| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Stroke. 1998;29:2607-2615.)
© 1998 American Heart Association, Inc.
Original Contributions |
Effect of the No-Flow Interval and Hypothermia on Cerebral Blood Flow and Metabolism During Cardiopulmonary Resuscitation in Dogs
From the Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Medical Institutions, Baltimore, Md.
Correspondence to Donald H. Shaffner, MD, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Hospital, 600 N Wolfe St, Baltimore, MD 21287-5842. E-mail dshaffne{at}welchlink.welch.jhu.edu
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
|---|
Background and Purpose—We sought (1) to determine the effect of brief periods of no flow on the subsequent forebrain blood flow during cardiopulmonary resuscitation (CPR) and (2) to test the hypothesis that hypothermia prevents the impact of the no-flow duration on cerebral blood flow (CBF) during CPR.
Methods—No-flow intervals of 1.5, 3, and 6 minutes before CPR at brain temperatures of 28°C and 38°C were compared in 6 groups of anesthetized dogs. Microsphere-determined CBF and metabolism were measured before and during vest CPR adjusted to maintain cerebral perfusion pressure at 25 mm Hg.
Results—Increasing the no-flow interval from 1.5 to 6 minutes at 38°C decreased the CBF (18.6±3.6 to 6.1±1.7 mL/100 g per minute) and the cerebral metabolic rate (2.1±0.3 to 0.7±0.2 mL/100 g per minute) during CPR. Cooling to 28°C before and during the arrest eliminated the detrimental effects of increasing the no-flow interval on CBF (16.8±1.0 to 14.8±1.9 mL/100 g per minute) and cerebral metabolic rate (1.1±0.1 to 1.3±0.1 mL/100 g per minute). Unlike the forebrain, 6 minutes of preceding cardiac arrest did not affect brain stem blood flow during CPR.
Conclusions—Increasing the no-flow interval to 6 minutes in normothermic animals decreases the supratentorial blood flow and cerebral metabolic rate during CPR at a cerebral perfusion pressure of 25 mm Hg. Cooling to 28°C eliminates the detrimental impact of the 6-minute no-flow interval on the reflow produced during CPR. The brain-protective effects of hypothermia include improving reflow during CPR after cardiac arrest. The effect of hypothermia and the impact of short durations of no flow on reperfusion indicate that increasing viscosity and reflex vasoconstriction are unlikely causes of the "no-reflow" phenomenon.
Key Words: cerebral blood flow • cerebral metabolism • heart arrest • hypothermia • dogs
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
|---|
Brain function after resuscitation from cardiac arrest depends on the duration of the no-flow period (arrest time).1 2 Unfortunately, the manual chest compressions delivered during cardiopulmonary resuscitation (CPR) in clinical practice produce peak aortic pressures of 60 to 80 mm Hg, with mean aortic pressures of 30 to 50 mm Hg.3 Intracranial pressure during CPR may be elevated to levels of one third of aortic pressure.4 Cerebral perfusion pressure (CPP; mean arterial pressure minus intracranial pressure) at low levels (<30 mm Hg) is associated with subnormal levels of cerebral blood flow (CBF) and poor outcome.5 6
With a CPP of 25 mm Hg during CPR in dogs when there is no arrest time, the level of CBF can be adequate to maintain brain oxygen utilization and ATP levels at 60% of baseline but not intracellular pH measured with MR spectroscopy.7 Several explanations are possible for the decrease in reflow during CPR with increasing no-flow interval, such as increased blood viscosity, perivascular swelling, and vasoconstriction.
In contrast, a 6-minute no-flow interval before CPR with a CPP of 25 mm Hg produces less CBF, and CPR at a CPP of 25 mm Hg is ineffective at restoring brain oxygen utilization, ATP, and intracellular pH.7 In the present study we prolonged the no-flow interval from 1.5 to 3 and to 6 minutes before starting CPR with a CPP of 25 mm Hg to better define the impact of arrest duration on cerebral hemodynamics during CPR. We used these intermediate lengths of arrest duration to determine whether the resistance to reflow increases gradually or abruptly after arrest occurs. We studied regional blood flows to determine regional variations in the processes causing resistance to reflow during CPR. We also tested the hypothesis that inducing hypothermia to 28°C would protect against the deterioration in supratentorial blood flow during CPR as the preceding no-flow interval increases. Preischemic hypothermia may delay perivascular swelling or vasospastic constriction but is unlikely to reduce blood viscosity. Understanding the response at smaller no-flow intervals, the regional variations, and the response to hypothermia of resistance to reflow will help to differentiate the underlying mechanisms.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
|---|
Animal Preparation
The protocol for these studies was approved by the Animal Care and Use Committee of the Johns Hopkins Medical Institutions. Thirty-six mongrel dogs weighing 10 to 15 kg were anesthetized with sodium pentobarbital (30 mg/kg IV) and fentanyl (50 µg/kg IV). The trachea was intubated, and the lungs were mechanically ventilated with 50% inspired O2. Minute ventilation was adjusted to maintain a normal range of end-tidal CO2 (35 to 40 mm Hg). Saline-filled catheters were advanced from the femoral vessels into the descending thoracic aorta, left ventricle, and right atrium. A midline burr hole was made in the skull, and a catheter was placed into the sagittal sinus at the level of the coronal sutures and advanced posteriorly 2 cm. Through the same burr hole, a thermistor was tunneled 1 cm between the skull and the dura. A vest with an inflatable bladder that covered two thirds of the thoracic circumference was secured snugly around the thorax with hook-and-loop fastener straps. A warm-water–perfused blanket was wrapped around the abdomen of dogs in the normothermic (38°C) group. The dogs in the hypothermic (28°C) group were covered with ice chips until their epidural and rectal temperatures were 28°C. Lactated Ringer's solution containing no glucose (30 mL/kg) was infused during the surgical preparation to ensure adequate cardiac filling pressures during subsequent CPR.
Measurements
All measurements were recorded immediately before arrest and
then at 5, 15, and 25 minutes during CPR. Pressures were measured in
the intrathoracic aorta, right atrium, and sagittal sinus referenced to
the level of the right atrium. Blood samples were obtained from the
aorta and sagittal sinus for blood gas and pH analysis with the
use of a Radiometer ABL3 analyzer. Blood gases and pH
were corrected to body temperature and maintained within normal range
after correction for body temperature. Oxygen content and hemoglobin
were measured with a model OSM3 hemoximeter (Radiometer). Blood glucose
concentration was measured with a model 2300A glucose analyzer
(Yellow Springs Instruments Inc).
Regional blood flows were measured with the radiolabeled
microsphere technique8 previously
validated for use during CPR.9 Radiolabeled
microspheres (15.0±0.5 µm in diameter; NEN Life Science
Products) were injected into the left ventricle as blood was
withdrawn from the ascending aorta. The pump withdrawal rate was 3.8
mL/min for 2 minutes during the prearrest measurement and 1.9 mL/min
for 5 minutes during CPR. Before injection, the microspheres
were vortexed for dispersion; 
1.5x106 spheres
were injected before arrest, and 5x105
spheres were injected at each point during CPR. The order of injection
of 6 isotope labels (153Gd,
114In, 113Sn,
103Ru, 95Nb,
46Sc) was randomized for each experiment. This
combination of sphere doses and withdrawal rates ensured collection of
2000 microspheres in the prearrest sample and 10 000 spheres
in each CPR sample. Vials of blood and tissue were analyzed on
an autogamma scintillation spectrophotometer (model 5530; Packard
Instrument Co). Spectra from pure isotope standards were used to
correct the overlap of counts between isotopes in the tissues by the
method of simultaneous equations.8
Tissue blood flow (Qt) was calculated as follows:
Qt=QrxCt/Cr,
where Qr is the arterial withdrawal
rate, Ct is the corrected tissue counts, and
Cr is the corrected counts in the reference
withdrawal blood sample. Cerebral oxygen uptake
(CMRO2) was calculated as the product of
arterial–sagittal sinus O2 content
difference and the blood flow to the cerebrum. Cerebral fractional
oxygen extraction was calculated as the arterial–sagittal
sinus O2 content difference divided by the
arterial oxygen content.
Experimental Protocol
Dogs were randomly assigned to 1 of 6 groups (n=6) with a
no-flow interval of either 1.5, 3, or 6 minutes and an epidural (brain)
temperature of either 38°C (normothermic) or 28°C
(hypothermic). After prearrest measurements were obtained,
ventricular fibrillation was induced by a 50-mA, 60-Hz
shock delivered through a pacing wire (V-Pacing Probe, American Edwards
Laboratory) advanced to the right heart from the femoral vein. CPR
commenced after 1.5, 3, or 6 minutes of arrest. The thorax was
compressed by cycling the vest pressure, as previously
described.10 The level of pressure in the vest
was adjusted by varying the pressure in the reservoir chamber. The rise
time to achieve a stable vest pressure was 150 milliseconds.
Compressions occurred at a rate of 60/min, with a 40% duty cycle. The
microprocessor also controlled a pressure-limited ventilator to deliver
100% oxygen at a variable airway pressure of 20 to 35 cm
H2O interposed after every fifth chest
compression to maintain arterial
PCO2 near normal levels. All animals
received a bolus 40 µg/kg of epinephrine at the start of CPR,
followed by a 10-µg/kg per minute continuous intravenous
infusion to maintain vascular tone without effect on cerebral
metabolism.11 12 Lactated Ringer's
was infused at a rate of 4 mL/min for 30 minutes of continuous CPR.
Vest pressure was continuously adjusted to maintain a CPP of 25
mm Hg. Mean sagittal sinus pressure, which is within a few millimeters
of mercury pressure of intracranial pressure during CPR in
dogs,13 was used as the downstream pressure for
estimating CPP.
Statistical Analysis
All measurement variables were analyzed with 2-way
ANOVA with repeated measures for the 4 groups and the 5 CPR time
points. When this analysis indicated an effect of time or
treatment group, 1-way ANOVA was performed within individual groups or
between groups at a common time. Post hoc Newman-Keuls multiple range
test was used to assess individual group differences. All values are
mean±SEM. Significance was detected at the <0.05 level.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
|---|
The CPP (mean thoracic aortic minus mean sagittal sinus pressure) during 30 minutes of vest CPR was easily maintained at the intended level of 25 mm Hg (Table 1
). The mean arterial
pressure needed during CPR to generate a CPP of 25 mm Hg was
similar in the normothermic and hypothermic groups despite
the lower baseline arterial pressures in the hypothermic
groups. The sagittal sinus pressure did not differ substantially among
the 6 groups at baseline or during CPR, but it did increase above
baseline during CPR in 5 of the 6 groups. The brain temperature was
maintained at 38°C in the normothermic groups throughout
CPR. The brain temperature fell slightly below 28°C in the
hypothermic groups during CPR.
|
Arterial blood analysis revealed no differences
between groups at the prearrest or CPR time points for carbon dioxide
or hemoglobin measurements (Table 2).
Glucose levels were greater and pH levels lower during CPR in the
normothermic groups than in the hypothermic groups.
Arterial O2 saturation during CPR was
lower in the 6-minute normothermic group, but levels were
maintained above 90%.
|
Supratentorial blood flow before fibrillation
(prearrest) was not different among the 3 normothermic
groups or among the 3 hypothermic groups (Figure 1, top panel). Prearrest
supratentorial blood flow in the hypothermic groups
was less than that in normothermic groups
(P<0.01 to P<0.001).
Supratentorial blood flow during CPR was less than
prearrest values in all 6 groups (P<0.005 to
P<0.0001) and varied with no-flow interval in the
normothermic group. Supratentorial flow
decreased during CPR as no-flow interval increased in the
normothermic groups but was unaffected by the arrest
duration in the hypothermic groups (Figure 1, bottom panel). In the
normothermic group after 6 minutes of arrest,
supratentorial flow during CPR was less than in all
5 other groups (P<0.01).
|
, 1.5 minutes of arrest at 38°C; 
, 3 minutes of
arrest at 38°C; 
, 6 minutes of arrest at 38°C;
, 1.5 minutes of arrest at 28°C; 
, 3 minutes of arrest at
28°C; and 
, 6 minutes of arrest at 28°C.
Supratentorial blood flow was less than that at
prearrest in all groups (P<0.005 to
P<0.0001). Supratentorial flow
during CPR was decreased in the group with 6 minutes of arrest at
38°C compared with the group with 6 minutes of arrest at 28°C
(P<0.01). Bottom,
Supratentorial blood flow during CPR
plotted to show effect of arrest duration (
, 38°C; 
,
28°C).
Regional blood flows showed different patterns within different
structures. Prearrest brain stem blood flow (combined medullary,
pontine, and midbrain blood flow) was greater in the
normothermic groups than in the hypothermic groups (Figure 2) (P<0.05 to
P<0.01). Brain stem flow after 5 minutes of CPR was lower
than prearrest levels only in the group with 1.5 minutes of arrest at
38°C (P<0.05). After 25 minutes of CPR, brain stem flow
was below prearrest levels in all groups except for 6 minutes of arrest
at both 38°C and 28°C (P<0.05). Brain stem blood flow
was restored to near prearrest levels early in CPR in most groups and
was greater in the normothermic groups than in the
hypothermic groups (value at 1.5 minutes of arrest at 38°C greater
than at 28°C; P<0.05) (value at 3 minutes of arrest at
38°C greater than at 28°C; P<0.001).
|
Individual regional blood flows during CPR at 38°C were less than
prearrest values in every region except the spinal cord and the pons
(P<0.05 to P<0.0001) and at 28°C were less
than prearrest values in every region except the spinal cord, pons, and
midbrain. Regional blood flows during CPR under
normothermic conditions fell as no-flow interval increased
in most supratentorial locations (Figure 3). Flow during CPR was less after 6
minutes than after 1.5 minutes of no flow in regions of the anterior
cerebral artery, middle cerebral artery, posterior cerebral artery,
hippocampus, caudate, and cerebellum (P<0.05 to
P<0.01). Flow during CPR after 6 minutes of arrest was
greater under hypothermic conditions than normothermic
conditions in the regions of the anterior cerebral artery, posterior
cerebral artery, hippocampus, and caudate (P<0.05 to
P<0.005).
|
difference from 38°C measurement at 1.5
minutes of arrest. See text for description of changes and
statistics.
Prearrest CMRO2 was not different among the 3
normothermic or among the 3 hypothermic groups (Figure 4, top panel). Prearrest
CMRO2 was decreased in the hypothermic compared
with the normothermic groups (P<0.01 to
P<0.0001). CMRO2 during CPR was less
than that at prearrest after 3 and 6 minutes of arrest at 38°C
(P<0.005 and 0.0001). CMRO2 at 38°C
after 6 minutes of arrest was lower than that at either shorter arrest
duration at 38°C (P<0.005). CMRO2
during CPR decreased as no-flow interval increased at 38°C but was
unaffected by the arrest duration at 28°C (Figure 4, bottom
panel).
|
Cerebral oxygen extraction was not different among groups at baseline
despite differences in temperature (Figure 5). Percent extraction increased above
prearrest levels during CPR in all 6 groups (P<0.01 to
P<0.0001). Extraction during CPR was greater in the
normothermic groups than in the hypothermic groups
(P<0.0005 to P<0.0001).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
|---|
The major new findings of this study are as follows: (1) CPR with a CPP of 25 mm Hg under normothermic conditions becomes progressively less effective in restoring supratentorial blood flow and CMRO2 as no-flow interval increases from 1.5 to 6 minutes. (2) Unlike supratentorial flow, these arrest durations have little effect on the reflow in the brain stem structures at this CPP under normothermic conditions. (3) Cooling the animals to 28°C before arrest prevents the detrimental effect of 6 minutes of arrest on the supratentorial blood flow and CMRO2 during CPR with this CPP. Remarkably, the absolute levels of blood flow in posterior and anterior cerebral artery distribution as well as hippocampus, caudate, and cerebellum in the hypothermic group were greater than those in the normothermic group during CPR after 6 minutes of cardiac arrest.
Others have shown that reflow in the brain decreases as the delay before CPR increases in cats,14 rabbits,15 and dogs.16 In these studies, unlike ours, there was a decrement in mean arterial pressure generated during CPR when the period of cardiac arrest was prolonged. As with our previous study, we were able to precisely control the level of CPP over a prolonged duration of CPR by continuously infusing epinephrine and by adjusting the vest inflation pressure. Despite the ability to hold CPP constant in both studies, we have shown a decrement in forebrain blood flow as arrest duration increases at low CPP. For example, we found that controlling CPP at 30 mm Hg during CPR and no period of arrest produced supratentorial blood flow of 27±4 mL/min per 100 g and maintained cerebral ATP at normal levels.17 A slightly lower CPP of 25 mm Hg during CPR with no arrest time generated a supratentorial blood flow of 20±3 mL/min per 100 g, and cerebral ATP fell to 64±14% of baseline at 10 minutes of CPR.7 Adding a 6-minute no-flow interval before CPR with a CPP of 30 mm Hg gave a heterogeneous response of supratentorial blood flows among dogs,17 suggesting that a CPP of 30 mm Hg is near the threshold required for generating supratentorial blood flow sufficient to restore cerebral ATP after 6 minutes of cardiac arrest. Setting the CPP during CPR to 25 mm Hg after 6 minutes of arrest resulted in a consistently low mean supratentorial flow of only 7±2 mL/min per 100 g at 10 minutes of CPR and an initial ATP recovery of 16±5%.7 Thus, increasing arrest duration from 0 to 6 minutes increased cerebrovascular resistance to reflow, and a CPP of 25 mm Hg was inadequate to overcome this resistance. In contrast to forebrain and cerebellar regions, brain stem regions did not display this effect of arrest duration on reflow, consistent with our previous work.7
Several mechanisms may be responsible for the increase in cerebral vascular resistance and the decrease in supratentorial blood flow as no-flow interval increases from 0 to 6 minutes. Increased viscosity of blood, constriction of blood vessels, and vascular/perivascular edema have all been implicated as increasing cerebral vascular resistance after ischemic episodes.14 Our present study attempts to improve our understanding of the causes of resistance to reflow after global ischemia by determining the amount and distribution of CBF after intermediate periods (1.5, 3, and 6 minutes) of arrest and the impact of preischemic hypothermia.
A potential redistribution of brain blood flow by sympathetic
vasoconstriction should occur with the onset of cardiac arrest and
should occur earlier than processes involving exhaustion of energy
substrates and perivascular swelling. Our present findings show
that under normothermic conditions,
supratentorial blood flow during CPR with a CPP of
25 mm Hg progressively decreases from 18±2 to 15±2 to 6±1
mL/min per 100 g as arrest duration increases from 1.5 to 3 to 6
minutes. CMRO2 levels correspond with blood flows
and decrease from 1.9±0.2 to 1.5±0.1 to 0.7±0.1 mL/min per 100
g as O2 extraction was near maximal (70% to
80%) for all 3 arrest durations during normothermia. The fall in
supratentorial blood flow, as arrest duration
increases, appears to be 2.8 mL/min per 100 g per minute of
arrest. Estimating a y-axis intercept indicates that a blood
flow of 21.3 mL/min per 100 g would be anticipated if CPR were
begun without preceding arrest. This estimation is close to the 20±3
mL/min per 100 g that we found after no arrest time in our
previous study.7 Thus, the relationship of
supratentorial blood flow to the preceding no-flow
interval is a constant decrement over the durations tested and not an
abrupt fall immediately following the onset of arrest. It is unlikely
that this progressive decrement in forebrain blood flow is related to
ischemia-induced sympathetic constriction of forebrain cerebral
vessels.
A second explanation is that stagnant blood has an increased viscosity within the microcirculation when water shifts from plasma to the intracellular compartment and causes red cell aggregation.14 Increased viscosity as the sole explanation of the increased vascular resistance to a CPP of 25 mm Hg during CPR after 6 minutes of arrest seems unlikely because similar water shifts should occur in brain stem as well. In both the present and previous studies, there was little effect of cardiac arrest duration on brain stem blood flow. Furthermore, the lack of effect of cardiac arrest duration on reflow under hypothermic conditions, which by itself increases blood viscosity, also suggests that increased viscosity is not the major mechanism. Alternatively, hypothermia may inhibit intravascular coagulation, which could be selectively activated in forebrain and which could impede reflow.
During normothermic arrest, neuronal depolarization and shifts of water into cells would be expected to be mostly complete by 3 minutes of arrest.18 19 20 Thus, if cell swelling is the mechanism of poor reflow, one might expect equivalent decrements in reflow after 3 and 6 minutes of arrest. However, the ability of the mitochondria to restore ATP rapidly may become impaired as ischemic duration is prolonged.21 Thus, another possibility is that low blood flow during CPR delivers additional water to the cells but inadequate O2 to restore ATP recovery necessary to restore cell volume. Further cell swelling, particularly in perivascular astrocyte processes, could cause capillary narrowing sufficient to limit reflow at low CPP in the early minutes of CPR. However, this hypothesis does not readily explain the lack of effect of ischemic duration on blood flow to the brain stem during CPR unless swelling is delayed in brain stem during ischemia or ATP is more easily restored in brain stem. Hypothermia decreases ATP utilization and delays the loss of ATP at the onset of ischemia. The beneficial effect of hypothermia on reflow in forebrain may be explained by delaying transcellular shifts of water during cardiac arrest and by better maintaining mitochondrial function necessary for rapid ATP regeneration.
Ordinarily, blood flow autoregulation extends to a lower CPP in brain stem than in cortex.22 A fourth possibility is that there are inherent differences in the regulation of arterioles in cerebral cortex and brain stem. Vasodilatory mediators such as adenosine, nitric oxide, and arachidonic acid metabolites, released during cerebral ischemia, may be further metabolized as ischemia is prolonged, and the rate of degradation may be different in different brain regions. Hypothermia could prolong the action of these vasodilatory metabolites by decreasing their rate of degradation or the degradation of vascular cAMP and cGMP evoked by these vasodilatory mediators. Degradation may be inherently slower in the brain stem.
Vasoconstrictive substances released during cerebral ischemia, such as high levels of potassium,23 may be accumulating after the first few minutes of circulatory arrest and be inhibited by the application of hypothermia. Neuronal depolarization under normothermic ischemia occurs in the first 90 seconds and can be delayed until approximately 4 minutes by hypothermia of this magnitude.24 25 26 This several-minute delay in the onset of depolarization from the metabolic protection of hypothermia probably occurs in our model. If so, an increase in vascular resistance may eventually occur with hypothermia when arrest is extended beyond the 6-minute duration used in the present study.
Hypothermia was applied to the whole animal before ischemia at a level considered moderate (28°C). Whole body, as opposed to selective, hypothermia was chosen for this model to help ensure uniformity of hypothermia. There was agreement of the rectal and brain temperatures in our hypothermic animals. Moderate hypothermia to 28°C, as opposed to mild hypothermia to 34°C, was chosen to ensure a substantial reduction in prearrest CMRO2 and ATP utilization rate without the cardiac instability seen with deep hypothermia in the dog. A considerable literature exists on the use of this level of hypothermia in the dog, and the changes in CBF, CMRO2, and cerebral vascular resistance are similar to what we observed in the prearrest state.27 28 29 30 31 32 In those studies, the mean level of hypothermia was 28.3°C (range, 26°C to 31°C), mean CBF was 28.2 mL/min per 100 g (range, 15 to 43; 48% of normothermia), mean CMRO2 was 2.2 mL/min per 100 g (range, 1.8 to 3; 43% of normothermia), and mean cerebral vascular resistance was 4.0 mm Hg/mL per minute per 100 g (range, 1.7 to 7.8; 222% of control). Our prearrest values showed a similar response to hypothermia with CBF of 28 mL/min per 100 g (range, 25 to 30; 57% of normothermia), CMRO2 of 0.9 mL/min per 100 g (range, 0.8 to 1.0; 38% of normothermia), and cerebral vascular resistance of 3.3 mm Hg/mL per minute per 100 g (range, 2.9 to 3.6; 142% of normothermia). As with these other whole body applications of hypothermia to 28°C in dogs, there was an increase in cerebral vascular resistance with decreases in CBF and CMRO2.
Our results indicate that in situations involving a period of reduced reflow, as in the clinical setting of inadequate CPR after a period of circulatory arrest, the resistance to reflow progressively increases in proportion to the length of the preceding no-flow period. This resistance to reflow at low perfusion pressures is most prominent in the supratentorial regions and may be one of the mechanisms underlying preserved brain stem function in cardiac arrest survivors. The attenuation by preischemic hypothermia of the processes during no flow responsible for resistance to reflow may explain some of the neuroprotective effects of hypothermia when applied before or during ischemia.
|
Acknowledgments |
|---|
This study was supported by US Public Health Service, National Institutes of Health grant NS20020 and an American Heart Association Established Investigator Award (to Dr Eleff).
Received May 21, 1998; revision received August 12, 1998; accepted August 18, 1998.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
|---|
1. Abramson NS, Safar P, Detre KM, and the Brain Resuscitation Trial I Study Group. Randomized clinical study of thiopental loading in comatose survivors of cardiac arrest. N Engl J Med. 1986;314:397–403.[Abstract]
2. Abramson NS, Sutton-Tyell K, Safar P, and the Brain Resuscitation Trial II Study Group. A randomized clinical study of a calcium-entry blocker (lidoflazine) in the treatment of comatose survivors of cardiac arrest. N Engl J Med. 1991;324:1225–1231.[Abstract]
3.
Paradis NA, Martin GM, Goetting MG, Rosenberg J,
Rivers EP, Appleton TJ, Nowak TJ. Simultaneous aortic,
jugular bulb, and right atrial pressures during cardiopulmonary
resuscitation in humans. Circulation. 1989;80:361–368.
4.
Guerci AD, Shi AY, Levin H, Tsitlik J, Weisfeldt ML,
Chandra N. Transmission of intrathoracic pressure to the intracranial
space during cardiopulmonary resuscitation in dogs. Circ
Res. 1985;56:20–30.
5. Koehler RC, Michael JR, Guerci AD, Chandra N, Schleien CL, Dean JM, Rogers MC, Weisfeldt ML, Traystman RJ. Beneficial effect of epinephrine infusion on cerebral and myocardial blood flows during CPR. Ann Emerg Med. 1985;14:744–749.[Medline] [Order article via Infotrieve]
6. Bircher N, Safar P. Cerebral preservation during cardiopulmonary resuscitation. Crit Care Med. 1985;13:185–190.[Medline] [Order article via Infotrieve]
7. Shaffner DH, Eleff SM, Brambrink AM, Sugimoto H, Izuta M, Koehler RC, Traystman RJ. Effect of no-flow interval and cerebral perfusion pressure during cardiopulmonary resuscitation on cerebral blood flow, metabolism, ATP recovery, and pH in dogs. Crit Care Med. In press.
8. Heymann MA, Payne BD, Hoffman JI. Blood flow measurements with radionuclide-labeled particles. Prog Cardiovasc Dis. 1977;20:55–79.[Medline] [Order article via Infotrieve]
9.
Koehler RC, Chandra N, Guerci AD, Tsitlik J, Traystman
RJ, Rogers MC, Weisfeldt ML. Augmentation of cerebral perfusion by
simultaneous chest compression and lung inflation with
abdominal binding after cardiac arrest in dogs. Circulation. 1983;67:266–275.
10. Halperin HR, Tsitlik JE. Programmable pneumatic generator for manipulation of intrathoracic pressure. IEEE Trans Biomed Eng. 1987;34:737–742.
11.
Michael JR, Guerci AD, Koehler RC, Shi AY, Tsitlik J,
Chandra N, Niedermeyer E, Rogers MC, Traystman RJ, Weisfeldt ML.
Mechanisms by which epinephrine augments cerebral and
myocardial perfusion during cardiopulmonary resuscitation in
dogs. Circulation. 1984;69:822–835.
12.
Gervais HW, Schleien CL, Koehler RC, Berkowitz ID,
Shaffner DH, Traystman RJ. Effect of adrenergic drugs on cerebral blood
flow, metabolism, and evoked potentials after delayed
cardiopulmonary resuscitation in dogs. Stroke. 1991;22:1554–1561.
13.
Schleien CL, Koehler RC, Gervais HW, Berkowitz ID, Dean
JM, Michael JR, Rogers MC, Traystman RJ. Organ blood flow and
somatosensory evoked potentials during and after
cardiopulmonary resuscitation with epinephrine or
phenylephrine. Circulation. 1989;79:1332–1342.
14. Fischer M, Hossmann KA. No-reflow after cardiac arrest. Intensive Care Med. 1995;21:132–141.[Medline] [Order article via Infotrieve]
15. Lee SK, Vaagenes P, Safar P, Stezoski SW, Scanlon M. Effect of cardiac arrest time on cortical cerebral blood flow during subsequent standard external cardiopulmonary resuscitation in rabbits. Resuscitation. 1989;17:105–117.[Medline] [Order article via Infotrieve]
16. Szmolenszky T, Szoke P, Halmagyi G, Roth E, Temes G, Toth I, Torok B. Organ blood flow during external massage. Acta Chir Acad Scient Hungar. 1974;15:283–288.
17.
Eleff SM, Hotek Kim, Shaffner DH, Traystman RJ, Koehler
RC. Effect of cerebral blood flow generated during
cardiopulmonary resuscitation in dogs on maintenance
versus recovery of ATP and pH. Stroke. 1993;24:2066–2073.
18. Davis D, Ulatowski J, Eleff S, Isuta M, Mori S, Shungu D, van Zijl PC. Rapid monitoring of changes in water diffusion coefficients during reversible ischemia in cat and rat brain. Magn Reson Med. 1994;31:454–460.[Medline] [Order article via Infotrieve]
19. Decanniere C, Eleff S, Davis D, van Zijl PC. Correlation of rapid changes in the average water diffusion constant and the concentrations of lactate and ATP breakdown products during global ischemia in cat brain. Magn Reson Med. 1995;34:343–352.[Medline] [Order article via Infotrieve]
20. Ekholm A, Katsura K, Siesjo BK. Coupling of energy failure and dissipative K+ flux during ischemia: role of preischemic plasma glucose concentration. J Cereb Blood Flow Metab. 1993;13:193–200.[Medline] [Order article via Infotrieve]
21.
Nishijima MK, Koehler RC, Hurn PD, Eleff SM, Norris S,
Jacobus WE, Traystman RJ. Postischemic recovery rate of
cerebral ATP, phosphocreatine, pH, and evoked potentials. Am
J Physiol.. 1989;257:H1860–H1870.
22. Sadoshima S, Thames M, Heistad D. Cerebral blood flow during elevation of intracranial pressure: role of sympathetic nerves. Am J Physiol. 1981;241:H78–H84.
23.
Wade JG, Amtorp O, Sorenson SC. No-flow state following
cerebral ischemia: role of increase in potassium concentration
in brain interstitial fluid. Arch Neurol. 1975;32:381–384.
24. Astrup J, Rehnerona S, Siesjo BK. The increase in extracellular potassium concentration in the ischemic brain in relation to the preischemic functional activity and cerebral metabolic rate. Brain Res. 1980;199:161–174.[Medline] [Order article via Infotrieve]
25. Nakashima K, Todd MM, Warner DS. The relation between cerebral metabolic rate and ischemic depolarization: a comparison of the effects of hypothermia, pentobarbital, and isoflurane. Anesthesiology. 1995;82:1199–1298.[Medline] [Order article via Infotrieve]
26.
Nakashima K, Todd MM. Effects of hypothermia on the
rate off excitatory amino acid release after ischemic
depolarization. Stroke. 1996;27:913–918.
27. Lafferty JJ, Keykhah MM, Shapiro HM, Van Horn K, Behar MG. Cerebral hypometabolism obtained with deep pentobarbital anesthesia and hypothermia (30 C). Anesthesiology. 1978;49:159–164.[Medline] [Order article via Infotrieve]
28. Michenfelder JD, Theye RA. Hypothermia: effect on canine brain and whole-body metabolism. Anesthesiology. 1968;29:1107–1112.[Medline] [Order article via Infotrieve]
29. Michenfelder JD, Milde JH. The relationship among canine brain temperature, metabolism, and function during hypothermia. Anesthesiology. 1991;75:130–136.[Medline] [Order article via Infotrieve]
30. Rosomoff HL, Holaday DA. Cerebral blood flow and cerebral oxygen consumption during hypothermia. Am J Physiol. 1954;179:85–88.
31. Steen PA, Milde JH, Michenfelder JD. The detrimental effects of prolonged hypothermia and rewarming in the dog. Anesthesiology. 1980;52:224–230.[Medline] [Order article via Infotrieve]
32. Steen PA, Newberg L, Milde JH, Michenfelder JD. Hypothermia and barbiturates: individual and combined effects on canine cerebral oxygen. Anesthesiology. 1983;58:527–532.[Medline] [Order article via Infotrieve]
Editorial Comment
Department of Emergency Medicine, Virginia Commonwealth University, Medical College of Virginia Campus, Richmond, Virginia
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
|---|
Every year approximately 250 000 to 300 000 Americans die of sudden, unexpected cardiac arrest. In the majority of cases, the trigger is a ventricular tachyarrhythmia, such as ventricular fibrillation or pulseless ventricular tachycardia.1 When such a catastrophic event occurs in a normothermic adult, brain tissue oxygen stores are exhausted in approximately 10 seconds; brain glucose and ATP are depleted within 5 minutes.2 It has long been known clinically that the incidence of post–cardiac arrest multiorgan failure, including cerebral injury, in resuscitated survivors increases progressively as the "downtime interval" before the onset of CPR is delayed.
Large clinical trials have documented that as few as 27% of adults who are resuscitated successfully regain good neurological function following the event.3 A common clinical scenario is that the patient survives the cardiac arrest with intact brain stem function but experiences little to no cerebral recovery. Unfortunately, the actual mechanism(s) responsible for postresuscitation cerebral injury are not yet fully understood, nor is there a clear understanding of the cerebrovascular hemodynamics and metabolic alterations that occur during resuscitation.
In their article, Shaffner et al report results of an important experimental study in which they maintained cerebral perfusion pressure at 25 mm Hg with a pneumatic vest chest compression device and an intravenous infusion of epinephrine in a canine cardiac arrest model. Normothermic or moderately hypothermic (38°C) pretreated animals were randomly assigned to 1.5-, 3-, or 6-minute downtime intervals of ventricular fibrillation prior to initiating 30 minutes of CPR. In normothermic animals, supratentorial blood flow after initiation of CPR decreased as the downtime interval increased, likely due to an increased resistance to reflow at low perfusion pressure. Pretreatment with moderate levels of generalized hypothermia eliminated this effect, which may (in part) help to explain the neuroprotective actions of hypothermia during global ischemia. In contrast to the effect noted on supratentorial blood flow, brain stem blood flow after initiation of CPR was relatively unaffected by the downtime interval.
This study has several potentially important clinical implications. First, the increased resistance to reflow at low perfusion pressure seen in supratentorial but not brain stem structures helps to explain why many patients survive a cardiac arrest with only brain stem function intact. Second, the experimental model can be used to further elucidate the mechanisms responsible for the detrimental cerebrovascular and metabolic changes that occur when CPR is initiated after even a relatively brief interval of cardiac arrest. Finally, the model can be used to explore future treatments to counteract the increased resistance to reflow noted in supratentorial structures during CPR. Such therapies might be mechanical or pharmacological, but they would have to be effective when administered after the onset of resuscitation to be of clinical importance and would have to be devoid of significant deleterious hemodynamic or metabolic effects. Thus, this study offers new hope for improving the neurological outcome of cardiac arrest victims.
Received May 21, 1998; revision received August 12, 1998; accepted August 18, 1998.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
|---|
1. Bayes de Luna A, Coumel P, Leclerco JF. Ambulatory sudden cardiac death: mechanisms of production of fatal arrhythmia on the basis of data from 157 cases. Am Heart J.. 1989;117:151–159.[Medline] [Order article via Infotrieve]
2. Siesjo BK. Cell damage in the brain: a speculative synthesis. J Cereb Blood Flow Metab.. 1981;1:155–185.[Medline] [Order article via Infotrieve]
3. Rogove HJ, Safar P, Sutton-Tyrrell K, Abramson NS. Old age does not negate good cerebral outcome after cardiopulmonary resuscitation: analyses from the brain resuscitation clinical trials. Crit Care Med.. 1995;23:18–25.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  S. Dichtwald, I. Matot, and S. Einav Improving the Outcome of In-Hospital Cardiac Arrest: The Importance of Being EARNEST Seminars in Cardiothoracic and Vascular Anesthesia, March 1, 2009; 13(1): 19 - 30. [Abstract] [PDF]
|
|
|
|
 |
|
 J.M. Pollock, C.T. Whitlow, A.R. Deibler, H. Tan, J.H. Burdette, R.A. Kraft, and J.A. Maldjian Anoxic Injury-Associated Cerebral Hyperperfusion Identified with Arterial Spin-Labeled MR Imaging AJNR Am. J. Neuroradiol., August 1, 2008; 29(7): 1302 - 1307. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Xu, S. Liachenko, and P. Tang Dependence of Early Cerebral Reperfusion and Long-Term Outcome on Resuscitation Efficiency After Cardiac Arrest in Rats Stroke, March 1, 2002; 33(3): 837 - 843. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||