Correspondence
Therapeutic Hypothermia after Cardiac Arrest
N Engl J Med 2002; 347:63-65July 4, 2002
- Article
To the Editor:
The results of two studies reported in the Journal (Feb. 21 issue)1,2 suggest that therapeutic hypothermia has a beneficial effect on neurologic outcome in survivors of out-of-hospital cardiac arrest. The authors of the accompanying editorial3 support the conclusions of these studies and firmly recommend the use of hypothermia for at least 12 hours after cardiac arrest. Before this complex intervention becomes accepted as standard therapy, a closer examination of these studies is warranted.
The authors of both studies cite problems in study design and in the interpretation of their results, but neither they nor the authors of the editorial acknowledge a flaw in both studies that should cast considerable doubt on the results and conclusions. Factors known to be of prognostic importance after cardiac arrest are the brain-stem reflexes and motor responses immediately after resuscitation.4,5 In this regard, neither study presents data reflecting the depth or severity of coma before randomization. Without these data, there is no reassurance that the hypothermia and normothermia groups were well matched according to the severity of the neurologic insult, thus raising the possibility of bias.
Although arrest and resuscitation times correlate with the severity of the neurologic insult and with mortality, they cannot be used as proxies for the neurologic examination. Furthermore, the small number of patients in these trials precludes any assumption that randomization would compensate for the noted deficiencies. It is premature to conclude that therapeutic hypothermia is effective or that it can be recommended for use in comatose survivors of cardiac arrest.
5 ReferencesJoseph M. Darby, M.D.
University of Pittsburgh, Pittsburgh, PA 15213
darbyjm@ccm.upmc. edu 1
The Hypothermia after Cardiac Arrest Study Group
Full Text | Web of Science | Medline2
Bernard SA ,Gray TW ,Buist MD , et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N EnglJ Med 2002;346:557-563
Full Text | Web of Science | Medline3
Safar PJ ,Kochanek PM . Therapeutic hypothermia after cardiac arrest. N Engl J Med 2002;346:612-613
Full Text | Web of Science | Medline4
Longstreth WT Jr ,Diehr P ,Inui TS . Prediction of awakening after out-of-hospital cardiac arrest. N Engl J Med 1983;308:1378-1382
Full Text | Web of Science | Medline5
Levy DE ,Caronna JJ ,Singer BH ,Lapinski RH ,Frydman H ,Plum F . Predicting outcome from hypoxic-ischemic coma. JAMA 1985;253:1420-1426
CrossRef | Web of Science | Medline
To the Editor:
The Hypothermia after Cardiac Arrest Study Group and Bernard et al. report a promising application of therapeutic hypothermia after cardiac arrest. In both studies, however, only highly selected subgroups of patients were enrolled: ventricular fibrillation as the initial cardiac rhythm and a return of spontaneous circulation were prerequisites for enrollment. In addition, the investigators enrolled only patients who had had a witnessed cardiac arrest. Previous analyses of long-term outcomes after cardiac arrest reported according to the Utstein guidelines, however, have revealed that only 13 to 19 percent of all patients with out-of-hospital cardiac arrest belong to these subgroups.1 Therefore, more than 80 percent of all patients with cardiac arrest will not be able to benefit from therapeutic hypothermia.
1 ReferencesStephan A. Padosch, M.D.
University of Heidelberg, 69120 Heidelberg, GermanyKarl B. Kern, M.D.
University of Arizona College of Medicine, Tucson, AZ 85724Bernd W. Böttiger, M.D.
University of Heidelberg, 69120 Heidelberg, Germany
bernd_boettiger@med.uni-heidelberg. de 1
Bottiger BW ,Grabner C ,Bauer H , et al. Long term outcome after out-of-hospital cardiac arrest with physician staffed emergency medical services: the Utstein style applied to a midsized urban/suburban area. Heart 1999;82:674-679
Web of Science | Medline
To the Editor:
Both Bernard and colleagues and the Hypothermia after Cardiac Arrest Study Group report that therapeutic hypothermia has significant neurologic benefits in patients who survive out-of-hospital cardiac arrest.
We use moderate hypothermia to treat selected patients after cardiac arrest, ischemic brain injury, and severe head injury. Our experience has been highly favorable, but we wish to sound a note of caution. We have reported that therapeutic hypothermia can have a number of severe side effects,1-3 including severe electrolyte disorders, which may be accompanied by a high risk of cardiac arrhythmias, and hypothermia-induced polyuria, which may cause hypovolemia and hypotension. These occur especially in the initial phase of cooling, when severe disruptions in fluid balance, blood pressure, and electrolyte levels are most likely to occur.2,3 We emphasize that these side effects, although potentially severe, are easily preventable by the administration of appropriate amounts of electrolytes and, if necessary, early administration of antiarrhythmic agents.2 In our opinion, the beneficial effects of hypothermia will be more pronounced if side effects are treated actively.
3 ReferencesKees H. Polderman, M.D., Ph.D.
Armand R.J. Girbes, M.D., Ph.D.
Vrije Universiteit Medical Center, 1007 MB Amsterdam, the Netherlands
k.polderman@tip. nl 1
Polderman KH, Girbes ARJ. Mechanisms of hypothermia-induced phosphate depletion. Crit Care Med (in press).
2
Polderman KH ,Peerdeman SM ,Girbes ARJ . Hypophosphatemia and hypomagnesemia induced by cooling in patients with severe head injury. J Neurosurg 2001;94:697-705
CrossRef | Web of Science | Medline3
Polderman KH ,Girbes ARJ ,Peerdeman SM ,Vandertop WP . Hypothermia. J Neurosurg 2001;94:853-858
Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: We can reassure Dr. Darby that the two study groups were balanced in terms of prerandomization brain-stem reflexes and motor responses. On admission to the hospital, the median score on the Glasgow Coma Scale was 3 (interquartile range, 3 to 4) in 132 patients in the hypothermia group and 3 (interquartile range, 3 to 5) in 135 patients in the normothermia group. Pupillary light reflexes were present in 73 of 123 patients in the hypothermia group and in 65 of 125 patients in the normothermia group.
Dr. Padosch and colleagues are right to say that only a small proportion of patients with cardiac arrest may currently benefit from therapeutic hypothermia. Their estimates roughly agree with those proposed in our article. Nationwide implementation would prevent 3 percent of all unfavorable neurologic outcomes (the population attributable fraction) in patients with cardiac arrest. It seems plausible, however, that other groups of patients, such as those with unwitnessed cardiac arrest or primary rhythms or causes of cardiac arrest other than those specified in our study, also may benefit. Further large-scale trials are necessary to prove this assumption and to clarify whether this intervention can be implemented successfully on an organizational level. Additional investigations would also help to answer questions about the optimal duration of cooling, the optimal temperature range, and the ideal cooling method.
Drs. Polderman and Girbes's comments give us an opportunity to share our clinical experiences. Potassium levels (Table 1Table 1
Potassium Levels and Fluid Balance.) and magnesium levels were similar between the groups over time. However, we did not assess whether electrolytes were administered differently in the two groups. Patients with mild hypothermia received more fluids during the 48-hour period after cardiac arrest than patients with normothermia (P<0.001) but had only a slightly higher urine output (P=0.18) (Table 1).Michael Holzer, M.D.
Universitätsklinik für Notfallmedizin, A-1090 Vienna, Austria
fritz.sterz@akh-wien. ac. at for the Hypothermia after Cardiac Arrest Study Group
Author/Editor Response
Dr. Darby suggests that the neurologic examination performed when the patient arrives at the hospital is an important indicator of the severity of neurologic injury and that such data are essential for comparing the two groups of patients in our study at the time of enrollment. There are a number of problems with this approach. The findings of the neurologic examination may progressively improve during the hours that follow resuscitation after cardiac arrest. In our study, the time to the initial neurologic evaluation in the emergency department ranged from 10 minutes to 40 minutes after the return of spontaneous circulation. The neurologic examination is therefore more accurately undertaken at 72 hours.1 Also, the assessment of the motor response to a painful stimulus may be inaccurate.2
With these limitations in mind, we present the findings of the initial neurologic examination in the patients in our study (Table 1Table 1
Results of the Initial Neurologic Examination after the Return of Spontaneous Circulation.). These data confirm that the patients in the hypothermia group had neurologic injury that was at least as severe as that in the patients in the normothermia group, presumably because the rate of cardiopulmonary resuscitation by a bystander was lower and the time from collapse to resuscitation was longer in the group with hypothermia than in the group with normothermia.With regard to the comments of Drs. Polderman and Girbes concerning fluid and electrolyte changes during the induction of hypothermia: we suggest that these changes are easily managed with close monitoring in a critical care unit. We would not characterize these effects as “severe” and disagree that there is a high risk of cardiac arrhythmias, since no such cases were seen in our studies of induced hypothermia in patients with anoxic brain injury3 and severe head injury.4 Although we routinely measure magnesium and phosphate levels in patients at the time of admission to the intensive care unit, we have not found low levels to be associated with adverse events, provided that supplementation is given as required.
4 ReferencesStephen A. Bernard, M.B., B.S.
Michael D. Buist, M.B., B.S.
Dandenong Hospital, Dandenong, VIC 3175, Australia
s.bernard@southernhealth. org. au 1
Edgren E ,Hedstrand U ,Kelsey S ,Sutton-Tyrrell K ,Safar P . Assessment of neurological prognosis in comatose survivors of cardiac arrest. Lancet 1994;343:1055-1059
CrossRef | Web of Science | Medline2
Knaus WA . Measuring the Glasgow Coma Scale in the intensive care unit: potentials and pitfalls. Intensive Care World 1994;11:102-1033
Bernard SA ,Jones BM ,Horne MK . Clinical trial of induced hypothermia in comatose survivors of out-of-hospital cardiac arrest. Ann Emerg Med 1997;30:146-153
CrossRef | Web of Science | Medline4
Bernard SA ,MacC Jones B ,Buist M . Experience with prolonged induced hypothermia in severe head injury. Crit Care 1999;3:167-172
CrossRef | Web of Science | Medline
Author/Editor Response
The editorialists reply:
To the Editor: Dr. Darby considers the matching of brain-stem reflexes and motor responses before randomization to be important. Such data would be interesting, but acquiring them during resuscitation attempts has low priority, may be impossible, and seems not important for the following reasons. First, matching should be addressed by randomization and the presence or absence of coma. Second, the data listed by Dr. Darby do not completely correlate with “awakening” (defined as the recovery of comprehensible speech or the ability to follow commands)1 or were obtained “within 6 hours” after arrest.2 Randomization in the European study was performed when the patient arrived in the emergency department and in the Australian study it was performed outside the hospital. Third, the European study selected patients within the therapeutic window (i.e., those who had a witnessed arrest, ventricular fibrillation, a first resuscitation attempt 5 to 15 minutes after the collapse, and restoration of spontaneous circulation not later than 60 minutes after collapse); insult time is more important than reflexes.3 Fourth, in the European study, Glasgow Coma Scores and Pittsburgh Brain Stem Scores (Sterz F: personal communication) were the same in both groups. In our recent study of 942 patients,4 we found only the absence of corneal or cough reflexes at 24 hours to be 100 percent predictive of a poor cerebral outcome. Fifth, reflexes and movements during or immediately after the restoration of spontaneous circulation are influenced by many variables other than the severity of insult.
Our recommendation that standard guidelines include the early initiation of mild hypothermia (which is simple, safe, and inexpensive) is based not only on the two current well-controlled studies but also on nonrandomized observations in Japan and the United States and on powerful, reproducible benefits documented in many controlled outcome studies in animals.5
5 ReferencesPeter Safar, M.D.
Patrick M. Kochanek, M.D.
Safar Center for Resuscitation Research, Pittsburgh, PA 15260
safarp@anes.upmc. edu 1
Longstreth WT Jr ,Diehr P ,Inui TS . Prediction of awakening after out-of-hospital cardiac arrest. N Engl J Med 1983;308:1378-1382
Full Text | Web of Science | Medline2
Levy DE ,Caronna JJ ,Singer BH ,Lapinski RH ,Frydman H ,Plum F . Predicting outcome from hypoxic-ischemic coma. JAMA 1985;253:1420-1426
CrossRef | Web of Science | Medline3
Abramson N, Safar P, Detre K, Brain Resuscitation Clinical Trial (BRCT) II Study Group 4
Sasser HC ,Safar P ,Kelsey SF ,Ricci EM ,Sutton-Tyrrell KC ,Wisniewski SR . Clinical signs early after CPR predict neurologic outcome. Crit Care Med 1999;27:Suppl 12:A30-A30 abstract.
CrossRef | Web of Science5
Safar P ,Xiao F ,Radovsky A , et al. Improved cerebral resuscitation from cardiac arrest in dogs with mild hypothermia plus blood flow promotion. Stroke 1996;27:105-113
CrossRef | Web of Science | Medline
- Citing Articles (9)
Citing Articles
1
Xu Xue, Jing Liu. (2011) Multi-scale modeling on human intravascular cooling to induce brain hypothermia via circle of Willis. Forschung im Ingenieurwesen 75:4, 257-269
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Rose Do, Francis Kim. (2011) Con: Therapeutic Hypothermia Should Not Be Applied to All Victims of Cardiac Arrest. Journal of Cardiothoracic and Vascular Anesthesia 25:2, 365-367
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Patrick M. Kochanek, Robert C. Tasker. (2009) Pediatric Neurointensive Care: 2008 Update for the Rogers’ Textbook of Pediatric Intensive Care. Pediatric Critical Care Medicine 10:4, 517-523
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David M. Greer. (2006) Hypothermia for cardiac arrest. Current Neurology and Neuroscience Reports 6:6, 518-524
CrossRef5
Alain Broccard. (2006) Therapeutic hypothermia for anoxic brain injury following cardiac arrest: A ???cool??? transition toward cardiopulmonary cerebral resuscitation*. Critical Care Medicine 34:7, 2008-2009
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Jiang-shu JIN, Toshiyuki SAKAEDA, Mikio KAKUMOTO, Kohshi NISHIGUCHI, Tsutomu NAKAMURA, Noboru OKAMURA, Katsuhiko OKUMURA. (2006) Effect of Therapeutic Moderate Hypothermia on Multi-drug Resistance Protein 1-Mediated Transepithelial Transport of Drugs. Neurologia medico-chirurgica 46:7, 321-327
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E. Popp, F. Sterz, B. W. B
ttiger. (2005) Therapeutische milde Hypothermie nach Herz-Kreislauf-Stillstand. Der Anaesthesist 54:2, 96-106
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Katsumi Okuyama, Takashi Matsukawa, Makoto Ozaki, Daniel I. Sessler, Tomoki Nishiyama, Makoto Imamura, Teruo Kumazawa. (2003) Doxapram Produces a Dose-Dependent Reduction in the Shivering Threshold in Rabbits. Anesthesia & Analgesia759-762
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Peter Vogel, Herman v.d. Putten, Erik Popp, Jakub J. Krumnikl, Peter Teschendorf, Roland Galmbacher, Malgorzata Kisielow, Christoph Wiessner, Albert Schmitz, Kevin J. Tomaselli, Bernd Schmitz, Eike Martin, Bernd W. Böttiger. (2003) Improved Resuscitation after Cardiac Arrest in Rats Expressing the Baculovirus Caspase Inhibitor Protein p35 in Central Neurons. Anesthesiology 99:1, 112-121
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