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Postanoxic coma: prognosis after therapeutic hypothermia
Bouwes, A.
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Bouwes, A. (2012). Postanoxic coma: prognosis after therapeutic hypothermia
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Download date: 19 Jun 2017
Chapter 10
General discussion and future perspectives
131
Chapter 10
Prediction of outcome
The studies described in this thesis show that a reliable prognosis of a poor outcome is
possible in patients with postanoxic coma who have been treated with hypothermia after
cardiopulmonary resuscitation (CPR), but current international guidelines need to be
revised. Use of those guidelines could lead to incorrect treatment withdrawal. It is also
clear that there are some important pitfalls of which clinicians involved in making a
prognosis should be aware. In this general discussion, current knowledge about
prognostication in postanoxic coma after hypothermia and potential neuroprotective
strategies will be described. Also future challenges will be addressed.
Several important issues should be kept in mind when reading this discussion. First, most
patients described in literature about prognostication after CPR are patients with a
primary cardiac cause for the cerebral anoxia-ischemia. This limits conclusions about
prognostication in patients with postanoxic coma from other causes. Second, the patient
population admitted to the intensive care unit (ICU) after CPR has changed over the last
decades and the mortality rate has decreased dramatically. Previously, patients who woke
up shortly after CPR were directly admitted to the coronary care unit and were therefore
not included in cohort studies on ICU patients. Nowadays, almost all patients are treated
with hypothermia on the ICU, which leads to different case mix in ICU cohort studies and
partly explains the improved survival in ICU populations.
Neurologic examination
Neurologic examination is always done as a first test in ICU patients who are expected to
wake up after CPR. Although the false-positive rates (FPRs) of “absent pupillary light
responses together with absent corneal reflexes” suggest a robust reliability in patients
treated with hypothermia, physicians should realize that the confidence intervals (CIs) are
wide, which leads to uncertainty. Future studies should provide more information about
the “exact” reliability.
The most remarkable finding in patients treated with hypothermia is the unreliability of an
absent or extensor motor response (M1 or M2) at 72 hours. In the PROgnosis in
PostAnoxic Coma II study (PROPACII), 14% of the patients with a M1 or M2 three days
1
after CPR had a good outcome after 6 months . A possible explanation for this decrease in
reliability of the motor score is the use of sedative drugs and neuromuscular blocking
agents during hypothermia. Hypothermia decreases metabolism and, therefore, reduces
2
clearance of sedative drugs and neuromuscular blocking agents . Physicians on the ICU
should preferably use sedative drugs and neuromuscular blocking agents with a short half132
Discussion
life during hypothermia in the lowest possible dosage. But even then, one should realize
that after discontinuation metabolites of these drugs still might influence neurological
examination. The motor score should therefore not be used anymore as a predictor of
poor outcome in this patient group.
Information about the value of motor scores examined later than 72 hours after CPR is
sparse. Most studies evaluated the prognostic value of motor score until 72 hours after
CPR. A retrospective study of Bisschops et al. reported the predictive value of motor
scores up to 7 days after CPR. In this study, 13% (1/8) with a M1 or M2 at day 7 awoke and
3
had a favorable outcome . Future large prospective cohort studies should investigate the
predictive value of neurologic examination, especially motor scores, at longer time
intervals, e.g. at 5, 7, 10, and 14 days in patients with uncertain outcome at 72 hours after
CPR.
The Glasgow Coma Scale (GCS) is the most widely used coma score. It consists of an eye,
motor and verbal score. It was initially designed to assess level of consciousness after
4
traumatic brain injury . The verbal score cannot be defined in intubated and mechanically
ventilated patients. The interobserver agreement for the GCS has been reported
5,6
variable . The accurate use of the scale has been shown to increase with the user’s
7
experience. Inexperienced users have been shown to make consistent errors . A recently
8
developed coma scale is the Full Outline of UnResponsiveness (FOUR) score . It
incorporates eye opening and eye movements, brainstem reflexes, respiration patterns,
motor responses, and specific ways to assess comprehension to a command. This scale
gives more specific information about the clinical condition of the patient in coma at the
6,9,10
ICU and interobserver agreement has been found to be good to excellent
. The FOUR
score seems useful to predict outcome after CPR, but further prospective (multicenter)
11
studies are necessary to confirm these preliminary results .
In 9-35% of the patients after CPR, a postanoxic status epilepticus (PSE) may contribute to
the comatose state. In most patients, this condition is a sign of extensive brain damage
and 90-100% of the patients with a PSE had a poor outcome. However, some patients
12-15
show a good recovery, often after prolonged intensive treatment
. No evidence is
available to guide (non)treatment decisions and clinicians are uncertain about what to do
16
with this condition in patients after CPR . Future research should focus on patient
characteristics and electroencephalography (EEG) patterns which may identify patients
who will benefit from prolonged intensive treatment. Furthermore, as continuous EEG
monitoring during hypothermia and rewarming increasingly will be implemented in daily
practice, effectiveness of (early) treatment should be investigated (see below).
133
Chapter 10
Clinical neurophysiology
Somatosensory evoked potentials
Bilateral absence of median nerve somatosensory evoked potentials (SEPs) after
rewarming was shown to have a good prognostic reliability in the PROPACII and other
studies. This could easily lead to the impression that SEP after rewarming is a perfect test.
However, there are two points that should be addressed. The results of SEP after
rewarming were disclosed to treating physicians, which limits robust conclusions due to
the possibility of a self-fulfilling prophecy (see Chapter 1). Furthermore, sporadic cases
have been published with good outcome despite absent cortical N20 responses, one after
treatment with hypothermia and subsequent rewarming and one without hypothermia
17,18
treatment . In my opinion, until more cases with detailed documentation are reported,
SEP after rewarming remains a reliable prognosticator.
An important advantage of SEP is the low susceptibility to metabolic changes or sedative
drugs compared to other prognosticators, such as neurologic examination or
electroencephalography. However, there are some well-known pitfalls. Muscle activity
and interference of electric devices are known to increase the noise levels of SEP
recording, with a concomitant increase in the possibility of misinterpretation.
Administration of muscle relaxants and turning electric equipment off in order to reduce
noise levels to < 0.25 μV will improve the interobserver reliability from “fair” to
19
“substantial agreement” . Another possible pitfall is the effect of hypothermia on the SEP
responses. Most literature available describes the influence of deep hypothermia (11.430.1ºC) on median nerve SEP when performed during hypothermic cardiopulmonary
20-25
bypass
. The cortical N20 response disappears with temperatures between 14.5 and
20-26
29.6ºC and latencies of peripheral and central components are prolonged
. These
changes, however, may be less prominent with the mild hypothermia (32-34°C), as used in
patients after CPR. We demonstrated an increase of both peripheral and central
conduction times during treatment with mild hypothermia compared with the recordings
in the same patient after rewarming. We also found that amplitudes did not differ
consistently between hypothermia SEP and SEP after rewarming. Furthermore, we
demonstrated that absent SEP responses during hypothermia predict the absence of SEP
responses after rewarming.
The clinician interpreting the SEP registration in patients after CPR should be aware of all
these problems. The results of the SEP strongly contribute to the decision of the treating
team to limit or withdraw treatment. In case of uncertainty about the recordings, the
clinician should assess the results as ‘‘undeterminable’’.
134
Discussion
Electroencephalogram
Electroencephalographic studies include routine EEG and continuous EEG (cEEG). An
important limitation of EEG is the substantial interobserver variability in determining EEG
27
patterns in intensive care patients . One study showed only a moderate agreement for
the presence of rhythmic or periodic patterns and a slight to fair agreement for other
28
patterns . Hypothermia itself can influence EEG patterns with appearance of unilateral or
29
bilateral periodic complexes and burst suppression . Studies with routine EEG have
shown that an isoelectric EEG or a low-voltage EEG (< 20 µV) is a reliable predictor for a
poor outcome. Any confounders, such as hypothermia, (ongoing) effects of sedative drugs,
intoxication, hypotension, or metabolic disturbances have to be excluded.
A rather new development is cEEG monitoring in post-CPR patients. There are two goals of
applying cEEG: identification of cEEG patterns in relation with good or poor outcome; and
early identification of (non-)convulsive seizures/status epilepticus to start treatment.
Rundgren et al. showed that more than half of the patients after CPR with a flat cEEG
30
during hypothermia treatment had a continuous pattern on the cEEG at rewarming . A
30,31
continuous pattern on the cEEG was strongly associated with regaining consciousness .
Studies evaluating cEEG monitoring showed that electrographic seizures or epileptiform
32,33
activity are common during hypothermia and/or rewarming . There are currently no
studies available comparing results of routine EEG (at specific times) with cEEG and
subsequently, the influence on outcome. Future research should focus on which cEEG
patterns during hypothermia and rewarming warrant treatment and its effectiveness; and
which patterns are correlated with good or poor outcome.
Neuron-specific enolase and other biomarkers
Serum neuron-specific enolase (NSE) is the most extensively investigated biomarker in
patients after CPR and hypothermia. Data on the prognostic reliability of NSE are
conflicting and NSE does not seem to be as “neuron-specific” as suggested. Reported NSE
levels above which a poor outcome could be predicted reliably, range from 28-85
1,34-36
μg/liter
. Other important technical restrictions of use of NSE in daily clinical practice
are different reference levels among laboratory methods and increased NSE levels due to
37,38
blood hemolysis .
Other reported biomarkers are S100beta, glial fibrillary acid protein, brain derived
neurotrophic factor, blood ammonia and serum procalcitonin. A relatively new biomarker
is neurofilament heavy chain. A recently published study showed a correlation of
neurofilament levels with outcome at 2 and 36 hours after cardiac arrest, but elevated
135
Chapter 10
39
plasma levels were also found in patients with a good outcome . Furthermore, a
substantial part of the cohort had neurologic comorbidities, which might already lead to
an elevated plasma neurofilament level. In conclusion, there are far too few data to draw
firm conclusions, but due to the limitations of each biomarker, it seems unlikely that one
of these will be reliable enough to use for prognostication in the individual patient.
Imaging
Imaging in ICU-patients, especially when they are hemodynamically unstable, encounters
practical problems of transportation. Furthermore, interpretation from literature is made
difficult by the small numbers of patients studied, and differences in timing of imaging.
A computed tomography (CT-)scan is often performed on admission to exclude other
causes for the collapse, such as subarachnoid hemorrhage which occurs in 4-16% of the
40,41
patients with CPR . Furthermore, it can reveal information about traumatic brain injury
caused by the fall. In patients with postanoxic coma the CT-scan can show brain edema
with diffuse swelling and loss of differentiation between grey and white matter. In my
opinion, the role of standard CT, except for exclusion of other causes of the comatose
state, is limited.
Magnetic resonance imaging (MRI) techniques may be a more promising method. Practical
problems, such as duration of scanning and availability of MRI-compatible ventilators, are
more prominent when compared with performance of a standard CT. MRI can show
abnormalities in different time frames after CPR. DWI/ADC imaging can show acute
ischemia within the first 24 hours, as abnormalities on T2/FLAIR sequences often appear
42
thereafter . Greer et al. recently showed a high sensitivity for DWI abnormalities and
43.
prediction of poor outcome, but a low specificity of only 46% Another problem is the
43
inter-observer reliability, which is only moderate .
Literature on this subject is limited and imaging alone should not be used for
prognostication. Future research should prospectively investigate the prognostic reliability
of MRI at different time points and sequences at fixed time points after CPR, for example
at day 1 or 2 and day 7. This would elucidate if any additional information on functional
outcome will be provided, but it has to be realized that in many hospitals an MRI is
impossible in ventilated ICU patients because of all the technical problems with the large
magnetic field.
136
Discussion
Improvement of outcome
Research concerning prediction of outcome in patients with postanoxic coma after CPR is
constantly on the move, as new potential treatment options are introduced and evaluated.
This might lead to different outcome in these patients and might also affect reliability of
prognostic variables. Already mentioned examples of measures which attribute to
improvement of outcome are change of the compression/ventilation ratio,
implementation of the Automatic External Defibrillator (AED), on field administration of
amiodarone, and treatment with therapeutic hypothermia.
After successful CPR, a complex pathophysiological process occurs. The term post-cardiac
arrest syndrome includes four components on which (potential) treatment should be
focused: post-cardiac arrest brain injury, post-cardiac arrest myocardial dysfunction,
systemic ischemia/reperfusion response, and persistent precipitating pathology. This
section will discuss some important subjects of current research of different treatment
options in the post-CPR period with regard to neuroprotection.
Target Temperature Management
Hypothermia treatment
Treatment with hypothermia is considered beneficial in patients after CPR because
hypothermia is associated with lower levels of proinflammatory cytokines and free
radicals, a reduced hyperexcitatory state of the brain, a lower cerebral metabolic rate,
reduced permeability of the blood-brain barrier and anticoagulant effects. Lower
temperatures may also decrease intracranial pressure. After the publication of two
positive randomized controlled trials this treatment was soon incorporated in the
international guidelines and has become standard care in many countries. However, a
recent systematic review concluded that the evidence is still inconclusive, even in patients
with ventricular fibrillation/ventricular tachycardia as initial rhythms and out-of-hospital
44
CPR . The major limitation of the existing literature is the occurrence of untreated fever
in the control patient and the poor methodological quality of the studies. Controlled
normothermia might be as effective, or even more effective, since the potential side
effects of hypothermia will be diminished. Currently, the optimal target temperature is
studied in the international multicenter Target Temperature Management Study
(NCT01020916), which investigates whether a controlled temperature of 36°C has a
45
similar effect as a controlled temperature of 33°C .
137
Chapter 10
Rewarming and fever
The current recommendation is to rewarm the patients after therapeutic hypothermia at a
rate of maximal 0.25-0.5 °C/h, but the optimal rewarming rate is unknown. A recent study
(177 patients) showed that longer duration of passive rewarming was associated with
46
increased in-hospital mortality . Our retrospective study showed that patients who
needed active rewarming after therapeutic hypothermia did not have a higher risk for a
poor outcome when compared to patients who rewarmed spontaneously. In addition,
speed of rewarming had no effect on outcome. However, the number of patients with a
high rewarming rate was very small which limited robust conclusions.
Another consensus in the current guidelines is that hyperthermia or fever should be
avoided. In patients who were not treated with hypothermia after CPR, fever occurred in
up to 83% and was associated with an unfavorable neurologic recovery and a prolonged
length of stay on ICU. In the two studies concerning patients treated with hypothermia
after CPR, fever was found in 47-76% of the patients. However, in these patients, it was
46,47
not associated with in-hospital mortality, nor with poor outcome after 6 months .
Future research should investigate the optimal rate of rewarming, the possible benefits of
fever treatment, different sedation regimens and the best methods to monitor patients
during hypothermia and rewarming. In daily practice, such studies would be quite a
challenge as large numbers of patients and strict treatment protocols will be needed.
Other methods of neuroprotection
Controlled re-oxygenation
As adenosine triphosphate production needs oxygen, one could assume that immediate
restoration of the oxygen supply is very important after return of spontaneous circulation.
Animal studies, however, indicate that hyperoxemia in the initial phase of reperfusion
exacerbates neuronal damage due to free radical production and mitochondrial injury.
Clinical data are conflicting. One retrospective study, using data from a large clinical
48
registry, found significant higher in-hospital mortality for the hyperoxemia group . This
study had significant limitations and further research is necessary to establish optimal
49,50
oxygenation strategies . Current consensus is to aim for normoxemia and to avoid
hypoxemia.
Helium
Helium inhalation has shown promising results in reducing ischemia and reperfusion injury
51-54
with reduction of cerebral and myocardial infarct volumes in animal studies
.
Preliminary results of a safety and feasibility study in patients after CPR showed that
138
Discussion
55
helium ventilation can be applied safely to patients after CPR . Further research with this
potential therapeutic agent is needed.
Erythropoietin
Erythropoietin (EPO) had neuroprotective qualities in animal studies and was shown to be
56
safe in a pilot study in patients after stroke . A subsequent randomized clinical trial
showed no benefits and an unexplained higher mortality rate in patients who received
EPO, especially in those who were also treated with recombinant tissue plasminogen
57
activator (rtPA) . A recent animal study confirmed the negative effect of the combination
58
of EPO with rtPA . Other clinical studies of EPO in patients with subarachnoid
hemorrhage (phase II trial) and severe traumatic brain injury (prospective observational
59,60
study) did show beneficial effects . In cardiac arrest patients, only one matched control
61
study was performed . In total 18 patients were treated. A higher survival rate was found,
which did not significantly differ with the control group. Potential side effects of EPO were
elevated platelet count (with coronary vascular thrombosis in 1 case). Currently, the same
research group investigates the efficacy EPO after cardiac arrest in a randomized
multicenter single-blinded trial comparing early high dose of EPO with standard care
(NCT00999583).
Other
Thiopentone has shown to be neuroprotective in animal models, but a large clinical trial
showed no benefit. Also magnesium, diazepam, calcium channel inhibition, or
62,63
glucocorticoids did not show an improvement in outcome . Future research should
investigate the role of potentially neuroprotective agents in the prevention of reperfusion
injury and improvement of outcome after CPR.
Outcome research and guidelines
As previously mentioned, research concerning prediction of outcome in patients with
postanoxic coma after CPR is constantly on the move, as new potential treatment options
are introduced and evaluated. New treatments may not only modify the clinical course of
the condition, but may also change the predictive values of prognostic variables, as we
have demonstrated for poor motor responses in patients treated with hypothermia.
Future research should ideally consist of large prospective clinical trials, which could
investigate both potentially effective treatments and prognostic variables in the same
group. In such studies, to avoid self-fulfilling prophecy, limited use of treatment
restrictions would be preferable.
139
Chapter 10
A related problem is that of the continuing update of prognostic guidelines. For instance,
the results of studies performed in the last five years in patients treated with hypothermia
after CPR, such as the studies described in this thesis, should lead to changes in
international guidelines. Methods currently recommended are based on studies
performed before the implementation of hypothermia. Some of these recommended
methods are no longer reliable and could lead to incorrect treatment withdrawal. In 2011
a new Dutch national guideline “Prognosis of postanoxic coma” was presented. This
guideline discusses prognostic variables of a poor outcome for patients after CPR with and
64
without subsequent hypothermia treatment . Although the FPRs of “absent pupillary light
responses together with absent corneal reflexes” or “absent SEP after rewarming” suggest
a robust reliability in patients treated with hypothermia, physicians should realize that the
CIs are wide, which may lead to uncertainty. In daily clinical practice, decisions about
prognostication in the individual patient should not be based on one single test but rather
65
on a multi-modality approach . In patients with an uncertain outcome after neurologic
and neurophysiologic testing, other clinical variables such as age, comorbidity, pre-existing
clinical condition, multiple organ failure, etc. should be taken into account when decisions
on treatment limitations are considered. The ongoing search for “a perfect test” to predict
outcome in patients after CPR seems a utopia. Every test has its own limitations due to the
technique, artifacts, influences of drugs, or interobserver agreement and withdrawal of
therapy in patients with a poor prognosis.
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