Published online March 1, 2006
PEDIATRICS Vol. 117 No. 3 March 2006, pp. 843-850 (doi:10.1542/peds.2004-1587)
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Hemodynamics Among Neonates With Hypoxic-Ischemic Encephalopathy During Whole-Body Hypothermia and Passive Rewarming

Corinna Mirjam Gebauer, MD, Matthias Knuepfer, MD, Eva Robel-Tillig, MD, Ferdinand Pulzer, MD and Christoph Vogtmann, MD

Department of Neonatology, Intensive Care Unit, Children's Hospital, University of Leipzig, Leipzig, Germany


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVE. To assess changes in cardiac performance, with Doppler echocardiography, among newborns with hypoxic-ischemic encephalopathy during mild therapeutic hypothermia and during rewarming.

METHODS. For 7 asphyxiated neonates (birth weight: 1840–3850 g; umbilical artery pH: 6.70–6.95) who received mild whole-body hypothermia, the following hemodynamic parameters were determined immediately before rewarming (33°C) and during passive rewarming (35°C and 37°C): heart rate, systolic and diastolic blood pressure, core and peripheral temperatures, left ventricular ejection time, mean velocity of aortic flow, stroke volume, and cardiac output.

RESULTS. Heart rate decreased during hypothermia. Bradycardia, with heart rates below 80 beats per minute, did not occur. The median difference between core and peripheral temperatures decreased from 2.0°C (range: 0–6.2°C) during hypothermia to 0.7°C (range: 0.4–1.9°C) at normothermia. Cardiac output was reduced to 67% and stroke volume to 77% of the posthypothermic level. The median heart rate was 129 beats per minute before rewarming and increased to 148 beats per minute during complete rewarming. Before and during passive rewarming, hypotension was not observed. Before, during, and at the end of rewarming, the following parameters increased: mean velocity of aortic flow (median: 44, 55, and 58 cm/second, respectively), stroke volume (median: 1.42, 1.55, and 1.94 mL/kg, respectively), and cardiac output (median: 169, 216, and 254 mL/kg per minute, respectively). Left ventricular ejection time remained unchanged.

CONCLUSIONS. Whole-body hypothermia resulted in reduced cardiac output, which reached normal levels at the end of passive rewarming, at normothermia. Physiologic cardiovascular mechanisms seemed to be intact to provide sufficient tissue perfusion, with normal blood lactate levels.

Key Words: hypothermia • newborn • cardiac function • left ventricular ejection time

Therapeutic hypothermia is used as a neuroprotective measure for patients during cardiac surgery and after traumatic and ischemic brain injury, cardiac arrest, and perinatal asphyxia. Animal experiments, clinical trials, and clinical experience demonstrated improved neurologic outcomes of hypothermia-treated subjects after cerebral hypoxia-ischemia.1–3

Severe perinatal asphyxia with hypoxic-ischemic encephalopathy occurs for approximately 1 or 2 newborns per 1000 live births. Randomized, clinical trials have shown a neuroprotective effect of therapeutic hypothermia among newborns with perinatal asphyxia.4–9

Therapeutic hypothermia for neonates is usually performed within clinical trials. Hypothermia is achieved through selective head cooling or whole-body cooling to a target core temperature of 33.5°C, starting within 6 hours after birth and lasting for 72 hours.

Adverse effects of hypothermia may include metabolic, pulmonary, coagulation, immunologic, and cardiovascular complications.10–15 The effects of hypothermia on the cardiovascular system have been studied mostly among sedated adult patients with head injuries or during heart surgery.16 During hypothermia, peripheral vasoconstriction, sinus bradycardia, cardiac arrhythmias, hypotension, and increases in blood viscosity have been observed.14,17,18 As known from clinical experience, cardiovascular changes among newborns during therapeutic hypothermia include minor cardiac arrhythmias, hypotension, hemoconcentration, sinus bradycardia, and peripheral vasoconstriction.9,19,20 Detailed examinations of hemodynamic changes among newborns during whole-body hypothermia and passive rewarming have not been published to date.

Thoresen and Whitelaw17 documented changes in heart rate and mean arterial blood pressure in 9 asphyxiated infants during mild hypothermia (33–34°C) and rewarming. The mean arterial blood pressure increased by 10 mm Hg during cooling and decreased by 8 mm Hg during rewarming; the heart rate decreased by 34 beats per minute during cooling and increased by 32 beats per minute on rewarming.

Fugelseth et al21 measured cardiac output parameters among nonsedated newborn pigs with Doppler echocardiography during global hypothermia (35°C) for 24 hours and slow rewarming after a global hypoxic-ischemic insult. Stroke volume was not affected by hypothermia, and cardiac output did not differ between normothermic and hypothermic pigs.

In contrast to these results, cardiac output, regional perfusion (myocardial, renal, adrenal, and mucosal), and left ventricular contractility decreased markedly during mild hypothermia in pigs.10,12 Deep (15°C) and moderate (30°C) hypothermia itself leads to cardiac impairment, which was shown in a dog model.22

Currently, echocardiography is common in NICUs. Measurements of cardiac performance with Doppler echocardiography among newborn infants during rewarming after global hypothermia because of perinatal asphyxia have not been published to date. Our investigations aimed to assess changes in cardiac performance during mild hypothermia and particularly during the transition to normothermia.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
During whole-body hypothermia (target rectal temperature: 33.5°C ± 0.5) for 72 hours, followed by a slow phase of passive rewarming (to a rectal temperature of 37°C), hemodynamic parameters were measured for 7 (male: 3; female: 4) asphyxiated newborns (including 1 preterm infant of 32 weeks of gestation). The term infants were part of a study population of a randomized, controlled, multicenter trial of induced systemic hypothermia among asphyxiated newborn infants (inclusion criteria were severe asphyxiation, umbilical artery pH of <7.0, umbilical artery base excess of >25 mmol/L, age of <6 hours, suppressed electroencephalographic findings or clinical signs of seizures, and parental consent). To classify the severity of the hypoxic-ischemic encephalopathy, all infants underwent amplitude-integrated electroencephalography (CFM MT2-5330, Lectromed; FBI Fred Berninger Importe OHG, Taufkirchen, Germany). Clinical and paraclinical characteristics of the infants are given in Table 1.


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  		TABLE 1 Neonatal Characteristics of 6 Term and 1 Preterm Infant Treated With Hypothermia Because of Hypoxic-Ischemic Encephalopathy

 
Hypothermia was achieved with a cooling mattress (Tecotherm TS 200; Tec Com, Halle, Germany). Core temperature was maintained at 33.5 ± 0.5°C for 72 hours. Thereafter, the neonates were rewarmed slowly, within 3 to 7 hours (median: 6 hours), to a normal rectal temperature between 36.6°C and 37.2°C, through discontinuation of cooling, covering of the infant, and adjustment of the overhead heater to the rising rectal temperature. Room temperature ranged between 22°C and 25°C.

We monitored core (measured at the back) and peripheral (sensor placed on the sole of the foot) temperatures, heart rate (electrocardiogram), and transcutaneous oxygen saturation simultaneously and continuously. Blood pressure (oscillometric method) was measured simultaneously with cardiac examination. Invasive blood pressure monitoring was not performed routinely. To ensure comparability, only oscillometric blood pressure values were selected for analysis.

Blood gas analyses, including lactate levels, were not performed routinely. To control ventilation and the metabolic condition of the infants, blood gas analyses were performed with blood collected from the heel. Measurements were recorded with a pediatric blood gas analyzer (Radiometer ABL 700; Radiometer A/S, Copenhagen, Denmark). For close meshed monitoring of ventilation, transcutaneous carbon dioxide measurements were performed for some patients.

The following hemodynamic parameters were assessed during hypothermia, directly before rewarming (step 33°C) and at defined steps during the rewarming phase (35°C and 37°C), for all participants. The baseline value at 33°C was obtained from 1 specific echocardiographic scan, with 3 measurements of all parameters, directly before the beginning of rewarming. With pulsed Doppler ultrasonography with a 5-MHz sector scan and with integrated electrocardiography, left ventricular ejection time, aortic flow, and aortic diameter were measured (Aloka SSD 5000; Aloka Deutschland, Meerbusch, Germany). The scans were performed by 3 experienced operators. During the process of rewarming, the operator did not change. The mean value of 3 measurements for each parameter was used for analyses. The measurements were assessed with the method described fundamentally by Alverson et al.23 Stroke volume and cardiac output were calculated.

The mean velocity of aortic blood flow was evaluated from the suprasternal approach, with the sample volume placed in the ascending aorta immediately distal to the aortic valve. The transducer was repositioned to minimize the angle. The aortic time-velocity integral was measured during systole. The time interval of systolic flow was characterized as the left ventricular ejection time. Examinations were performed while infants were sleeping or quiet. The infants lay in the supine position, with slightly reclined head.

The aortic inner diameter (in centimeters) was measured at the side of the flow analysis. The diameter was measured 3 times at 33°C. For additional calculations at 35°C and 37°C, the initial value was used. Stroke volume (in milliliters per kilogram) was calculated as (mean velocity across aortic root x mean aortic cross-sectional area x left ventricular ejection time)/body weight (in kilograms) and cardiac output (in milliliters per kilogram per minute) as stroke volume x heart rate.23 Ductus arteriosus patency was recorded with ultrasonography.

Inotropic agents (eg, dobutamine) were used when signs of myocardial dysfunction were present on clinical examination (increased difference in temperature between core and feet, prolonged time of skin recapillarization, hypotension, or metabolic acidosis) and echocardiographic evaluation. The latter included prolonged preejection time, which leads to an increased ratio of preejection period to left ventricular ejection time (in particular, a value of >0.5). Hypovolemia was treated first, before dobutamine administration was started. At the beginning of hypothermia, all infants received morphine (0.1 mg/kg 6 times per day) and phenobarbitone (initial dose of 20 mg/kg, followed by 2.5 mg/kg twice per day). All infants were nonsedated for ≥8 hours before rewarming was started. None of the infants showed a patent ductus arteriosus at the time of rewarming. After 51 hours of cooling, none of the infants showed a patent ductus arteriosus.

For statistical evaluation, SPSS version 11.5 (SPSS, Chicago, IL) and Statistica 5.5 (StatSoft, Tulsa, OK) software programs were used. The Friedman test was used to test for global differences. The Wilcoxon test was used for posthoc pairwise comparisons. The margins of the box-whisker plots indicate the 25th and 75th percentiles. The study was approved by the local ethics committee, and the parents gave their written informed consent.


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Patient Characteristics
The neonatal clinical and paraclinical characteristics for the 7 infants are given in Table 1. All infants suffered from severe birth asphyxia, with Apgar scores of ≤5 at 5 minutes, metabolic acidosis with cord arterial pH values of <7, negative base excesses of ≥23 mmol/L, and depressed electroencephalographic findings, measured with amplitude-integrated electroencephalography. There were no substantial differences regarding clinical characteristics.

None of the infants required volume expansion during rewarming. Four infants were still receiving dobutamine; dosages ranged from 8 to 28 µg/[r]kg per minute. All infants underwent mechanical ventilation throughout rewarming, and 1 of the infants underwent nitric oxide inhalation (18 ppm) during rewarming because of ongoing persistent pulmonary hypertension. Median pH values before rewarming (at the 72nd hour of cooling) and during rewarming at 35°C and 37°C were not significantly different, ie, 7.38 (range: 7.35–7.44), 7.43 (range: 7.37–7.43), and 7.37 (range: 7.33–7.45), respectively. Median carbon dioxide levels did not change significantly during rewarming, ie, 42 mmol/L (range: 35–52 mmol/L), 42 mmol/L (range: 33–46 mmol/L), and 48 mmol/L (range: 35–57 mmol/L), respectively. The corresponding base excess values were 0.7 mmol/L (range: 0–4.0 mmol/L), –1.2 mmol/L (range: –1.6 to 4.9 mmol/L), and 1.6 mmol/L (range: 0.2–4.7 mmol/L) (not significant). Lactate levels ranged from 1.3 to 2.2 mmol/L.

Heart Rate and Arterial Blood Pressure
The median heart rate during 72 hours of hypothermia was 130 beats per minute (range: 82–160 beats per minute). Heart rates below 80 beats per minute or arrhythmias were not observed during cooling. The median systolic blood pressure was 64 mm Hg (range: 32–96 mm Hg), and the mean diastolic blood pressure was 38 mm Hg (range: 19–71 mm Hg).

Immediately before rewarming was started, the median heart rate was 129 beats per minute (range: 86–144 beats per minute), the median systolic blood pressure was 62 mm Hg (range: 47–88 mm Hg), and the median diastolic blood pressure was 34 mm Hg (range: 30–55 mm Hg). During rewarming, the heart rate increased by 19 to 148 beats per minute (range: 127–162 beats per minute). The median systolic blood pressure at the end of rewarming was 68 mm Hg (range: 53–81 mm Hg), with no significant change, compared with 71 mm Hg (range: 53–85 mm Hg) immediately before passive rewarming. Hypotension during rewarming was not observed.

Core and Peripheral Temperatures
During hypothermia, the peripheral skin temperature decreased to a median of 31.1°C (range: 26.7–33.8°C), which resulted in an increased core-peripheral temperature difference of 2.0°C (range: 0–6.2°C); this provides major information on peripheral vasoconstriction. After rewarming, the mean difference in temperatures decreased to 0.7°C (range: 0.4–1.9°C).

Left Ventricular Ejection Time, Mean Velocity of Aortic Flow, Stroke Volume, and Cardiac Output
During hypothermia, left ventricular cardiac output amounted to only 67.0% of the posthypothermic value, which was caused by a decreased heart rate and a decreased stroke volume (77.2%). During passive rewarming, cardiac output increased significantly, along with rising core temperature (Fig 1 and Table 2). An increase in stroke volume with rising core temperature is caused particularly by an increase in the mean velocity of aortic flow with an unaffected left ventricular ejection time (Table 2). Infants who were still receiving dobutamine at rewarming showed higher values for cardiac output at 35°C and 37°C (Fig 2). Cardiac output during hypothermia was rather independent of the heart rate (Fig 3).


Figure 1
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  		FIGURE 1 Cardiac output at the end of hypothermia and during rewarming. There was a significant increase with increasing core temperature. The lower and upper margins of the boxes represent the 25th and 75th percentiles, respectively. The line within the boxes represents the median, and the lines below and above the boxes represent the minimum and maximum values, respectively.

 

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  		TABLE 2 Heart Rate, Left Ventricular Ejection Time, Mean Velocity of Aortic Flow, Stroke Volume, and Cardiac Output Before Rewarming at Step 33°C (Range: 32.4–33.4°C) and During Rewarming at Step 35°C (Range: 34.5–35.3°C) and Step 37°C (Range: 36.6–37.2°C)

 

Figure 2
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  		FIGURE 2 Cardiac output (A) and mean velocity of aortic flow (B) at 3 steps of rewarming. Both factors increased with increasing temperature during rewarming. Infants who were still receiving dobutamine reached higher levels at 33°C, 35°C, and 37°C. The lower and upper margins of the boxes represent the 25th and 75th percentiles, respectively. The line within the boxes represents the median, and the lines below and above the boxes represent the minimum and maximum values, respectively.

 

Figure 3
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  		FIGURE 3 Relationship between heart rate and cardiac output during hypothermia (rectal temperature of <35°C) (correlation coefficient: r = 0.1115; P = .5113). The linear regression model (solid line) was y = 178.102 + 0.374 · x. Dashed lines indicate the 95% confidence interval for the regression model.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
Effects of hypothermia on myocardial contractility have been studied in animal models in vitro and in vivo. Studies of human newborns during passive rewarming after whole-body hypothermia have not been published to date. Some studies describe changes in heart rate, blood pressure, pulmonary hypertension, and skin temperature.4,9,17–19 We aimed for closer insight into the changes in cardiac performance after whole-body hypothermia, during passive rewarming.

Treating the effects of severe birth asphyxia of near-term newborns with hypothermia is practiced within international clinical trials.4,6–9 Six infants in our analysis were born at term. Although 1 infant was born preterm, at a gestational age of 32.6 weeks, the infant was enrolled after parental consent was obtained. Therapeutic hypothermia treatment did not differ from that for term infants and was started within 2 hours after birth. In particular, this preterm infant showed an excellent neurologic outcome, although hypothermia has not been evaluated among preterm infants with severe asphyxia.

As expected, the heart rate was reduced during hypothermia and rose during passive rewarming, to the normal range. Hypothermia leads to sinus bradycardia, characterized by a prolonged QT interval, a prolonged PR interval, and so-called Osborn waves.24 These effects usually occur with hypothermia at ≤32.2°C.25 The current regimen for therapeutic hypothermia among asphyxiated newborns recommends core temperatures of 33°C to 34°C. Therefore, severe bradycardia attributable to hypothermia usually is not expected.

Previous studies and our own experience showed quite constant values for systolic and diastolic blood pressure. Data from Shankaran et al19 showed similar levels for both normothermic and hypothermic infants during 72 hours of cooling, with slightly higher values for hypothermic infants. In contrast to the results described by Thoresen and Whitelaw,17 a drop in blood pressure was not observed during rewarming. None of our infants received additional volume expansion or additional inotropic agents during rewarming. Four infants were receiving dobutamine when hypothermia was started, and the dosage was not changed during rewarming.

If a normal blood pressure is maintained despite a decreased cardiac output, it signifies adequate working blood pressure regulation. Changes in peripheral vasoconstriction as well as changes in rheologic properties of blood attributable to lower temperature may contribute to this phenomenon.

Skin perfusion is decreased, as can be judged from the increased core-peripheral temperature difference in hypothermia. It seems that the capability of the circulatory system to save heat to increase core temperature through strong peripheral vasoconstriction is not exhausted. In that case, the skin temperature should approximate the ambient temperature. Blood lactate levels were within the normal range at the end of hypothermia and decreased slightly during rewarming. The pH values did not change, and base excess first decreased at 35°C and then increased above the initial value at the end of rewarming. If the slightly reduced skin temperature and skin perfusion reflect tissue perfusion in general, then this could partially explain the stable blood pressure. Another contributing factor for increased peripheral resistance may be higher blood viscosity, which increases with decreasing body temperature.26 During cooling, we observed greater core-peripheral temperature differences among infants without dobutamine therapy; however, severe circulatory centralization was not observed.

Stroke volume and cardiac output were lower during hypothermia, compared with normal values for stroke volume (mean: 2.02 ± 0.42 mL/kg) and cardiac output (mean: 241 ± 33 mL/kg per minute or 260 ± 53 mL/kg per minute) for healthy newborns.27–29 During passive rewarming, left ventricular cardiac output increased 1.5-fold, from 169 mL/kg per minute at 33°C to the posthypothermic value of 254 mL/kg per minute. Passive rewarming was performed within a median time interval of 6 hours. The observed significant increases in both stroke volume and cardiac output seem to be caused mainly by improved cardiac contractility in normothermia, rather than effects of convalescence itself. The mean aortic flow increased independently from temperature-related increasing heart rate during rewarming. Ductus arteriosus patency with a higher cardiac output did not interfere with our results, because closure of the ductus arteriosus occurred until the 51st hour of cooling for all infants. Varying degrees of myocardial damage because of hypoxia were not considered separately; however, the severity of asphyxia was similar in all cases. It is of interest to note that in some cases the cardiac output measured during hypothermia was in the normal range for normothermic newborns, for unknown reasons.

In the literature, there is evidence for both increased and decreased myocardial contractility. Increased contractility has been observed in guinea pigs, rabbits, rats, and dogs,13,16,30 presumably through increased intracellular calcium contents in hypothermia. Lewis et al16 showed that left ventricular contractility was impaired in hypothermia (33°C and 31°C) if the heart rate was maintained at 100 beats per minute. Increasing the heart rate in hypothermia induced additional depression. Sidi et al31 found increases in cardiac output and heart rate in lambs in a cool environment. In contrast to our results, Zhou et al32 found no significant differences in ejection fraction, stroke volume, and cardiac output between normothermic asphyxiated newborns and asphyxiated newborns treated with hypothermia through selective head cooling. A negative correlation was found by comparing the left ventricular ejection time and the stroke volume with the heart rate during 72 hours of cooling. This phenomenon indicates that the normal physiologic regulatory mechanisms are working in the same manner as in normothermic infants. In this way, a nonconcomitant change in mean aortic blood flow is partially compensated for. This results in the finding that, almost irrespective of the heart rate, the cardiac output is maintained (Fig 3). Which heart rate is chosen to provide sufficient cardiac output may depend on myocardial contractility and preload.

We observed higher levels of cardiac output at 33°C and more evidently at 35°C and 37°C during rewarming among infants who were still receiving dobutamine. This presumes the efficacy of inotropic agents even during hypothermia. Animal models have shown inotropic effects of dopamine and dobutamine.13,33 Another effect of dobutamine was noted in regard to the core-peripheral temperature difference during cooling, which was lower among infants receiving dobutamine (data not shown). The effect of dobutamine during hypothermia needs to be verified with a larger number of infants.

Cerebral perfusion is related directly to cardiac output in the absence of major shunts across the foramen ovale or ductus arteriosus. This relationship is even closer if cerebral autoregulation is impaired, such as in severe asphyxia.34 Measuring systemic blood flow by determining superior vena cava flow reflects the perfusion of the brain more precisely.35

Birth asphyxia itself leads to myocardial dysfunction, with reduced cardiac output until 2 days after birth.36 Our data show an evident correlation between cardiac output and hypothermia at the age of 72 hours.

The neuroprotective effect of therapeutic hypothermia is associated with reduced cerebral metabolism, reduced apoptosis and necrosis, and reduced production of free radical nitric oxide and excitatory amino acids.5 Cerebral blood flow is decreased during hypothermia in newborn piglets, to ~72% at a cerebral cortex temperature of 35°C, with the most significant decrease in the brainstem.37 Recent trials of therapeutic hypothermia among newborns monitored heart rate, mean arterial blood pressure, persistent pulmonary hypertension, and peripheral temperature. To determine the optimal brain perfusion and to prevent additional neuronal damage attributable to diminished cerebral blood flow after birth asphyxia, during hypothermia it may be necessary to monitor systematically the left ventricular cardiac output or, even more precisely, the superior vena cava flow in the critical period after birth asphyxia.

Is normal cardiac output necessary during hypothermia (with the help of catecholamines), or should the physiologic lower output during whole-body hypothermia be accepted? A comparison of cardiac output and superior vena cava flow with neurologic outcomes might be performed with a larger number of infants.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
During mild hypothermia, cardiac output is reduced to ~67% of the posthypothermic level. In addition to a decreased heart rate, stroke volume is impaired because of a decrease in the mean velocity of aortic flow during cooling. The peripheral circulation showed moderate impairment during hypothermia, which became evident in an increased core-peripheral temperature difference that decreased during rewarming. One purpose of therapeutic generalized hypothermia is the reduction of metabolic demand; therefore, the decreased cardiac output may reflect the altered metabolic condition. Tissue perfusion and oxygenation seemed to be sufficient, because blood lactate levels were within the normal range. The present investigation involves only a very small number of patients because of the single-center character of the analysis and the overall rare incidence of asphyxia. Additional investigations need to be performed. Future trials of therapeutic whole-body hypothermia for treatment of birth asphyxia probably should monitor cardiac output and superior vena cava flow, to recommend an optimal range of systemic and cerebral blood flow.


   FOOTNOTES
 
Accepted Jul 27, 2005.

Address correspondence to Corinna Mirjam Gebauer, MD, Department of Neonatology, Intensive Care Unit, Children's Hospital, University of Leipzig, Philipp-Rosenthal-Strasse 55, 04317 Leipzig, Germany. E-mail: corinna.gebauer{at}kksl.uni-leipzig.de

The authors have indicated they have no financial relationships relevant to this article to disclose.


   REFERENCES
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 DISCUSSION
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PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics



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S. Shankaran, A. Pappas, A. R. Laptook, S. A. McDonald, R. A. Ehrenkranz, J. E. Tyson, M. Walsh, R. N. Goldberg, R. D. Higgins, A. Das, et al.
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