clinical study heart rate and arterial pressure...

Hindawi Publishing CorporationISRN PediatricsVolume 2013 Article ID 140213 6 pageshttpdxdoiorg1011552013140213

Clinical StudyHeart Rate and Arterial Pressure Changesduring Whole-Body Deep Hypothermia

Giacomo Cavallaro1 Luca Filippi2 Genny Raffaeli1 Gloria Cristofori1

Federico Schena1 Elisa Agazzani3 Ilaria Amodeo1 Alice Griggio1

Simona Boccacci3 Patrizio Fiorini2 and Fabio Mosca1

1 NICU Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico Universita degli Studi di MilanoVia Della Commenda 12 20122 Milan Italy

2 NICU Medical Surgical Feto-Neonatal Department ldquoA Meyerrdquo University Childrenrsquos Hospital Viale G Pieraccini24 50139 Florence Italy

3 Neonatal Intensive Care Unit ldquoCarlo Pomardquo Hospital Mantova Italy

Correspondence should be addressed to Giacomo Cavallaro giacomocavallaromangiagalliit

Received 31 January 2013 Accepted 18 March 2013

Academic Editors A Maheshwari and B Vasarhelyi

Copyright copy 2013 Giacomo Cavallaro et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Whole-body deep hypothermia (DH) could be a new therapeutic strategy for asphyxiated newborn This retrospective studydescribes howDHmodified the heart rate and arterial blood pressure if compared tomild hypothermia (MH) Fourteen in DH and17 inMHwere cooled within the first six hours of life and for the following 72 hours Hypothermia criteria were gestational age ge 36weeks birth weight ge 1800 g clinical signs of moderatesevere hypoxic-ischemic encephalopathy Rewarming was obtained in thefollowing 6ndash12 hours (05∘Ch) after cooling Heart rates were the same between the two groups there was statistically significantdifference at the beginning of hypothermia and during rewarming Three babies in the DH group and 2 in the MH group showedHR lt 80 bpm and QTc gt 520ms Infant submitted to deep hypothermia had not bradycardia or Qtc elongation before coolingand after rewarming Blood pressure was significantly lower in DH compared to MH during the cooling and peculiar was thehypotension during rewarming in DH group Conclusion The deeper hypothermia is a safe and feasible only if it is performed bya well-trained team DH should only be associated with a clinical trial and prospective randomized trials to validate its use

1 Introduction

Hypoxic-ischemic encephalopathy (HIE) is a disease thatinduces death and severe neurological damage in newborns[1] Hypothermia is now the first effective neuroprotectiveintervention for newborns that are critically ill following anasphyxial insult Hypothermia showed a decrease in death ordisability at 18 months [2ndash5] Parkins et al firstly introducedhypothermia as a neuroprotectivemethod but the side effectswere higher so the practice had been abandoned [6] Meta-analysis about eight largest RCTs had confirmed that coolingreduced mortality without increasing handicap in survivors[7] Two meta-analyses have confirmed that hypothermiawas associated with a lower risk of death or moderatesevereneurodevelopmental disorder in childhood but with an

increased risk of arrhythmia and thrombocytopenia [8 9]Perlman suggested that deeper or more prolonged coolingcould be able to treat more severe neonatal asphyxia [2]The early studies of deep hypothermia (20ndash27∘C) have foundsome neurological benefits but the side effects dramaticallyincreased below 32∘C and passed all potential clinical ben-efits [10] Shivering and cardiac arrhythmias were the mostpronounced of these side effects [11 12] Cardiac arrhythmiashypotension hemoconcentration sinus bradycardia andperipheral vasoconstriction are common adverse events inneonatal hypothermia [13ndash15] Safety and respiratory func-tion during deep hypothermia (DH) in asphyxiated newbornwere previously reported [16 17] Retrospective analysisof circulatory parameters is part of a prospective studydesigned to investigate the safety of the topiramate [18 19]

2 ISRN Pediatrics

The objective of this retrospective analysis was to investigatehow heart rate and systemic arterial pressure were modifiedbyDH (core temperature 30ndash33∘C) Results were compared toa group of term infants with hypoxic-ischemic encephalopa-thy (HIE) treated with milder levels of hypothermia (MH)(core temperature 33-34∘C)

2 Methods

Asphyxiated newborns included in the analysis were thosetreated with whole-body DH or MH within the first 6 hoursof life and if the two following criteria were fulfilled (1)gestational age ge36 weeks and birth weight ge1800 g with atleast one of the following (a) Apgar score le5 at 10 minutes(b) endotracheal intubation or mask ventilation for morethan 10 minutes after birth (c) acidosis (pH le 70 andorbasic excess geminus16mmolL in umbilical cord blood or arterialvenous or capillary blood) within 60 minutes from birth (2)moderate to severe encephalopathy consisting of altered stateof consciousness (irritability lethargy stupor or coma) andge1 of the following signs (a) hypotonia (b) abnormal reflexesincluding oculomotor or pupillary abnormalities (c) absentor weak suctioning and (d) clinical seizures [3 10] BetweenNovember 2004 and May 2010 78 asphyxiated newbornswith HIE were retrospectively compared 37 patients weretreated with DH and 41 with MH Four patients in eachgroup were excluded because they were cooled with icepacks Nineteen patients in DH and 20 patients in MH wereexcluded because they received inotropic supply Fourteenpatients in DH and 17 in MH were analyzed

Patients were cooled by two different cooling blanketsNIG 2 (IemmiMedical Srl Mantova Italy) and Blanketrol III(Hyper-Hypothermia System Cincinnati Sub-Zero Cincin-nati OH USA) Monitoring was performed by a rectal andesophageal probe Skin temperature was monitored on theabdominal wall with a skin probe by the radiant warmerthermal sensor or a temperature-monitoring unit (Mon-a-therm Mallinckrodt Medical St Louis MO USA) Thetarget of the core temperaturewas 31∘Cand 335∘C forDHandMH respectively Coolingwasmaintained between the statedtargets for 72 h and rewarming to 365ndash37∘C was graduallyobtained over the following 6ndash12 h (05∘Ch)

Arterial blood gas coagulation and biochemistry weredaily checked and temperature corrected Chest X raysand echocardiography (Acuson Sequoia C512 Siemens Ger-many) were performed at the admission The scans wereperformed by 2 experienced operators Respiratory rateheart rate (HR) blood pressure (BP) and oxygen satura-tion were continuously monitored during hypothermia andrewarming BP was measured by using standard oscillo-metric methods Invasive blood pressure monitoring wasnot performed routinely Only oscillometric blood pressurevalues were selected for analysis to reduce the bias Standardelectrocardiogram was obtained when bradycardia (HR oflt80 bpm) or arrhythmia (extrasystoles bundle branch block)was observed Hypotension defined as mean arterial bloodpressure (MAP) lt40mm Hg was firstly treated with sin-gle or repeated normal saline boluses (10ndash20mLkg) and

subsequently by dopamine while dobutamine was infusedwhen the reduction of myocardial contractility was foundDopamine or dobutamine was started at an initial doseof 5 ugkgmin and was increased by 5 ugkgmin up to amaximum dose of 15 ugkgmin Fluid intake was started at60 to 70mLkg and increased by 10 to 20mLkg each daybased on changes in bodyweight and serum electrolyte levelsClinical seizures were treated with phenobarbital (loadingdose 20mgkg followed by 15ndash25mgkg every 12 hours)Oral topiramate was administered as neuroprotective drugat starting time of hypothermia once a day for 3 days[18 19] Inhaled nitric oxide was started when PPHN wasechographically demonstrated

Brain magnetic resonance imaging (MRI) was plannedwithin the first week of life Brain lesions were classified asisolated lesions of white matter basal ganglia and thalamuswith or without involvement of posterior limb of the internalcapsule cortex or various combinations of the earlier lesions[20]

3 Statistical Analyses

Results were shown as mean plusmn SD or percentage Statisti-cal analyses were performed using Studentrsquos 119905-test Mann-Whitney test and ANOVA categorical variables were ana-lyzed using Fisher exact test or 1205942 analyses A paired 119905-testwas used to determine the effect of a single treatment119875 valueof le005 was considered significant

4 Results

Newborns reported in three earlier study were included [17ndash19] Seventy-eight asphyxiated newbornswere retrospectivelycompared from November 2004 to May 2010 37 patientswere treated with DH and 41 with MH Four patients inboth groups were excluded because they were cooled with icepacks Nineteen patients in DH and 20 patients in MH wereexcluded because they received inotropic supply Fourteenpatients inDHand 17 inMHwere analyzed and therewas nota statistically significant difference between the two groups(119875 = 0855) Perinatal and basic characteristics of the infantswere not significantly different (Table 1) Core temperatureswere the same between the two groups at hypothermicstarting time During treatment the core temperature wasrespectively maintained at 31∘C and 335∘C in DH and MHThere was a statistical significant difference (119875 lt 0001)from 6 to 72 hours between the two groups (Figure 1) Atstarting cooling mean HR was 110 bpm and 111 bpm duringDH and MH whereas it was reduced at 97 bpm and 105 bpmduring DH and MH (Figure 2) Three babies in DH (20)and 2 in MH (117) showed a sinus bradycardia (HRlt 80 bpm) with a significant increase in QTc (gt520ms)during hypothermia (119875 = 0326) Newborns did not havebradycardia before cooling and after rewarming Heart ratedecreased significantly by a mean of 11 bpm in DH and ninebpm inMH on cooling (Figure 2) Sinus bradycardia was notassociated with a decrease of mean arterial pressure (MAP)and arrhythmia has not been reported Mean systolic arterial

ISRN Pediatrics 3

Table 1 Basic characteristics of the group (mean plusmn SD or n and )

Group DHn = 1431 (451)

Group MHn = 1731 (549) P value 95 CI

Weight g (SD) 3296 (plusmn659) 3292 (plusmn608) 119875 = 0982 minus2990ndash3057Gestational age weeks (SD) 396 (plusmn17) 392 (plusmn19) 119875 = 0488 minus0737ndash1222Inborn 119899 () 514 (357) 717 (235) 119875 = 0738 minus0482ndash0726Male 119899 () 614 (428) 1217 (705) 119875 = 0533 minus0754ndash0200Caucasian race 119899 () 1114 (785) 1317 (764) 119875 = 0714 minus0315ndash0357Vaginal delivery 119899 () 614 (428) 1017 (588) 119875 = 0897 minus0606ndash0406Apgar 51015840 (SD) 48 (plusmn20) 41 (plusmn21) 119875 = 0419 minus0334ndash1607Umbilical cord pH (SD) 6881 (plusmn01) 6996 (plusmn02) 119875 = 0066 minus0397ndash0079Umbilical cord paCO2 (mmHg) (SD) 902 (plusmn340) 683 (plusmn324) 119875 = 0080 minus2730ndash46423Umbilical cord BE (mmolL) (SD) minus170 (plusmn41) minus177 (plusmn71) 119875 = 0981 minus2592ndash7207Umbilical cord lactate (mmolL) (SD) 121 (plusmn63) 141 (plusmn46) 119875 = 0378 minus6694ndash2632Onset of hypothermia h (SD) 32 (plusmn15) 33 (plusmn12) 119875 = 0957 minus0697ndash0528Length of hospitalization (days) (SD) 167 (plusmn129) 131 (plusmn72) 119875 = 0270 minus0201ndash9171DH deep hypothermia MH mild hypothermia SD standard deviation BE basic excess h hours

pressure was 66mmHg and mean diastolic blood pressurewas 41mmHg during DH During MH mean systolic bloodpressure was 72mmHg and mean diastolic blood pressurewas 46mmHg (Figure 3) Blood pressure was significantlylower in DH than MH and DH group presented a greaterdecrease inMAP during rewarming compared withMHwithseveral statistical significance Two newborns in MH andone in DH died and that occurred 72 hours after hypother-mia Length of hospitalisation was similar in both groups(Table 1)

5 Discussion

Cardiovascular changes during cooling have a significantincidence on systemic sequelae in infants with HIE Theexperimental data have shown that duringmild hypothermialeft ventricular contractility and cardiac output decreased[21ndash23]This is the first report that compares the cardiovascu-lar function in treated asphyctic newborns with two differentdegrees of hypothermia This report has demonstrated howthe MAP changed during DH while HR remained the samechanging degrees of cooling In both treatment groupstarget temperature was reached andmaintained Cooling wasthe same even using two different devices and statisticaldifference was significant during hypothermia (Figure 1)Indeed Hoedemaekers et al showed that the use of differentblankets did not change the induction and maintenance ofcooling [24]

Thoresen and Whitelaw have documented how HR andMAP changed in asphyxiated newborns during hypothermiaand rewarming In fact while the MAP increased HRdecreased during the cooling and the opposite occurredduring the rewarming [25] Already three randomized con-trolled trials have been reported as a decrease in HR wasreversible [3 4 13] In the same way it was already described

29303132333435363738

Pre 0 6 12 18 24 30 36 42 48 54 60 66 72 PostHypothermia (h)

Core temperature during DH and MH

DHMH

Cor

e tem

pera

ture

(∘C)

lowast

⧫

119875 lt 0001

lowast

119875 lt 005

Figure 1 Core temperature during DH and MH (mean standarddeviation) The black and grey solid lines represent the coretemperature during DH and MH The black asterisk (lowast) representsthe statistical significance with 119875 lt 005 The black diamond (⧫)represents the statistical significance with 119875 lt 0001 Core tempera-tures were the same between the two groups at starting hypothermictime then the mean core temperature was 31∘C and 335∘C in DHand MH respectively DH and MH had an analogous trend duringcooling and rewarmingThere was a statistical significant difference(119875 lt 0001) from 6 to 72 hours between the two trends duringcooling There was statistical significance between prehypothermicand hypothermic temperature and hypothermic and postrewarmingtemperature (119875 lt 0001)

as neonates undergoing hypothermia were also exposed tosinus bradycardia and hypotension [7 12 26] FurthermoreQTc elongation is a typical anomaly during hypothermiaGunn et al reported that HR of infants submitted to headcooling decreased and at the same time increased the QTinterval After rewarming HR and QT interval came back tonormal range [20 27ndash30]

4 ISRN Pediatrics

60

80

100

120

140

160

Pre 0 6 12 18 24 30 36 42 48 54 60 66 72 Post

HR

(bpm

)

Hypothermia (h)

Heart rate during DH and MH

DHMH

⧫

119875 lt 0001

Figure 2 Heart rate during DH and MH (mean standard devia-tion) The black dashed line represents the heart rate (HR) of new-borns in deep hypothermia (DH) The grey dashed line representstheHR of newborns inmild hypothermia (MH)The black diamond(⧫) represents the statistical significance with 119875 lt 0001 HR wasvery comparable between the two groups at starting hypothermictime and during hypothermia There was statistical significancebetween prehypothermic and hypothermic HR and hypothermicand postrewarming HR (119875 lt 0001)

In this report HR rapidly decreased during coolinginduction and quickly increased during passive rewarmingSinus bradycardia has been observed in both groups whilea significant increase in QTc developed only in 5 patientsThe depth of hypothermia did not appear to affect HR whilethe induction of cooling and the gradual warming seemed toaffect it (Figure 3)

Studies on pressure data are contradictory because somehave reported a pressure decrease while others have docu-mented an increase in blood pressure during hypothermia[7 25]

In this report blood pressures inevitably fall after thebeginning of hypothermia in both groups and more inthat subjected on deep hypothermia (Figure 3) However afurther decrease in blood pressure had been observed duringrewarming only in DH group as described by Thoresen andWhitelaw [25] Although the rewarming rate was similar inboth groups (05∘Ch) we assumed that this rate was tooelevated for those patients undergoing a more deep coolingTherefore based on previous studies it is to suggest that theremay be some benefit to give volume at the time of rewarmingto ldquoprimerdquo the circulation [31]

Blood pressure significantly lower in the DH may beexplained with inhibition of endogenous catecholaminesactivity following the further reduction on body temperaturebelow 33∘C Indeed Chernow et al measured HR MAPand plasma levels of catecholamines during progressivehypothermia to 29∘C and then during rewarming to 37∘Con baboon HR MAP and plasma levels of epinephrine andnorepinephrine increased significantly when the temperaturedropped to 33∘C A further reduction in temperature to29∘C corresponded with a reduction in HR MAP and cate-cholamine to prehypothermic levels Therefore sympatheticnervous system immediately responds to hypothermia but

405060708090

SAP

(mm

Hg)

Arterial pressure during DH and MH


lowastlowastlowastlowast

(a)

304050607080

MA

P (m

mH

g)



(b)

2030405060

Pre 0 6 12 18 24 30 36 42 48 54 60 66 72 PostD

AP

(mm

Hg)

Hypothermia (h)

DHMH

lowast

lowast119875 lt 005

(c)

Figure 3 Change in arterial pressure during DH and MH (meanstandard deviation) The systolic (SAP) mean (MAP) and dias-tolic arterial pressure (DAP) was represented with black and greydashed lines in patients during deep hypothermia (DH) and mildhypothermia (MH) respectively The black asterisk (lowast) representsthe statistical significance with 119875 lt 005

may be ldquoswitched offrdquo at threshold temperature of about 29∘C[32]

We also speculated that hypotension was probably alsodue to hypoxic multiorgan or multisystemic dysfunction(MOD) [33] It is necessary to remember that MOD asrenal cardiovascular pulmonary or hepatic involvement isfrequent in postasphyxial infants and is respectively presentin 70 62 86 and 85 of infants with HIE [33]

The adverse effects of deep cooling may be more severein asphyxiated newborns with multiorgan dysfunction ormultiorgan dysfunction could be amplified by superimposedcold-injury syndrome [34 35] In an experimental adultdog model deep hypothermia (15∘C) produced worse cere-bral and cardiac outcomes [36] whereas controlled mildhypothermia (34ndash36∘C) provided consistent neuroprotectivebenefits [37] The mechanisms of adverse effect of deephypothermia or ldquoovercoolingrdquo on cerebral outcome are notclear but might be related to myocardial dysfunction leadingto decrease in cardiac output systemic hypotension andcompromised cerebral perfusion [22 36 38 39] Deephypothermia used in this study did not seem to be asprofound as that used on the dogs by Dudgeon et al [22] butit could itself be responsible to hypotension

ISRN Pediatrics 5

6 Conclusion

In conclusion the present report confirms that patients underDH are also subjected to cardiovascular dysfunction IndeedDH patients are subject to an increased risk of hypoten-sion both during and after hypothermia Small sample sizeretrospective data collection BP recording method andobservational clinical markers of cardiovascular status limitthe power of our conclusions However deep hypothermia issafe and feasible treatment only if performedby awell-trainedteam [16 17] While moderate hypothermia can now beconsidered a ldquostandard carerdquo in asphyxiated term infants DHshould only be associated to a clinical trial New prospectiverandomized trials are needed to validate its use

Ethical Approval

The study protocol was approved by the Medical EthicalCommittee of the ldquoCarlo Pomardquo Hospital Mantova and theldquoA Meyerrdquo University Childrenrsquos Hospital Florence Italy

Consent

A parental consent was obtained

Disclosure

This paper is not commissioned externally peer reviewed

Conflict of Interests

None of the authors has any conflict of interests to disclose

References

[1] J J Kurinczuk M White-Koning and N Badawi ldquoEpi-demiology of neonatal encephalopathy and hypoxic-ischaemicencephalopathyrdquo Early Human Development vol 86 no 6 pp329ndash338 2010

[2] J M Perlman ldquoSummary proceedings from the neurologygroup on hypoxic-ischemic encephalopathyrdquo Pediatrics vol 117no 3 pp S28ndashS33 2006

[3] P D Gluckman J S Wyatt D Azzopardi et al ldquoSelectivehead cooling with mild systemic hypothermia after neonatalencephalopathy multicentre randomised trialrdquoThe Lancet vol365 no 9460 pp 663ndash670 2005

[4] S Shankaran A R Laptook R A Ehrenkranz et alldquoWhole-body hypothermia for neonates with hypoxic-ischemicencephalopathyrdquoNew England Journal of Medicine vol 353 no15 pp 1574ndash1584 2005

[5] D V Azzopardi B Strohm A D Edwards et al ldquoModeratehypothermia to treat perinatal asphyxial encephalopathyrdquo NewEngland Journal of Medicine vol 361 no 14 pp 1349ndash13582009

[6] W M Parkins J M Jensen and H M Vars ldquoBrain cooling inthe prevention of brain damage during periods of circulatoryocclusion in dogsrdquo Annals of Surgery vol 140 no 3 pp 284ndash289 1954

[7] S Jacobs R Hunt W Tarnow-Mordi T Inder and P DavisldquoCooling for newborns with hypoxic ischaemic encephalopa-thyrdquo Cochrane Database of Systematic Reviews no 4 pCD003311 2007

[8] P S Shah ldquoHypothermia a systematic review andmeta-analysisof clinical trialsrdquo Seminars in Fetal and Neonatal Medicine vol15 no 5 pp 238ndash246 2010

[9] A D Edwards P Brocklehurst A J Gunn et al ldquoNeurologicaloutcomes at 18 months of age after moderate hypothermiafor perinatal hypoxic ischaemic encephalopathy synthesis andmeta-analysis of trial datardquo British Medical Journal vol 340 pc363 2010

[10] R EHoesch andRGGeocadin ldquoTherapeutic hypothermia forglobal and focal ischemic brain injurymdasha cool way to improveneurologic outcomesrdquo Neurologist vol 13 no 6 pp 331ndash3422007

[11] K H Polderman ldquoApplication of therapeutic hypothermia inthe ICU opportunities and pitfalls of a promising treatmentmodality Part 1 indications and evidencerdquo Intensive CareMedicine vol 30 no 4 pp 556ndash575 2004

[12] K H Polderman ldquoApplication of therapeutic hypothermia inthe intensive care unit opportunities and pitfalls of a promisingtreatment modality Part 2 practical aspects and side effectsrdquoIntensive Care Medicine vol 30 no 5 pp 757ndash769 2004

[13] D J Eicher C L Wagner L P Katikaneni et al ldquoModeratehypothermia in neonatal encephalopathy efficacy outcomesrdquoPediatric Neurology vol 32 no 1 pp 11ndash17 2005

[14] S Shankaran A Laptook L L Wright et al ldquoWhole-bodyhypothermia for neonatal encephalopathy animal observationsas a basis for a randomized controlled pilot study in terminfantsrdquo Pediatrics vol 110 no 2 pp 377ndash385 2002

[15] A J Gunn andM Battin ldquoHypothermic centralization new usefor old knowledgerdquo Pediatrics vol 106 no 1 pp 133ndash134 2000

[16] G Compagnoni C Bottura G Cavallaro G Cristofori GLista and F Mosca ldquoSafety of deep hypothermia in treatingneonatal asphyxiardquo Neonatology vol 93 no 4 pp 230ndash2352008

[17] G Cavallaro L Filippi G Cristofori et al ldquoDoes pul-monary function change during whole-body deep hypother-miardquo Archives of Disease in Childhood vol 96 no 5 pp F374ndashF377 2011

[18] L Filippi G La Marca P Fiorini et al ldquoTopiramate con-centrations in neonates treated with prolonged whole bodyhypothermia for hypoxic ischemic encephalopathyrdquo Epilepsiavol 50 no 11 pp 2355ndash2361 2009

[19] L Filippi C Poggi G La Marca et al ldquoOral topiramate inneonates with hypoxic ischemic encephalopathy treated withhypothermia a safety studyrdquo Journal of Pediatrics vol 157 no3 pp 361ndash366 2010

[20] M J Ree ldquoElectrocardiographic changes in accidentalhypothermiardquo British Heart Journal vol 26 pp 566ndash571 1964

[21] J M Perlman ldquoSystemic abnormalities in term infants fol-lowing perinatal asphyxia relevance to long-term neurologicoutcomerdquo Clinics in Perinatology vol 16 no 2 pp 475ndash4841989

[22] D L Dudgeon P A Randall and J GMcAfee ldquoMild hypother-mia its effect on cardiac output and regional perfusion in theneonatal pigletrdquo Journal of Pediatric Surgery vol 15 no 6 pp805ndash810 1980

[23] P S Greene D E Cameron M L Mohlala J M Dinatale andT J Gardner ldquoSystolic and diastolic left ventricular dysfunction

6 ISRN Pediatrics

due to mild hypothermiardquo Circulation vol 80 no 5 pp 44ndash481989

[24] C W Hoedemaekers M Ezzahti A Gerritsen and J Gvan der Hoeven ldquoComparison of cooling methods to induceand maintain normo- and hypothermia in intensive care unitpatients a prospective intervention studyrdquo Critical Care vol 11p R91 2007

[25] MThoresen and A Whitelaw ldquoCardiovascular changes duringmild therapeutic hypothermia and rewarming in infants withhypoxic-ischemic encephalopathyrdquo Pediatrics vol 106 no 1 pp92ndash99 2000

[26] R E Lasky N A Parikh A L Williams N S Padhye andS Shankaran ldquoChanges in the PQRST intervals and heartrate variability associated with rewarming in two newbornsundergoing hypothermia therapyrdquo Neonatology vol 96 no 2pp 93ndash95 2009

[27] T R Gunn N J Wilson S Aftimos and A J Gunn ldquoBrainhypothermia andQT intervalrdquo Pediatrics vol 103 no 5 p 10791999

[28] R Thompson J Rich F Chmelik and W Nelson ldquoEvolu-tionary changes in the electrocardiogram of severe progressivehypothermiardquo Journal of Electrocardiology vol 10 no 1 pp 67ndash70 1977

[29] M Okada ldquoThe cardiac rhythm in accidental hypothermiardquoJournal of Electrocardiology vol 17 no 2 pp 123ndash128 1984

[30] D Emslie-Smith ldquoChanges in the electrocardiogram duringpreoperative hypothermia in manrdquo Australasian annals ofmedicine vol 5 no 1 pp 62ndash67 1956

[31] M R Battin M Thoresen E Robinson R A Polin A DEdwards and A J Gunn ldquoDoes head cooling with mildsystemic hypothermia affect requirement for blood pressuresupportrdquo Pediatrics vol 123 no 3 pp 1031ndash1036 2009

[32] B Chernow C R Lake and A Zaritsky ldquoSympathetic nervoussystem ldquoswitch offrdquo with severe hypothermiardquo Critical CareMedicine vol 11 no 9 pp 677ndash680 1983

[33] P Shah S Riphagen J Beyene and M Perlman ldquoMultiorgandysfunction in infants with post-asphyxial hypoxic-ischaemicencephalopathyrdquo Archives of Disease in Childhood vol 89 no2 pp F152ndashF155 2004

[34] P B Tsivyan and A D Vasenina ldquoLeft ventricular systolicand diastolic function in term neonates after mild perinatalasphyxiardquoEuropean Journal of Obstetrics Gynecology andRepro-ductive Biology vol 40 no 2 pp 105ndash110 1991

[35] V Weinrauch P Safar S Tisherman K Kuboyama ARadovsky and R C Koehler ldquoBeneficial effect of mildhypothermia and detrimental effect of deep hypothermia aftercardiac arrest in dogsrdquo Stroke vol 23 no 10 pp 1454ndash14621992

[36] R A Primhak R Jedeikin and G Ellis ldquoMyocardial ischaemiain aphyxia neonatorum Electrocardiographic enzymatic andhistological correlationsrdquoActa Paediatrica Scandinavica vol 74no 4 pp 595ndash600 1985

[37] P Safar F Xiao A Radovsky et al ldquoImproved cerebral resusci-tation from cardiac arrest in dogs with mild hypothermia plusblood flow promotionrdquo Stroke vol 27 no 1 pp 105ndash113 1996

[38] C M Gebauer M Knuepfer E Robel-Tillig F Pulzer andC Vogtmann ldquoHemodynamics among neonates with hypoxic-ischemic encephalopathy during whole-body hypothermia andpassive rewarmingrdquo Pediatrics vol 117 no 3 pp 843ndash850 2006

[39] S Sarkar and JD Barks ldquoSystemic complications andhypother-miardquo Seminars in Fetal and Neonatal Medicine vol 15 no 5 pp270ndash275 2010

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

2 ISRN Pediatrics

The objective of this retrospective analysis was to investigatehow heart rate and systemic arterial pressure were modifiedbyDH (core temperature 30ndash33∘C) Results were compared toa group of term infants with hypoxic-ischemic encephalopa-thy (HIE) treated with milder levels of hypothermia (MH)(core temperature 33-34∘C)

2 Methods

Asphyxiated newborns included in the analysis were thosetreated with whole-body DH or MH within the first 6 hoursof life and if the two following criteria were fulfilled (1)gestational age ge36 weeks and birth weight ge1800 g with atleast one of the following (a) Apgar score le5 at 10 minutes(b) endotracheal intubation or mask ventilation for morethan 10 minutes after birth (c) acidosis (pH le 70 andorbasic excess geminus16mmolL in umbilical cord blood or arterialvenous or capillary blood) within 60 minutes from birth (2)moderate to severe encephalopathy consisting of altered stateof consciousness (irritability lethargy stupor or coma) andge1 of the following signs (a) hypotonia (b) abnormal reflexesincluding oculomotor or pupillary abnormalities (c) absentor weak suctioning and (d) clinical seizures [3 10] BetweenNovember 2004 and May 2010 78 asphyxiated newbornswith HIE were retrospectively compared 37 patients weretreated with DH and 41 with MH Four patients in eachgroup were excluded because they were cooled with icepacks Nineteen patients in DH and 20 patients in MH wereexcluded because they received inotropic supply Fourteenpatients in DH and 17 in MH were analyzed

Patients were cooled by two different cooling blanketsNIG 2 (IemmiMedical Srl Mantova Italy) and Blanketrol III(Hyper-Hypothermia System Cincinnati Sub-Zero Cincin-nati OH USA) Monitoring was performed by a rectal andesophageal probe Skin temperature was monitored on theabdominal wall with a skin probe by the radiant warmerthermal sensor or a temperature-monitoring unit (Mon-a-therm Mallinckrodt Medical St Louis MO USA) Thetarget of the core temperaturewas 31∘Cand 335∘C forDHandMH respectively Coolingwasmaintained between the statedtargets for 72 h and rewarming to 365ndash37∘C was graduallyobtained over the following 6ndash12 h (05∘Ch)

Arterial blood gas coagulation and biochemistry weredaily checked and temperature corrected Chest X raysand echocardiography (Acuson Sequoia C512 Siemens Ger-many) were performed at the admission The scans wereperformed by 2 experienced operators Respiratory rateheart rate (HR) blood pressure (BP) and oxygen satura-tion were continuously monitored during hypothermia andrewarming BP was measured by using standard oscillo-metric methods Invasive blood pressure monitoring wasnot performed routinely Only oscillometric blood pressurevalues were selected for analysis to reduce the bias Standardelectrocardiogram was obtained when bradycardia (HR oflt80 bpm) or arrhythmia (extrasystoles bundle branch block)was observed Hypotension defined as mean arterial bloodpressure (MAP) lt40mm Hg was firstly treated with sin-gle or repeated normal saline boluses (10ndash20mLkg) and

subsequently by dopamine while dobutamine was infusedwhen the reduction of myocardial contractility was foundDopamine or dobutamine was started at an initial doseof 5 ugkgmin and was increased by 5 ugkgmin up to amaximum dose of 15 ugkgmin Fluid intake was started at60 to 70mLkg and increased by 10 to 20mLkg each daybased on changes in bodyweight and serum electrolyte levelsClinical seizures were treated with phenobarbital (loadingdose 20mgkg followed by 15ndash25mgkg every 12 hours)Oral topiramate was administered as neuroprotective drugat starting time of hypothermia once a day for 3 days[18 19] Inhaled nitric oxide was started when PPHN wasechographically demonstrated

Brain magnetic resonance imaging (MRI) was plannedwithin the first week of life Brain lesions were classified asisolated lesions of white matter basal ganglia and thalamuswith or without involvement of posterior limb of the internalcapsule cortex or various combinations of the earlier lesions[20]

3 Statistical Analyses

Results were shown as mean plusmn SD or percentage Statisti-cal analyses were performed using Studentrsquos 119905-test Mann-Whitney test and ANOVA categorical variables were ana-lyzed using Fisher exact test or 1205942 analyses A paired 119905-testwas used to determine the effect of a single treatment119875 valueof le005 was considered significant

4 Results

Newborns reported in three earlier study were included [17ndash19] Seventy-eight asphyxiated newbornswere retrospectivelycompared from November 2004 to May 2010 37 patientswere treated with DH and 41 with MH Four patients inboth groups were excluded because they were cooled with icepacks Nineteen patients in DH and 20 patients in MH wereexcluded because they received inotropic supply Fourteenpatients inDHand 17 inMHwere analyzed and therewas nota statistically significant difference between the two groups(119875 = 0855) Perinatal and basic characteristics of the infantswere not significantly different (Table 1) Core temperatureswere the same between the two groups at hypothermicstarting time During treatment the core temperature wasrespectively maintained at 31∘C and 335∘C in DH and MHThere was a statistical significant difference (119875 lt 0001)from 6 to 72 hours between the two groups (Figure 1) Atstarting cooling mean HR was 110 bpm and 111 bpm duringDH and MH whereas it was reduced at 97 bpm and 105 bpmduring DH and MH (Figure 2) Three babies in DH (20)and 2 in MH (117) showed a sinus bradycardia (HRlt 80 bpm) with a significant increase in QTc (gt520ms)during hypothermia (119875 = 0326) Newborns did not havebradycardia before cooling and after rewarming Heart ratedecreased significantly by a mean of 11 bpm in DH and ninebpm inMH on cooling (Figure 2) Sinus bradycardia was notassociated with a decrease of mean arterial pressure (MAP)and arrhythmia has not been reported Mean systolic arterial

ISRN Pediatrics 3


Group DHn = 1431 (451)




5 Discussion



29303132333435363738



DHMH

Cor

e tem

pera

ture

(∘C)

lowast

⧫

119875 lt 0001

lowast

119875 lt 005



4 ISRN Pediatrics

60

80

100

120

140

160

Pre 0 6 12 18 24 30 36 42 48 54 60 66 72 Post

HR

(bpm

)

Hypothermia (h)


DHMH

⧫

119875 lt 0001






405060708090

SAP

(mm

Hg)




(a)

304050607080

MA

P (m

mH

g)



(b)

2030405060

Pre 0 6 12 18 24 30 36 42 48 54 60 66 72 PostD

AP

(mm

Hg)

Hypothermia (h)

DHMH

lowast

lowast119875 lt 005

(c)





ISRN Pediatrics 5

6 Conclusion


Ethical Approval


Consent


Disclosure




References
























6 ISRN Pediatrics























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















ISRN Pediatrics 3


Group DHn = 1431 (451)




5 Discussion



29303132333435363738



DHMH

Cor

e tem

pera

ture

(∘C)

lowast

⧫

119875 lt 0001

lowast

119875 lt 005



4 ISRN Pediatrics

60

80

100

120

140

160

Pre 0 6 12 18 24 30 36 42 48 54 60 66 72 Post

HR

(bpm

)

Hypothermia (h)


DHMH

⧫

119875 lt 0001






405060708090

SAP

(mm

Hg)




(a)

304050607080

MA

P (m

mH

g)



(b)

2030405060

Pre 0 6 12 18 24 30 36 42 48 54 60 66 72 PostD

AP

(mm

Hg)

Hypothermia (h)

DHMH

lowast

lowast119875 lt 005

(c)





ISRN Pediatrics 5

6 Conclusion


Ethical Approval


Consent


Disclosure




References
























6 ISRN Pediatrics























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















4 ISRN Pediatrics

60

80

100

120

140

160

Pre 0 6 12 18 24 30 36 42 48 54 60 66 72 Post

HR

(bpm

)

Hypothermia (h)


DHMH

⧫

119875 lt 0001






405060708090

SAP

(mm

Hg)




(a)

304050607080

MA

P (m

mH

g)



(b)

2030405060

Pre 0 6 12 18 24 30 36 42 48 54 60 66 72 PostD

AP

(mm

Hg)

Hypothermia (h)

DHMH

lowast

lowast119875 lt 005

(c)





ISRN Pediatrics 5

6 Conclusion


Ethical Approval


Consent


Disclosure




References
























6 ISRN Pediatrics























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















ISRN Pediatrics 5

6 Conclusion


Ethical Approval


Consent


Disclosure




References
























6 ISRN Pediatrics























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















6 ISRN Pediatrics























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















clinical study heart rate and arterial pressure...

Documents