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Epinephrine treatment of hypotension in very low birthweight infants*

M Heckmann, A Trotter, F Pohlandt and W Lindner

Division of Neonatology and Pediatric Critical Care, Department of Pediatrics, University of Ulm, Germany

Heckmann M, Trotter A, Pohlandt F, Lindner W. Epinephrine treatment of hypotension in verylow birthweight infants. Acta Pdiatr 2002; 91: 566570. Stockholm. ISSN 0803-5253

The aim of this study was to examine the inuence of a continuous infusion of epinephrine(adrenaline) on mean arterial blood pressure (MABP), heart rate, urine output and base decit invery low birthweight infants (VLBWI) with systemic hypotension. In VLBWI who received aninfusion of epinephrine for at least 12 h the mean urine output, administered uid volume, basedecit and administered buffer 12 h before and 12 h during the infusion were recorded. If theinfusion was shorter, but given for at least 2 h, the mean heart rate and MABP 2 h before and 2 hduring the infusion were recorded. Thirty-one infants with a gestational age of 26 (2330) wk[median (minimummaximum)] and birthweight 690 (3901310) g were included in this retro-spective chart review. The patients received an infusion of epinephrine at a postnatal age of 3

(121) d. The doses ranged between 0.05 and 2.6 mg kg1

per minute within the rst 24 h ofadministration. Three of 31 infants received epinephrine on 2 different occasions. The MABP [7(1 to 13) mmHg, p = 0.000001] and the heart rate [10 (10 to 42) bpm, p = 0.000036]increased signicantly (n = 34), whereas total volume administration and urine output remained thesame between the 2 periods (Wilcoxon matched pairs test). The base decit increased signicantly[3 (10.2 to 2.6), p = 0.0014, n = 19] without a change in the administration of buffer.

Conclusion: The infusion of epinephrine increased the MABP and the heart rate withoutdecreasing urine output in VLBWI with hypotension not responding to a dopamine infusion up to15 mg kg

1 per minute. A potential adverse effect was an increase in metabolic acidosis.

Key words: epinephrine, hypotension, very low birthweight infants

M Heckmann, Division of Neonatology and Pediatric Critical Care, Department of Pediatrics,University of Gieen, DE-35385 Gieen, Germany (Tel. 49 641 9943 552, fax. 49 641 9943

559, e-mail. Matthias.Heckmann@paediat.med.uni-giessen.de )

Severe systemic hypotension is associated with anincreased risk of cerebral damage in critically illpreterm neonates (1). If volume loading and dopamineadministration up to 15 mg kg

1per minute fail to

restore the blood pressure, the addition of epinephrine(adrenaline) may be effective in increasing the bloodpressure to the normal range (2). However, theadministration of epinephrine carries the risk of an a-

receptor-mediated decrease in renal perfusion possiblyinducing oliguria (3). Epinephrine may also decreasethe mesenteric perfusion, thus increasing the risk ofnecrotizing enterocolitis (4). The proarrhythmic effectand the elevation of lactate levels are further adverseeffects of epinephrine administered as a continuousinfusion in adults (46). In addition, raised lactateconcentrations were associated with increased mortalityin sick, ventilated neonates (7). Finally, it has beendemonstrated that epinephrine at high doses (1 mg kg

1

per minute) can cause irreversible myocardial damage

in the neonatal myocardium consisting of sarcolemmalrupture and loss of mitochondrial architecture (8).

The purpose of this study was to review the cardio-vascular, renal and metabolic effects of epinephrine in acohort of very low birthweight infants (VLBWI).

Patients and methods

PatientsVLBWI who received a continuous infusion of epi-nephrine for a duration of at least 2 h were eligible forthe retrospective chart review. These infants wereidentied by their participation in two prospective trials(9, 10). Exclusion criteria were congenital heart dis-eases or other major congenital malformations. Addi-tional exclusion criteria were incomplete data recordingand no arterial line for blood pressure monitoring.

Infant morbidity

Respiratory distress syndrome was categorized accord-ing to the criteria of Giedion, intraventricular haemor-rhage according to the criteria of Papile, and periven-

*Some of the results were presented at the European Society forPediatric Research Conference in Copenhagen, Denmark, June 1999.

2002 Taylor & Francis. ISSN 0803-5253

Acta Pdiatr 91: 566570. 2002

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tricular leucomalacia according to the criteria of Volpe(1113).

Pulmonary hypertension was dened as right-to-left

shunting across the ductus arteriosus and/or the foramenovale as determined by echocardiography and Dopplerultrasound. If echocardiographic imaging was notavailable, pulmonary hypertension was diagnosed by adifference between preductal and postductal oxygensaturation greater than 10% which was measured bypulse oximetry.

The Score for Neonatal Acute PhysiologyPerinatalExtension and the Neonatal Therapeutic InterventionScoring System were applied at the time of infusion ofepinephrine as an assessment of the severity of illness(14, 15).

Denition and measurement of mean arterial bloodpressure and treatment of hypotension

Although this was a retrospective study, the assessmentand treatment of arterial hypotension followed a strictlydened protocol because the patients participated in twoprospective trials (9, 10). In brief, arterial hypotensionwas dened as a mean arterial blood pressure (MABP)measured by arterial line and lower than the individu-ally determined minimum blood pressure. An individualminimum blood pressure was established for each

infant. This was dened as the pressure required tomaintain adequate diuresis at a capillary relling time

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identied who received an infusion of epinephrine. Twowere excluded because of incomplete data and one wasexcluded because of discontinuous invasive bloodpressure monitoring.

Infant morbidity

Table 1 shows the characteristics and morbidity ofthe included VLBWI. Three of 31 infants receivedepinephrine on 2 different occasions.

Treatment of hypotension

Epinephrine was infused for 17.25 (3124) h [median(minimummaximum)] with doses between 0.05 and2.6 mg kg

1per minute in the rst 24 h of administra-

tion. In 29/34 episodes the infusion of dopamine wascontinued with 24 mg kg

1per minute. Twelve infants

received steroids at the same time as the infusion ofepinephrine was started. The data on severity of illness

and the cause of systemic hypotension at the time whenthe infusion of epinephrine was started are given inTable 2.

The MABP [7 (1 to 13) mmHg, p = 0.000001]

and the heart rate [

10 (

10 to 42) bpm,p

= 0.000036]increased signicantly (Fig. 1A, B). The infusion ofepinephrine restored blood pressure to the target rangein all infants. In addition, the MABP remained abovethe dened individual minimum blood pressure duringthe 12 h interval of continuous infusion of epinephrinein all infants. The changes in the total volumeadministration [7.2 (3.115.5) ml kg

1per hour before

and 8.2 (2.816.0) ml kg1

per hour during, p = 0.49]and urine output (Fig. 1C; p = 0.98) before and duringinfusion of epinephrine were not signicant. However,in 5 of 6 infants with oliguria

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of buffer before and after the start of epinephrine( p = 0.088), the base decit [3 (10.2 to 2.6) mmoll1

, p = 0.0014] increased signicantly (Fig. 1D).In 15/34 episodes of an epinephrine infusion of at

least 2 h duration and in 5 of 19 episodes of anepinephrine infusion of at least 12 h duration steroidswere administered. A subgroup analysis did not showany differences in the MABP, heart rate, administered

volume, urine output, administered buffer and basedecit between VLBWI who received steroid treatmentand those who did not (MannWhitney U-test).

Cardiac arrhythmias such as supraventricular extra-systole, ventricular extrasystole or ventricular brilla-tion were not noted. Necrotizing enterocolitis was notdiagnosed in any patient during or 24 h after terminatingthe infusion of epinephrine.

At the start of epinephrine 7 of 31 infants had anintraventricular haemorrhage III, whereas 13/31infants had an intraventricular haemorrhage III atthe nal diagnostic evaluation.

Discussion

To the authors knowledge this is the rst investigationto have studied the effects of epinephrine administeredas a continuous infusion in hypotensive VLBWI.Epinephrine was effective in raising the blood pressureto the target range in all seriously ill VLBWI non-responsive to dopamine at a dose of 15 mg kg

1per

minute.At the start of continuous infusion of epinephrine the

majority of patients suffered from infection (Table 2).Myocardial depression and peripheral vasodilatation arefound in septic shock leading to systemic hypotension

(16, 17). Thus, an agent that combines positive ino-tropic effects with vasoconstrictive properties seems tobe useful.

These a-receptor-mediated vasoconstrictive proper-ties of epinephrine may decrease renal perfusion (3). Inan animal model, however, it was shown that low dosesof epinephrine given by systemic infusion to the

halothane-anaesthetized newborn pig resulted in renalvasodilatation (18). In this study, urine output did notchange signicantly before and during infusion ofepinephrine, and in 5 out of 6 infants with oliguriabelow 2 ml kg

1per hour urine output increased after

starting epinephrine. The majority of infants received anadditional infusion of dopamine at 24 mg kg

1per

minute. Thus, it was not possible to differentiatewhether the effect on renal function was mediated byepinephrine-induced improvement in the cardiac outputor by a dopamine-induced increase in renal blood ow(19, 20).

VLBWI are more vulnerable to the development of ametabolic acidosis because of the low renal thresholdfor bicarbonate. This may result in a low serumbicarbonate concentration and a low buffering capacityof the serum. In this study, there was no signicantdifference in the administration of buffer before andafter the start of epinephrine, but using each infant as itsown control, the base decit increased signicantlyafter starting epinephrine. The infants in this study werevery sick. They were hypotensive and probably haddepressed myocardial function with poor organ per-fusion. It was suggested that epinephrine may have a

negative effect on oxygen utilization (21), possibly bycausing maldistribution of blood ow and thus worsen-ing tissue hypoxia with a resultant hyperlactataemia.The blood lactate concentration was not reportedbecause it was not measured during the study period.However, recently, an increase in blood lactate con-centration and base decit was reported under theinfusion of epinephrine in an animal model and inhuman adults (4, 6).

The maximum dose of epinephrine in the rst 24 h ofadministration was 2.6 mg kg

1per minute. In the

newborn pig epinephrine can cause irreversible myo-

cardial damage in the neonatal myocardium at doses of1 mg kg1 per minute (8). However, it was found thatincreasing cardiac oxygen demands were oversuppliedby increases in coronary blood ow during infusion ofepinephrine in the same species (22).

In adults with septic shock no arrhythmias orsignicant electrocardiographic changes indicatingmyocardial ischaemia were noted during infusion ofepinephrine at a mean dose of 0.16 mg kg

1per minute

(21). No cardiac arrhythmias were seen on the monitorscope, but routine electrocardiographic recordings werenot performed to detect abnormalities in rhythm andventricular repolarization.

Glucocorticoids were shown to be effective in thetreatment of arterial hypotension in preterm infants (9).

Table 2. Patients characteristic s at the time when the infusion ofepinephrine was started.

Age at start of epinephrine (d)a 3 (121)Oxygenation indexa 0.085 (0.010.56)Mean airway pressure (cmH2O)

a 11 (317.5)

Patent ductus arteriosusb 2/34 (6)Pulmonary hypertensionb 4/30 (13)

Administration of drugs lowering the blood

pressureb,c29/34 (85)

Infection (CRP 10 mg l1)b 22/34 (65)

Positive blood culture in infectionb 2/22 (10)Administration of fresh frozen plasma in

infectionb17/22 (77)

Administration of thrombocytes in infectionb 11/22 (50)Lowest pH 24 h before starting epinephrine

a7.19 (7.07.5)

SNAP-PEa 50.5 (2275)

NTISSa 36.5 (2651)

Data are amedian (minimummaximum) or bn (%).

Oxygenation index = mean airway pressure FiO2/PaO2; CRP: C-reactive protein; SNAP-PE: Score for Neonatal Acute PhysiologyPerinatal Extension; NTISS: Neonatal Therapeutic Intervention Scoring

System.c Morphine, fentanyl, vecuronium, phenobarbital , phenytoin, diaze-

pam, midazolam.

ACTA PDIATR 91 (2002) Epinephrine in hypotension 569

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In the present study, no differences in MABP werefound between infants who received steroid treatmentand those who did not. However, the analysis focusedon the rst 2 h of administration of epinephrine,whereas it has been shown that dexamethasone has aneffect in reducing the demand of epinephrine 38 h afteradministration (9).

Although epinephrine increased the MABP withoutdecreasing urine output in hypotensive VLBWI who didnot respond to dopamine infusion of 15 mg kg

1per

minute, there is concern about the associated metabolicacidosis and severe cerebral haemorrhages in this groupof patients. The current knowledge about the safety,dosage and indication of epinephrine and alternativetreatments for severe hypotension in preterm infants,such as steroids, is highly insufcient.

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Received July 2, 2001; revision received Dec. 3, 2001; accepted Jan.25, 2002

570 M Heckmann et al. ACTA PDIATR 91 (2002)