Hypothermic Centralization: New Use for Old Knowledge?

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COMMENTARIES

Opinions expressed in this commentary are those of the authors and not necessarily those of the American Academy of Pediatrics or its Committees.

Should We Try to Prevent

Hyperthermia After Cardiac Arrest?

D

ealing with the sequelae of cardiac arrest or

asphyxia in a previously normal adult or child is always very difficult, for the pedia-trician as much as the family. We now know that following resuscitation there can be a “latent” phase with transient recovery of cerebral energy metabo-lism, before a secondary phase of deterioration as determined by seizures, cytotoxic edema,1_and cere-bral energy failure.2,3_{This latent phase may persist as} long as 6 to 15 hours after reperfusion in infants.3_It is highly likely that the processes active during this latent period involve activation of the intracytoplas-mic phase of programmed cell death.4,5

There is now strong experimental evidence that changes in postischemic cerebral temperature initi-ated during the latent phase can critically modulate these processes. As reviewed elsewhere, whereas brief hypothermia immediately after resuscitation has limited and inconsistent results, extended peri-ods of mild to moderate cerebral cooling started in the latent period are neuroprotective.6 _Conversely, hyperthermia of approximately 3°C maintained for 24 hours after circulatory arrest in the piglet wors-ened outcome at 72 hours.7_{In reports from one} re-search group, as little as 3 hours of moderate hyper-thermia (39.6°C), induced 24 hours after either brief global or focal ischemia in the adult rat was delete-rious.8,9

Spontaneous hyperthermia is now well-known to the clinician to be associated with early neurologic deterioration, increased morbidity, and mortality af-ter acute cerebral ischemia.10_{Early onset fever,} start-ing within the first 24 hours, is associated with larger cerebral infarction,11 _{whereas later onset of fever,} typically attributable to secondary infection, does not appear to be as significant. In this light, the observa-tions by Hickey et al12 _{are of potential concern} be-cause all 6 patients who were not actively warmed

developed hyperthermia (⬎38°C) for many hours,

mostly within the first 24 hours. It is important to note that the actively warmed group were much younger—almost all were infants. The findings in the actively warmed group of deeper early hypothermia, which then required active rewarming, overshoot hyperthermia in 5 of 7, and severe mortality (6/7 of

the actively rewarmed children vs 1/6 passively re-warmed) are almost certainly related to their age and consequently low thermal inertia rather than to the warming strategy per se.

Observational studies by their nature cannot reli-ably distinguish the direction of causality: whether hyperthermia is attributable to worse brain injury, or whether the fever is also worsening injury as sug-gested by the experimental studies. The most consis-tent way of reducing brain temperature in adults short of active cooling is simply regular use of anti-pyretics.13_{Experimentally, the use of such} antipyret-ics for 72 hours after ischemia is associated with better short-term outcome,14_{although early mild} hy-pothermia was also needed for long-term protec-tion.15 _{The time has come when use of antipyretic} therapy in older children and adults, possibly com-bined with gradual rewarming from the early spon-taneous hypothermia, should be empirically tested to establish its safety and efficacy.

Alistair J. Gunn, MD, PhD, FRACP Peter D. Gluckman, MBChB, DSc, FRACP

University of Auckland School of Medicine Department of Paediatrics

Private Bag 92019, Auckland, New Zealand

REFERENCES

1. Gunn AJ, Gunn TR, de Haan HH, Williams CE, Gluckman PD. Dra-matic neuronal rescue with prolonged selective head cooling after isch-emia in fetal lambs.J Clin Invest.1997;99:248 –256

2. Lorek A, Takei Y, Cady EB, et al. Delayed (’’secondary’’) cerebral energy failure after acute hypoxia-ischemia in the newborn piglet: continuous 48-hour studies by phosphorus magnetic resonance spectroscopy. Pedi-atr Res.1994;36:699 –706

3. Roth SC, Baudin J, Cady E, et al. Relation of deranged neonatal cerebral oxidative metabolism with neurodevelopmental outcome and head cir-cumference at 4 years.Dev Med Child Neurol.1997;39:718 –725 4. Samejima K, Tone S, Kottke TJ, et al. Transition from caspase-dependent

to caspase-independent mechanisms at the onset of apoptotic execution. J Cell Biol.1998;143:225–239

5. Joashi UC, Greenwood K, Taylor DL, et al. Poly(ADP ribose) polymer-ase cleavage precedes neuronal death in the hippocampus and cerebel-lum following injury to the developing rat forebrain.Eur J Neurosci. 1999;11:91–100

6. Gunn AJ, Gunn TR. The ‘pharmacology’ of neuronal rescue with cere-bral hypothermia.Early Hum Dev.1998;53:19 –35

7. Shum-Tim D, Nagashima M, Shinoka T, et al. Postischemic hyperther-mia exacerbates neurologic injury after deep hypothermic circulatory arrest.J Thorac Cardiovasc Surg.1998;116:780 –792

8. Baena RC, Busto R, Dietrich WD, Globus MY, Ginsberg MD. Hyper-thermia delayed by 24 hours aggravates neuronal damage in rat hip-pocampus following global ischemia.Neurology.1997;48:768 –773 9. Kim Y, Busto R, Dietrich WD, Kraydieh S, Ginsberg MD. Delayed

postischemic hyperthermia in awake rats worsens the histopathological outcome of transient focal cerebral ischemia.Stroke.1996;27:2274 –2280 10. Reith J, Jorgensen HS, Pedersen PM, et al. Body temperature in acute stroke: relation to stroke severity, infarct size, mortality, and outcome. Lancet.1996;347:422– 425

11. Castillo J, Davalos A, Marrugat J, Noya M. Timing for fever-related brain damage in acute ischemic stroke.Stroke.1998;29:2455–2460 12. Hickey RW, Kochanek PM, Ferimer H, Graham SH, Safar P. Hypother-Received for publication Mar 17, 2000; accepted Mar 17, 2000.

Reprint requests to (A.J.G.) University of Auckland School of Medicine, Department of Paediatrics, Private Bag 92019, Aukland, New Zealand. E-mail: aj㛭[email protected]

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mia and hyperthermia in children after resuscitation from cardiac ar-rest.Pediatrics.2000;106:118 –122

13. Mellergard P. Changes in human intracerebral temperature in response to different methods of brain cooling.Neurosurgery.1992;31:671– 677 14. Coimbra C, Boris-Moller F, Drake M, Wieloch T. Diminished neuronal

damage in the rat brain by late treatment with the antipyretic drug dipyrone or cooling following cerebral ischemia.Acta Neuropathol (Berl). 1996;92:447– 453

15. Coimbra C, Drake M, Boris-Moller F, Wieloch T. Long-lasting neuro-protective effect of postischemic hypothermia and treatment with an anti-inflammatory/antipyretic drug. Evidence for chronic encephalo-pathic processes following ischemia.Stroke.1996;27:1578 –1585

Hypothermic Centralization: New

Use for Old Knowledge?

P

otential neuroprotective effects with mild to

moderate cerebral cooling have been clearly demonstrated after experimental hypoxic–isch-emic injury.1_{However, the difficulties of establishing} an effective regime in clinical practice are formida-ble. In the absence of definitive evidence of clinical efficacy, it is essential that hypothermia be used safely. Pilot studies have suggested that, under tightly defined conditions, hypothermia is generally safe even in the severely asphyxiated infant,2– 4 _and multicenter, randomized, controlled trials are cur-rently underway to further investigate different hy-pothermic strategies. Many of the clinical issues

raised by Thoresen and Whitelaw5 _{can be readily}

understood in relation to the physiology of adapta-tion to hypothermia, including both the conservaadapta-tion and production of heat.

Hypothermia leads to rapid peripheral vasocon-striction, ie, centralization of blood flow. This vaso-constriction occurs in a spatially and temporally con-trolled manner, dependent on tightly integrated input from central and skin thermoreceptors.6 Al-though both core and skin temperatures are physio-logically relevant, in man, the latter contributes only 20% to the onset threshold for vasoconstriction dur-ing cooldur-ing.7_{Thus, external local warming with} cen-tral hypothermia does not produce local vasodilata-tion, but rather leads to a small reduction in the core temperature threshold for vasoconstriction.8,9 _Even very high skin temperatures cannot abolish the cen-tral initiation of vasoconstriction.8

The effect of hypothermic centralization of blood flow is clearly demonstrated in Fig 1 of the article by Thoresen and Whitelaw.5 _{In both protocols, an} in-crease in blood pressure occurs when cooling is ini-tiated, followed by a resolution during rewarming, similar to previous reports, for example, in fetal sheep.10 _{In our experience, rewarming, performed} slowly, does not result in clinically significant

hypo-tension.4 _{A component of the changes observed in} Fig 6B is potentially related to a handling effect, with a rise in blood pressure before rewarming.5

The case described in Fig 3 of the article by Thore-sen and Whitelaw5_{was highly unstable, with swings} in blood pressure not clearly attributable to heater activity before the selected event (A. Whitelaw, per-sonal communication, 1999). The infant seems to have reached an equilibrium at a relatively low core temperature with little or only modest heater activ-ity, and then was challenged with a rapid rise in both core and skin temperature. It is possible that hypo-thermic centralization temporarily supported this in-fant’s blood pressure that, otherwise, for reasons such as impaired cardiac output, would have been marginal. Under these conditions, if rapidly warmed or otherwise challenged, cardiovascular instability would become manifest. In the combined Auckland and University College London experience,4 _there were no cases of rapid rewarming, but the consider-ations discussed above suggest that it is improbable that changes in overhead warming without core tem-perature change can significantly impact on central-ization.

The other major response to hypothermia is in-creased heat production. This response is typically seen at a similar but not identical temperature threshold to vasoconstriction. During active cooling, temperature must be determined by the balance of endogenous heat production, external heat input from the overhead heater, and heat removal. Unlike adults, infants preferentially use brown fat (nonshiv-ering thermogenesis) rather than shiv(nonshiv-ering to pro-duce heat.11 _{Postasphyxial seizures may also be an} important source of both cerebral and peripheral thermogenesis.12 _{Thus, factors that inhibit} nonshiv-ering thermogenesis or muscle activity, such as hy-poxia and many anesthetic or sedative agents, result in altered heat production. Furthermore, spontane-ous changes in the metabolic rates of infants during the evolution of hypoxic–ischemic encephalopathy may occur more frequently than previously recog-nized and also need to be met by appropriate adjust-ments in heat removal.

In contrast to the present report,5 _{rapid falls in} either rectal temperature or blood pressure were not observed during the maintenance phase of cooling in a larger, controlled pilot study of infants cooled to 34.5°C ⫾ .5°C.4 _{Although, for example,} anticonvul-sants consistently reduced infant temperatures, this was a relatively slow change that could be readily anticipated. The major difference seems to be in the

cooling strategies used. Thoresen and Whitelaw5

used fixed, usually low-output external heating, with limited cooling and relatively high cap temperatures, whereas the original protocol used lower cap tem-peratures, balanced by servo-controlled, maximal or near-maximal radiant heater activity.2,4 _{The use of} maximal external heating must greatly reduce the relative contribution of endogenous thermal produc-tion to the infant’s thermal balance and attenuate the impact of any reduction in thermogenesis.

Received for publication May 8, 2000; accepted May 8, 2000.

Address correspondence to Alistair Jan Gunn, MBChB, PhD, FRACP, De-partment of Paediatrics, Faculty of Medicine and Health Science, University of Auckland, Private Bag 92019, Auckland, New Zealand. E-mail: [email protected]

COMMENTARIES 133

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CONCLUSION

The use of therapeutic hypothermia unmasks dy-namic changes in infant circulation and metabolism that we can usually ignore, because of the routine use of servo-controlled warming. This does not indicate that cooling is unsafe or difficult to manage, but rather that, as with any therapy, it must be applied with caution and knowledge of underlying physio-logic principles.

Alistair J. Gunn, MBChB, PhD, FRACP Malcolm Battin, MBChB, MRCP, FRCH

Department of Paediatrics

Faculty of Medicine and Health Science University of Auckland

Auckland, New Zealand

REFERENCES

1. Gunn AJ, Gunn TR. The ‘‘pharmacology’ of neuronal rescue with cere-bral hypothermia.Early Hum Dev. 1998;53:19 –35

2. Gunn AJ, Gluckman PD, Gunn TR. Selective head cooling in newborn infants after perinatal asphyxia: a safety study. Pediatrics. 1998;102: 885– 892

3. Simbruner G, Haberl C, Harrison V, Linley L, Willeitner AE. Induced brain hypothermia in asphyxiated human newborn infants: a retrospec-tive chart analysis of physiological and adverse effects.Intensive Care Med. 1999;25:1111–1117

4. Gunn TR, Penrice J, Battin M, Gunn AJ. Head cooling with mild sys-temic hypothermia following birth asphyxia: a safety study.Proc Annu Congress Perinatal Soc Aust N Z. 1999;3:P18. Abstract

5. Thoresen M, Whitelaw A. Cardiovascular changes during mild thera-peutic hypothermia and rewarming in infants with hypoxic–ischemic encephalopathy.Pediatrics. 2000;106:

6. Gordon CJ, Heath JE. Integration and central processing in temperature regulation.Annu Rev Physiol. 1986;48:595– 612

7. Cheng C, Matsukawa T, Sessler DI, et al. Increasing mean skin temper-ature linearly reduces the core-tempertemper-ature thresholds for vasoconstric-tion and shivering in humans.Anesthesiology. 1995;82:1160 –1168 8. Jessen C. Independent clamps of peripheral and central temperatures

and their effects on heat production in the goat.J Physiol (Lond). 1981; 311:11–22

9. Proppe DW. Influence of skin temperature on central thermoregulatory control of leg blood flow.J Appl Physiol. 1981;50:974 –978

10. Gunn AJ, Gunn TR, Gunning MI, Williams CE, Gluckman PD. Neuro-protection with prolonged head cooling started before postischemic seizures in fetal sheep.Pediatrics. 1998;102:1098 –1106

11. Gunn TR, Gluckman PD. Perinatal thermogenesis. Early Hum Dev. 1995;42:169 –183

12. Jordan KG. Status epilepticus: a perspective from the neuroscience intensive care unit.Neurosurg Clin N Am. 1994;5:671– 686

IMPRISONMENT

California alone holds more inmates in its jails and prisons than do France, Great Britain, Germany, Japan, Singapore, and The Netherlands combined, although those nations have 10 times California’s population.

Easterbrook G. Run-on sentencing.The New Republic.May 3, 1999

Submitted by Student

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DOI: 10.1542/peds.106.1.133

2000;106;133

Pediatrics

Alistair J. Gunn and Malcolm Battin

Hypothermic Centralization: New Use for Old Knowledge?

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DOI: 10.1542/peds.106.1.133

2000;106;133

Pediatrics

Alistair J. Gunn and Malcolm Battin

Hypothermic Centralization: New Use for Old Knowledge?

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