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Acta Pñ diatr 91: 566± 570.

2002

Epinephrine treatment of hypotension in very low birthweight infants*


M Heckmann, A Trotter, F Pohlandt and W Lindner
Division of Neonatolog y and Pediatric Critical Care, Department of Pediatrics, University of Ulm, Germany

Heckmann M, Trotter A, Pohlandt F, Lindner W. Epinephrine treatment of hypotension in very


low birthweight infants. Acta Pædiatr 2002; 91: 566–570. Stockholm. ISSN 0803-5253
The aim of this study was to examine the in uence of a continuous infusion of epinephrine
(adrenaline) on mean arterial blood pressure (MABP), heart rate, urine output and base deŽ cit in
very low birthweight infants (VLBWI) with systemic hypotension. In VLBWI who received an
infusion of epinephrine for at least 12 h the mean urine output, administered  uid volume, base
deŽ cit and administered buffer 12 h before and 12 h during the infusion were recorded. If the
infusion was shorter, but given for at least 2 h, the mean heart rate and MABP 2 h before and 2 h
during the infusion were recorded. Thirty-one infants with a gestational age of 26 (23–30) wk
[median (minimum–maximum)] and birthweight 690 (390–1310) g were included in this retro-
spective chart review. The patients received an infusion of epinephrine at a postnatal age of 3
(1–21) d. The doses ranged between 0.05 and 2.6 mg kg¡1 per minute within the Ž rst 24 h of
administration. 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 signiŽ cantly (n = 34), whereas total volume administration and urine output remained the
same between the 2 periods (Wilcoxon matched pairs test). The base deŽ cit increased signiŽ cantly
[¡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 without
decreasing urine output in VLBWI with hypotension not responding to a dopamine infusion up to
15 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 Gießen, DE-35385 Gießen, 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 an in the neonatal myocardium consisting of sarcolemmal
increased risk of cerebral damage in critically ill rupture and loss of mitochondrial architecture (8).
preterm neonates (1). If volume loading and dopamine The purpose of this study was to review the cardio-
administration up to 15 mg kg¡1 per minute fail to vascular, renal and metabolic effects of epinephrine in a
restore the blood pressure, the addition of epinephrine cohort of very low birthweight infants (VLBWI).
(adrenaline) may be effective in increasing the blood
pressure to the normal range (2). However, the
administration of epinephrine carries the risk of an a- Patients and methods
receptor-mediated decrease in renal perfusion possibly Patients
inducing oliguria (3). Epinephrine may also decrease
the mesenteric perfusion, thus increasing the risk of VLBWI who received a continuous infusion of epi-
necrotizing enterocolitis (4). The proarrhythmic effect nephrine for a duration of at least 2 h were eligible for
and the elevation of lactate levels are further adverse the retrospective chart review. These infants were
effects of epinephrine administered as a continuous identiŽ ed by their participation in two prospective trials
infusion in adults (4–6). In addition, raised lactate (9, 10). Exclusion criteria were congenital heart dis-
concentrations were associated with increased mortality eases or other major congenital malformations. Addi-
in sick, ventilated neonates (7). Finally, it has been tional exclusion criteria were incomplete data recording
demonstrated that epinephrine at high doses (1 mg kg¡1 and no arterial line for blood pressure monitoring.
per minute) can cause irreversible myocardial damage
Infant morbidity
Respiratory distress syndrome was categorized accord-
*Some of the results were presente d at the European Society for ing to the criteria of Giedion, intraventricular haemor-
Pediatric Research Conference in Copenhagen , Denmark, June 1999. rhage according to the criteria of Papile, and periven-

Ó 2002 Taylor & Francis. ISSN 0803-525 3


ACTA PÆDIATR 91 (2002) Epinephrin e in hypotensio n 567

Table 1. Clinical characteristic s of very low birthweigh t infants with infusion of 15 mg kg¡1 per minute, infusion of epi-
an infusion of epinephrine . nephrine at a dose of 0.2 mg kg¡1 per minute was
No. 31 started. In addition, the dopamine infusion was dis-
Gestational age (wk)a 26 (23–30) continued (n = 5) or lowered to 2–4 mg kg¡1 per minute
Birthweight (g)a 690 (390–1310) (n = 29). The dosage of epinephrine was increased by
Female 16 0.1 mg kg¡1 per minute until the target MABP was
Apgar scores at 5 mina 7 (1–9)
Umbilical cord artery pHa 7.27 (6.95–7.42) reached. The rate of infusion was reduced if the
Respiratory distress syndrome ¶III°b 23 (74) measured MABP remained at least 5 mmHg above the
Intraventricular haemorrhage ¶III°b 13 (42) predetermined minimum blood pressure for at least
Periventricular leucomalaciab 3 (10) 30 min. Further volume expansion was possible when-
Mortalityb 8 (26)
Mortality predicted by SNAP-PE 50%
ever there was evidence for volume deŽ ciency. During
the Ž rst 12 h of infusion of epinephrine some infants
Data are a median (minimum–maximum) or b n (%). were treated with hydrocortisone (60 mg m¡2 body
SNAP-PE: Score for Neonatal Acute Physiology—Perinatal Extension. surface area per day, n = 3), or a single dose of dexa-
methasone (0.25 mg kg¡1, n = 16) (9).
An important goal of the treatment regimen for
tricular leucomalacia according to the criteria of Volpe arterial hypotension was to restore an adequate blood
(11–13). pressure quickly. To detect the fast pressure-response of
Pulmonary hypertension was deŽ ned as right-to-left epinephrine, the mean heart rate and MABP measured
shunting across the ductus arteriosus and/or the foramen during the 2 h intervals directly before and after starting
ovale as determined by echocardiography and Doppler the infusion of epinephrine were compared in all
ultrasound. If echocardiographic imaging was not VLBWI who received an infusion of epinephrine for
available, pulmonary hypertension was diagnosed by a at least 2 h. The 2 h interval was chosen to exclude the
difference between preductal and postductal oxygen in uence of steroids on MABP (see Discussion). During
saturation greater than 10% which was measured by these 2 h intervals the MABP was documented every
pulse oximetry. 15–20 min. After stabilization the MABP was docu-
The Score for Neonatal Acute Physiology—Perinatal mented every hour.
Extension and the Neonatal Therapeutic Intervention To detect the slower effects of epinephrine on
Scoring System were applied at the time of infusion of diuresis and metabolism, a longer period was chosen.
epinephrine as an assessment of the severity of illness The mean urine output, administered  uid volume, base
(14, 15). deŽ cit and administered buffer during the 12 h intervals
before and after starting the infusion of epinephrine
were compared in all VLBWI who received an infusion
DeŽ nition and measurement of mean arterial blood of epinephrine for at least 12 h. During these 12 h
pressure and treatment of hypotension intervals urine output was documented every 4 h and
Although this was a retrospective study, the assessment blood gas analysis was performed 3 or 4 times. It was
and treatment of arterial hypotension followed a strictly also reviewed if the MABP remained above the deŽ ned
deŽ ned protocol because the patients participated in two individual minimum blood pressure during the 12 h
prospective trials (9, 10). In brief, arterial hypotension interval of continuous infusion of epinephrine.
was deŽ ned as a mean arterial blood pressure (MABP)
measured by arterial line and lower than the individu- Statistics
ally determined minimum blood pressure. An individual All data were analysed using the Statistica1 (Version 5)
minimum blood pressure was established for each software package (StatSoft, Tulsa, USA). For the
infant. This was deŽ ned as the pressure required to explorative statistics the Wilcoxon matched pairs test
maintain adequate diuresis at a capillary reŽ lling time was used to compare differences in MABP, heart rate,
<2–3 s. The following minimum blood pressure levels urine output, administered volume of  uids, base deŽ cit
had been applied: 23 mmHg (birthweight <750 g), and administered buffer, before and during infusion of
25 mmHg (750–999 g) and 28–30 mmHg (1000– epinephrine. The Mann–Whitney U-test was used to
1500 g). Arterial hypotension was treated as follows. compare differences between infants who received
Initially, a maximum of 3 individual doses of 10– steroid treatment and those who did not. A p-value
15 ml kg¡1 of either crystalloid  uid or blood substi- <0.05 was considered signiŽ cant.
tutes was administered intravenously over a period of
15 min. In cases of persistent arterial hypotension,
infusion of dopamine at a dose of 5 mg kg¡1 per minute Results
was started. Dopamine doses were increased by
5 mg kg¡1 per minute at 15 min intervals until an Subjects
adequate MABP was attained and sustained for at least In total, 538 VLBWI were admitted between November
30 min. If this was not achieved at a maximum rate of 1994 and October 1998. Thirty-four VLBWI were
568 M Heckmann et al. ACTA PÆDIATR 91 (2002)

Fig. 1. Individua l and mean values (&): (A) mean arterial blood pressure and (B) heart rate 2 h before and 2 h during infusion of epinephrin e
(EPI) (p < 0.0001; n = 34); (C) urine output ( p = 0.98; n = 18) and (D) base deŽ cit ( p = 0.0014; n = 19) 12 h before and 12 h during infusion of
epinephrine . The dotted lines represent infants with additiona l steroid treatment for arterial hypotension .

identiŽ ed who received an infusion of epinephrine. Two and the cause of systemic hypotension at the time when
were excluded because of incomplete data and one was the infusion of epinephrine was started are given in
excluded because of discontinuous invasive blood Table 2.
pressure monitoring. The MABP [‡7 (¡1 to 13) mmHg, p = 0.000001]
and the heart rate [‡10 (¡10 to 42) bpm, p = 0.000036]
Infant morbidity increased signiŽ cantly (Fig. 1A, B). The infusion of
epinephrine restored blood pressure to the target range
Table 1 shows the characteristics and morbidity of
in all infants. In addition, the MABP remained above
the included VLBWI. Three of 31 infants received
the deŽ ned individual minimum blood pressure during
epinephrine on 2 different occasions.
the 12 h interval of continuous infusion of epinephrine
in all infants. The changes in the total volume
Treatment of hypotension administration [7.2 (3.1–15.5) ml kg¡1 per hour before
Epinephrine was infused for 17.25 (3–124) h [median and 8.2 (2.8–16.0) ml kg¡1 per hour during, p = 0.49]
(minimum–maximum)] with doses between 0.05 and and urine output (Fig. 1C; p = 0.98) before and during
2.6 mg kg¡1 per minute in the Ž rst 24 h of administra- infusion of epinephrine were not signiŽ cant. However,
tion. In 29/34 episodes the infusion of dopamine was in 5 of 6 infants with oliguria <2 ml kg¡1 per hour urine
continued with 2–4 mg kg¡1 per minute. Twelve infants output increased. There was no signiŽ cant difference
received steroids at the same time as the infusion of between the administration of diuretics before and after
epinephrine was started. The data on severity of illness the start of epinephrine. With the same administration
ACTA PÆDIATR 91 (2002) Epinephrin e in hypotensio n 569

Table 2. Patients’ characteristic s at the time when the infusion of (16, 17). Thus, an agent that combines positive ino-
epinephrin e was started. tropic effects with vasoconstrictive properties seems to
Age at start of epinephrine (d) a 3 (1–21) be useful.
Oxygenation indexa 0.085 (0.01–0.56) These a-receptor-mediated vasoconstrictive proper-
Mean airway pressure (cmH2O)a 11 (3–17.5) ties of epinephrine may decrease renal perfusion (3). In
Patent ductus arteriosusb 2/34 (6) an animal model, however, it was shown that low doses
Pulmonary hypertensionb 4/30 (13)
Administration of drugs lowering the blood 29/34 (85) of epinephrine given by systemic infusion to the
pressure b,c halothane-anaesthetized newborn pig resulted in renal
Infection (CRP ¶10 mg l¡1) b 22/34 (65) vasodilatation (18). In this study, urine output did not
Positive blood culture in infectionb 2/22 (10) change signiŽ cantly before and during infusion of
Administration of fresh frozen plasma in 17/22 (77)
infection b
epinephrine, and in 5 out of 6 infants with oliguria
Administration of thrombocytes in infectionb 11/22 (50) below 2 ml kg¡1 per hour urine output increased after
Lowest pH 24 h before starting epinephrinea 7.19 (7.0–7.5) starting epinephrine. The majority of infants received an
SNAP-PEa 50.5 (22–75) additional infusion of dopamine at 2–4 mg kg¡1 per
NTISSa 36.5 (26–51) minute. Thus, it was not possible to differentiate
Data are amedian (minimum–maximum) or bn (%). whether the effect on renal function was mediated by
Oxygenation index = mean airway pressure £ FiO2/PaO2; CRP: C- epinephrine-induced improvement in the cardiac output
reactive protein; SNAP-PE: Score for Neonatal Acute Physiology— or by a dopamine-induced increase in renal blood  ow
Perinatal Extension; NTISS: Neonatal Therapeutic Intervention Scoring
System.
(19, 20).
c
Morphine, fentanyl, vecuronium , phenobarbital , phenytoin, diaze- VLBWI are more vulnerable to the development of a
pam, midazolam. metabolic acidosis because of the low renal threshold
for bicarbonate. This may result in a low serum
bicarbonate concentration and a low buffering capacity
of buffer before and after the start of epinephrine of the serum. In this study, there was no signiŽ cant
( p = 0.088), the base deŽ cit [¡3 (¡10.2 to ¡2.6) mmol difference in the administration of buffer before and
l¡1, p = 0.0014] increased signiŽ cantly (Fig. 1D). after the start of epinephrine, but using each infant as its
In 15/34 episodes of an epinephrine infusion of at own control, the base deŽ cit increased signiŽ cantly
least 2 h duration and in 5 of 19 episodes of an after starting epinephrine. The infants in this study were
epinephrine infusion of at least 12 h duration steroids very sick. They were hypotensive and probably had
were administered. A subgroup analysis did not show depressed myocardial function with poor organ per-
any differences in the MABP, heart rate, administered fusion. It was suggested that epinephrine may have a
volume, urine output, administered buffer and base negative effect on oxygen utilization (21), possibly by
deŽ cit between VLBWI who received steroid treatment causing maldistribution of blood  ow and thus worsen-
and those who did not (Mann–Whitney U-test). ing tissue hypoxia with a resultant hyperlactataemia.
Cardiac arrhythmias such as supraventricular extra- The blood lactate concentration was not reported
systole, ventricular extrasystole or ventricular Ž brilla- because it was not measured during the study period.
tion were not noted. Necrotizing enterocolitis was not However, recently, an increase in blood lactate con-
diagnosed in any patient during or 24 h after terminating centration and base deŽ cit was reported under the
the infusion of epinephrine. infusion of epinephrine in an animal model and in
At the start of epinephrine 7 of 31 infants had an human adults (4, 6).
intraventricular haemorrhage ¶ III°, whereas 13/31 The maximum dose of epinephrine in the Ž rst 24 h of
infants had an intraventricular haemorrhage ¶ III° at administration was 2.6 mg kg¡1 per minute. In the
the Ž nal diagnostic evaluation. newborn pig epinephrine can cause irreversible myo-
cardial damage in the neonatal myocardium at doses of
1 mg kg¡1 per minute (8). However, it was found that
increasing cardiac oxygen demands were oversupplied
Discussion by increases in coronary blood  ow during infusion of
To the authors’ knowledge this is the Ž rst investigation epinephrine in the same species (22).
to have studied the effects of epinephrine administered In adults with septic shock no arrhythmias or
as a continuous infusion in hypotensive VLBWI. signiŽ cant electrocardiographic changes indicating
Epinephrine was effective in raising the blood pressure myocardial ischaemia were noted during infusion of
to the target range in all seriously ill VLBWI non- epinephrine at a mean dose of 0.16 mg kg¡1 per minute
responsive to dopamine at a dose of 15 mg kg¡1 per (21). No cardiac arrhythmias were seen on the monitor
minute. scope, but routine electrocardiographic recordings were
At the start of continuous infusion of epinephrine the not performed to detect abnormalities in rhythm and
majority of patients suffered from infection (Table 2). ventricular repolarization.
Myocardial depression and peripheral vasodilatation are Glucocorticoids were shown to be effective in the
found in septic shock leading to systemic hypotension treatment of arterial hypotension in preterm infants (9).
570 M Heckmann et al. ACTA PÆDIATR 91 (2002)

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