Download Left ventricular dysfunction following rewarming from experimental

Left ventricular dysfunction following rewarming
from experimental hypothermia
TORKJEL TVEITA,1,2 KIRSTI YTREHUS,1 EIVIND S. P. MYHRE,1 AND OLAV HEVRØY2
of Medical Physiology and 2Department of Anesthesiology,
University of Tromsø, N-9037 Tromsø, Norway
1Department
resuscitation; hemodynamics; diastolic function; cold; temperature
may
be complicated by inadequate cardiac output and hypotension (20–22, 29, 31). This clinical situation has often
been termed ‘‘the rewarming shock’’ (22). Despite it
being a well-recognized concept, its underlying pathophysiology is still obscure. Thus the issue of optimal
management of accidental hypothermia has not been
settled, and further experimental studies elucidating
how hypothermia and rewarming influence the cardiovascular system are mandatory.
Hypothermia has been reported to enhance myocardial contractility (2). Cooling has been shown to aug-
REWARMING IN VICTIMS OF ACCIDENTAL HYPOTHERMIA
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ment both the strength and duration of contractions as
well as the load-independent measure of cardiac contractility (35). However, most of these observations were
performed in isolated in vitro preparations subjected to
moderate hypothermia (4, 30). In more intact animal
preparations, marked depressed left ventricular (LV)
function has been reported even at mild (34°C) levels of
hypothermia (15). In a report using excised crosscirculated dog hearts, the efficiency of myocardial LV
contractile function could not be shown as improving
during a temperature decrease of 7°C from normothermia (35).
In clinical practice, a part of rewarming therapy has
been liberal infusion of intravenous fluid to prevent
cardiovascular collapse (19). This strategy has been
based on the assumption that hypothermia is associated with intravascular hypovolemia caused by plasma
loss (8, 10, 32). However, experimental studies have
shown that rewarming causes spontaneous return of
this fluid. Thus the plasma volume levels are restored
and may even become greater than before cooling
(10, 18). As a consequence, some reports advocate
restriction of intraventricular fluids (12, 20, 21, 24)
during and after rewarming to avoid volume overload.
Thus it appears more rational to focus on myocardial
function to elucidate rewarming shock mechanisms.
We have reported earlier a deterioration of myocardial function and cardiac output in an in vivo dog model
after rewarming from hypothermia (25°C) (36). In this
model, systolic and diastolic LV functions were recorded. To avoid confounding effects due to changes in
circulating plasma volume and ventricular load alterations, we used a load-independent index, preload
recruitable stroke work (PRSW) (14), to describe
changes in LV systolic function during cooling and
rewarming. To describe diastolic function, we calculated the isovolumic relaxation index (t) and ventricular segmental stiffness constant (Kp ) (33).
MATERIALS AND METHODS
Eight overnight-fasted mongrel dogs of either sex, average
weight 20.3 kg, were used. Anesthesia was induced by an
injection of 30 mg/kg iv of pentobarbital sodium, followed by a
continuous infusion of 3.5 mg · kg21 · h21. The dogs were placed
in the right supine position and ventilated with a volumecontrolled ventilator (Servo 900C, Siemens Elema, Stockholm, Sweden). Ventilator volumes were adjusted to achieve
normocapnia, reported to be 5.06 6 0.73 (SD) kPa in normothermic dogs (16). Arterial blood gases and pH were determined by a Radiometer ABL 1 Acid-Base Laboratory (Radiometer, Copenhagen, Denmark). In accordance with Ashwood et
al. (1), pH and blood-gas values from hypothermic dogs were
not temperature corrected. The respirator adjustment was
left unchanged throughout the experimental period, and
8750-7587/98 $5.00 Copyright r 1998 the American Physiological Society
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Tveita, Torkjel, Kirsti Ytrehus, Eivind S. P. Myhre,
and Olav Hevrøy. Left ventricular dysfunction following
rewarming from experimental hypothermia. J. Appl. Physiol.
85(6): 2135–2139, 1998.—This study was aimed at elucidating whether ventricular hypothermia-induced dysfunction
persisting after rewarming the unsupported in situ dog heart
could be characterized as a systolic, diastolic, or combined
disturbance. Core temperature of 8 mongrel dogs was gradually lowered to 25°C and returned to 37°C over a period of 328
min. Systolic function was described by maximum rate of
increase in left ventricular (LV) pressure (dP/dtmax ), relative
segment shortening (SS%), stroke volume (SV), and the
load-independent contractility index, preload recruitable
stroke work (PRSW). Diastolic function was described by the
isovolumic relaxation constant (t) and the LV wall stiffness
constant (Kp ). Compared with prehypothermic control, a
significant decrease in LV functional variables was measured
at 25°C: dP/dtmax 2,180 6 158 vs. 760 6 78 mmHg/s, SS%
20.1 6 1.2 vs. 13.3 6 1.0%, SV 11.7 6 0.7 vs. 8.5 6 0.7 ml,
PRSW 90.5 6 7.7 vs. 29.1 6 5.9 J/m · 1022, Kp 0.78 6 0.10 vs.
0.28 6 0.03 mm21, and t 78.5 6 3.7 vs. 25.8 6 1.6 ms. After
rewarming, the significant depression of LV systolic variables
observed at 25°C persisted: dP/dtmax 1,241 6 108 mmHg/s,
SS% 10.2 6 0.8 J, SV 7.3 6 0.4 ml, and PRSW 52.1 6
3.6 m · 1022, whereas the diastolic values of Kp and t returned
to control. Thus hypothermia induced a significant depression of both systolic and diastolic LV variables. After rewarming, diastolic LV function was restored, in contrast to the
persistently depressed LV systolic function. These observations indicate that cooling induces more long-lasting effects
on the excitation-contraction coupling and the actin-myosin
interaction than on sarcoplasmic reticulum Ca21 trapping
dysfunction or interstitial fluid content, making posthypothermic LV dysfunction a systolic perturbation.
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computer using a commercially available program (Asystant,
Macmillan Software, New York, NY) and stored for further
processing.
Calculations. LV dP/dtmax and maximum rate of decrease in
LV pressure (LV dP/dtmin ) were obtained by differentiating
the LV pressure signal. The systolic part of the aortic flowmeter signal was integrated to obtain LV SV. Mean aortic
pressure (AoP) was obtained by electronic averaging of the
aortic pressure signal. Peak LV systolic pressure was measured as maximum LV pressure during systole. LV enddiastolic pressure and segment length (LVED-SL) were measured at the instant of maximum R wave in the
electrocardiographic signal. LV end-systolic segment length
(LVES-SL) was determined at the instant of maximum negative LV dP/dt.
Relative segment shortening in percent (SS%) was calculated as
SS% 5 [(LVED-SL 2 LVES-SL)/LVED-SL] 3 100
LV segmental stroke work (LVSW) was calculated by point-topoint integration of the loop created by LV pressure and
segment length over the entire cardiac cycle. Values were
obtained at baseline recordings at the different temperatures.
To assess regional PRSW, the slope (Mw ) of the linear
relationship between LVSW and LVED-SL was obtained by
deloading the heart by caval balloon inflations (13, 14). Data
were obtained from at least 10 consecutive beats during the
abrupt reductions of preload, and a linear regression analysis
was employed
LVSW 5 Mw(LVED-SL 2 k)
where k is the x-axis intercept at zero pressure.
The time constant of isovolumic relaxation t was calculated
assuming a nonzero asymptote of LV pressure decay by using
the method of Raff and Glantz (27). LV negative dP/dt was
plotted against ventricular pressure, as measured every 5 ms
between peak negative dP/dt and 5 mmHg above enddiastolic pressure of the next beat (corresponding to the
opening of the mitral valve) to yield t as the negative inverse
of the slope.
Segmental ventricular stiffness was determined by fitting
the series of end-diastolic pressure-segment length data
obtained by caval occlusion to an exponential relationship
according to the formula
Ped 5 aeksLVED-SL 1 b
where Ped is end-diastolic pressure, Ks is segmental stiffness,
and b is the extrapolated Ped intercept at zero length. This
analysis was done by using a commercially available program
package (Asystant, Macmillan Software).
Statistics. Data, presented as means 6 SE, were analyzed
by analysis of variance for repeated measurements. When
significant differences were observed, values were compared
by using Tukey’s test. P , 0.05 was considered significant.
RESULTS
All animals survived cooling and rewarming. Except
for single ectopic beats, there were no episodes of other
arrhythmias during cooling and rewarming.
Hemodynamic variables are given in Table 1.
Cooling. Cooling to 25°C resulted in depression of LV
function, demonstrated as a significant depression of
all variables measured, except LVES-SL and LV enddiastolic pressure. The latter remained unchanged
throughout the experiment.
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normocapnia was maintained. Saline (0.15 ml · kg21 · min21 )
was administered continuously. The heart was exposed
through a left-sided thoracotomy and the pericardium was
opened by a longitudinal incision, reflected to form a cradle
for suspending the heart. Approval for the experiments was
obtained from the National Animal Research Committee, and
the experiments conformed with the recommendations of the
European Council for Laboratory Animal Science.
Hemodynamic measurements. An electromagnetic probe
was positioned around the ascending aorta to measure stroke
volume (SV) flow (Scalar Instruments, Delft, The Netherlands). Left ventricular pressure was obtained by a microtransducer catheter (Dräger Medical Electronics, The Netherlands) inserted via the left carotid artery. Aortic pressure was
measured through a fluid-filled polyvinyl catheter positioned
in the thoracic part of descending aorta via the left femoral
artery and connected to a Statham P23 ID transducer
(Spectramed).
To measure instantaneous segmental dimensions, a pair of
5-MHz piezoelectric ultrasonic crystals (diameter 2–3 mm)
was positioned through stab wounds in the anterior part of
the LV wall and connected to an ultrasound dimension meter
(Schleusseler). The crystals were placed ,10 mm apart and
oriented in parallel to the diagonal branches of the left
descending coronary artery.
Two 5-ml Fogarty balloon-occlusion catheters (23-Fr) were
placed proximally in both caval veins via the left jugular and
femoral veins. Rapid alterations of ventricular preload were
achieved by inflating the balloons simultaneously. Position of
catheters was controlled by fluoroscopy. Balloon inflation
created a transient venous occlusion resulting in a progressive fall in LV pressure and segment length. During an
expiratory pause, caval occlusion was performed over a 10- to
15-s period, resulting in a reduction in LV systolic pressure by
25–30 mmHg over 10–15 cardiac cycles. Recordings during
bicaval occlusion were rejected if heart rate increased above
10% or if arrhythmia occurred. In this case, LV pressure and
segment length recordings during caval occlusion were repeated after a short stabilization period.
Stability of the model with respect to hemodynamics was
confirmed, as no alterations were observed during 5 h at
normothermia in two sham-operated animals. Especially
cardiac output, peak LV systolic pressure, and maximum rate
of increase in LV pressure (LV dP/dtmax ) remained unchanged.
Core cooling and rewarming. The method of core cooling
and rewarming has been previously described (36). Briefly,
the animals were cooled and rewarmed by circulating water
of different temperatures through heat-exchanging tubes
placed in the esophagus and lower bowel. The desired temperature was easy to achieve and to maintain stable (60.2°C)
during measurements by using this method. Core temperature was continuously recorded by a thermocouple wire
portioned in the thoracic aorta and monitored on a thermocouple controller (Bailey Instruments). The animals were
cooled gradually to 25°C and subsequently rewarmed to 37°C.
The cooling and rewarming procedure lasted 328 6 9 min,
with the time equally devided between cooling and rewarming stages.
Experimental protocol. Electrocardiogram, aortic pressure
and flow, LV pressure, and segment length were continuously
recorded on a Gould ES 200 recorder (Gould, Cleveland, OH).
At different core temperatures, after a short stabilization
period with stable temperature, baseline recordings of all
parameters were made over a 10-s period. In addition,
measurements of LV pressure and segment length were
acquired during bicaval occlusion at the different core temperatures. All recordings were digitized at 200 Hz to an online
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REWARMING AND MYOCARDIAL FUNCTION
Table 1. Hemodynamic effects of hypothermia and rewarming
HR, beats/min
AoP, mmHg
LVSP, mmHg
LVEDP, mmHg
SV, ml/beat
LV dP/dtmax , mmHg/s
LV dP/dtmin , mmHg/s
TPR, mmHg · l21 · min21
LVED-SL, mm
LVES-SL, mm
SS, %
t, ms
Kp , mm21
SW, mmHg/mm
Prehypothermic
31°C Cooling
25°C
31°C Rewarming
Posthypothermic
145 6 4
120 6 5
131 6 5
7.9 6 0.7
11.7 6 0.7
2,180 6 158
2,243 6 139
72.5 6 5
11.3 6 0.7
9.0 6 0.5
20.1 6 1.2
25.8 6 1.6
0.28 6 0.03
305.9 6 28.9
105 6 4
84 6 4
92 6 4
7.8 6 0.7
9.9 6 0.5
1,577 6 103
1,701 6 122
83 6 6
11.0 6 0.7
9.1 6 0.5
17.0 6 1.2
41.5 6 1.6
0.41 6 0.05
167.3 6 13.9
58 6 3*
60 6 3*
70 6 3*
9.1 6 0.9
8.5 6 0.7*
760 6 78*
874 6 79*
129 6 8*
10.3 6 0.6*
9.0 6 0.5
13.3 6 1.0*
78.5 6 3.7*
0.73 6 0.10*
77.4 6 11.3*
116 6 3†
77 6 2†
81 6 4†
7.4 6 0.7
8.0 6 0.2†
1,228 6 68†
1,284 6 68†
84 6 3
10.9 6 0.6
9.5 6 0.4
11.9 6 1.0†
42.6 6 2.2
0.43 6 0.06
122.1 6 16.1†
139 6 4
93 6 3*
88 6 11*
6.7 6 0.6
7.3 6 0.4*
1,241 6 108*
1,353 6 98*
95 6 8
10.9 6 0.6
9.8 6 0.5*
10.2 6 0.8*
33.2 6 3.4
0.36 6 0.02
139.0 6 16.5*
Corresponding to prehypothermic control values, an
approximately threefold increase in both t and stiffness
Kp was found at 25°C. At 25°C, the LV PRSW index Mw
decreased 70% compared with baseline (Fig. 1). In
accordance with this, LV stroke work was 25% of what
was observed before cooling. Total peripheral resistance (TPR) significantly increased at 25°C.
Rewarming. During rewarming, an increase in heart
rate was measured, whereas AoP, LV pressure, SV,
dP/dtmax, dP/dtmin, and SS% were all still lowered at
31°C compared with the corresponding values at 31°C
during cooling (Table 1). Values for t and Kp shown
during cooling (31°C) returned to within the same level
at 31°C rewarming, whereas PRSW index Mw at 31°C
rewarming was 40% less than during cooling (Fig. 1).
LVSW was 73% of what was observed at 31°C during
cooling (Table 1).
Fig. 1. Effects of cooling and rewarming on left ventricular preload
recruitable stroke work. Values are means 6 SE (n 5 8 dogs). * P ,
0.05, significantly different compared with prehypothermic values.
† P , 0.05, significantly different when comparing cooling at 31°C
with rewarming at 31°C.
Posthypothermic depression. Posthypothermic depression of LV function was demonstrated as a 40% reduction in PRSW index Mw (Fig. 1), and a 54% reduction in
LVSW, compared with prehypothermic baseline values
(Table 1). However, heart rate, LVED-SL, t, and Kp
returned to within control values. Posthypothermic
TPR was not significantly changed from control values.
DISCUSSION
This study was aimed at elucidating whether ventricular hypothermia-induced dysfunction persisting
after rewarming could be characterized as a systolic,
diastolic, or combined disturbance. Systolic function
was significantly depressed after rewarming, as indicated by a reduced LV dp/dtmax, reduced SS%, reduced
SV, and a reduced contractility index Mw. These findings indicate depressed isovolumic pressure generation
and ventricular wall shortening, i.e., the excitationcontraction coupling and the actin-myosin interaction
may be persistingly depressed despite normalized body
temperature. Because heart rate returned to baseline
after rewarming, this factor does not confound these
observations.
AoP was still depressed after rewarming. TPR was
nonsignificantly increased despite a depressed SV. During such conditions, a significant increase in peripheral
arterial tonus should be expected and reflected in a
significantly increased TPR. The reported insignificant
increase of TPR indicates a persisting cooling-induced
paralysis of peripheral arteriolar tonus, which may
contribute to the depressed AoP. However, if this was a
dominant factor and contractility was normal, SV
should have increased or, at least, been unchanged
compared with baseline. Thus the depressed AoP must
partly be caused by persisting reduced cardiac contractility causing a decreased cardiac output. Our findings
of posthypothermic reduction in SV and AoP are in
accordance with those of other investigators (5, 11, 25,
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Values are means 6 SE; n 5 8 dogs. HR, heart rate; AoP, mean aortic pressure; LVSP, peak left ventricular systolic pressure; LVEDP, left
ventricular end-diastolic pressure; SV, stroke volume; LV dP/dtmax , maximum rate of left ventricular pressure rise; LV dP/dtmin , maximum rate
of left ventricular pressure decline; TPR, total peripheral resistance; LVED-SL, left ventricular end-diastolic segment length; LVES-SL, left
ventricular end-systolic segment length; SS, segment length shortening; t, constant of isovolumic relaxation; Kp , modus of segmental stiffness;
SW, segmental stroke work. * P , 0.05, significantly different compared with prehypothermic values; † P , 0.05, significantly different when
comparing cooling at 31°C with rewarming at 31°C.
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The skilled technical assistance of Fredrik Bergheim is gratefully
acknowledged.
This study was supported by grants from the Norwegian Research
Council for Science and the Humanities, the Norwegian Council on
Cardiovascular Diseases, and the Laerdal Foundation for Acute
Medicine.
Address for reprint requests: T. Tveita, Institute of Medical
Biology, Univ. of Tromsø, N-9037 Tromsø, Norway.
Received 21 April 1998; accepted in final form 21 August 1998.
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cooling-induced decreased sarcoplasmic Ca21 trapping
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baseline and so was end-diastolic stiffness. Thus none
of these observations indicates that ventricular diastolic dysfunction persisted after rewarming. Because
neither end-diastolic pressure nor segment length differed from baseline after rewarming, end-diastolic preload must be considered similar to baseline, excluding a
preload decrease as a possible explanation for the
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probably the main reason for the reduction of cardiac
output and systemic arterial pressure, occasionally
observed after rewarming.
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