical dilation with contractions
who requested an epidural
Randomly assigned to receive either:
Cefoxitin 2 grams or an identical
appearing placebo – with follow up dosing
6 hours later
If fever was detected: >38 C
Patients were treated intravenously with:
Ampicillin 2g Q6h + Gentamicin 5mg/kg
Q8h
Epidural Technique:
1. 500 mL bolus of LR
2. Placement of epidural catheter using a
17 gauge Tuohy needle
3. Tests dose 3 mL of 1.5% lidocaine +
epinephrine 1:200,000
4. 3 mL increments of 0.25% bupivacaine
titrated to a level of T10
Pelvic Exams Q2H
Oxytocin augmentation if dilation <1
cm/hr
Tympanic temperature measured hourly
using Genius® Tympanic Thermometer
Placentas were collected for histological
examination
Blind evaluation by a single pathologist for
presence and severity of neutrophilic
infiltrates - used to characterize severity of
inflammation
To detect a significant difference in fevers between
those treated with antibiotics and those without, at
least 200 patients per arm were required
according to a power study of 80% where alpha =
0.05
Student t-test for normally distributed data
Wilcoxon Rank Sum Test for non normal data
distribution
Outcome data analyzed with Breslow-Day statistic
to determine differences in odds ratios
95% CI
Labor characteristics and events were not
statistically significant between the two arms.
Within each arm 40% developed fevers and 15%
required cesarean delivery.
Squares represent cefoxitin group
Circles represent placebo group
As shown, there were no significant
findings in placental characteristics
between the two groups. No significant
effect on any grade of neutrophillic
infiltration was seen.
No statistically significant differences
were seen in infant outcomes: APGAR
scores, cord gases, temperature at
birth, birth weight, presence of
meconium.
Antibiotic prophylaxis did not reduce rate of fever
between the two arms
Antibiotic prophylaxis had no effect on any
neonatal outcome
Placental neutrophilic infiltration was associated
with fever, but antibiotics did not reduce the fever
Conclude: epidural fever cannot
be attributed to maternal
infection
 Riley
et al. performed an observational
study where chorion-amnion culture was
not different between CLE and non CLE
groups (5% vs 4%) despite a higher rate
of fever among the CLE patients (23% vs
6%)
 This study agrees that CLE fever may not
be infections in nature…..
We tried to treat this fever with
antibiotics…
 Single
Center Study, Randomized, double
blinded
 Jiaxing
Maternity and Child Health Care
Hospital, Jiaxing China
 Between
 78
November 2008 and March 2009
healthy participants
 78
healthy nulliparous women
 Singleton cephalic presentation at term
Enrollment Exclusion Criteria:
- Baseline temp of 37.5 C or more
- Metabolic disease
- Pregnancy related complications like
DM/preeclampsia
- Increased risk of cesarean delivery
- Contraindications to CLE
 Epidural
analgesia initiated at first
request for pain relief
 Prior to analgesia patient data was
recorded:




Temperatures were recorded with a Mon-a-therm
tympanic probe (thermistor YSI 400 series)
Patients were randomly assigned Group I (PCEA
alone) or in Group II (epidural PCEA +
dexamethasone 0.2 mg/mL)
PCEA: bupivacaine 0.125% and fentanyl 1ug/mL
Women who delivered within two hours of
analgesia or required surgical delivery were
excluded
 Tympanic
membrane temperature was
measured hourly
 Fever
was defined as at least one reading
measuring 38 C or more
 Maternal
blood at baseline, full dilatation,
and cord venous blood was sampled for: IL6, TNF alpha, and IL-10
 Placentas
were also collected for
pathological examination of the degree of




Sample size of 25 patients was required at the 5%
significance level (1-tailed) and a power of 90%
assuming a SD of 0.6 C (P<0.05 = significance)
Comparisons using independent-sample t test or
Mann-Whitney U test
The change in temperature over time was
evaluated with repeated-measures analysis of
variance
Categorical variables were measured using Chi
Squared or Fisher exact tests
Protocol violated meaning that
the patient delivered within 2
hours or had a cesarean delivery
No No
differences
betweendifference
the 2 groups with
to
significant
inregard
the mean
obstetric and neonatal outcomes. No parturient had
temperature
atchorioamnionitis
corresponding
points
evidence of clinical
and notime
neonate
met
was
seenfor
between
the 2 groups, but a trend
the criteria
sepsis evaluation.
toward elevation in the mean temperature
with time was seen in group I
 Temperature
increased by 0.4 C at 4 hours
after analgesia began
 This
mirrored an elevation in IL-6
 Epidural
dexamethasone reduces CLE fever
and could be due to reductions in IL-6 levels
 IL-6
levels were not associated with clinical
chorioamnionitis – indicates that infection is
not responsible
 IL-6
could be responsible for the fever
seen in CLE
 This
finding supports that the mechanism
may be due to an underlying maternal
inflammatory process
 Epidural
dexamethasone relives epidural
related fever and could offer a promising
prophylactic intervention
 Goetzl
et al. showed that 100 mg of
methylprednisone Q4h reduced fever by
90% but resulted in a significant increase
in asymptomatic neonatal bacteremia
 Thomas
et al. and Khafagy et al. show that
epidural dexamethasone have opioid
sparing, antiemetic, and antiinflammatory effects, AND reduce post
epidural backache
 Adhesive
 Increased
Arachadonitis
Risk of Epidural abscess
 Hyperglycemia
 Risk
of Meningitis
So it is not for everyone: diabetics or the
immunosuppressed
These results are certainly interesting they
may not change clinical practice today, but
beg us to conduct future studies which
could very well alter our standard of
practice.
There is a need for larger studies and
furthermore dose finding studies
Staff Consultant: Dr. Eli Torgeson