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Acta Pdiatrica ISSN 08035253

REGULAR ARTICLE

Noradrenaline for management of septic shock refractory to uid loading and dopamine or dobutamine in full-term newborn infants
Pierre Tourneux (tourneux.pierre@chu-amiens.fr)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 dAmiens, France Lille II, Lille, France 3.UPRES JE2490, Universite de Picardie Jules Verne, Amiens, France 4.DMAG (BA 3901), Universite

Keywords Blood pressure, Newborn infant, Noradrenaline, Septic shock Correspondence Tourneux Pierre, Service de Medecine Neonatale et Reanimation Pediatrique Polyvalente, Centre Hospitalier et UniversitaireHopital Nord, 1 place Victor Pauchet 80054 Amiens cedex 1, France. Tel.: +33(0)3-22-66-82-86 | Fax.: +33(0)3-22-66-82-81 | Email: tourneux.pierre@chu-amiens.fr Received 22 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 uid 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 g/kg/min or dobutamine of 12 6 g/kg/min. Three hours after starting noradrenaline (rate 0.5 0.4 g/kg/min), the mean arterial 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 mortality in critically ill newborns (1). Early fluid and cardiovascular resuscitation are essential to improve the outcome (2). In case of nonresponse to fluid resuscitation, initiation of inotropic and vasoactive agents are warranted to increase cardiac output, maintain adequate blood pressure and enhance oxygen (O 2 ) delivery to the tissue (3). Dopamine is the sympathomimetic amine most frequently used for vasoplegic shock in newborns (3). The ability of dopamine to raise systemic blood pressure (SBP) has been clearly documented (3). However, failure to sustain 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 infants with systemic hypotension (6). Thus, particular lifethreatening conditions may require the use of other vasoactive 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 vasopressor agent to correct hypotension (58). Such recommendation 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 noradrenaline in full-term newborn infants with septic shock refractory to 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 eligible for inclusion were: (i) newborn infants of >35 weeks gestation, and <1-month old; (ii) admitted in the NICU between 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 or leucocyte count, or at least two of the following criteria: Creactive protein [CRP] >50 mg/L, leucopenia <4000/mm3 or thrombocytopenia <80 000/mm3 (11)); (iv) and with persistent shock despite adequate fluid resuscitation and high dose of dopamine/dobutamine or substitutive dose of hydrocortisone 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

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(heart rate >160 beats/min); (ii) abnormal peripheral pulses; (iii) modified extremities colouration; (iv) prolonged capillary refill time >3 sec and (v) urine output <1 mL/kg/h (2,9). The following echocardiographic markers were used to ensure that fluid resuscitation was adequate: inferior vena cava diameter >5 mm in infants treated by conventional mechanical ventilation and left ventricular end diastolic dimension between 2 and +2 standard deviation (SD) for the body weight in infants treated by high-frequency oscillatory ventilation (12). Exclusion criteria were: (i) congenital structural heart disease, except patent ductus arteriosus; (ii) cardiac arrest or terminal disease (pulse oxygen saturation value [SpO 2 ] <60%, arterial pH <6.80, bradycardia <90 beats/min and no measurable blood pressure) prior to inclusion 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 g) infused in a central catheter at an initial rate between 0.2 to 0.5 g/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 the normal 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 (FiO 2 ) was set to maintain SpO 2 above 95%. The outcome was evaluated for extracorporeal membrane oxygenation (ECMO) requirement, 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 interquartile range (IQ) was mentioned in the text. Data were analysed using Wilcoxon signed rank test to compare paired data before and during noradrenaline use. Significance was set as p < 0.05.

Mean arterial pressure (mm Hg)

80 70 60 50 40 30 20 10 0 Before norepinephrine

***

3 hours after norepinephrine start

Figure 1 Mean ( SD, outer dots) and individual mean arterial blood pressure measured just before and 3 h after starting noradrenaline infusion. Mean arterial blood pressure increased in each newborn ( p < 0.001).

RESULTS Twenty-two newborns fulfilled the entry criteria. Mean gestational 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, respectively. 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 pulmonary hypertension of the newborn (PPHN) assessed by echocardiography. The mean FiO 2 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 g/kg/min and 12 6 g/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

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 g/kg/min. Five newborns required an increase in noradrenaline to normalize SBP. The mean noradrenaline infusion rate to correct the systemic hypotension was 0.5 0.4 g/kg/min (range 0.22.0 g/kg/min). The median duration of noradrenaline use was 61 59 h (range 8 116 h). The individual maximum noradrenaline infusion rate to sustain normal SBP ranged from 0.2 to 7.1 g/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 (from 51 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 noradrenaline infusion (from 1 0.5 mL/kg/h during the 3 h preceding the start of noradrenaline, to 1.7 0.4 mL/kg/h during the 3 h following the start of noradrenaline; p < 0.05). After starting the noradrenaline infusion, a lower mean FiO 2 was required to achieve a postductal SpO 2 of 95% (74 27% vs. 66 28%, p < 0.05). Mean airway pressure (16 5 cm H 2 O vs. 16 5 cm H 2 O, p = 0.38) and both preductal SpO 2 (96 5% vs. 94 4%, p = 0.47) and postductal SpO 2 (92 14% vs. 92 14%, p = 0.09) were unchanged. Arterial pH (7.25 0.13 vs. 7.28 0.09, p = 0.90), arterial carbon dioxide pressure (paCO 2 ) (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/L vs. 18 6 mmol/L, p = 0.78) did not change significantly over the first 3 h of noradrenaline infusion. Plasma lactate 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 noradrenaline infusion. Four newborns died despite an initial 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

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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 children. 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 rate of 0.5 0.4 g/kg/min. No impairment of the respiratory function was observed after starting the noradrenaline infusion. In contrast, an increase in urine output and a decrease in O 2 need and in blood lactate concentration suggest that noradrenaline may improve cardiac function and tissue perfusion. There are many controversial and unresolved issues regarding the most effective vasopressor agent to manage septic shock. While dopamine is preferred worldwide for the initial management of hypotension in sepsis, several reports mentioned a failure to sustain adequate tissue perfusion pressure with dopamine, even at high doses (2,46). 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 evidence suggests that noradrenaline may represent an optimal vasopressor 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 mesenteric and renal blood flows, and improves survival (15,16). Moreover, whereas dopamine may elevate pulmonary artery resistance (13,14), noradrenaline could exhibit a pulmonary vasodilator effect, especially at elevated basal pulmonary vascular tone (1720). We found that similar beneficial effects of noradrenaline can be obtained in full-term newborn infants with life-threatening septic shock unresponsive 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 organ blood flow and functions in newborns with refractory septic shock. Supporting this hypothesis are the decrease in blood lactate concentrations and the elevation of urine output shortly after starting noradrenaline infusion. Although lactate concentration requires careful interpretation, a high lactate level is generally considered as a marker of hypoxia and 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 septic shock: (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 output because of an increased right ventricular afterload and myocardial dysfunction (21). Noradrenaline improved cir-

culatory adaptation at birth in a newborn lamb with persistent pulmonary hypertension (20). Other data suggest that noradrenaline can improve cardiac performance in pulmonary hypertension (22,23). Our results are consistent with these studies as the O 2 need decreased during the noradrenaline infusion, suggesting that noradrenaline-induced increase in aortic pressure may be associated with improvement of PPHN-induced cardiac dysfunction. (ii) In shock, a decrease in blood pressure may result in decreased regional blood flow, which in turn may contribute to tissue hypoxia and to organ failure (7). Beneficial effect of noradrenaline 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 treated infant. As mentioned earlier, in this study, four infants died (18%) despite an initial correction of hypotension. The mortality rate ranges from 7 to 40% in the population of paediatric and neonatal shocks (2,11). In adult patients with septic shock, noradrenaline could improve survival (8). However, whether or not noradrenaline may improve outcome in the newborn with refractory septic shock remains an open question. 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 therapy (7). When these recommendations were applied, no adverse effect on tissue perfusion was mentioned during noradrenaline infusion (24,25). In the present study, the shock was unresponsive to dopamine or dobutamine infusion. Although systemic vascular resistances were not measured in the present study, the haemodynamic profile of the shock was probably mainly hyperdynamic, as indicated by the low values of diastolic blood pressure. Whether or not noradrenaline may be beneficial in other conditions is still unknown. 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 improved tissue oxygenation, as indicated by an increase in urine output and by a decrease in blood lactate concentration. We suggest that noradrenaline may be used in septic full-term newborn infants with life-threatening hypotension after correction of possible hypovolaemia. Adequate titration of noradrenaline infusion is required to prevent excessive vasoconstriction.

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