Noradrenalina en shock refractario

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Acta Pædiatrica ISSN 0803–5253

R E G U L A R A R T I C L E

Noradrenaline for management of septic shock refractory to fluid loadingand dopamine or dobutamine in full-term newborn infantsPierre Tourneux ([email protected])1,2,3,4, Thameur Rakza1,3, Abdel Abazine1,3, Gerard Krim2, Laurent Storme1,3

1.Clinique de Medecine Neonatale, Hopital Jeanne de Flandre, CHRU de Lille, France

2.Service de Medecine Neonatale et Reanimation Pediatrique Polyvalente, Hopital Nord, CHU d’Amiens, France3.UPRES JE2490, Universite Lille II, Lille, France4.DMAG (BA 3901), Universite de Picardie Jules Verne, Amiens, France

Keywords

Blood pressure, Newborn infant, Noradrenaline,Septic shock

Correspondence

Tourneux Pierre, Service de Medecine Neonatale etReanimation Pediatrique Polyvalente, CentreHospitalier et Universitaire—Hopital Nord, 1 placeVictor Pauchet 80054 Amiens cedex 1, France.Tel.: +33(0)3-22-66-82-86 |Fax.: +33(0)3-22-66-82-81 |Email: [email protected]

Received22 June 2007; revised 31 August 2007;accepted 24 October 2007.

DOI:10.1111/j.1651-2227.2007.00601.x

Abstract

Aim: To determine the effects of noradrenaline in full-term newborns with refractory septic shock.

Methods: Newborns of >35 weeks’ gestation with persistent septic shock, despite adequate fluid

resuscitation and high dose of dopamine/dobutamine were eligible. In this prospective observational

study, we recorded respiratory and hemodynamic parameters prior to and 3 h after starting

noradrenaline infusion.

Results: Twenty-two newborns were included (gestational age [GA] 39 ± 1.7 weeks, birth weight

(BW) 3110 ± 780 g). Before starting noradrenaline, the infants received a mean volume expansion

of 31 ± 15 mL/kg and a mean infusion rate of dopamine of 14 ± 5 µg/kg/min or dobutamine of

12 ± 6 µg/kg/min. Three hours after starting noradrenaline (rate 0.5 ± 0.4 µg/kg/min), the meanarterial blood pressure rose from 36 ± 5 to 51 ± 7 mmHg (p < 0.001). Urine output increased from

1 ± 0.5 to 1.7 ± 0.4 mL/kg/h (p < 0.05). Blood lactate concentration decreased from 4.8 ± 2.3 to

3.3 ± 1.8 mmol/L (p < 0.01). Despite an initial correction of hypotension, four infants died later.

Conclusion: Noradrenaline was effective in increasing systemic blood pressure. An increase in urine output and a

decrease in blood lactate concentration suggest that noradrenaline may have improved cardiac function and

tissue perfusion.

INTRODUCTION

Shock represents an important cause of morbidity and mor-

tality in critically ill newborns (1). Early fluid and cardio-

vascular resuscitation are essential to improve the outcome(2). In case of nonresponse to fluid resuscitation, initiationof inotropic and vasoactive agents are warranted to increase

cardiac output, maintain adequate blood pressure and en-

hance oxygen (O2) delivery to the tissue (3).

Dopamine is the sympathomimetic amine most frequently

used for vasoplegic shock in newborns (3). The abilityof dopamine to raise systemic blood pressure (SBP) has

been clearly documented (3). However, failure to sus-

tain adequate blood pressure despite high dopamine doses

has also been reported (2,4,5). Dopamine failed to raise

blood pressure in more than 30% preterm newborn in-fants with systemic hypotension (6). Thus, particular life-

threatening conditions may require the use of other vasoac-tive drugs.

In adult patients with septic shock, noradrenaline was

more effective than dopamine in reversing hypotension, and

has recently been recommended as the first-choice vasopres-sor agent to correct hypotension (5–8). Such recommen-

dation has also been proposed in children with vasoplegic

shock (2,9). Noradrenaline was found to raise SBP and O 2

uptake without adverse effect on organ blood flow (5,10).Furthermore, noradrenaline may improve the outcome of

septic shock patients (8). However, no published data are

available about the clinical effects of noradrenaline in the

newborn.

In this prospective observational study, we evaluated the

respiratory and the haemodynamic effects of noradrenalinein full-term newborn infants with septic shock refractoryto fluid resuscitation and to dobutamine or dopamine

infusion.

MATERIAL AND METHODS

The study was conducted in the neonatal intensive care unit

(NICU) of Lille University Hospital, France. Newborns eli-gible for inclusion were: (i) newborn infants of >35 weeks’

gestation, and <1-month old; (ii) admitted in the NICU be-

tween January 1, 2002 and December 31, 2004; (iii) with

sepsis (proven infection or clinical syndrome associated with

a high probability of infection, and a systemic inflammatory

response syndrome defined as an abnormal temperature orleucocyte count, or at least two of the following criteria: C-

reactive protein [CRP] >50 mg/L, leucopenia <4000/mm3

or thrombocytopenia <80 000/mm3 (11)); (iv) and with per-

sistent shock despite adequate fluid resuscitation and highdose of dopamine/dobutamine or substitutive dose of hy-

drocortisone and (v) mechanically ventilated and sedated.

Shock was defined by systemic hypotension (mean blood

pressure <10th percentile of the normal range for birth

weight [BW] and postnatal age) with at least three of the

following criteria for decreased perfusion: (i) tachycardia

C2007 The Author(s)/Journal Compilation C2007 Foundation Acta Pædiatrica/ Acta Pædiatrica 2008 97, pp. 177–180 177



Noradrenaline for septic shock in the newborn Tourneux et al.

(heart rate>160 beats/min); (ii) abnormal peripheral pulses;

(iii) modified extremities colouration; (iv) prolonged capil-

lary refill time >3 sec and (v) urine output <1 mL/kg/h

(2,9). The following echocardiographic markers were usedto ensure that fluid resuscitation was adequate: inferior vena

cava diameter >5 mm in infants treated by conventional

mechanical ventilation and left ventricular end diastolic di-

mension between −2 and +2 standard deviation (SD) for

the body weight in infants treated by high-frequency oscil-latory ventilation (12). Exclusion criteria were: (i) congeni-

tal structural heart disease, except patent ductus arteriosus;

(ii) cardiac arrest or terminal disease (pulse oxygen satu-

ration value [SpO2] <60%, arterial pH <6.80, bradycardia

<90 beats/min and no measurable blood pressure) prior toinclusion in the study or (iii) start of noradrenaline before

inclusion in the study.

The included newborns received noradrenaline (diluted

in dextrose 5% to a concentration of 1 mL = 100 µg) in-

fused in a central catheter at an initial rate between 0.2 to0.5 µg/kg/min, at the discretion of the practitioner. The rate

of infusion was eventually increased every 30 min until the

mean blood pressure normalized (>10th percentile of thenormal range for BW and postnatal age). No change in the

dopamine/dobutamine infusion rate was performed during

the 3 h following the beginning of noradrenaline infusion.Haemodynamic and respiratory parameters were

recorded just before and 3 h after starting noradrenaline

infusion. Inspired oxygen concentration (FiO2) was set to

maintain SpO2 above 95%. The outcome was evaluated forextracorporeal membrane oxygenation (ECMO) require-

ment, cranial ultrasound and neurological examination

at the time of discharge from the unit. The protocol was

approved by the Regional Ethics Committee of Picardy.

Results were expressed as mean± SD. Use of median± in-

terquartile range (IQ) was mentioned in the text. Data wereanalysed using Wilcoxon signed rank test to compare paired

data before and during noradrenaline use. Significance was

set as p < 0.05.

RESULTS

Twenty-two newborns fulfilled the entry criteria. Mean ges-tational age (GA) and BW were, respectively, 39.1 ± 1.7

weeks’ gestation and 3110 ± 780 g. The mean Apgar score

was 7.4 ± 2.4 and 8.1 ± 1.9 at 1 and 5 min of life, respec-

tively. The postnatal age at the onset of the shock was 15 ±

37 h. Fifteen newborns required high-frequency oscillatory

ventilation and inhaled nitric oxide (iNO) for persistent pul-monary hypertension of the newborn (PPHN) assessed by

echocardiography. The mean FiO2 was 75 ± 20%. All the

newborns required vascular expansion with saline serum

or 10% albumin (mean volume expansion 31 ± 15 mL/kg).Mean dopamine (8 of 22 newborns) or dobutamine (12 of 22

newborns) infusion rate prior to noradrenaline infusion was,

respectively, 14± 5 µg/kg/min and 12± 6µg/kg/min. Three

received substitutive doses of hydrocortisone (0.5 mg/kg, 3

times a day). Just before starting noradrenaline, mean SBP

was 36 ± 5 mmHg. Mean arterial blood pH and lactate

0

10

20

30

40

50

60

70

80

Before

norepinephrine

3 hours after

norepinephrine start

M e a n a r t e r i a l p r e s s u r e ( m m H

g )

***************

Figure 1 Mean (± SD, outer dots) and individual mean arterial blood pressure

measured just beforeand 3 h after starting noradrenaline infusion.Mean arterial

blood pressure increased in each newborn (∗∗∗p < 0.001).

concentration were, respectively, 7.25 ± 0.13 and 4.8 ±2.3 mmol/L. The mean urine output was 1 ± 0.5 mL/kg/h

during the 3 h preceding the noradrenaline infusion.

The initial noradrenaline infusion rate was 0.4 ±

0.15 µg/kg/min. Five newborns required an increase in no-radrenaline to normalize SBP. The mean noradrenaline in-

fusion rate to correct the systemic hypotension was 0.5 ±0.4 µg/kg/min (range 0.2–2.0 µg/kg/min). The median du-

ration of noradrenaline use was 61 ± 59 h (range 8–

116 h). The individual maximum noradrenaline infusion rateto sustain normal SBP ranged from 0.2 to 7.1 µg/kg/min.

SBP rose by 40% (from 36 ± 5 to 51 ± 7 mmHg, p <

0.001) within the first 3 h of noradrenaline infusion (Fig. 1).

The change in SBP was greater for diastolic pressure (from

29 ± 4 to 43 ± 8 mmHg) than for systolic pressure (from51 ± 8 to 66 ± 9 mmHg, p < 0.01). The heart rate increased

from 143 ± 26 to 154 ± 24 beats/min (p < 0.05).

The mean urine output increased by 70% after nora-drenaline infusion (from 1 ± 0.5 mL/kg/h during the 3 h

preceding the start of noradrenaline, to 1.7 ± 0.4 mL/kg/hduring the 3 h following the start of noradrenaline; p < 0.05).

After starting the noradrenaline infusion, a lower mean FiO2

was required to achieve a postductal SpO2 of 95% (74 ±27% vs. 66 ± 28%, p < 0.05). Mean airway pressure (16 ±5 cm H2O vs. 16 ± 5 cm H2O, p = 0.38) and both preduc-tal SpO2 (96 ± 5% vs. 94 ± 4%, p = 0.47) and postductal

SpO2 (92 ± 14% vs. 92 ± 14%, p = 0.09) were unchanged.

Arterial pH (7.25 ± 0.13 vs. 7.28 ± 0.09, p = 0.90), arte-

rial carbon dioxide pressure (paCO2) (47 ± 17 torr vs. 43 ±10 torr, p = 0.78), BE (−6 ± 7 mmol/L vs. −7 ± 5 mmol/L,

p = 0.48) and bicarbonates concentrations (19 ± 4 mmol/Lvs. 18 ± 6 mmol/L, p = 0.78) did not change significantly

over the first 3 h of noradrenaline infusion. Plasma lac-

tate concentration decreased significantly from 4.8 ± 2.3 to

3.3 ± 1.8 mmol/L (p < 0.05).No newborn presented ischaemic distal lesions during no-

radrenaline infusion. Four newborns died despite an ini-

tial correction of systemic hypotension was obtained. The

cause of death was refractory hypoxaemia and shock. Three

infants required ECMO for PPHN. Eighteen infants were

alive at the discharge home. Two newborn infants had a

178 C2007 The Author(s)/Journal Compilation C2007 Foundation Acta Pædiatrica/ Acta Pædiatrica 2008 97, pp. 177–180



Tourneux et al. Noradrenaline for septic shock in the newborn

hyperechogenicity of the white mater at 7 days after birth.

At 1 month after birth, despite the electroencephalogram

was normal, magnetic resonance imaging (MRI) confirmed

temporo-occipital ischaemic lesions in one of the two chil-dren. Cranial ultrasound and clinical examination were

considered as normal in the other infant at the discharge

home.

DISCUSSION

In this observational study, we found that noradrenaline

was effective in increasing the SBP at a mean infusion rateof 0.5 ± 0.4 µg/kg/min. No impairment of the respiratory

function was observed after starting the noradrenaline in-

fusion. In contrast, an increase in urine output and a de-

crease in O2 need and in blood lactate concentration suggest

that noradrenaline may improve cardiac function and tissueperfusion.

There are many controversial and unresolved issues re-

garding the most effective vasopressor agent to manage sep-

tic shock. While dopamine is preferred worldwide for the

initial management of hypotension in sepsis, several reportsmentioned a failure to sustain adequate tissue perfusion

pressure with dopamine, even at high doses (2,4–6). Other

studies highlighted the potential side effect of dopamine to

raise pulmonary vascular resistance and pulmonary artery

pressure in newborns (13,14). In contrast, growing evidencesuggests that noradrenaline may represent an optimal vaso-

pressor drug to manage septic shock. Both experimental and

clinical studies showed that noradrenaline raises systemic

arterial blood pressure, cardiac output, oxygen delivery and

consumption and regional blood flow, including mesentericand renal blood flows, and improves survival (15,16). More-

over, whereas dopamine may elevate pulmonary artery re-

sistance (13,14), noradrenaline could exhibit a pulmonaryvasodilator effect, especially at elevated basal pulmonary

vascular tone (17–20). We found that similar benefi-cial effects of noradrenaline can be obtained in full-term

newborn infants with life-threatening septic shock unre-

sponsive to fluid resuscitation and high doses of dopamine

or dobutamine. Our data show that noradrenaline not only

raises perfusion pressure, but may also help to improve or-

gan blood flow and functions in newborns with refractoryseptic shock. Supporting this hypothesis are the decrease in

blood lactate concentrations and the elevation of urine out-

put shortly after starting noradrenaline infusion. Although

lactate concentration requires careful interpretation, a high

lactate level is generally considered as a marker of hypoxiaand a reliable indicator of poor outcome. Thus, a drop in

lactate concentration strongly suggests that noradrenaline

can decrease tissue hypoxia in septic neonates.

Several potential mechanisms may explain the beneficial

effect of noradrenaline in newborns with refractory septicshock: (i) In most infants included in the present study,

PPHN was associated with septic shock. PPHN is usually

associated with low systemic pressure and low cardiac out-

put because of an increased right ventricular afterload and

myocardial dysfunction (21). Noradrenaline improved cir-

culatory adaptation at birth in a newborn lamb with per-

sistent pulmonary hypertension (20). Other data suggest

that noradrenaline can improve cardiac performance in pul-

monary hypertension (22,23). Our results are consistent

with these studies as the O2 need decreased during the no-

radrenaline infusion, suggesting that noradrenaline-induced

increase in aortic pressure may be associated with improve-

ment of PPHN-induced cardiac dysfunction. (ii) In shock,

a decrease in blood pressure may result in decreased re-gional blood flow, which in turn may contribute to tissue

hypoxia and to organ failure (7). Beneficial effect of nora-

drenaline in shock may be explained at least, in part, by

its striking effectiveness in raising arterial blood pressure.

In our study, noradrenaline increased SBP in each treatedinfant.

As mentioned earlier, in this study, four infants died (18%)

despite an initial correction of hypotension. The mortal-

ity rate ranges from 7 to 40% in the population of paedi-

atric and neonatal shocks (2,11). In adult patients with sep-tic shock, noradrenaline could improve survival (8). How-

ever, whether or not noradrenaline may improve outcome in

the newborn with refractory septic shock remains an openquestion.

This study has some limitations. The population of our

study was highly selected. Despite shock, the circulating blood volume was normal. Special care was taken to ensure

an appropriate fluid therapy before using noradrenaline.

Present recommendations clearly stated that adequate fluid

resuscitation is a prerequisite for using vasopressor ther-

apy (7). When these recommendations were applied, noadverse effect on tissue perfusion was mentioned during no-

radrenaline infusion (24,25). In the present study, the shock

was unresponsive to dopamine or dobutamine infusion. Al-

though systemic vascular resistances were not measured in

the present study, the haemodynamic profile of the shockwas probably mainly hyperdynamic, as indicated by the low

values of diastolic blood pressure. Whether or not nora-

drenaline may be beneficial in other conditions is still un-

known.

CONCLUSION

Severe septic shock in the newborn may not respond to fluid

resuscitation and to dopamine or dobutamine infusion. We

found that noradrenaline could be beneficial in raising the

perfusion pressure. In contrast, noradrenaline may have im-

proved tissue oxygenation, as indicated by an increase in

urine output and by a decrease in blood lactate concentra-tion. We suggest that noradrenaline may be used in septic

full-term newborn infants with life-threatening hypotension

after correction of possible hypovolaemia. Adequate titra-

tion of noradrenaline infusion is required to prevent exces-sive vasoconstriction.

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