British Journal of Anaesthesia 1996; 77: 591–596
Effect of hypothermia on rectal mucosal perfusion in infants
undergoing cardiopulmonary bypass
P. D. BOOKER, D. P. PROSSER AND R. FRANKS
Summary
We have examined the effect of profound
hypothermia on gut mucosal perfusion in 20
infants, aged 1.4–45 weeks, requiring cardiopulmonary bypass (CPB). After induction of anaesthesia, a laser Doppler probe was inserted 8 cm
into the patient’s rectum to allow monitoring of
rectal mucosal perfusion (“flux”) throughout
operation. Steady-state observation periods (5 min
with no change in temperature or mean arterial
pressure (MAP)) were achieved after 10 min on
CPB at 35 ⬚C, after CPB-induced cooling to 15–25 ⬚C,
immediately before rewarming and after rewarming to 35 ⬚C. Throughout these periods flow rate
9
9
was 100 ml kg 1 min 1, packed cell volume was
kept constant and Pa CO2 maintained at 5.3 ⫾ 0.5
kPa. No vasoactive drugs were used. Initial warm
and rewarm MAP values (46 mm Hg) were significantly lower (P : 0.008) than during the cold CPB
periods (63 and 64 mm Hg). Mean flux in the first
cold period (152) was significantly lower (P :
0.001) than that in the first warm CPB period (211).
Post-rewarm flux (127) was significantly lower
than all other CPB flux values (P : 0.004). We conclude that although hypothermia significantly
reduced mucosal blood flow, rewarming produced
even greater reductions in mucosal perfusion that
may prove crucial in the development of mucosal
hypoxia. (Br. J. Anaesth. 1996; 77: 591–596)
Key words
Heart, cardiopulmonary bypass. Measurement techniques,
flowmetry.
Gastrointestinal
tract,
mucosal
perfusion.
Infants. Hypothermia. Surgery, cardiovascular.
Splanchnic perfusion during cardiopulmonary
bypass (CPB) may be jeopardized by vasoconstriction secondary to hypocapnia1 or to increased concentrations of angiotensin II,2–5 vasopressin6 or
thromboxane.7 8 Haemodilution,9 hypottension10 and
microvessel occlusion, secondary to platelet and
leucocyte aggregation,11 may also reduce oxygen
delivery to the gut during CPB. Furthermore,
animal8 12 13 and adult clinical studies14–17 have confirmed that transient gut mucosal ischaemia may
occur during or after CPB. A sufficient reduction in
gut mucosal blood flow to induce mucosal hypoxia
can cause mucosal barrier breakdown and allow
bacterial translocation,18 as the integrity of the intercellular “tight” junctions is an ATP-dependent
process.19 The incidence of post-CPB gut dysfunction20 21 and endotoxaemia during CPB22 23 show a
positive correlation with increasing CPB time in
adults. Translocation of bacteria and endotoxins
from the gut lumen into the portal and systemic circulations is usually self-limiting but may cause
sepsis, multiple organ failure (MOF), or both.24–27
The incidence of MOF in infants and children
undergoing CPB (1.6–3.5%)28–30 is apparently much
higher than that in adults (0.37%).27 31 32 Although
differences in diagnostic criteria or pathophysiology, or both, could account for this disparity,
the major dissimilarities between adult and paediatric CPB techniques may be equally important.
Profound hypothermia is used in paediatric cardiac
surgery to protect vital organs during periods of
reduced flow CPB or circulatory arrest. Although
the potential for hypothermic CPB to cause gut
mucosal hypoxia may be mitigated by the reduction
in cellular metabolic rate, hypothermia also increases
the affinity of haemoglobin for oxygen and may
reduce gut mucosal blood flow.12 33–35 We studied
infants
undergoing
CPB-induced
profound
hypothermia and, using laser Doppler flowmetry
(LDF), determined how rectal mucosal blood flow
changed with temperature, maintaining all other
factors constant.
Patients and methods
With local Ethics Committee approval and written,
informed parental consent, we studied 20 infants,
aged 1.4–45 weeks, requiring profound hypothermia
during CPB for elective or urgent cardiac surgery.
Infants :2.5 kg in weight or with coarctation of the
aorta were excluded. No premedication was used.
Anaesthesia was induced with thiopentone 4 mg
kg91 and neuromuscular block was produced with
vecuronium 0.2 mg kg91 h91. Anaesthesia was maintained with i.v. infusions of midazolam 240 ␮g kg91
h91 and diamorphine 24 ␮g kg91 h91, supplemented
with 0.25% isoflurane in oxygen or air, or both,
before CPB.
P.D. BOOKER, FRCA, D.P. PROSSER, FRCA, R. FRANKS, FRCS,
Royal Liverpool Children’s NHS Trust, Eaton Road, Liverpool
L12 2AP. Accepted for publication: May 13, 1996.
Correspondence to P. D. B.
592
British Journal of Anaesthesia
PCV was maintained constant at 25–30 and Ca2;
concentration and arterial base deficit were kept
within normal limits, although no drugs were given
during or within 10 min of any study period.
Maintenance of a constant PaO (20 ⫾ 5 kPa)
throughout CPB was aided by the use of an in-line
PaO monitor (Polystan), and a capnograph (Datex
Ltd), attached to the gas outlet port of the oxygenator,
helped maintain a constant PaCO2 (5.3 ⫾ 0.5 kPa,
temperature uncorrected, i.e. alpha-stat regulation36),
together with intermittent arterial blood-gas measurements. All patients maintained MAP at 30–80 mm
Hg with a CPB flow rate of 100 ml kg91 min91, without the use of vasoactive drugs. Inotropic support was
given as required to aid weaning from CPB, when the
warm-2 readings were complete.
Comparisons between mean flux and mean MAP
obtained during the initial warm CPB period and other
flux and MAP values were analysed using the Wilcoxon
matched pairs signed rank test and exact two-tailed
tests (SPSS). Kendall’s tau-b correlation coefficient was
used to examine the relationships between MAP and
flux and between CPB time and flux.
2
2
Figure 1 Laser Doppler probe with attached silastic ring. The
proximal 10 cm of glass fibre cable had been thickened to
provide sufficient rigidity to insert the probe 8 cm into the
rectum. The probe’s optical prism is located at point P.
A central venous catheter was inserted, a femoral
artery cannulated for monitoring of systemic arterial
pressure and temperature probes placed in the midoesophagus, rectum and nasopharynx. A laser
Doppler probe (Moor Instruments Ltd) was inserted
8 cm into the patient’s rectum, the probe’s special
design ensuring that its optical prism lay against the
mucosa (fig.1). The probe was connected to a
MBF3/D monitor (Moor Instruments Ltd) and
computer; later analysis of recordings was made
using Moorsoft data interpretation software (Moor
Instruments Ltd). The hollow fibre D701 oxygenator (Dideco) used for CPB was primed with a
warmed mixture of blood and crystalloid such that
the packed cell volume (PCV) 10 min after initiation
of CPB was 25 ⫾ 5% and blood and core temperatures 35 ⫾ 0.5⬚C.
When the patient had been established on non-pulsatile CPB at a flow rate of 100 ml kg91 min91 for 10
min and nasopharyngeal and rectal temperatures were
constant at 35 ⫾ 0.5⬚C, baseline measurements of
femoral mean arterial pressure (MAP) and rectal
mucosal flux were recorded for another 5 min
(“warm-1”). Patients were then cooled on CPB to
15–25 ⬚C, depending on the anticipated duration of
low flow or circulatory arrest required. The rate of
cooling and rewarming was controlled to approximately 1 ⬚C min91. All measurements were repeated
during another three “steady-state” 5-min periods:
immediately before initiation of low flow (“cold-1”),
10 min after resumption of full flow (“cold-2”) and
after rewarming to 35 ⬚C (“warm-2”). “Steady state”
was defined as a period when nasopharyngeal and
rectal temperatures did not vary by 90.1 ⬚C and MAP
did not vary by 92%. Arterial blood-gas tensions,
PCV and ionic calcium (Ca2;) concentrations were
measured immediately before and after each period.
Results
Median age of the patients was 16.5 (range 1.4–45)
weeks and median weight 5.3 (2.9-7.9) kg (table 1).
Patients were cooled to a median nasopharyngeal
temperature of 17.9 (14.5–24.6) ⬚C during CPB for
periods of 21–132 min. Median CPB time was 122
(102–355) min.
Mean flux values were compared with the mean
flux obtained during the first normothermic CPB
period (warm-1) (table 2, fig. 2). All CPB data were
measured while cardiac output (pump flow rate) was
controlled and while the patient was not subject to
the effects of vasoactive drugs. Mean cold-1 flux was
significantly lower than mean warm-1 flux (P :
0.001). Mean cold-2 flux was not significantly different from mean cold-1 flux (P : 0.12). Mean warm2 flux was significantly lower than mean warm-1 flux
(P : 0.001), mean cold-1 flux (P : 0.004) and cold2 flux (P : 0.001). Mean flux values before and after
CPB were also recorded and compared with mean
warm-1 flux, although non-CPB data were obtained
during periods when cardiac output was uncontrolled and vasoactive drugs were being used.
MAP increased significantly on cooling (P :
0.001), returning to baseline values on rewarming
(table 3, fig. 2). There were no significant differences
between MAP during the warm-1 and warm-2
periods (P : 0.91) or between the cold-1 and cold-2
periods (P : 0.98). Table 4 shows the correlations
between flux and MAP at different periods. There
were no significant correlations between MAP and
flux at any time other than at warm-1 (r : 0.33; P :
0.04). Table 5 shows that there were no significant
correlations between CPB time and flux.
Discussion
We have demonstrated that rectal mucosal perfusion
or “flux”, measured using LDF, was reduced significantly secondary to CPB-induced core cooling to
Hypothermia and rectal mucosal perfusion in infants during CPB
593
Table 1 Patient data. VSD:Ventricular septal defect, TGA:transposition of the great arteries, TAPVC:total
anomalous pulmonary venous connection, AVSD:atrioventricular septal defect, PAB:pulmonary artery band,
DILV:double inlet left ventricle, APW:aortic–pulmonary artery window, FALLOT:tetralogy of Fallot,
TA:tricuspid atresia
Patient
No.
Age
(weeks)
Weight
(kg)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Median (range)
41
11
23
38
16
44
26
18
14
13
1.3
45
6.8
8.5
16
17
17
36
9.0
1.4
16.5 (1.4–45)
6.8
3.8
5.7
7.8
4.2
6.1
5.8
4.6
3.9
5.1
4.5
7.9
4.0
7.3
5.2
5.2
5.4
7.3
5.3
2.9
5.3 (2.9–7.9)
Diagnosis
TAPVC
VSD
APW
FALLOT
AVSD
DILV
VSD
AVSD
AVSD
AVSD
TGA
TGA, VSD
TGA
VSD, PAB
AVSD
AVSD
VSD, AS
TA
VSD
TGA, VSD
Lower temp
(⬚C)
Time at lowest
temp. (min)
16.4
16.0
17.5
21.2
17.6
14.5
16.5
15.3
17.9
21.6
18.3
24.6
16.6
17.9
22.0
19.3
21.0
23.4
18.5
15.9
17.9 (14.5–24.6)
55
43
51
31
34
132
51
72
82
60
71
29
100
44
21
46
33
37
53
81
51 (21–132)
Table 3 Mean femoral arterial pressures during each study
period (mean (SD)). Values are compared with data obtained
during the warm-1 period. Warm-1:initial normothermic CPB,
cold-1:pre-surgery hypothermic CPB, cold-2:post-surgery
hypothermic CPB, warm-2:at end of rewarming, normothermic
CPB, and post-CPB .20 min after CPB
Pre-CPB
Warm-1
Cold-1
Cold-2
Warm-2
Post-CPB
Arterial pressure (mm Hg)
P
54.4 (12.9)
46.2 (15.1)
62.5 (14.9)
63.7 (21.0)
45.8 (13.4)
55.0 (15.8)
0.03
—
0.0001
0.008
0.91
0.06
Table 4 Correlations between MAP and flux at different times.
Warm-1:Initial normothermic CPB, cold-1:pre-surgery
hypothermic CPB, cold-2:post-surgery hypothermic CPB,
warm-2:at end of rewarming, normothermic CPB, and postCPB .20 min after CPB
Figure 2 Mean (SD) arterial pressure (MAP) (●)and rectal
mucosal flux (■)at each observation period. All readings were
obtained over 5 min during steady state conditions. Pre : Before
CPB; warm-1 : initial normothermic CPB; cold-1 : before
surgery hypothermic CPB; cold-2 : after surgery, hypothermic
CPB; warm-2 : at the end of rewarming, normothermic CPB;
and post : 920 min after CPB. *Significantly different from
values at warm-1 (P : 0.05).
Pre-CPB
Warm-1
Cold-1
Cold-2
Warm-2
Post-CPB
Table 2 Mean rectal mucosal flux during each study period
(mean (SD)). Values are compared with data obtained during the
warm-1 period. Warm-1=Initial normothermic CPB, cold1:pre-surgery hypothermic CPB, cold-2:post-surgery
hypothermic CPB, warm-2:at end of rewarming, normothermic
CPB, and post-CPB .20 min after CPB
Table 5 Correlations between CPB time and flux at different
times. Warm-1:Initial normothermic CPB, cold-1:pre-surgery
hypothermic CPB, cold-2:post-surgery hypothermic CPB,
warm-2:at end of rewarming, normothermic CPB, and postCPB .20 min after CPB
Pre-CPB
Warm-1
Cold-1
Cold-2
Warm-2
Post-CPB
Flux (arbitrary units)
P
251 (67)
211 (93)
152 (67)
159 (59)
127 (51)
209 (55)
0.03
—
0.001
0.001
0.001
0.99
Pre-CPB
Warm-1
Cold-1
Cold-2
Warm-2
Post-CPB
r
P
0.06
0.33
0.24
0.18
0.07
90.11
0.72
0.04
0.14
0.28
0.65
0.52
r
P
90.16
90.042
90.095
90.063
0.021
90.074
0.33
0.80
0.56
0.70
0.90
0.65
594
14–24⬚C compared with flux during normothermic
CPB at the same flow rate. Further reductions in
flux were seen during and after rewarming, although
ventricular ejection sometimes produced pulsatile
flow during this period. Pulsatile flow would be
expected to increase rather than decrease mucosal
perfusion,2 5 compared with non-pulsatile flow which
was invariable during the hypothermia period.
Furthermore, changes in flux at different temperatures did not correlate with changes in MAP (table
4) and, therefore, reflect variable shunting of blood
away from the mucosa.
Experimental animal work8 13 37 has shown that
gut mucosal ischaemia may occur during normothermic CPB despite maintenance of pre-CPB
superior mesenteric arterial (SMA) flow rates.
Recent animal work has suggested that overall gut
blood flow and oxygen consumption may increase
progressively during normothermic CPB but are
associated with a decrease in mucosal blood flow in
the stomach, ileum and rectum.13 This diversion of
blood away from the gut mucosa is thought to be
caused by CPB-induced release of vasoactive
substances that affect regional blood flow at the
macro- or microcirculatory levels, or both.38
Vasoconstrictors known to be released during CPB
in adults include vasopressin,6 catecholamines,4 39 40
angiotensin II 2–5 and thromboxane A2 and B2.7 8 41
Experimental CPB studies using animal models
have demonstrated either a reduction,34 no
change12 35 or an increase42 in SMA flow during
hypothermic (25⬚C) CPB. These inconsistent
results may be explained by the use of different
methodologies, different baseline references and
varying perfusion flow rates, and PaCO2 control.
Nevertheless, it would seem from these studies that
shunting of blood away from the mucosa is unlikely
to be occurring at the arteriolar regulatory level. The
decrease in mucosal flux during profound hypothermia, compared with the initial warm CPB value,
therefore, must reflect either arteriovenous shunting
at the sub-mucosa level or redistribution of blood
from the mucosa to the muscularis and serosa. Blood
distribution within the gut wall, regulated by precapillary sphincter tone, is thought to be governed by
local tissue oxygen tension.43 Thus gut mucosa,
which has a high metabolic rate, normally receives
65–92% of total gut blood flow.44 45 This theory of
pre-capillary sphincter regulation, although compatible with the decrease in flux during hypothermia,
does not explain the decrease in flux seen during
rewarming. We postulate that normal local regulation of pre-capillary sphincter tone was overwhelmed
by high concentrations of circulating vasoconstrictors, as demonstrated during normothermic CPB in
adults (see above).
Laser Doppler flowmetry (LDF) provides a direct
measure of tissue blood flow by using the fact that
when laser light is reflected off a moving red blood
cell, it undergoes a Doppler frequency shift, the
amount of shift being dependent on the speed of the
moving object. The laser light is delivered to the
tissue surface via a single glass fibre, another fibre
being used to collect a portion of the back-scattered
light. This photodetector signal is then amplified and
British Journal of Anaesthesia
the signal-to-noise ratio improved by eliminating
noise that is outside the bandwidth of the Doppler
frequencies. The analogue signal is then converted
into a digital signal for spectral analysis, which is
primarily a measure of the average Doppler frequency. The output from a LDF is referred to as
“flux”, which is a measure of the number of red
blood cells flowing through a unit volume of tissue
per unit time.
There are problems in using LDF to measure
tissue perfusion. First, the technique generates only
arbitrary units of measure; however, gut mucosal
flux values have been shown experimentally to correlate linearly with changes in gut mucosal blood flow
measured using other techniques, over a wide range
of flow rates.46–48 Second, the probe tends to be
position-sensitive, although this is not a problem
when making successive measurements over a relatively short time period in paralysed patients.
Finally, to draw any meaningful conclusions from
flux data, it has to be assumed that the tissue
measurement volume, at most 6 mm,3 49 is representative of a larger region of tissue, although fortunately, rectal mucosa has a relatively homogeneous
vascular anatomy. Although it cannot be assumed
that rectal mucosal blood flow is representative of
mucosal blood flow in other areas of the gut, recent
animal work has suggested that rectal mucosal perfusion decreases during CPB in a similar manner to
that of gastric and ileal mucosa, as measured
tonometrically.13
Haemodilution results in a reduced density of red
blood cells reflecting light back to the monitoring
probe, causing a decrease in flux levels with no
change in “perfusion”. Similarly, a decrease in mean
MAP during CPB, compared with levels before
CPB, may result theoretically in an increase in mean
red cell transit time at the capillary level, further
tending to reduce flux values. Thus a reduction in
flux during the initial warm CPB period compared
with the value before CPB was not unexpected.
Thereafter, however, PCV was maintained at a constant level and changes in flux during CPB cannot be
attributed to changes in PCV. MAP values changed
significantly with temperature, although they did not
correlate with flux other than at the initial warm-1
period (table 4, fig. 2). We found no correlation
between flux values and duration of CPB (table 5).
Our results contrast with those of Ohri and
colleagues, who found no significant difference in
jejunal mucosal flux at 28⬚C during CPB in dogs
compared with baseline readings obtained before
CPB.12 After rewarming, they measured a 70%
increase in flux and a simultaneous decrease in
jejunal mucosal pHi from 7.42 to 7.12. These latter
results agree with tonometric pHi data from other
experimental and clinical studies in adults and confirm that mucosal hypoxia is most likely to occur
during the rewarming phase.15 50 51 Although a
significant correlation between pHi and blood flow
may occur under some conditions,50 52 pHi relates to
blood flow only insofar as it relates to the adequacy
of tissue oxygenation.53
Lactate concentrations in skeletal muscle and
plasma have been shown, in adult patients during
Hypothermia and rectal mucosal perfusion in infants during CPB
CPB, to increase after rewarming, suggesting that a
shift towards anaerobic cellular metabolism may
occur even during normothermic full flow CPB.54 55
Profound hypothermia and low flow perfusion are
likely to exacerbate this tendency. Gut mucosa
becomes hypoxic during rewarming not only
because of diversion of blood to other parts of the
gut but also because of increased oxygen consumption.12 Increased mucosal oxygen consumption
would be expected as the cellular metabolic rate
increases with increasing temperature, but hypoxia
may also be exacerbated by an oxygen debt being
incurred during cooling. CPB-induced hypothermia
immediately decreases mucosal oxygen delivery
because of decreased blood flow, haemodilution,
hypotension and the increased affinity of haemoglobin for oxygen, while tissue cooling and reductions in cellular metabolism occurred more slowly.
Although increased tissue requirements for oxygen
during rewarming may be met to some extent by
increased oxygen extraction,12 56 experimental
work52 suggests that blood flow is the major factor
limiting intestinal oxygen consumption.52 We have
found no evidence that capillary recruitment or precapillary sphincter vasodilatation occurs after
rewarming from profound hypothermia, rather the
reverse.
In conclusion, our finding of reduced rectal
mucosal flux during hypothermia is probably of less
clinical relevance than that of decreased flux during
and after rewarming, a period when the likelihood of
mucosal hypoxia is highest. We recommend that
strategies for improving gut perfusion, such as supranormal CPB flow rates or administration of dopexamine57 58 or epoprostenol,59 should be directed at
the rewarming phase, which represents a particularly
critical time for the continued maintenance of
normal mucosal barrier function.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
Acknowledgements
18.
Financial support for the study was given by the Royal Liverpool
Children’s NHS Trust Research Fund.
19.
20.
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