Anoxic brain injury: Difference between revisions
No edit summary |
|||
| Line 13: | Line 13: | ||
In a review of 68 studies through 1997, the incidence of survival to discharge was higher at 14% with a wide range of 0-28%.<ref name="pmid9167565">{{cite journal |author=Ballew KA |title=Cardiopulmonary resuscitation |journal=BMJ |volume=314 |issue=7092 |pages=1462–5 |year=1997 |month=May |pmid=9167565 |pmc=2126720 |doi= |url=http://bmj.com/cgi/pmidlookup?view=long&pmid=9167565}}</ref> | In a review of 68 studies through 1997, the incidence of survival to discharge was higher at 14% with a wide range of 0-28%.<ref name="pmid9167565">{{cite journal |author=Ballew KA |title=Cardiopulmonary resuscitation |journal=BMJ |volume=314 |issue=7092 |pages=1462–5 |year=1997 |month=May |pmid=9167565 |pmc=2126720 |doi= |url=http://bmj.com/cgi/pmidlookup?view=long&pmid=9167565}}</ref> | ||
== | ==Natural History== | ||
Patients with anoxic injury due to cardiac arrest are at risk of death from a variety of causes including recurrent [[sudden cardiac death]], [[congestive heart failure]], [[pneumonia]], [[sepsis]] from a variety of sources and [[pulmonary embolism]]. | |||
==Signs and Symptoms== | ==Signs and Symptoms== | ||
| Line 49: | Line 42: | ||
If there is absence of bilateral [[somatosensory evoked potentials]], then it is unlikely that the patient will survive.<ref>Chen R, Bolton CF, Young B: Prediction of outcome in patients with anoxic coma: A clinical and electrophysiological study. Crit Care Med 1996;24:672-678.</ref><ref>Kaplan PW: Electrophysiological prognostication and brain injury from cardiac arrest. Semin Neurol 2006;26:403-412.</ref><ref>Young GB, Doig G, Ragazzoni A: Anoxic-ischemic encephalopathy: Clinical and electrophysiological associations with outcome. Neurocrit Care 2005;2:159-164.</ref> In particular, if there is no N20 response, there is a very highly likelihood of a vegetative state or death, with only 1 patient of 21 surviving in one study compared with survival in 11 of 26 patients surviving if the N20 response was positive.<ref>Young GB, Doig G, Ragazzoni A: Anoxic-ischemic encephalopathy: Clinical and electrophysiological associations with outcome. Neurocrit Care 2005;2:159-164.</ref> | If there is absence of bilateral [[somatosensory evoked potentials]], then it is unlikely that the patient will survive.<ref>Chen R, Bolton CF, Young B: Prediction of outcome in patients with anoxic coma: A clinical and electrophysiological study. Crit Care Med 1996;24:672-678.</ref><ref>Kaplan PW: Electrophysiological prognostication and brain injury from cardiac arrest. Semin Neurol 2006;26:403-412.</ref><ref>Young GB, Doig G, Ragazzoni A: Anoxic-ischemic encephalopathy: Clinical and electrophysiological associations with outcome. Neurocrit Care 2005;2:159-164.</ref> In particular, if there is no N20 response, there is a very highly likelihood of a vegetative state or death, with only 1 patient of 21 surviving in one study compared with survival in 11 of 26 patients surviving if the N20 response was positive.<ref>Young GB, Doig G, Ragazzoni A: Anoxic-ischemic encephalopathy: Clinical and electrophysiological associations with outcome. Neurocrit Care 2005;2:159-164.</ref> | ||
==Incidence and Predictors of Entering Into a Vegetative State versus Making a Full Neurologic Recovery== | ===Imaging Findings=== | ||
In the early hours and days after anoxic brain injury, there is often diffuse [[cerebral edema]] and blurring of the border between the grey and white matter. In some patients there may be discrete infarcts after a few days. | |||
If there is irreversible bilateral medial tegmental [[brainstem]] injury, then patients do not survive. | |||
==Treatment== | |||
===Therapeutic Hypothermia=== | |||
While patients with a shockable rhythm such as VT/VF derive significant benefits | |||
Background— Although the level of evidence of improvement is significant in cardiac arrest patients resuscitated from a shockable rhythm (ventricular fibrillation or pulseless ventricular tachycardia [VF/VT]), the use of therapeutic mild hypothermia (TMH) is more controversial in nonshockable patients (pulseless electric activity or asystole [PEA/asystole]). We therefore assessed the prognostic value of hypothermia for neurological outcome at hospital discharge according to first-recorded cardiac rhythm in a large cohort. | |||
Methods and Results— Between January 2000 and December 2009, data from 1145 consecutive out-of-hospital cardiac arrest patients in whom a successful resuscitation had been achieved were prospectively collected. The association of TMH with a good neurological outcome at hospital discharge (cerebral performance categories level 1 or 2) was quantified by logistic regression analysis. TMH was induced in 457/708 patients (65%) in VF/VT and in 261/437 patients (60%) in PEA/asystole. Overall, 342/1145 patients (30%) reached a favorable outcome (cerebral performance categories level 1 or 2) at hospital discharge, respectively 274/708 (39%) in VF/VT and 68/437 (16%) in PEA/asystole (P<0.001). After adjustment, in VF/VT patients, TMH was associated with increased odds of good neurological outcome (adjusted odds ratio, 1.90; 95% confidence interval, 1.18 to 3.06) whereas in PEA/asystole patients, TMH was not significantly associated with good neurological outcome (adjusted odds ratio, 0.71; 95% confidence interval, 0.37 to 1.36). | |||
Conclusions— In this large cohort of cardiac arrest patients, hypothermia was independently associated with an improved outcome at hospital discharge in patients presenting with VF/VT. By contrast, TMH was not associated with good outcome in nonshockable patients. Further investigations are needed to clarify this lack of efficiency in PEA/asystole. | |||
==Prognosis== | |||
===Predictors of Survival=== | |||
====Improved Prognosis with In-Hospital versus Out-of-Hospital Cardiac Arrest==== | |||
Out-of-hospital cardiac arrest (OHCA) has a worse survival rate (2-8% survival at discharge) than in-hospital cardiac arrest (15% survival at discharge). | |||
====Improved Prognosis with VT/VF versus PEA or Asystole==== | |||
A major determining factor in survival is the initially documented electrocardiographic rhythm. Patients with [[ventricular fibrilation]] ([[VF]]) or [[ventricual tachycardia]] ([[VT]]) (aka VT/VF) have a 10-15 fold greater chance of survival than patients with [[pulseless electrical activity]] ([[PEA]]) or [[asystole]]. VT and VF are responsive to [[defibrillation]], whereas asystole and PEA are not. | |||
====Rapid Defibrillation is Associated with Imporved Survival==== | |||
Rapid intervention with a [[defibrillator]] increases survival rates.<ref>{{cite journal |author=Eisenberg MS, Mengert TJ |title=Cardiac resuscitation |journal=N. Engl. J. Med. |volume=344 |issue=17 |pages=1304–13 |year=2001 |month=April |pmid=11320390 |doi= |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=11320390&promo=ONFLNS19}}</ref><ref name="pmid12826637">{{cite journal |author=Bunch TJ, White RD, Gersh BJ, ''et al'' |title=Long-term outcomes of out-of-hospital cardiac arrest after successful early defibrillation |journal=N. Engl. J. Med. |volume=348 |issue=26 |pages=2626–33 |year=2003 |month=June |pmid=12826637 |doi=10.1056/NEJMoa023053 |url=}}</ref> | |||
===Incidence and Predictors of Entering Into a Vegetative State versus Making a Full Neurologic Recovery=== | |||
Cardiac arrest is the third leading cause of [[coma]]. Approximately 80% of patients who suffered a cardiac arrest who survived to be admitted to the hospital will be in coma for varying lengths of time. Of these patients, approximately 40% will enter into a persistent vegetative state and 80% die within 1 year. In contrast, those rare patients who survive until discharge without significant neurological impairment can expect a fair to good quality of life. | Cardiac arrest is the third leading cause of [[coma]]. Approximately 80% of patients who suffered a cardiac arrest who survived to be admitted to the hospital will be in coma for varying lengths of time. Of these patients, approximately 40% will enter into a persistent vegetative state and 80% die within 1 year. In contrast, those rare patients who survive until discharge without significant neurological impairment can expect a fair to good quality of life. | ||
| Line 73: | Line 92: | ||
*Seizures that occur after the initial 24 hours are associated with a poorer outcomes. In one study only 3 of 15 patients who seized recovered consciousness, and only one patient lived a year<ref>Roine RO: Neurological Outcome of Out-of-Hospital Cardiac Arrest [dissertation]. University of Helsinki, 1993.</ref>. The presence of [[status epilepticus]] at any time following cardiac arrest is associated with a very poor prognosis as all nine patients with status epilepticus died in one series.<ref>Roine RO: Neurological Outcome of Out-of-Hospital Cardiac Arrest [dissertation]. University of Helsinki, 1993.</ref> | *Seizures that occur after the initial 24 hours are associated with a poorer outcomes. In one study only 3 of 15 patients who seized recovered consciousness, and only one patient lived a year<ref>Roine RO: Neurological Outcome of Out-of-Hospital Cardiac Arrest [dissertation]. University of Helsinki, 1993.</ref>. The presence of [[status epilepticus]] at any time following cardiac arrest is associated with a very poor prognosis as all nine patients with status epilepticus died in one series.<ref>Roine RO: Neurological Outcome of Out-of-Hospital Cardiac Arrest [dissertation]. University of Helsinki, 1993.</ref> | ||
*The absence of spontaneous eye opening and intermittent visual fixation by the end of the first day is associated with a poor prognosis. Although eye opening is necessary for a good outcomes, it alone is not sufficient, as many patients who have spontaneous eye opening still go on to have a poor prognosis. Roving eye movements in the absence of visual fixation is often indicative of extensive bilateral cerebral hemispheral damage and portends a poor prognosis. If the gaze is sustained in an upeard direction, this carries a poor prognosis as well.<ref>Keane JR: Sustained upgaze in coma. Annals of Neurolology 1981;9:409-412.</ref> | *The absence of spontaneous eye opening and intermittent visual fixation by the end of the first day is associated with a poor prognosis. Although eye opening is necessary for a good outcomes, it alone is not sufficient, as many patients who have spontaneous eye opening still go on to have a poor prognosis. Roving eye movements in the absence of visual fixation is often indicative of extensive bilateral cerebral hemispheral damage and portends a poor prognosis. If the gaze is sustained in an upeard direction, this carries a poor prognosis as well.<ref>Keane JR: Sustained upgaze in coma. Annals of Neurolology 1981;9:409-412.</ref> | ||
==References== | ==References== | ||
Revision as of 18:41, 1 March 2011
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Associate Editors-In-Chief: Varun Kumar, M.B.B.S.; Lakshmi Gopalakrishnan, M.B.B.S.
Overview
Anoxic or hypoxic brain injury is often seen after cardiac arrest. Major efforts are underway to improve "The Chain of Survival" based upon early access to medical care, early defibrillation, early CPR and early hospital care. Therapeutic hypothermia may improve outcomes. Steroids, manitol, diuresis and hyperventilation have not been documented to meaningfully improve clinical outcomes.
Epidemiology
In a 1990s study from the UK, resuscitation for cardiac arrest was attempted in 10,081 patients. Of these only 1476 (14.6%) survived to be admitted to the hospital [1][2]. Of these small number of patients who survived to admission, 59.3% died during that admission, half of these within the first 24 hours. 46.1% survived to hospital discharge (this is 6.75% of those who had been resuscitated by ambulance staff). Of those who were successfully discharged from hospital, 70% were still alive 4 years after their discharge.
In a review of 68 studies through 1997, the incidence of survival to discharge was higher at 14% with a wide range of 0-28%.[3]
Natural History
Patients with anoxic injury due to cardiac arrest are at risk of death from a variety of causes including recurrent sudden cardiac death, congestive heart failure, pneumonia, sepsis from a variety of sources and pulmonary embolism.
Signs and Symptoms
Serial neurologic examinations are critical in the assessment of long term prognosis.
Assessment of the Brain Stem
The brainstem is more resistant to hypoperfusion that the cerebral cortex, and if the brainstem does not recover, the cerebral cortex is not likely to recover. The presence of brain stem reflexes is therefore critical to recovery. Preservation of brainstem function is indicated by the presence of blinking, coughing, gagging, sneezing, and yawning.
Pupillary Size
The presence of peristently dilated pupils is a poor prognostic sign [4]. It should be noted that both catecholamines and atropine, can affect pupillary size, and confound the assessment of pupillary size.
Diagnosis of Brain Death
If there is no longer brain activity, and there is 0% chance of the recovery of the patient, a patient is declared "Brain Dead". Brain death is diagnosed when all four of the following criteria are met:[5][6][7]
1. There is coma with a loss of cerebral reactivity.
2. There is absence of spontaneous respiration.
3. There is a loss of brainstem reflexes (pupillary, corneal, oculovestibular, and oculocephalic). In some definitions this is qualified by a requirement that the loss of reflexes exceeds 24 hours in duration.
4. There is no activity on the electroencephalogram ("electrocerebral silence", a "flat electroencephalogram") for > than 12 hours. This last criteria requires that the patient is not hypothermic or on sedative drugs. In some definitions > 24 hours is required.
The Electroencephalogram (EEG)
Most often the EEGs of patients in coma after cardiac arrest shows diffuse slowing of both the theta and delta waves, and periodic epileptiform firing. Severe slowing or a flat line appearance is associated with a poor prognosis.
Evoked-Response Testing
If there is absence of bilateral somatosensory evoked potentials, then it is unlikely that the patient will survive.[8][9][10] In particular, if there is no N20 response, there is a very highly likelihood of a vegetative state or death, with only 1 patient of 21 surviving in one study compared with survival in 11 of 26 patients surviving if the N20 response was positive.[11]
Imaging Findings
In the early hours and days after anoxic brain injury, there is often diffuse cerebral edema and blurring of the border between the grey and white matter. In some patients there may be discrete infarcts after a few days.
If there is irreversible bilateral medial tegmental brainstem injury, then patients do not survive.
Treatment
Therapeutic Hypothermia
While patients with a shockable rhythm such as VT/VF derive significant benefits
Background— Although the level of evidence of improvement is significant in cardiac arrest patients resuscitated from a shockable rhythm (ventricular fibrillation or pulseless ventricular tachycardia [VF/VT]), the use of therapeutic mild hypothermia (TMH) is more controversial in nonshockable patients (pulseless electric activity or asystole [PEA/asystole]). We therefore assessed the prognostic value of hypothermia for neurological outcome at hospital discharge according to first-recorded cardiac rhythm in a large cohort.
Methods and Results— Between January 2000 and December 2009, data from 1145 consecutive out-of-hospital cardiac arrest patients in whom a successful resuscitation had been achieved were prospectively collected. The association of TMH with a good neurological outcome at hospital discharge (cerebral performance categories level 1 or 2) was quantified by logistic regression analysis. TMH was induced in 457/708 patients (65%) in VF/VT and in 261/437 patients (60%) in PEA/asystole. Overall, 342/1145 patients (30%) reached a favorable outcome (cerebral performance categories level 1 or 2) at hospital discharge, respectively 274/708 (39%) in VF/VT and 68/437 (16%) in PEA/asystole (P<0.001). After adjustment, in VF/VT patients, TMH was associated with increased odds of good neurological outcome (adjusted odds ratio, 1.90; 95% confidence interval, 1.18 to 3.06) whereas in PEA/asystole patients, TMH was not significantly associated with good neurological outcome (adjusted odds ratio, 0.71; 95% confidence interval, 0.37 to 1.36).
Conclusions— In this large cohort of cardiac arrest patients, hypothermia was independently associated with an improved outcome at hospital discharge in patients presenting with VF/VT. By contrast, TMH was not associated with good outcome in nonshockable patients. Further investigations are needed to clarify this lack of efficiency in PEA/asystole.
Prognosis
Predictors of Survival
Improved Prognosis with In-Hospital versus Out-of-Hospital Cardiac Arrest
Out-of-hospital cardiac arrest (OHCA) has a worse survival rate (2-8% survival at discharge) than in-hospital cardiac arrest (15% survival at discharge).
Improved Prognosis with VT/VF versus PEA or Asystole
A major determining factor in survival is the initially documented electrocardiographic rhythm. Patients with ventricular fibrilation (VF) or ventricual tachycardia (VT) (aka VT/VF) have a 10-15 fold greater chance of survival than patients with pulseless electrical activity (PEA) or asystole. VT and VF are responsive to defibrillation, whereas asystole and PEA are not.
Rapid Defibrillation is Associated with Imporved Survival
Rapid intervention with a defibrillator increases survival rates.[12][13]
Incidence and Predictors of Entering Into a Vegetative State versus Making a Full Neurologic Recovery
Cardiac arrest is the third leading cause of coma. Approximately 80% of patients who suffered a cardiac arrest who survived to be admitted to the hospital will be in coma for varying lengths of time. Of these patients, approximately 40% will enter into a persistent vegetative state and 80% die within 1 year. In contrast, those rare patients who survive until discharge without significant neurological impairment can expect a fair to good quality of life.
The duration of hypoxia/ischemia determines the extent of neuronal injury i.e. in patients who suffer hypoxia for less than 5 minutes, are less likely to have permanent neurologic deficits, while with prolonged, global hypoxia, patients may develop myoclonus or a persistent vegetative state.[14]
The duration of coma is an important predictor of the recovery of neurologic function. In a 1979 study of 181 cardiac arrest patients who survived to hospital admission, 84% were comatose for more than 1 hour and 56% were comatose for more than 24 hours[15]. There was minimal neurologic deficit if coma lasted less than 24 hours. However, among the 85 patients who were comatose for more than 24 hours, only 7 of them were discharged alive. The severity of neurological impairment increased with increased duration of coma. Of the patients who were in coma for more than 7 days, none regained consciousness. It should be noted that 80 patients died in a coma.
A JAMA article in 1985 attempted to identify the multivariate predictors neurologic prognosis in 210 patients with coma due to cerebral hypoxia. A total of 13% of patients regained neurologic function and independent function at some time during the first year.
Initial Neurologic Findings:
- Patients who had the initial absence of pupillary light reflexes did not recover independent functioning (52 patients, 25% of patients)[15].
- In contrast, patients who had the initial presence of pupillary light reflexes, the development of spontaneous eye movements that were roving conjugate or better, and the presence of either extensor, flexor, or withdrawal responses to pain had a 41% chance of regaining independent function (of the 27 patients in this group, 11 (41%) regained independence).[15].
- In a study by Snyder et al, the absence of corneal or pupillary light reflexes at 3 hours after cardiac arrest was associated with death in all patients [16][17]. By 6 hours, all the patients who survived had the presence of three brainstem reflexes: pupillary light response, corneal reflex, and reflex eye movements.
- The absence of spontaneous limb movements and the absence of withdrawal to pain in the early hours is a poor prognostic sign.
- The presence of either decorticate or decerebrate posturing is a poor prognostic sign.
- Frequent myoclonic jerking is associated with a poor prognosis.
- The presence of seizures in the initial 24 hours is modestly associated with outcomes: 53% of patients who seize survive compared to 70% of those who do not seize during the first day[18].
24 Hour Neurologic Findings:
- Most patients who survive become alert by 24-48 hours. In one series, of those patients who were in a coma through day 2, only 2 of the 27 (7%) survived.[19] In a second series, no patient who remained in a coma by the third day sirvived.[20]
- Absent motor responses, the presence of posturing (extensor / flexor motor responses) and the lack of spontaneous eye movements that were either orienting or roving conjugate was associated with a lack of independent recovery in 92 of 93 patients. [15].
- In contrast, of the 30 patients who showed improvement in their eye-opening responses, obeyed commands or had withdraw to pain, 19 (63%) regained independent function.[15].
- Seizures that occur after the initial 24 hours are associated with a poorer outcomes. In one study only 3 of 15 patients who seized recovered consciousness, and only one patient lived a year[21]. The presence of status epilepticus at any time following cardiac arrest is associated with a very poor prognosis as all nine patients with status epilepticus died in one series.[22]
- The absence of spontaneous eye opening and intermittent visual fixation by the end of the first day is associated with a poor prognosis. Although eye opening is necessary for a good outcomes, it alone is not sufficient, as many patients who have spontaneous eye opening still go on to have a poor prognosis. Roving eye movements in the absence of visual fixation is often indicative of extensive bilateral cerebral hemispheral damage and portends a poor prognosis. If the gaze is sustained in an upeard direction, this carries a poor prognosis as well.[23]
References
- ↑ Lyon RM, Cobbe SM, Bradley JM, Grubb NR (2004). "Surviving out of hospital cardiac arrest at home: a postcode lottery?". Emerg Med J. 21 (5): 619–24. doi:10.1136/emj.2003.010363. PMC 1726412. PMID 15333549. Unknown parameter
|month=ignored (help) - ↑ Cobbe SM, Dalziel K, Ford I, Marsden AK (1996). "Survival of 1476 patients initially resuscitated from out of hospital cardiac arrest". BMJ. 312 (7047): 1633–7. PMC 2351362. PMID 8664715. Unknown parameter
|month=ignored (help) - ↑ Ballew KA (1997). "Cardiopulmonary resuscitation". BMJ. 314 (7092): 1462–5. PMC 2126720. PMID 9167565. Unknown parameter
|month=ignored (help) - ↑ Steen-Hansen JE, Hansen NN, Vaagenes P, Schreiner B: Pupil size and light reactivity during cardiopulmonary resuscitation. A clinical study. Crit Care Med 1988;16:69-70.
- ↑ Ad Hoc Committee of the Harvard Medical School: A defi nition of irreversible coma. Report of the Ad Hoc Committee of the Harvard Medical School to examine the defi nition of brain death. JAMA 1968;205:337-340.
- ↑ Walker A: An appraisal of the criteria of cerebral death. JAMA 1977;237:982-986.
- ↑ Shemie SD, Pollack MM, Morioka M, Bonner S: Diagnosis of brain death in children. Lancet Neurol 2007;6:87-92.
- ↑ Chen R, Bolton CF, Young B: Prediction of outcome in patients with anoxic coma: A clinical and electrophysiological study. Crit Care Med 1996;24:672-678.
- ↑ Kaplan PW: Electrophysiological prognostication and brain injury from cardiac arrest. Semin Neurol 2006;26:403-412.
- ↑ Young GB, Doig G, Ragazzoni A: Anoxic-ischemic encephalopathy: Clinical and electrophysiological associations with outcome. Neurocrit Care 2005;2:159-164.
- ↑ Young GB, Doig G, Ragazzoni A: Anoxic-ischemic encephalopathy: Clinical and electrophysiological associations with outcome. Neurocrit Care 2005;2:159-164.
- ↑ Eisenberg MS, Mengert TJ (2001). "Cardiac resuscitation". N. Engl. J. Med. 344 (17): 1304–13. PMID 11320390. Unknown parameter
|month=ignored (help) - ↑ Bunch TJ, White RD, Gersh BJ; et al. (2003). "Long-term outcomes of out-of-hospital cardiac arrest after successful early defibrillation". N. Engl. J. Med. 348 (26): 2626–33. doi:10.1056/NEJMoa023053. PMID 12826637. Unknown parameter
|month=ignored (help) - ↑ Mellion ML (2005). "Neurologic consequences of cardiac arrest and preventive strategies". Medicine and Health, Rhode Island. 88 (11): 382–5. PMID 16363390. Unknown parameter
|month=ignored (help) - ↑ 15.0 15.1 15.2 15.3 15.4 Thomassen A, Wernberg M (1979). "Prevalence and prognostic significance of coma after cardiac arrest outside intensive care and coronary units". Acta Anaesthesiologica Scandinavica. 23 (2): 143–8. PMID 442945. Unknown parameter
|month=ignored (help) - ↑ Snyder BD, Loewenson RB, Gumnit RJ, et al: Neurologic prognosis after cardiopulmonary arrest: II. Level of consciousness. Neurology 1980;30:52-58.
- ↑ Snyder BD, Gumnit RJ, Leppik IE, et al: Neurologic prognosis after cardiopulmonary arrest: IV. Brainstem refl exes. Neurology 1981;31: 1092-1097
- ↑ Roine RO: Neurological Outcome of Out-of-Hospital Cardiac Arrest [dissertation]. University of Helsinki, 1993.
- ↑ Snyder BD, Loewenson RB, Gumnit RJ, et al: Neurologic prognosis after cardiopulmonary arrest: II. Level of consciousness. Neurology 1980;30:52-58.
- ↑ Bell JA, Hodgson HJF: Coma after cardiac arrest. Brain 1974;97:361-372.
- ↑ Roine RO: Neurological Outcome of Out-of-Hospital Cardiac Arrest [dissertation]. University of Helsinki, 1993.
- ↑ Roine RO: Neurological Outcome of Out-of-Hospital Cardiac Arrest [dissertation]. University of Helsinki, 1993.
- ↑ Keane JR: Sustained upgaze in coma. Annals of Neurolology 1981;9:409-412.