Therapeutische Hypothermie bei Neugeborenen und Kindern

Kernaussagen

Es gibt wenige neue Therapieverfahren, die einen so eindeutig positiven Effekt auf die Langzeitprognose haben, wie die therapeutische Hypothermie nach schwerer perinataler Asphyxie des Neugeborenen. Sowohl die Überlebensrate als auch das neurologische Outcome verbessert sich signifikant.

Es ist möglich, dass die therapeutische Hypothermie auch nach Kreislaufstillstand im Kindesalter zu besseren Behandlungsergebnissen beitragen kann. Die diesbezüglichen Daten und Empfehlungen sind uneinheitlich und machen Einzelfallentscheidungen im Rahmen eines individuellen Heilversuchs notwendig. Weitere mögliche Indikationen werden untersucht und haben heute noch experimentellen Charakter.

Trotz des gut belegten Nutzens der Hypothermiebehandlung für einige Indikationen sind grundlegende Mechanismen, Wirkungsweise und optimaler Modus der Durchführung nicht vollständig geklärt. In den kommenden Jahren ist eine weitere Optimierung der klinischen Anwendung zu erwarten.

Die Durchführung der Hypothermie ist mit temperaturabhängigen physiologischen Veränderungen und Risiken verbunden, die vorausschauend überwacht und ggf. gezielt therapiert werden müssen.

Bei gegebener Indikation sollte ein früher Behandlungsbeginn angestrebt werden. Zur Kühlung eignen sich bei Neugeborenen und Kleinkindern neben Coolpacks und kalten Tüchern temperaturgesteuerte Kühlmatten. Die Wiederaufwärmung erfolgt sehr langsam und kontrolliert.

Die neurologische Beurteilbarkeit ist unter Hypothermie eingeschränkt. Die neurologische Gesamtprognose ergibt sich im Einzelfall aus der Anamnese und dem Verlauf aller klinischen, apparativen und Laborbefunde.

• Literatur

• 1 Edwards AD. The discovery of hypothermic neural rescue therapy for perinatal hypoxic-ischemic encephalopathy. Semin Pediatr Neurol 2009; 16: 200-206
• 2 Varon J, Acosta P. Therapeutic hypothermia: past, present, and future. Chest 2008; 133: 1267-1274
• 3 Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002; 346: 549-556
• 4 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
• 5 Eicher DJ, Wagner CL, Katikaneni LP et al. Moderate hypothermia in neonatal encephalopathy: efficacy outcomes. Pediatr Neurol 2005; 32: 11-17
• 6 Gluckman PD, Wyatt JS, Azzopardi D et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet 2005; 365: 663-670
• 7 Shankaran S, Laptook AR, Ehrenkranz RA et al. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med 2005; 353: 1574-1584
• 8 Richmond S, Wyllie J. Versorgung und Reanimation des Neugeborenen. Notfall Rettungsmed 2010; 13: 665-678
• 9 Deakin CD, Nolan JP, Soar J et al. Erweiterte Reanimationsmaßnahmen für Erwachsene („advanced life support“). Notfall + Rettungsmedizin 2010; 13: 559-620
• 10 Drury PP, Bennet L, Gunn AJ. Mechanisms of hypothermic neuroprotection. Semin Fetal Neonatal Med 2010; 15: 287-292
• 11 Gunn AJ, Thoresen M. Hypothermic neuroprotection. NeuroRx 2006; 3: 154-169
• 12 Johnston MV, Fatemi A, Wilson MA et al. Treatment advances in neonatal neuroprotection and neurointensive care. The Lancet Neurology 2011; 10: 372-382
• 13 Walters JH, Morley PT, Nolan JP. The role of hypothermia in post-cardiac arrest patients with return of spontaneous circulation: a systematic review. Resuscitation 2011; 82: 508-516
• 14 Hypothermienetzwerk. Freiwilliger Zusammenschluss von Einrichtungen, in welchen die Hypothermie als Therapieoption bei neonatologischen bzw. pädiatrischen Patienten zum Einsatz kommt. 2012 Im Internet: http://www.hypothermienetzwerk.de
• 15 Hoffmann F, Gräsner JT, Brenner S. Etablierung eines Reanimations- und Hypothermieregisters für Kinder. Anasth Intensivmed 2011; 11: 727-729
• 16 Polderman KH. Induced hypothermia and fever control for prevention and treatment of neurological injuries. Lancet 2008; 371: 1955-1969
• 17 Azzopardi DV, Strohm B, Edwards AD et al. Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med 2009; 361: 1349-1358
• 18 Simbruner G, Mittal RA, Rohlmann F et al. Systemic hypothermia after neonatal encephalopathy: outcomes of neo.nEURO. network RCT. Pediatrics 2010; 126: e771-778
• 19 Zhou W, Cheng G, Shao X et al. Selective Head Cooling with Mild Systemic Hypothermia after Neonatal Hypoxic-Ischemic Encephalopathy: A Multicenter Randomized Controlled Trial in China. The Journal of Pediatrics 2010; 157: 367-372
• 20 Jacobs SE, Morley CJ, Inder TE et al. Whole-body hypothermia for term and near-term newborns with hypoxic-ischemic encephalopathy: a randomized controlled trial. Arch Pediatr Adolesc Med 2011; 165: 692-700
• 21 Edwards AD, Brocklehurst P, Gunn AJ et al. Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: synthesis and meta-analysis of trial data. BMJ 2010; 340: c363
• 22 Jacobs S, Hunt R, Tarnow-Mordi W et al. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev 2007;
• 23 Guillet R, Edwards AD, Thoresen M et al. Seven- to eight-year follow-up of the CoolCap trial of head cooling for neonatal encephalopathy. Pediatr Res 2012; 71: 205-209
• 24 Shankaran S, Pappas A, McDonald SA et al. Predictive value of an early amplitude integrated electroencephalogram and neurologic examination. Pediatrics 2011; 128: e112-120
• 25 Thoresen M, Hellström-Westas L, Liu X et al. Effect of hypothermia on amplitude-integrated electroencephalogram in infants with asphyxia. Pediatrics 2010; 126: e131-139
• 26 Shah PS. Hypothermia: a systematic review and meta-analysis of clinical trials. Semin Fetal Neonatal Med 2010; 15: 238-246
• 27 Edwards AD, Brocklehurst P, Gunn AJ et al. Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: synthesis and meta-analysis of trial data. BMJ 2010; 340: c363
• 28 Kattwinkel J, Perlman JM, Aziz K et al. Part 15: Neonatal Resuscitation. Circulation 2010; 122: 909-919
• 29 Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). Late Hypothermia after Hypoxic-Ischemic Encephalopathy. 2011 Im Internet: http://clinicaltrials.gov/ct2/show/NCT00614744 [Stand: 25.05.2012]
• 30 Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). Optimizing (Longer, Deeper) Cooling for Neonatal Hypoxic-Ischemic Encephalopathy(HIE). 2012 Im Internet: http://clinicaltrials.gov/ct2/show/NCT00614744 [Stand: 25.05.2012]
• 31 Finer NN, Robertson CM, Richards RT et al. Hypoxic-ischemic encephalopathy in term neonates: perinatal factors and outcome. J Pediatr 1981; 98: 112-117
• 32 Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress. A clinical and electroencephalographic study. Arch Neurol 1976; 33: 696-705
• 33 Biarent D, Bingham R, Eich C et al. Lebensrettende Maßnahmen bei Kindern („paediatric life support“). Notfall Rettungsmed 2010; 13: 635-664
• 34 Arrich J, Holzer M, Herkner H et al. Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation. Cochrane Database Syst Rev 2009;
• 35 Nielsen N, Friberg H, Gluud C et al. Hypothermia after cardiac arrest should be further evaluated--a systematic review of randomised trials with meta-analysis and trial sequential analysis. Int J Cardiol 2011; 151: 333-341
• 36 Zeiner A, Holzer M, Sterz F et al. Hyperthermia after cardiac arrest is associated with an unfavorable neurologic outcome. Arch Intern Med 2001; 161: 2007-2012
• 37 Topjian AA, Nadkarni VM, Berg RA. Cardiopulmonary resuscitation in children. Curr Opin Crit Care 2009; 15: 203-208
• 38 Vaagenes P, Safar P, Moossy J et al. Asphyxiation versus ventricular fibrillation cardiac arrest in dogs. Differences in cerebral resuscitation effects – a preliminary study. Resuscitation 1997; 35: 41-52
• 39 Kochanek PM, Fink EL, Bell MJ et al. Therapeutic hypothermia: applications in pediatric cardiac arrest. J Neurotrauma 2009; 26: 421-427
• 40 Hutchison JS, Doherty DR, Orlowski JP et al. Hypothermia Therapy for Cardiac Arrest in Pediatric Patients. Pediatric Clinics of North America 2008; 55: 529-544
• 41 Fink EL, Clark RSB, Kochanek PM et al. A tertiary care center’s experience with therapeutic hypothermia after pediatric cardiac arrest. Pediatr Crit Care Med 2010; 11: 66-74
• 42 Doherty DR, Parshuram CS, Gaboury I et al. Hypothermia therapy after pediatric cardiac arrest. Circulation 2009; 119: 1492-1500
• 43 Ringe H, Varnholt V, Reich S et al. Therapeutic Hypothermia Guidance by Cerebral Perfusion Control by Dopplerultrasound After CPR in Children. Pediatric Research 2011; 70: 205
• 44 The Hospital for Sick Children. Hypothermia for Cardiac Arrest in Paediatrics. 2008 Im Internet: http://clinicaltrials.gov/ct2/show/NCT00754481 [Stand: 25.05.2012]
• 45 Moler FW. Therapeutic Hypothermia to Improve Survival After Cardiac Arrest in Pediatric Patients-THAPCA-OH Trial. 2011 Im Internet: http://clinicaltrials.gov/ct2/show/NCT00878644 [Stand: 25.05.2012]
• 46 University of Pittsburgh. Duration of Hypothermia for Neuroprotection After Pediatric Cardiac Arrest. 2011 Im Internet: http://clinicaltrials.gov/ct2/show/NCT00797680 [Stand: 25.05.2012]
• 47 Scholefield BR, Duncan HP, Morris KP. Survey of the use of therapeutic hypothermia post cardiac arrest. Arch Dis Child 2010; 95: 796-799
• 48 Hoffmann F, Rüdiger M, Nicolai T et al. Retrospektive Umfrage zur Häufigkeit von Reanimationen und Hypothermiebehandlungen auf pädiatrischen Intensivstationen in Deutschland. DIVI 2011; 4: 148
• 49 Sydenham E, Roberts I, Alderson P. Hypothermia for traumatic head injury. Cochrane Database Syst Rev 2009;
• 50 Fox JL, Vu EN, Doyle-Waters M et al. Prophylactic hypothermia for traumatic brain injury: a quantitative systematic review. CJEM 2010; 12: 355-364
• 51 Andrews PJD, Sinclair HL, Battison CG et al. European society of intensive care medicine study of therapeutic hypothermia (32-35 °C) for intracranial pressure reduction after traumatic brain injury (the Eurotherm3235Trial). Trials 2011; 12: 8
• 52 Tokutomi T, Morimoto K, Miyagi T et al. Optimal temperature for the management of severe traumatic brain injury: effect of hypothermia on intracranial pressure, systemic and intracranial hemodynamics, and metabolism. Neurosurgery 2007; 61: 256-265 ; discussion 265–266
• 53 Hutchison JS, Ward RE, Lacroix J et al. Hypothermia therapy after traumatic brain injury in children. N Engl J Med 2008; 358: 2447-2456
• 54 Hutchison JS, Frndova H, Lo TYM et al. Impact of Hypotension and Low Cerebral Perfusion Pressure on Outcomes in Children Treated with Hypothermia Therapy following Severe Traumatic Brain Injury: A post hoc Analysis of the Hypothermia Pediatric Head Injury Trial. Developmental Neuroscience 2010; 32: 406-412
• 55 Adelson PD, Ragheb J, Kanev P et al. Phase II clinical trial of moderate hypothermia after severe traumatic brain injury in children. Neurosurgery 2005; 56: 740-754 ; discussion 740–754
• 56 Adelson PD. Hypothermia following pediatric traumatic brain injury. J Neurotrauma 2009; 26: 429-436
• 57 Higgins RD, Shankaran S. Hypothermia: Novel approaches for premature infants. Early Human Development 2011; 87: 17-18
• 58 Great Ormond Street Hospital for Children NHS Foundation Trust. Therapeutic Controlled Hypothermia in the Treatment of Neonates With Severe Necrotizing Enterocolitis. 2012 Im Internet: http://clinicaltrials.gov/ct2/show/NCT01330576 Stand: 25.05.2012
• 59 Harbert MJ, Tam EWY, Glass HC et al. Hypothermia is correlated with seizure absence in perinatal stroke. J Child Neurol 2011; 26: 1126-1130
• 60 Stravitz RT, Larsen FS. Therapeutic hypothermia for acute liver failure. Crit Care Med 2009; 37: 258-264
• 61 Devictor D, Tissieres P, Afanetti M et al. Acute liver failure in children. Clin Res Hepatol Gastroenterol 2011; 35: 430-437
• 62 Kawano G, Iwata O, Iwata S et al. Determinants of outcomes following acute child encephalopathy and encephalitis: pivotal effect of early and delayed cooling. Archives of Disease in Childhood 2011; 96: 936-941
• 63 Cortes GA, Marini JJ. Update: adjuncts to mechanical ventilation. Current Opinion in Anaesthesiology 2012;
• 64 Thoresen M. Hypothermia after perinatal asphyxia: selection for treatment and cooling protocol. J Pediatr 2011; 158: e45-49
• 65 Polderman KH, Herold I. Therapeutic hypothermia and controlled normothermia in the intensive care unit: practical considerations, side effects, and cooling methods. Crit Care Med 2009; 37: 1101-1120
• 66 He X, Su F, Taccone FS et al. Cardiovascular and microvascular responses to mild hypothermia in an ovine model. Resuscitation 2011;
• 67 Fischer UM, Cox jr CS, Laine GA et al. Mild hypothermia impairs left ventricular diastolic but not systolic function. J Invest Surg 2005; 18: 291-296
• 68 Lebiedz P, Meiners J, Samol A et al. Electrocardiographic changes during therapeutic hypothermia. Resuscitation 2011;
• 69 Benumof JL, Wahrenbrock EA. Dependency of hypoxic pulmonary vasoconstriction on temperature. J Appl Physiol 1977; 42: 56-58
• 70 Sarkar S, Barks JD. Systemic complications and hypothermia. Seminars in Fetal and Neonatal Medicine 2010; 15: 270-275
• 71 Lo L, Singer ST, Vichinsky E. Pancytopenia induced by hypothermia. J Pediatr Hematol Oncol 2002; 24: 681-684
• 72 Rosenkranz L. Bone marrow failure and pancytopenia in two patients with hypothermia. South Med J 1985; 78: 358-359
• 73 Diestel A, Roessler J, Berger F et al. Hypothermia downregulates inflammation but enhances IL-6 secretion by stimulated endothelial cells. Cryobiology 2008; 57: 216-222
• 74 Laupland KB, Zahar JR, Adrie C et al. Severe hypothermia increases the risk for intensive care unit-acquired infection. Clin Infect Dis 2012; 54: 1064-1070
• 75 Peterson K, Carson S, Carney N. Hypothermia treatment for traumatic brain injury: a systematic review and meta-analysis. J Neurotrauma 2008; 25: 62-71
• 76 Kamps M, Bisschops LA, van der Hoeven JG et al. Hypothermia does not increase the risk of infection: a case control study. Crit Care 2011; 15: R48
• 77 Strohm B, Hobson A, Brocklehurst P et al. Subcutaneous fat necrosis after moderate therapeutic hypothermia in neonates. Pediatrics 2011; 128: e450-452
• 78 Fumagalli M, Ramenghi LA, Pisoni S et al. Total body cooling: skin and renal complications. Arch Dis Child Fetal Neonatal Ed 2011; 96: F377
• 79 Thoresen M, Satas S, Løberg EM et al. Twenty-four hours of mild hypothermia in unsedated newborn pigs starting after a severe global hypoxic-ischemic insult is not neuroprotective. Pediatr Res 2001; 50: 405-411
• 80 Tooley JR, Satas S, Porter H et al. Head cooling with mild systemic hypothermia in anesthetized piglets is neuroprotective. Ann Neurol 2003; 53: 65-72
• 81 Angeles DM, Wycliffe N, Michelson D et al. Use of opioids in asphyxiated term neonates: effects on neuroimaging and clinical outcome. Pediatr Res 2005; 57: 873-878
• 82 Zhou J, Poloyac SM. The effect of therapeutic hypothermia on drug metabolism and response: cellular mechanisms to organ function. Expert Opin Drug Metab Toxicol 2011; 7: 803-816
• 83 van den Broek MPH, Groenendaal F, Egberts ACG et al. Effects of hypothermia on pharmacokinetics and pharmacodynamics: a systematic review of preclinical and clinical studies. Clin Pharmacokinet 2010; 49: 277-294
• 84 Polderman KH. Application of therapeutic hypothermia in the intensive care unit. Intensive Care Medicine 2004; 30: 757-769
• 85 Soliman HM, Mercan D, Lobo SSM et al. Development of ionized hypomagnesemia is associated with higher mortality rates. Crit Care Med 2003; 31: 1082-1087
• 86 Rubeiz GJ, Thill-Baharozian M, Hardie D et al. Association of hypomagnesemia and mortality in acutely ill medical patients. Crit Care Med 1993; 21: 203-209
• 87 Weisinger JR, Bellorín-Font E. Magnesium and phosphorus. Lancet 1998; 352: 391-396
• 88 Rosenthal TB. The effect of temperature on the pH of blood and plasma in vitro. J Biol Chem 1948; 173: 25-30
• 89 Nichols DG, Cameron DE. Critical Heart Disease in Infants and Children. Philadelphia: Mosby; 2006
• 90 Abdul Aziz KA, Meduoye A. Is pH-stat or alpha-stat the best technique to follow in patients undergoing deep hypothermic circulatory arrest?. Interact Cardiovasc Thorac Surg 2010; 10: 271-282
• 91 Fink EL, Kochanek PM, Clark RSB et al. Fever control and application of hypothermia using intravenous cold saline. Pediatr Crit Care Med 2012; 13: 80-84
• 92 Maxwell WL, Watson A, Queen R et al. Slow, medium, or fast re-warming following post-traumatic hypothermia therapy? An ultrastructural perspective. J Neurotrauma 2005; 22: 873-884
• 93 Kawahara F, Kadoi Y, Saito S et al. Slow rewarming improves jugular venous oxygen saturation during rewarming. Acta Anaesthesiol Scand 2003; 47: 419-424
• 94 Lavinio A, Timofeev I, Nortje J et al. Cerebrovascular reactivity during hypothermia and rewarming. Br J Anaesth 2007; 99: 237-244
• 95 Bissonnette B, Holtby HM, Davis AJ et al. Cerebral hyperthermia in children after cardiopulmonary bypass. Anesthesiology 2000; 93: 611-618
• 96 Gunn AJ, Wyatt JS, Whitelaw A et al. Therapeutic hypothermia changes the prognostic value of clinical evaluation of neonatal encephalopathy. J Pediatr 2008; 152: 55-58 , 58. e1
• 97 Tao JD, Mathur AM. Using amplitude-integrated EEG in neonatal intensive care. J Perinatol 2010; 30 : 73-81
• 98 Murray DM, Boylan GB, Fitzgerald AP et al. Persistent lactic acidosis in neonatal hypoxic-ischaemic encephalopathy correlates with EEG grade and electrographic seizure burden. Arch Dis Child Fetal Neonatal Ed 2008; 93: F183-186
• 99 Karlsson M, Wiberg-Itzel E, Chakkarapani E et al. Lactate dehydrogenase predicts hypoxic ischaemic encephalopathy in newborn infants: a preliminary study. Acta Paediatr 2010; 99: 1139-1144
• 100 Rutherford M, Ramenghi LA, Edwards AD et al. Assessment of brain tissue injury after moderate hypothermia in neonates with hypoxic-ischaemic encephalopathy: a nested substudy of a randomised controlled trial. Lancet Neurol 2010; 9: 39-45
• 101 Rutherford MA, Pennock JM, Counsell SJ et al. Abnormal magnetic resonance signal in the internal capsule predicts poor neurodevelopmental outcome in infants with hypoxic-ischemic encephalopathy. Pediatrics 1998; 102: 323-328
• 102 Thayyil S, Chandrasekaran M, Taylor A et al. Cerebral magnetic resonance biomarkers in neonatal encephalopathy: a meta-analysis. Pediatrics 2010; 125: e382-395
• 103 Wilkinson D. MRI and withdrawal of life support from newborn infants with hypoxic-ischemic encephalopathy. Pediatrics 2010; 126: e451-458
• 104 Bennet L, Booth L, Gunn AJ. Potential biomarkers for hypoxic-ischemic encephalopathy. Semin Fetal Neonatal Med 2010; 15: 253-260
• 105 Cronberg T, Rundgren M, Westhall E et al. Neuron-specific enolase correlates with other prognostic markers after cardiac arrest. Neurology 2011; 77: 623-630
• 106 Daubin C, Quentin C, Allouche S et al. Serum neuron-specific enolase as predictor of outcome in comatose cardiac-arrest survivors: a prospective cohort study. BMC Cardiovasc Disord 2011; 11: 48
• 107 Sun J, Li J, Cheng G et al. Effects of hypothermia on NSE and S-100 protein levels in CSF in neonates following hypoxic/ischaemic brain damage. Acta Paediatrica (Oslo, Norway: 1992) 2012;
• 108 Massaro AN, Chang T, Kadom N et al. Biomarkers of Brain Injury in Neonatal Encephalopathy Treated with Hypothermia. The Journal of Pediatrics 2012;
• 109 Shankaran S, Pappas A, McDonald SA et al. Childhood outcomes after hypothermia for neonatal encephalopathy. N Engl J Med 2012; 366: 2085-2092