Cardiovascular performance of neonates with hypoxic-ischemic encephalopathy under therapeutic hypothermia evaluated by conventional and advanced echocardiographic techniques

doi:10.21203/rs.3.rs-4714069/v1

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Cardiovascular performance of neonates with hypoxic-ischemic encephalopathy under therapeutic hypothermia evaluated by conventional and advanced echocardiographic techniques

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This study aimed to evaluate hemodynamic and ventricular performance of neonates with hypoxic-ischemic encephalopathy under therapeutic hypothermia using conventional and advanced echocardiographic techniques. This was an observational, prospective study including 22 neonates with hypoxic-ischemic encephalopathy matched with 22 healthy neonates. The echocardiographic studies were performed during hypothermia and after rewarming. Echo parameters included ejection and shortening fractions, right ventricular fractional area change, biventricular Tei index, right ventricular s´ wave velocity, tricuspid annular plane systolic excursion, biventricular stroke volume and cardiac output, left and right ventricular global longitudinal strain, left ventricular circumferential and radial strain, twist and torsion.

Results: Left ventricular ejection and shortening fractions did not change during therapeutic hypothermia (hypothermia:72±7% and 39±6%, rewarming:74±5% and 41±5%, p=0.21 and p=0.25) however they were higher after rewarming compared to the control group (70±5%, p=0.003 and 36±4%, p=0.002 respectively). There was no difference on left ventricular global longitudinal, circumferential and radial strain, twist and torsion during the therapeutic process. Higher pulmonary artery systolic pressure and worse right ventricular global longitudinal strain were observed in the study group (hypothermia:44±24mmHg and 17,9±4,9%, rewarming:53±24mmHg and 19,2±3,8%, control group:29±11mmHg and 20,5±2,2% respectively).

Conclusion: Left ventricular parameters remain stable during the two phases of therapeutic hypothermia what suggests no impact of the induced cooling on left ventricular systolic function. Right ventricular global longitudinal strain was the only echocardiographic tool able to identify some degree of systolic function impairment during therapeutic hypothermia. This could be explained by the pulmonary hypertension identified in the study group during this period.

hypoxic-ischemic encephalopathy

therapeutic hypothermia

neonate

cardiac function/echocardiography

Hypoxic-ischemic encephalopathy corresponds to a major cause of neonatal morbidity and mortality. It is consequence of acute perinatal asphyxia, with low Apgar scores and evidence of neurological compromise at birth [1]. In moderate or severe hypoxic-ischemic encephalopathy, the risk of death varies between 10 and 60% with neurological sequelae in 30 to 100% of survivors [2]. Therapeutic hypothermia has demonstrated significant benefits in the long term neurological prognosis [3]. In this setting, cerebral metabolism is reduced in 5% for each cooling degree, promoting vasoconstriction and blood flow restriction, delaying the onset of the hypoxic depolarization at the cellular level [3]. Bradycardia and cardiac output reduction have been described however, other potential cardiovascular effects of therapeutic hypothermia have been poorly understood [4]. Echocardiography is an excellent noninvasive tool for cardiac evaluation [5]. In the last 10 years, assessment of myocardial deformation has shown to be a sensitive parameter to assess subclinical ventricular dysfunction [6]. The aim of the study was to evaluate the hemodynamic and ventricular performance of neonates with hypoxic-ischemic encephalopathy under therapeutic hypothermia applying conventional and advanced echocardiographic techniques.

Study design and patient selection

This is an observational, prospective study, developed in three different institutions: two general hospitals associated to medical schools and a tertiary cardiology center. It was approved by the research ethics committee. The study group corresponded to 22 consecutive neonates with hypoxic-ischemic encephalopathy who underwent therapeutic hypothermia between January 2014 to December 2017.

Therapeutic hypothermia was indicated according to the following criteria: gestacional age ≥ 35 weeks; time from birth to therapy < 6 hours; birth weight > 1.8 Kg; clinical evidences of moderate or severe hypoxic-ischemic encephalopathy associated to, at least, one of the following criteria: a) Apgar score < 5 in the 5th minute of life, b) neonatal resuscitation maneuvers required for more than 5 minutes, c) pH < − 7.0 or Base Excess < − 12 in the umbilical cord blood or arterial blood in the first hour of life.

Patients with congenital heart defects, septic shock or with inadequate images for echocardiographic evaluation were excluded.

The target temperature (between 33.5° and 34°C) was reached placing the neonate in a crib with no additional heat source. Cooling lasted 72 hours, and ice packs were frequently used to keep low temperatures. Rewarming process was performed increasing 0.2 to 0.5°C per hour until the body temperature reached 36°C [7]. During the therapeutic process, the neonates were under eletrocardiographic, pulse oximetry and electroencephalographic continuous monitoring. Ventilatory and inotropic support with sedation were employed if needed.

The control group consisted of 22 healthy neonates with gestational age ≥ 35 weeks, weight > 2 Kg and normal body temperature.

Clinical data such as blood pressure, oxygen saturation, heart rate, rectal temperature, need and type of ventilatory support, dose and type of inotropic drugs and nitric oxide were collected.

Echocardiogram

Echocardiographic studies were performed employing the Vivid 7 and Vivid I ultrasound systems (GE Healthcare - Wauwatosa, WI, USA) equipped with M4S (1.5–3.6 MHz) and 7S (2.7–8 MHz) transducers. All images were obtained by a single operator and analyzed offline at EchoPac PC version 11.2 (GE Vingmed Ultrasound) workstation.

The study protocol consisted of an echocardiogram performed during hypothermia 24 hours after the target temperature was achieved, and a second one, performed 24 hours after the rewarming process was finished. In the control group, the studies were performed after 24 hours of life.

The echocardiographic parameters evaluated included: ejection and shortening fraction calculated by Teicholz method, left and right outflow tracts diameters, right ventricular fractional area change (B-mode), biventricular myocardial performance index (Tei index), pulmonary and systemic flow velocity time integral (pulsed Doppler), right ventricular s´ wave velocity (tissue Doppler) and tricuspid anullar plane systolic excursion (M-mode). Biventricular stroke volume and cardiac output were calculated. Two-dimensional speckle tracking technique was used to assess ventricular strain. Images were obtained in four, three and two apical chambers views, parasternal short axis from base to apex. Longitudinal right and left ventricular strain, and left ventricular circumferential and radial strain, twist and torsion were calculated. Images were acquired under continuous electrocardiographic monitoring in, at least, three cardiac cycles, with a frame rate between 75–80 frames per second. The frame rate/heart rate ratio ranged from 0.53 to 0.73. At least, two image blocks were obtained in each projection. Pulmonary systolic pressure was calculated if a significant tricuspid regurgitant jet allowed to measure the peak gradient between right ventricle and right atrium.

Statistical analysis

Statistical analysis was performed employing the SPSS 12.0 for Windows software. Pearson’s Chi-Squared and, when appropriate, Fisher’ Exact Tests were used for the qualitative variables. Analysis of Variance was applied for multivariable analysis. The significance level stipulated was of 5% (α = 0.05) being considered statistically significant results with p < 0.05.

All neonates from the study group had neurological abnormalities consistent with moderate or severe hypoxic-ischemic encephalopathy. Eight (36%) babies developed seizures in the first hours of life. First and 5th minutes Apgar scores were significantly lower in the study group (Apgar 1st min: 1.4 and Apgar 5th min: 3.6 versus Apgar 1st min: 8.5 and Apgar 5th min: 9.8 in the control group, p < 0.001). Time between birth and cooling ranged from 10 minutes to 5.5 hours (median: 60 minutes). During hypothermia, 18 neonates needed any kind of ventilatory support (82%). Of them, 12 (67%) were on mechanical ventilation, three (16,5%) on CPAP and three (16,5%) on nasal oxygen catheter. After rewarming, seven patients (32%) remained on ventilatory support. Vasoactive drugs were employed mainly during hypothermia. Dobutamine was the most common medication used, in association or not to dopamine.

Echocardiographic examinations

The first echocardiogram was performed between 17 and 72 hours of hypothermia (median: 44 hrs) and the second one between 17 and 130 hours after the end of rewarming (median: 48 hrs). In the control group the exam was performed between 29 and 144 hours of life (median: 45 hrs).

Hemodynamic status during hypothermia:

Systemic arterial pressure and peripheral oxygen saturation were similar in both periods studied. During hypothermia, heart rate decreased with significant rise after rewarming. There was no change on stroke volume during the two periods with values similar to the control’s group. Higher pulmonary artery systolic pressure was observed in the study group (hypothermia: 44 ± 24 mmHg, rewarming: 53 ± 24 mmHg, control group: 29 ± 11 mmHg). Pulmonary hypertension was considered when pulmonary artery systolic pressure was higher than 50% of the systemic pressure or absolute value > 35 mmHg. According to this definition, 11 neonates (58%) had pulmonary hypertension during hypothermia, 10 (59%) after rewarming and five (29%) in the control group. Table 1 displays the hemodynamic parameters during the study-periods.

Table 1

Hemodynamic data of neonates with hypoxic-ischemic encephalopathy submitted to therapeutic hypothermia (during hypothermia and rewarming) and of the control group.
Average ± SD	Hypothermia (1)	Rewarming (2)	Control group (3)	p (1 x 2)	p (1 x 3)	p (2 x 3)
HR (bpm)	111 ± 19	144 ± 20	130 ± 16	< 0.001	< 0.001	0.013
SAP (mmHg)	72 ± 10	74 ± 7	NA	0.06	NA	NA
O₂ Sat (%)	94 ± 4	94 ± 4	NA	0.87	NA	NA
Left CO (ml/Kg/min)	155 ± 47	214 ± 39	174 ± 47	< 0.001	0.20	0.004
Right CO (ml/Kg/min)	269 ± 113	369 ± 141	288 ± 74	0.005	0.45	0.02
LV SV (ml/Kg)	1.41 ± 0.36	1.52 ± 0.39	1.35 ± 0.42	0.89	0.65	0.28
RV SV (ml/Kg)	2.38 ± 0.81	2.57 ± 0.83	2.21 ± 0.55	0.39	1.00	0.30
PASP (mmHg)	45 ± 24	53 ± 34	29 ± 11	0.32	0.01	0.01
Systemic VTI (mm)	13 ± 3	14 ± 4	12 ± 2	0.47	0.13	0.04
Pulmonary VTI (mm)	14 ± 4	15 ± 3	16 ± 3	0.10	0.02	0.42
LVOT diam (cm)	0.65 ± 0.07	0.67 ± 0.07	0.68 ± 0.08	0.28	0.30	0.68
RVOT diam (cm)	0.85 ± 0.15	0.82 ± 0.12	0.75 ± 0.09	0.23	0.02	0.04
SD – standart deviation, HR – heart rate, SAP – systolic artery pressure, Sat – saturation, CO – cardiac output, SV – stroke volume, PASP – pulmonary artery systolic pressure, VTI – velocity time integral, LVOT diam – left ventricular outflow tract diameter, RVOT diam – right ventricular outflow tract diameter, NA – not applicable.

All neonates had patent foramen ovale. Persistent ductus arteriosus was present in 18 cases (90%) during hypothermia, in 10 (45%) after rewarming and in six (30%) in the control group, all with small diameters without evidence of hemodynamic consequences.

Left ventricular performance

There was no difference between ejection and shortening fractions during the two phases of therapeutic hypothermia. After rewarming, higher values were observed when compared to the control group. Global longitudinal, circumferential and radial strain and twist and torsion were similar during the two therapeutic periods. The study group had lower values of LV Tei index in both periods when compared to the control group (Table 2).

Table 2

Left and right ventricular performance of neonates with hypoxic-ischemic encephalopathy submitted to therapeutic hypothermia (during hypothermia and rewarming) and of the control group.
Left ventricle
Average ± SD	Hypothermia (1)	Rewarming (2)	Control group (3)	p (1 x 2)	p (1 x 3)	p (2 x 3)
EF (%)	73 ± 7	74 ± 5	70 ± 5	0.21	0.09	0.003
SF (%)	39 ± 6	41 ± 5	36 ± 4	0.26	0.08	0.002
GLS (%)	-20 ± 4	-21 ± 4	-20 ± 2	0.33	0.85	0.12
CS (%)	-23 ± 6	-24 ± 9	-21 ± 5	0.75	0.15	0.15
RS (%)	32 ± 16	29 ± 15	25 ± 13	0.50	0.09	0.28
Twist (º)	7.65 ± 6.66	10.03 ± 7.65	9.79 ± 6.99	0.29	0.30	0.28
Torsion (º/cm)	2.8 ± 2.3	3.5 ± 2.6	3.8 ± 2.6	0.38	0.19	0.78
Tei index	0.51 ± 0.13	0.51 ± 0.13	0.63 ± 0.18	0.92	0.02	0.02
Right ventricle
Average ± SD	Hypothermia (1)	Rewarming (2)	Control group (3)	p (1 x 2)	p (1 x 3)	p (2 x 3)
s´ (m/s)	0.07 ± 0.02	0.09 ± 0.01	0.07 ± 0.01	< 0.001	0.42	< 0.001
FAC (%)	38 ± 11	36 ± 11	43 ± 10	0.36	0.13	0.03
TAPSE (mm)	8.6 ± 1.5	9.6 ± 1.3	8.8 ± 1.3	0.12	0.60	0.08
GLS (%)	-18 ± 5	-18 ± 4	-21 ± 2	0.85	0.02	0.01
FWLS (%)	-19 ± 5	-20 ± 5	-22 ± 4	0.74	0.04	0.22
Tei index	0.46 ± 0.33	0.36 ± 0.24	0.29 ± 0.13	0.15	0.03	0.22
SD – standart deviation, EF – efection fraction, SF – shortening fraction, GLS – global longitudinal strain, CS - circumferencial strain, RS – radial strain, FAC – fractional area change, TAPSE – tricuspid anullar plane systolic excursion, FWLS – free wall longitudinal strain.

Right ventricular performance

The study group demonstrated an increase on basal s´ wave velocity and a decrease on fractional area change values after rewarming. Right ventricular global longitudinal strain values were worse when compared to those from the control group. Right ventricular Tei index values were higher during hypothermia (Table 2).

Although hypothermia has been employed as therapeutic tool to prevent hypoxic-ischemic encephalopathy after perinatal asphyxia for many years, there is still a paucity of information regarding the myocardial performance during the therapeutic process. Therefore, this study is innovative, especially because regular and advanced echocardiographic parameters, including longitudinal, circumferential, and radial strain, twist and torsion deformations were employed.

According to the results, three major functional and hemodynamical manifestations can be taken into discussion: left ventricular cardioprotective effect; the hyperdynamic state after rewarming and right ventricular systolic function impairment.

Therapeutic hypothermia and its cardioprotective effect

According to our results, all parameters employed for assessing left ventricular function, both conventional (ejection and shortening fractions and Tei index) and with the advanced technologies (longitudinal, radial, circumferential strain, twist, and torsion), remained similar to the control group during the hypothermic stage. Following a hypoxic event, ventricular impairment resulting from a myocardial injury should be expected. However, hypothermia can reduce myocardial metabolism, in the same way that it reduces cerebral metabolism, and, therefore, less cell damage and myocardial function impairment is expected. The protective effect of hypothermia is provided mainly by decreasing its oxygen consumption and energy demand [8].

Analogously to our findings, Aggarwal and Natarajan [9] found similar shortening fractions in infants with hypoxic-ischemic encephalopathy (submitted or not to therapeutic hypothermia) and in the control group. Hochwald et al [11] also did not find differences in the shortening fraction in newborns with hypoxic-ischemic encephalopathy during hypothermia and after rewarming, when compared with the control group. Czernik et al [10] reported a similar shortening fraction in four examinations performed in the same population, two during hypothermia (beginning and end) and another two after rewarming (final and after 5 to 7 days). There was also no changes in the bidimensional global longitudinal strain, during and after hypothermia. In this study, no control group was included in the analysis.

Therefore, the maintenance of good ventricular function in the presence of an acute hypoxic insult could perhaps be attributed to a cardioprotective effect of hypothermia, in addition to denoting the safety of this treatment. This cardioprotection could only be proven if a statistical difference was demonstrated regarding the left ventricular function between babies with hypoxic insult at birth submitted or not to therapeutic hypothermia.

Hyperdynamic state after rewarming

The major hemodynamic change observed during the hypothermia was a lower heart rate. It was around 10 bpm lower for each cooling degree when compared to the rewarming period, similar to data described in the literature [4, 12]. After rewarming, the heart rate increased to levels above the control group. This finding may be justified as a consequence of a hyperdynamic cardiac state to reestablish the basal hemodynamic conditions [13, 14]. Neestas et al [15], described a similar heart rate behavior during hypothermia, however with no increase after rewarming.

Some echocardiographic ventricular systolic function parameters (left ventricular ejection/ shortening fraction and right ventricular s´ wave) were higher after rewarming compared to the control group. Such findings endorse the hyperdynamic heart state theory in this therapeutic phase. As mentioned before, Hochwald et al [11] described similar shortening fraction during hypothermia and after rewarming in neonates with hypoxic-ischemic encephalopathy when compared to the control group. However, the exams were performed much earlier after rewarming, what could interfere in the results found. We did not find other literature references about left ejection fraction and right ventricular s´ wave velocity performance in this population.

According to other reports⁴, both ventricles cardiac output, during hypothermia, corresponded to only 72% of the values calculated after rewarming. An interesting point was that, as in the study group (in both moments) as in the control group, the right cardiac output was up to 69% higher than the left cardiac output, what should not have been found, regarding that, in all cases, the patent foramen ovale and the persistent ductus arteriosus were so small that it would not explain systemic and pulmonary flows unbalance. We suspect this occurs because of a bigger right ventricular outflow tract diameter immediately after birth, due to predominance of right-side circulation in fetal life. Considering that it is used the outflow tract radius value squared for the cardiac output calculation, small differences in the outflow tracts diameters result in large divergences in the final value. Other factors that could influence the results would be that the outflow tract might not be exactly round but elliptic, and the Doppler sample placement for the velocity time integral measurement was not exactly in the same location where the outflow tract diameter was measured for the calculation of its area.

Right ventricular systolic function impairment

We could observe a similar pattern of right ventricular global longitudinal strain as well as pulmonary artery systolic pressure, both worse in the case group (two periods) in relation to the control group. Probably the high pulmonary pressure contributes directly for the right ventricular deformation decline, even though this has not been sufficient to modify the stroke volume. Regarding the right ventricular free wall longitudinal strain, such pattern was not seen after rewarming. The interventricular septum reflects the left ventricular vector forces in a bigger proportion than the right forces, this being the conceptual base to use only the free wall to evaluate the right ventricular deformation. Although, in the neonatal period, the interventricular septum must reflect right ventricular vector forces in bigger proportion, once this is the ventricle which connects to the systemic intrauterine flow. Therefore, we believe that the right ventricular global longitudinal strain can be more appropriate to evaluate the right ventricular deformation in the first days of life.

The fractional area change value was inferior only after rewarming, probably due to a greater number of neonates with pulmonary hypertension in this phase. Right ventricular Tei index also presented higher values during hypothermia, as observed in the right ventricular global longitudinal strain pattern.

The results of this investigation showed that, despite small changes in the right ventricular function and in both ventricles cardiac output, the induced hypotermia arose as a very reliable therapeutic technique regarding the cardiovascular performance of the neonate with moderate or severe hypoxia. The right ventricular impairment was observed when pulmonary pressure was accentuated, showing the negative effects of an increased after-load in the systolic performance of this ventricle. The right ventricular global longitudinal strain was the most sensitive echocardiographic parameter for the right ventricular dysfunction in this population, emphasizing the advanced echocardiography contribution for the heart functional evaluation.

The principal limitation of this study is the small number of patients evaluated. We cannot assure that the hemodynamic stability observed in these patients is due to a cardioprotective effect of the therapeutic hypothermia or to the natural evolution of the hypoxic-ischemic encephalopathy, although the literature data do not indicate it. This cardioprotective effect could only be proved in a case-control study, in which one of the groups would be composed of asphyxiated neonates not submitted to therapeutic hypotermia. However, regarding the technique benefits evidence, this study would not be ethically correct.

Financial Support

This research received no specific grant from any funding agency, commercial or not-for-profit sectors.

Conflicts of Interest

None

Ethical Standards

The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national guidelines on human experimentation in Brazil and with the Helsinki Declaration of 1975, as revised in 2008, and has been approved by the regional committees for medical and health research, Brazil.

Author Contribution

1- JEA - advisor for the doctoral thesis of this research2- DCSLB and RBMB - consultants and reviewers of the materials and methods3- MM - consultant of hypothermia protocols4- SRFFP - co advisor for the doctoral thesis of this research, reviewer of all manuscript

Acknowledgements

The authors want to thank João Ítalo Dias França, statistical laboratory of Instituto Dante Pazzanese de Cardiologia, for his assistance with the statistical analysis.

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No competing interests reported.

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You are reading this latest preprint version

Cardiovascular performance of neonates with hypoxic-ischemic encephalopathy under therapeutic hypothermia evaluated by conventional and advanced echocardiographic techniques

Status:

Version 1

Abstract

Introduction

Materials and methods

Study design and patient selection

Echocardiogram

Statistical analysis

Results

Echocardiographic examinations

Hemodynamic status during hypothermia:

Left ventricular performance

Right ventricular performance

Discussion

Therapeutic hypothermia and its cardioprotective effect

Hyperdynamic state after rewarming

Right ventricular systolic function impairment

Conclusions

Limitations

Declarations

Financial Support

Conflicts of Interest

Ethical Standards

Author Contribution

Acknowledgements

References

Additional Declarations

Status:

Version 1