Neurology -- Correspondence for Longstreth et al., 59 (4) 506-514

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Correspondence published:

Reply to First Letter to the Editor: Sandra Schneider (1 April 2003)

Randomized clinical trial of magnesium, diazepam, or both after out-of-hospital cardiac arrest: Calixto Machado (1 April 2003)

Reply to Letters to the Editor: Will Longstreth (1 April 2003)

Randomized clinical trial of magnesium, diazepam, or both after out-of-hospital cardiac arrest: William M Landau (1 April 2003)

Reply to First Letter to the Editor 1 April 2003

Sandra Schneider
University of Rochester New York
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Re: Reply to First Letter to the Editor

Sandra_Schneider{at}urmc.rochester.edu Sandra Schneider

Dr. Landau raises several issues, both scientific and ethical. He is correct in his comments about the criteria used to describe the neurologic outcome of the patients in the paper and by the Utstein categories. There is clearly a need for well-defined, rigorous outcome criteria for resuscitation and in fact for the outcome of other neurologic catastrophes such as stroke, subarachnoid hemorrhage and traumatic brain injury. A carefully defined assessment tool that could be used by emergency physicians, intensivists and neurologists would assist researchers and clinicians compare studies and therapies.
Beyond this need for scientific rigor, Dr. Landau raises an ethical question on the value of resuscitation. Survival from sudden out of hospital cardiac arrest varies from 2-25% depending on the paramedic system and response times [1]. Survival appears to be related to age and disease state of the patient, time to CPR and time to defibrillation. Mortality increases by 3% for every minute after arrest without CPR and 4% for every minute without successful defibrillation [2]. In hospital cardiac arrest victims have a poorer prognosis, clearly related to their underlying disease. Some arrest victims regain consciousness rapidly in the ED while the majority experience coma for a variable period of time. Those who regain full consciousness rapidly generally make a full neurologic recovery. Those who do not awaken in the ED have a variable outcome ranging from full recovery to chronic vegetative state. It is no possible to predict this outcome early. The outcomes are admittedly poor; yet for the few fully functional survivors, the outcome is a miracle.
While the outcome in the cited study is very poor, it should be noted that the study was limited to patients who had not awakened in the field. The outcome in this group of patients is clearly worse than those who awaken rapidly.
The problem with resuscitation is the unknown prognosis. Every attempt to revive a victim holds the promise of a restored fruitful life and the potential for long-term disability. Research to improve our ability to predict outcome is overdue.
References:
1. Eisenber MS, Horwood BT, Cummins RO, et al. Cardiac arrest and resuscitation: a tale of 29 cities. Ann Emerg Med 1990; 19:179-186.
2. Weaver WD, Cobb LA, Hallstrom AP, et al. Considerations for improving survival from out-of-hospital cardiac arrest. Ann Emerg Med 1986; 15:1181-1186.

Randomized clinical trial of magnesium, diazepam, or both after out-of-hospital cardiac arrest 1 April 2003

Calixto Machado
Cuban Society of Clinical Neurophysiology Havana Cuba
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Re: Randomized clinical trial of magnesium, diazepam, or both after out-of-hospital cardiac arrest

braind{at}infomed.sld.cu Calixto Machado

Longstreth et al. presented a well designed double-blind, placebo- controlled, randomized clinical trial to test if magnesium, diazepam, or both, given immediately following resuscitation, would improve neurologic outcome after cardiac arrest. They concluded, "neither magnesium nor diazepam significantly improved neurologic outcome from cardiac arrest". [1]
Among their criteria for including patients in this trial was "a systolic blood pressure of at least 90 mm Hg, regardless of vasopressor medications, for long enough to be entered into the trial before arrival at hospital". Hence, patients included in this report had been already in cardiac arrest for an uncertain period of time, before they regained a measurable systolic blood pressure.
Thus one can question, "Did Magnesium and diazepam show to be ineffective for improving outcome because during the period of cardiac arrest ischemia (no flow) had already damaged the brain"?
Hypothermia provides the most effective neuroprotection related to brain resuscitation. [2] Safar et al. have stressed that dog experimental models of prolonged exsanguination have resulted in brain and organ preservation during cardiac arrest (no-flow) durations of up to 90 or 120 minutes, at tympanic temperature of 100 C. [3]
The benefit of hypothesis is supported by reports of patients suffering accidental hypothermia (immersion/submersion in cold water, snow avalanche or prolonged exposure to cold surroundings) combined with circulatory arrest or severe circulatory failure, who were rewarmed to normothermia by use of extracorporeal circulation, with good outcome in several cases. In these patients the neuroprotective effect of accidental hypothermia was initiated very early, even before a complete cardiac arrest had occurred, because of the progressive decrement of body temperature. [4]
Therefore, it is important to stress that any actual of future developed neuroprotective treatment to prevent brain damage to ischemia, should be initiated as soon as possible after diagnosing cardiac arrest, even during the application of cardiopulmonary resuscitation (CPR). Of course, this has technical limitation hitches, because in most cases this treatment should be applied by paramedics at the site of accident and inside ambulances, in subjects with a slow and unstable blood flow provoked by CPR. Nonetheless, this may be the only way to achieve a neuroprotective effect for preventing brain damage after cardiac arrest. [3, 5]
REFERENCES
1. Longstreth WT, Fahrenbruch CE, Olsufka M, Walsh TR, Copass MK, Cobb LA. Randomized clinical trial of magnesium, diazepam, or both after out-of-hospital cardiac arrest. Neurology 2002; 59:506-514.
2. Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002; 346:557-563.
3. Safar P, Behringer W, Bottiger BW, Sterz F. Cerebral resuscitation potentials for cardiac arrest. Crit Care Med 2002; 30(Suppl 4):S140-S144.
4. Farstad M, Andersen KS, Koller ME, Grong K, Segadal L, Husby P. Rewarming from accidental hypothermia by extracorporeal circulation. A retrospective study. Eur J Cardiothorac Surg 2001; 20:58-64.
5. Safar PJ, Kochanek PM. Therapeutic hypothermia after cardiac arrest. N Engl J Med 2002; 346:612-613.

Reply to Letters to the Editor 1 April 2003

Will Longstreth
Harborview Medical Center Seattle WA
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Re: Reply to Letters to the Editor

wl{at}u.washington.edu Will Longstreth

We appreciate the comments of Dr. Machado and Dr. Landau but only wish that more investigators would seek means to improve the neurologic outcome of patients resuscitated from cardiac arrest, despite the challenges of when therapy is initiated and how outcome is measured.

Randomized clinical trial of magnesium, diazepam, or both after out-of-hospital cardiac arrest 1 April 2003

William M Landau
Washington University School of Medicine St Louis MO
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Re: Randomized clinical trial of magnesium, diazepam, or both after out-of-hospital cardiac arrest

landauw{at}neuro.wustl.edu William M Landau

Precise description of acute cardiac arrest management with medication by Longstreth et al. contrasts with their standard, but egregiously crude outcome data. [1] "The primary outcome was wakening at any time by three months after the cardiac arrest�.. "Wakening was defined by the patient's having comprehensible speech or following commands, and was based on review of medical records and telephone contact�. secondary outcomes were days to awakening, days to death, being awake and independent at any time by three months, and being awake and independent at three months�. Personnel conducted a telephone follow -up with the patient or surrogate at three months after the cardiac arrest. Patients or their surrogates were asked a number of questions to assess level of neurologic function and independence. Based on the responses to these questions, all patients who are discharged from the hospital were classified as being dead, alive but not awake, awake but dependent or awake and independent."
Beyond the medication failure is the calculated outcome estimate for the role model Seattle area. Of 2714 candidate patients, 47% were dead; 32% were immediate treatment failures. At 3 months, 5% attained the telephone label "independent", 1% "dependent" and 0.1% "vegetative". Of immediate survivors, 20% fewer were "awake" and 9% fewer " independent" at 3 months. This is the numerical window of humane hope and disappointment.
The editorially cited Utstein categories of favorable outcome are: "Moderate cerebral disability is Conscious. Sufficient cerebral function for part-time work in sheltered environment or independent activities of daily life (dressing, traveling by public transportation, and preparing food). May have hemiplegia, seizures, ataxia, dysarthria, dysphasia or permanent memory or mental changes." " Good cerebral performance is Conscious, alert, able to work and lead an normal life. May have minor psychological or neurological deficits (mild dysphasia, non incapacitating hemiparesis, or minor cranial nerve abnormalities)." [2] Undefined are measures of work quality, normal life, memory, and complete recovery.
The requirement of independent comprehensive neuropsychological measurement is established for valid research concerning cardiorespiratory and brain disease and cardiac surgery. Although cardiac arrest patients enter treatment without informed consent, many don't want to suffer resuscitation. [3] Precise state of the art prognosis of anoxic encephalopathy treatment, ranging from rigorously defined total recovery to devastating disability is a social and economic necessity for physicians, citizens, and their government. [4, 5] Beyond the casual Utstein guesswork, the ethical cost factors of public policy require reliable assessment and open public discussion.
References:
1. Longstreth WT, Fahrenbruch CE, Olsufka, M, Walsh TR, Copass MK, Cobb LA. Randomized clinical trial of magnesium, diazepam, or both after out-of-hospital cardiac arrest. Neurology 2002; 57:506-514.
2. Cummins RD, Chamberlain DA, Abramson NS, et al. Recommended guidelines for uniform reporting of data from out-of-hospital cardiac arrest: the Utstein style. Circulation 1991; 84:960-975.
3. Murphy DJ, Barrows D, Santilli S, et al. The influence of the probability of survival on patients' preferences regarding cardiopulmonary resuscitation. N Engl J Med 1994; 330:545-549.
4. Jaffe AS, Landau WM. Clinical neuromythology XI Death after death: the presumption of informed consent for cardiopulmonary resuscitation ethical paradox and clinical conundrum. Neurology 1993; 43:2173-2178.
5. Jaffe AS, Landau WM, Wetzel RD. Editorial: Resuscitation 2000: The need for improved databases in regard to neurological outcomes. Resuscitation 1998; 37:65-66.