Double-Blind Randomized Clinical Trial Comparing
Dopamine and Epinephrine in Pediatric Fluid-
Refractory Hypotensive Septic Shock*
Karthik Narayanan Ramaswamy, MD, DM; Sunit Singhi, MD; Muralidharan Jayashree, MD;
Arun Bansal, MD; Karthi Nallasamy, MD, DM
Objective: We compared efficacy of dopamine and epinephrine
as first-line vasoactive therapy in achieving resolution of shock in
fluid-refractory hypotensive cold septic shock.
Design: Double-blind, pilot, randomized controlled study.
Setting: Pediatric emergency and ICU of a tertiary care teaching
hospital.
Patients: Consecutive children 3 months to 12 years old, with
fluid-refractory hypotensive septic shock, were enrolled between
July 2013 and December 2014.
Intervention: Enrolled children were randomized to receive either
dopamine (in incremental doses, 10 to 15 to 20 μg/kg/min)
or epinephrine (0.1 to 0.2 to 0.3 μg/kg/min) till end points of
resolution of shock were achieved. After reaching maximum
doses of test drugs, open-label vasoactive was started as per
discretion of treating team. Primary outcome was resolution of
shock within first hour of resuscitation. The study was registered
(CTRI/2014/02/004393) and was approved by institute ethics
committee.
Measurements and Main Results: We enrolled 29 children in epi-
nephrine group and 31 in dopamine group. Resolution of shock
within first hour was achieved in greater proportion of children
receiving epinephrine (n = 12; 41%) than dopamine (n = 4; 13%)
(odds ratio, 4.8; 95% CI, 1.3–17.2; p  =  0.019); the trend per-
*See also p. 1099.
All authors: Division of Pediatric Intensive and Emergency Care, Depart-
ment of Pediatrics, Advanced Pediatrics Centre, Post Graduate Institute
of Medical Education and Research, Chandigarh, India.
This work was performed at Advanced Pediatrics Centre, Post Graduate
Institute of Medical Education and research, Chandigarh, India.
Supplemental digital content is available for this article. Direct URL cita-
tions appear in the printed text and are provided in the HTML and PDF
versions of this article on the journal’s website (http://journals.lww.com/
pccmjournal).
Supported, in part, by the departmental fund.
The authors have disclosed that they do not have any potential conflicts
of interest.
For information regarding this article, E-mail: sunit.singhi@gmail.com
Copyright © 2016 by the Society of Critical Care Medicine and the World
Federation of Pediatric Intensive and Critical Care Societies
DOI: 10.1097/PCC.0000000000000954
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sisted even at 6 hours (48.3% vs 29%; p = 0.184). Children in
epinephrine group had lower Sequential Organ Function Assess-
ment score on day 3 (8 vs 12; p = 0.05) and more organ failure–
free days (24 vs 20 d; p  =  0.022). No significant difference in
adverse events (16.1% vs 13.8%; p = 0.80) and mortality (58.1%
vs 48.3%; p = 0.605) was observed between the two groups.
Conclusion: Epinephrine is more effective than dopamine in
achieving resolution of fluid-refractory hypotensive cold shock
within the first hour of resuscitation and improving organ func-
tions. (Pediatr Crit Care Med 2016; 17:e502–e512)
Key Words: children; dopamine; epinephrine; fluid-refractory
septic shock; septic shock
S
eptic shock is a leading cause of mortality and mor-
bidity among children in developed and developing
countries. Mortality ranging 10–50% is observed in
developed countries and up to 80% in developing countries
(1–4). Guidelines and recommendations for the management
of pediatric septic shock have been published since 2002 by the
American College of Critical Care Medicine (ACCM)-Pediat-
ric Advanced Life Support and were updated in 2007 (5). The
Surviving Sepsis Campaign 2012 guidelines endorse dopamine
as first-line vasoactive agent in fluid-refractory septic shock
(6). This recommendation is based more on the knowledge
of pharmacologic effects of dopamine rather than any strong
clinical evidence. Dopamine has a dose-dependent agonist
effects on dopaminergic and adrenergic (α and β) receptors.
In the general dosing range of 5–10 μg/kg/min, dopamine is
inotropic via β-adrenergic stimulation; in the dosing range ~
10–15 μg/kg/min, in addition to predominant inotropic effect,
dopamine has a mild vasopressor effect via α1-adrenergic
stimulation; and in the doses more than 15 μg/kg/min, it is
predominantly a vasopressor (via α1-adrenergic effect) with
minimal inotropic action (7).
There is no clinical trial that has demonstrated unequivocal
benefit of dopamine on outcomes of pediatric septic shock in
any of the above dose range. Furthermore, in adults with septic

shock, dopamine has been observed to increase mortality and
occurrence of arrhythmias when compared with norepineph-
rine (7, 8). Dopamine infusion in septic shock reduces release
of prolactin, increases oxidative stress, and suppresses proin-
flammatory cytokine production and increases anti-inflam-
matory cytokine production, causing immunosuppression
(9). Dopamine also suppresses secretion of growth hormone
and thyroid hormone (10). In young children and infants,
dopamine response may be unpredictable because of recep-
tor insensitivity to dopamine or catecholamine depletion in
decompensated hypotensive septic shock (11). This may lead
to the usage of increased infusion dosages to attain similar
effects (10–15 μg/kg/min for enhancing inotropic action and
> 15 μg/kg/min for vasopressor action) (11). Epinephrine, on
the other hand, has the advantage of predictable response and
increasing mean arterial pressure and cardiac output, in the
absence of immunosuppression (12). At lower infusion doses
(0.05–0.2 μg/kg/min), epinephrine provides predominantly
inotropic support via β1 receptor stimulation and modest
vasodilatation via β2 receptor stimulation. At doses more
than 0.2 μg/kg/min, epinephrine leads to increase in systemic
vascular resistance by causing peripheral vasoconstriction due
to α1 receptor stimulation along with β1-mediated inotropic
action (12). Though epinephrine may increase serum lac-
tate and impair gut perfusion in adult septic shock patients
(13, 14), it has not been shown to have adverse effects in when
used for pediatric septic shock. We have therefore compared
efficacy of dopamine and epinephrine as first-line vasoactive
therapy in children with fluid-refractory hypotensive cold
septic shock. Since the focus of the study was on early initia-
tion of an agent that had potent inotropic action with mini-
mal effect on systemic vascular resistance in a hypotensive
septic child, we compared dopamine infusion dosage ranging
from 10 to 20 μg/kg/min with epinephrine infusion dosage
ranging from 0.1 to 0.3 μg/kg/min.
METHODS
Participants
All children between 3 months and 12 years in fluid-refractory
hypotensive cold septic shock admitted to pediatric emergency
or PICU of a tertiary care referral center between July 2013 and
December 2014 were eligible for inclusion in the study. “Septic
shock” was diagnosed in presence of signs of sepsis with cardio-
vascular dysfunction. “Cardiovascular dysfunction” was defined
as presence of “either” hypotension (systolic blood pressure < fifth
percentile: < 70 mm Hg in infants; 70 + [age in years × 2] after
1 yr of age) “or” two or more signs of poor perfusion—namely,
decreased pulse volume (weak or absent radial or dorsalis pedis
pulse), capillary refill more than 2 seconds, central (rectal or oral)-
to-peripheral (skin-toe) temperature gap greater than 3°C, mottled
or cool extremities, and oliguria (< 1.0 mL/kg/hr), unexplained
metabolic acidosis or increased lactate (> 2 mmol/L). “Fluid-
refractory hypotensive cold septic shock” was defined as persistence
of hypotension and signs of poor perfusion in spite of resuscitation
with infusion of at least 40 mL/kg of isotonic saline bolus.
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Online Clinical Investigations
Children were excluded if they had any of the follow-
ing: preexisting heart disease or rhythm disturbance, on
vasoactive agent infusion at the time of screening, raised
intracranial pressure, known immune compromised state,
and severe acute malnutrition. Written informed con-
sent was obtained from the parents prior to enrollment.
The study was registered in Clinical Trial Registry of India
(CTRI/2014/02/004393) and was approved by institute eth-
ics committee. Since this was a pilot study, a convenient sam-
ple of 60 children was enrolled.
Randomization
Subjects were randomly assigned to two groups. Group I received
dopamine infusion (10–20 μg/kg/min) and placebo, and group
II received epinephrine infusion (0.1–0.3 μg/kg/min) and pla-
cebo. Randomization sequence was generated using computer-
ized random generator in variable blocks of 2, 4, and 8, by an
independent biostatistician who was not involved in the study.
The biostatistician prepared serially numbered, sealed, identical
opaque envelopes containing the random numbers as per the
allocation sequence. All sealed envelopes were placed with the
nurse in charge of pediatric emergency. The randomization was
done only after informed consent from the parents.
The nurse in charge prepared the test drug and placebo solu-
tions for infusion in 5 mL syringes and distributed those to the
staff nurse of the treating team after putting study labels. The
labels had random allocation number with a suffix “A” or “B.”
“A” contained either epinephrine (if randomized into group I)
or placebo (if randomized into group II), and “B” contained
either dopamine (if randomized into group II) or placebo (if
randomized into group I). The concentration and volume of
the trial drugs and number of syringes supplied were based on
the body weight of the child.
The treating pediatricians and the investigators were blinded
throughout the treatment and follow-up period. The random-
ization codes were revealed to the investigating team by the
nurse in charge after completion of initial statistical analysis.
Study Interventions
Infusions A and B were started simultaneously at the rate of
0.5 mL/hr via infusion pumps through separate peripheral
catheters and were shifted to a central line as soon as the
line was established. The rate of infusion A was increased
by 0.5 mL/hr after every 10 minutes to a maximum of
1.5 mL/hr till resolution of shock. Infusion B was increased
simultaneously with A by 0.25 mL/hr every 10 minutes
to a maximum of 1.0 mL/hr till resolution of shock. This
delivered dopamine in increments of 5 μg/kg/min, from
10 up to 20 μg/kg/min, and epinephrine in increments of
0.1 μg/kg/min, from 0.1 μg/kg up to 0.3 μg/kg/min, at
intervals of 10 minutes, (Fig. 1). If the child remained in
hypotensive shock with maximal infusion rate of test drugs
and adequate fluid resuscitation, open-label epinephrine
(0.1–0.3 μg/kg/min) was added and titrated (in addition
to continued infusion of test drugs) in line with “surviving
sepsis campaign” guidelines.
 Ramaswamy et al

Further decision about addition of fluids and open-label clinical signs of fluid overload (such as rales on auscultation
vasoactive drugs, glucocorticoids, and use of mechanical venti- and increase in liver size), and if echocardiographic measure-
lation to achieve therapeutic endpoints for resolution of shock ments showed ejection fraction greater than 40% and respi-
was made by the treating team according to our unit’s protocol, rophasic variation in inferior vena cava diameter greater than
which is based on the ACCM guidelines (Fig. 1). The therapeu- 18%. Norepinephrine (0.1–1.0 μg/kg/min) with dobutamine
tic decisions were based on clinical assessment, echocardiog- (10–20 μg/kg/min) was added, if needed, to stabilize blood
raphy assessment of respirophasic variation of inferior vena pressure in hypotensive patients. Dobutamine and/or milri-
cava diameter and ejection fraction, central venous pressure none (0.25–0.75 μg/kg/min) was used in normotensive cold
(CVP), and mixed central venous oxygen saturation (Scvo2). shock if ejection fraction was less than 50% and Svco2 less than
The echocardiographic assessment was done by pediatric 70% in spite of adequate fluid repletion. If Svco2 was less than
critical care fellows, and were trained in functional echocar- 70% and hemoglobin less than 10 g/dL, packed RBCs transfu-
diography. Fluid boluses were administered if there were no sion was given and arterial oxygenation was optimized through
oxygen therapy and mechanical
ventilation. Ketamine was used
for sedation for intubation and
central line insertion.
Weaning of vasoactive agents
was initiated 48 hours after
resolution of shock. Open-label
vasoactive support was tapered
off first followed by the infu-
sions of test drugs; the rate of
weaning was decided by treat-
ing team. In case of adverse
events such as ventricular or
atrial arrhythmia, intracranial
bleed, gangrene attributed to
test drugs; the treating team
was free to withdraw the patient
from the study.

Measurements and Data

Recording
Continuous hemodynamic
monitoring was done in all
enrolled patients. A central
venous line was established as
soon as possible after enroll-
ment (generally within 15 min
of starting infusion of trial
drug). Heart rate, systolic, dia-
stolic, and mean blood pressure,
oxygen saturation, and capillary
filling time were recorded before
starting trial drug solutions and
at every step of escalation of
the trial drugs till end of first
hour of resuscitation. The CVP
obtained at the time of estab-
lishing the line was considered
as the baseline CVP. After the
first hour, the above-mentioned
parameters were recorded
every half hour till shock was
Figure 1. Study protocol. CVP = central venous pressure, Hb = hemoglobin, IO= intraosseous, Scvo2 = mixed reversed. After attainment of
central venous oxygen saturation. hemodynamic stabilization,

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these parameters were recorded as an average value of every
4 hours until withdrawal of all vasoactive support. Doses of
vasoactive agents were recorded before each change. The maxi-
mum total Vasoactive-Inotropic Score was calculated at the
time of analysis (15). Mixed central venous oxygen satura-
tion (Scvo2) and arterial lactate were recorded at baseline and
every 6 hourly, till withdrawal of trial drugs or death. The first
value of Scvo2 following the establishment of central venous
jugular line was considered as the baseline Scvo2. Urine output
was measured hourly till the withdrawal of vasoactive drugs.
Data on fluid balance, blood and body fluid cultures, sero-
logic assays, respiratory support, and antibiotic therapy were
recorded. The severity of illness was calculated using Pediatric
Risk of Mortality (PRISM) III score at 24 hours of admission
to PICU. Sequential Organ Function Assessment score (SOFA)
was calculated daily till the patient was discharged from PICU.
Organ failure–free days until day 28 of enrollment were calcu-
lated in patients who survived.
Outcomes
The primary outcome was resolution of shock within first hour
of resuscitation. Resolution of shock was defined as achieve-
ment of therapeutic end points of resuscitation, viz, systolic
blood pressure greater than fifth percentile for age, heart rate
within normal range, urine output more than 1 mL/kg/hr, capil-
lary refill time less than 3 seconds, normal pulses with no differ-
ential between peripheral and central pulses, warm extremities,
and normal mental status (except in suspected meningitis and
in mechanically ventilated children on sedation).
The secondary outcomes included resolution of shock
within 6 hours of resuscitation, day-28 all-cause mortality,
length of PICU stay, length of mechanical ventilation, time
to achieve central venous saturation (Scvo2) greater than 70%
(defined as time from which Scvo2 remained > 70% for at least
12 hr) and lactate below 2 mmol/L (defined as time from which
arterial lactate remained below 2 mmol/L for at least 12 hr),
requirement of other vasoactive agents, improvement in SOFA
at 72 hours, organ failure–free days (defined as number of days
on which the child did not have component SOFA score > 2)
(16), occurrence of nosocomial infections, and adverse events.
Statistical Methods
Results were analyzed on “intention-to-treat” basis. Unblinding
of the study groups was done after the preliminary data analy-
ses. All variables were assessed for normality of distribution.
Continuous variable was expressed as mean ± sd or median
with interquartile range (IQR) and were compared using stu-
dent t test or Mann-Whitney U test, respectively. Categoric vari-
ables were analyzed using chi-square test or Fischer exact test as
appropriate. Unadjusted chi-square test was used for primary
outcome and day-28 all-cause mortality. Odds ratio (OR) or
risk ratio (RR) and 95% CIs were calculated. Kaplan-Meier esti-
mates of survival were performed and compared using log-rank
test. Cox-proportional hazard regression was done to evaluate
the effect of test drugs on day-28 all-cause mortality, includ-
ing potential confounding factors such as age, sex, PRISM III,
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Online Clinical Investigations
and SOFA score at admission. Repeated-measures analyses
of mean arterial pressure, arterial lactate, pH, and Scvo2 were
performed with mixed linear model using a first-order autore-
gressive covariance structure. Covariate included the time fac-
tor. The fixed effects included the intercept, the group to which
the subject belonged; an interaction term of group and time;
and the covariate. The random effect was intercept plus time.
A p value (two-tailed) less than 0.05 was considered significant.
SPSS 19.0.0 (SPSS, Chicago, IL) was used for analyses.
RESULTS
Of the 210 patients screened, 61 children were eligible for
enrollment (Fig. 2). One parent refused consent, 29 children
were randomized to epinephrine group and 31 to dopamine
group. All the enrolled subjects completed the study and were
followed up to 28 days. There was no crossover between the
groups following randomization. Blinding was disclosed in
two children (one in each group), as they had to be taken
up for surgical procedure for source debridement following
enrollment in the study.
There were no statistically significant differences in the
demographic characteristics or the causes of septic shock
between the two groups. Specifically, the age (p = 0.063), the
source of sepsis, PRISM III score, SOFA score at admission,
treatment received prior to randomization, and the baseline
physiologic and laboratory variables of organ functions were
not different between the two groups (Table 1).
Primary Outcome
Resolution of shock was achieved in 16 children (26.6%) within
first hour resuscitation; 12 (41.4%) had received epinephrine
and four (12.9%) dopamine as the first-line vasoactive therapy
(p = 0.019). Resolution of shock in the first hour was more likely
with epinephrine as compared to dopamine (OR, 4.8; 95% CI,
1.3–17.2) (Table 1). The absolute risk reduction was 28.5% and
the number needed to treat was 3, which was significant. At
the end of first hour, 24 children were still in hypotensive cold
shock, and 20 were in normotensive cold shock.
The individual clinical therapeutic end points achieved at
each and every stage of escalation of trial drugs were compared
between the two groups (Supplemental Table 1, Supplemental
Digital Content 1, http://links.lww.com/PCC/A316). The
number of children who achieved the targeted therapeu-
tic endpoints was more at the maximal infusion rate of trial
drugs, that is, dopamine at 20 μg/kg/min and epinephrine
at 0.3 μg/kg/min. The achievement of normal systolic blood
pressure, heart rate normal for age, and urine output was simi-
lar between both the groups (Table 2). However, greater pro-
portion of children randomized into epinephrine group had
achieved a capillary filling time less than 3 seconds (RR, 1.94;
95% CI, 1.21–3.09; p = 0.019).
On multivariate regression analysis, which included age,
sex, PRISM III, and SOFA score at admission and fluid bolus
received in first 6 hours, epinephrine was significantly associ-
ated with resolution of shock within first hour (RR, –0.132;
95% CI, 0.018–0.950; p = 0.044) along with SOFA score at
 Ramaswamy et al

admission (RR, –1.35; 95% CI,

1.04–1.75; p = 0.024).

Secondary Outcomes
The proportion of children who
achieved resolution of shock
within 6 hours of resuscitation
was higher in children who
received epinephrine (48.3%)
than dopamine (29%), but
was not statistically significant
(OR, 2.01; 0.7–5.7; p = 0.18)
(Table 2).
The day-28 all-cause mor-
tality in the study cohort was
53.3% (32/60): 48.3% in epi-
nephrine group and 58.1% in
dopamine groups (RR, 0.83;
95% CI, 0.51–1.34; p = 0.605)
(Table 2). No significant differ-
ence was observed between the
two groups on survival analy-
sis (log-rank p = 0.27) (Fig. 3).
On multivariate Cox-regression
analysis, adjusted for covariates
age, sex, SOFA at admission, and
PRISM III at admission, no sta-
tistically significant difference
in hazard ratio was observed
between the two groups (hazard
ratio, 1.16; 95% CI, 0.53–2.53;
p = 0.706). The number of
deaths due to refractory shock
was more in dopamine group
(16/18 deaths) than in epineph-
rine group (9/14 deaths), though
Figure 2. Study flow chart. the difference was not statisti-
cally significant (p = 0.19).

Table 1. Comparison of Baseline Clinical Characteristics of Epinephrine and Dopamine

Groups
Epinephrine Group Dopamine Group
Characteristic (n = 29) (n = 31)

Age (yr)a 7 (1–11) 4 (0.8–8)

Male sex (%) 15 (51.7) 15 (48.9)
Referred from other hospitals (%) 22 (76) 25 (80)
Received fluids prior to referral (%) 5 (17) 4 (13)
Received antibiotics prior to referral (%) 16 (55.2) 15 (48.4)
Pediatric Risk of Mortality IIIa 20 (15–28) 21 (13–29)
Sequential Organ Failure Assessment score at admission a
8 (3–12) 11 (9–12)
(Continued)

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 Online Clinical Investigations

Table 1. (Continued). Comparison of Baseline Clinical Characteristics of Epinephrine and

Dopamine Groups
Epinephrine Group Dopamine Group
Characteristic (n = 29) (n = 31)

Respiratory support (%)

  Nasal prongs oxygen 11 (37.9) 6 (19.4)
  Nasal continuous positive airway pressure 7 (24.1) 8 (25.8)
  Mechanical ventilation (invasive) 10 (34.5) 17 (54.8)
  Noninvasive mechanical ventilation 1 (3.4) 0
Received glucocorticoids (%) 20 (69) 24 (77.4)
Physiologic variables
  Heart rate (/min) 139 ± 24 146 ± 29
  Systolic blood pressure (mm Hg) 71 ± 15 71 ± 11
  Diastolic blood pressure (mm Hg) 36 ± 10.8 37 ± 10.4
  Mean arterial pressure (mm Hg) 48 ± 11 48 ± 10
  Oxygen saturation by pulse oximetery on supplemental 97 (95–98) 97 (93–99)
oxygen (%)a
  Baseline serum lactate (mmol/L)a 3.0 (1.8–5.2) 2.75 (2.1–5.2)
  Baseline pH a
7.25 (7.19–7.34) 7.27 (7.11–7.35)
  Baseline mixed central venous oxygen saturation (%) 65 ± 13.3 63 ± 12.5
  Baseline Pao2-to-Fio2 ratio a
112 (95–134) 108 (92–122)
Laboratory variablesb
  Hemoglobin (g/dL) 9.7 (7.8–10.7) 8.9 (7.0–10.0)
  Total leukocyte count (× 103/mm3) 18.9 (11.7–26.6) 15.2 (11.3–24.1)
  Total neutrophil count (× 103/mm3) 12.6 (4.0–18.3) 9.2 (2.2–16.4)
  Platelet count (× 10 /mm )
3 3
56 (20–111) 99 (35–171)
  Random blood sugar (mg/dL) 222 (150–313) 250 (174–350)
  Ionized calcium (mmol/L) 0.96 (0.89–1.09) 1.02 (0.86–1.21)
  C-reactive protein (mg/L) 136 (77.7–226) 134 (36.6–225)
  Baseline creatinine (mg/dL) 0.7 (0.5–1.0) 0.7 (0.5–1.0)
  Prothrombin index (%) 65 (47.5–84) 61.5 (48–74)
  International normalized ratio 1.54 (1.4–2.33) 1.61 (1.33–2.66)
  Total serum bilirubin (g/dL) 0.7 (0.7–1.45) 0.7 (0.7–1.33)
  Serum aspartate transaminase (IU/L) 117 (74.7–259.5) 201 (108–395.7)
  Serum alanine transaminase (IU/L) 86 (52–132) 110 (68–173)
Source of sepsis
  Community-acquired infection 26 30
  Healthcare-associated infection 3 1
Focus of infection
 Systemic 14 12
 Lungs 10 4
 Liver 0 1
 Gastrointestinal 1 5
 CNS 1 4
  Skin and soft tissue 1 5
 Others 2 0
Positive blood culture (%) 9 (31) 5 (16)
Data expressed as median (interquartile range).
a

b
All values mean (sd).

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 Ramaswamy et al

Table 2. Comparison of Primary and Secondary Outcomes, and Treatments Received by

Patients in Epinephrine and Dopamine Groups
Epinephrine Dopamine Risk Ratio
Outcome Measures (n = 29) (n = 31) (95% CI) p

Primary outcome—at end of 1 hr

  Resolution of shocka 12 (41.4%) 4 (12.9%) 3.2 (1.16–8.82) 0.019
  Shock unresolveda 17 27
   Hypotensive cold shock 13 11
   Normotensive cold shock 4 16
  Heart rate normal for age a
15 (51.7) 16(51.7) 1.00 (0.59–1.7) 1.000
  Blood pressure for age within normal range a
16(55.2) 20 (64.5) 0.82 (0.49–1.38) 0.599
  Capillary filling time ≥ 2 s a
12 (41.4) 4 (12.9) 1.94 (1.22–3.1) 0.019
  Urine output ≥ 1 mL/Kg/hr a
18 (62.1) 26 (83.9) 0.59 (0.37–0.97) 0.08
Secondary outcomes
  Resolution of shock within 6 hra 14 (48.3%) 9 (29%) 1.50 (0.90–2.49) 0.184
  Day-28 all-cause mortality a
14 (48.3%) 18 (58.1%) 0.83 (0.51–1.34) 0.605
  Time to achieve mixed central venous oxygen 12.0 (7.8–16.2) 17.2 (11.2–23.2) — 0.193c
saturation > 70%b (hr)
  Time to achieve lactate < 2 mmol/Lb 18 (54–6) 18 (18–12) — 0.336c
  Vasoactive-Inotropic Scoreb 95 (30–147.5) 67.5 (40–107.5) — 0.594
  Length of mechanical ventilation, days b
7.9 (7.9–3.7) 7.0 (11.5–3.0) — 0.627c
  Length of PICU stay, daysb 8 (12–4) 7 (12–5) — 0.770c
  Length of hospital stay, daysb 9 (17–8) 11 (13–9) — 0.907c
  Adverse eventsa 4(13.8) 5 (16.1) 0.85 (0.25–2.87) 0.800
   Rhythm disturbance (ventricular tachycardia) 1 (3.4) 3 (9.7) 0.36 (0.04–3.23) 0.613
  Arterial gangrene 3 (10.3) 2 (6.9) 1.60 (0.28–8.91) 0.613
  Nosocomial infections a
3 (10.3) 5 (16.1) 0.64 (0.16–2.45) 0.708
Treatments received after first hour
  Crystalloid fluid boluses in the first 6 hr (mL/Kg)b 40 (40–60) 40 (40–40) — 0.060
 Dobutamine/milrinonea 17 (58.6) 22 (71) 1.21 (0.83–1.77) 0.418
  Packed RBCs transfusiona 12 (41.4) 16 (51.6) 0.80 (0.47–1.38) 0.427
  Mechanical ventilation 19(65.5) 28(90.3) 0.72 (0.54–0.97) 0.028
  Requirement of renal replacement therapya 12/29 (41.4) 12/31 (38.7) 1.06 (0.57–1.98) 1.000
Incidence of acute kidney injurya 15 (51.7) 23 (74.2) 0.69 (0.46–1.04) 0.108
Sequential Organ Failure Assessment scoresb
  Day 1 8 (3–12) 11 (9–12) — 0.096
  Day 2 10 (2–13) 12 (8–13) — 0.132
  Day 3 8 (2–13) 12 (6–14) — 0.050
Organ failure–free days among survivors 24 (23–26) 20 (18.5–24) — 0.022
Data expressed as number of patients (%).
a

b
Data expressed as median (interquartile range).
Log-rank p value.
c

Boldface values indicate statistically significant. Dashes indicate risk ratios cannot be calculated.

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 Online Clinical Investigations

There was no significant differ-

ence in length of mechanical ven-
tilation, length of PICU stay, and
length of hospital stay between
the study groups (Table 2).
Physiologic and Biochemi-
cal Measurements. Repeated-
measures analysis to compare
the changes in trends of arterial
lactate, arterial pH, Scvo2, and
mean arterial pressure for the
first 24 hours revealed no sig-
nificant differences between the
two groups with time (Fig. 4).
There was no significant dif-
ferences in the time to achieve
Scvo2 greater than 70% (log-
rank p = 0.19) (Table 2) and
time to achieve normalization
of arterial lactate less than 2
mmol/L (log-rank p = 0.34).
The fall in arterial lactate over
24 hours observed with epi-
nephrine was 0.8 mmol/L as
Figure 3. Probabilities of survival from the day of enrollment to day 28, according to whether children received compared to 0.4 mmol/L with
dopamine or epinephrine. dopamine (p = 0.18) (Fig. 4).

Figure 4. Graphical representation of the trends of mean arterial pressure (A), arterial pH (B), arterial lactate (C), and mixed venous oxygen saturation
(D) between the two study groups. ap value of repeated measure mixed linear model trend analysis.

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 Ramaswamy et al

Organ Function Assessment. There was no statistical differ-
ence in SOFA scores on days 1 and 2 between the two groups.
However, on day 3 (after 72 hr), children in the epinephrine
group had significantly lower median SOFA scores (8; IQR,
2–13) than in dopamine group (12; IQR, 6–14; p = 0.05)
(Table 2). Epinephrine group also had more organ failure–free
days (24 d; IQR, 23–26 d), than dopamine group (20 d; IQR,
18.5–24 d), which was statistically significant (p = 0.022)
Adverse Events. Adverse events were recorded in four children
(13.8%) in epinephrine group and five (16.1%) in dopamine
group (Table 2). Between the two groups, there was no statisti-
cally significant difference either in the total number or specific
adverse events namely, rhythm disturbance and arterial gangrene
(Table 2). The radial artery was involved in four patients and the
posterior tibial artery in one patient. Arterial gangrene occurred
after a median of 46 (14–72) hours of enrollment. The gangrene
site was not related to arterial line. Thrombotic disseminated
intravascular coagulation was present in all patients with arterial
gangrene. Healthcare-associated infections occurred in five chil-
dren (16.1%) (ventilator-associated pneumonia, 3; catheter-asso-
ciated bloodstream infection, 1; and peritoneal dialysis–induced
intra-abdominal sepsis, 1) in dopamine group as compared to
three children (10.3%) (catheter-associated urinary tract infec-
tion, 3) in epinephrine group (p = 0.71).
Major Therapeutic Interventions. The groups were simi-
lar with respect to administration of crystalloid fluid boluses,
vasopressors and inodilator infusion, packed red cell transfu-
sion within first 6 hours of enrollment, and renal replacement
therapy (Table 2).
Survivors Versus Nonsurvivors. Children who died were
younger, had higher PRISM III and SOFA scores, higher admis-
sion lactate, and more profound hypotension as compared to

Table 3. Comparison of Survivors and Nonsurvivors in the Study Cohort

Survived Died Odds Risk
Variables (n = 28) (n = 32) and 95 % CI p

Agea 6.0 (1.3–9.7) 4.5 (0.9–8.0) — 0.005

Sequential Organ Function Assessmenta 8 (3–11) 12 (9–13) — < 0.001
Pediatric Risk of Mortality III a
14 (10–16) 27 (22–32.5) — < 0.001
Admission arterial lactate (mmol/L) a
2.4 (1.7–3.1) 4.0 (2.3–6.3) — 0.011
Baseline mean arterial pressure a
52 (48–58) 43 (38–56) — 0.024
Resolution of shock within first hour b
13 3 8.4 (2.1–34.0) < 0.001
Resolution of shock within first 6 hr b
19 4 14.7 (3.97–54.98) < 0.001
Maximum vasoactive score a
40 (26–60) 130 (77–566) — < 0.001
Refractory shock b
0 25 — < 0.001
Intubated within first hour b
6 20 0.14 (0.04–0.45) 0.001
Intubated after first hour b
10 11 1.06 (0.36–3.07) 1.000
Mechanical ventilation b,c
17 30 9.70 (1.92–49.03) 0.004
Time to normalization of mixed central venous 6 (6–18) 12 (6–18) — 0.019d
oxygen saturation (hr)
Time to normalization of arterial lactate (hr) 24 (6–46) 33 (12–54) — < 0.001d
Fluid balance in mL/kg in first 24 hr +12.8 (–1.14 to 22.8) +34.9 (13.7–66) — < 0.001
Vasoactive infusions doses µg/kg/hr a

 Dobutamine 0 (0–10) 20 (5–20) — < 0.001

 Adrenaline 0.3 (0.2–0.3) 0.45 (0.3–0.7) — < 0.001
 Noradrenaline 0 (0–0.08) 0.35 (0.2–0.50) — < 0.001
 Milrinone 0 (0–0.5) 0.5 (0–0.8) — < 0.001
 Vasopressin — 0 (0–0.042) — —
Data expressed as median (interquartile range).
a

b
Data expressed as proportion.
c
Among survivors, out of 17 patients who received mechanical ventilation, one patient received noninvasive ventilation and was not intubated. Hence, the total
number of patients intubated among survivors was only 16. Among nonsurvivors, one patient died due to hypotensive shock before he could be mechanically
ventilated in PICU.
d
Log-rank p value.
Boldface values indicate statistically significant. Dashes indicate odds ratios cannot be calculated.

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those who survived (Table 3). The time taken to achieve nor-
malization of lactate and Scvo2 were significantly prolonged in
nonsurvivors as compared to survivors. The fluid balance on day
1 was also significantly more in nonsurvivors when compared
with survivors (Table 3). Failure to achieve resolution of shock
within 6 hours of resuscitation was associated with increased
risk of mortality (OR, 5.4; 95% CI, 2.09–14.05; p < 0.001).
DISCUSSION
We observed that epinephrine was three times more likely to
achieve resolution of shock within first hour of resuscitation as
compared to dopamine. Similar trends were also observed at 6
hours of resuscitation. In our study, early resolution of shock
with epinephrine was also associated with improved organ
functions, as demonstrated by lower SOFA score on day 3 and
increased organ failure–free days as compared to dopamine.
Both dopamine and epinephrine were equally effective in achiev-
ing targeted systolic blood pressure and heart rate. However,
epinephrine had the benefit of significantly improving capillary
filling time, which is indicative of improved microcirculation,
and a mild decrease in systemic vascular resistance and afterload.
This combination of vasopressors and afterload reducing effect
of epinephrine could have benefitted myocardial dysfunction,
and improved cardiac output and organ perfusion. The observed
results are similar to a cross over study in adults, that compared
dopamine and epinephrine in sepsis and malaria, in which epi-
nephrine resulted in significant increase in cardiac index along
with increase in arterial pressure with mild decrease in systemic
vascular resistance as compared to dopamine (13).
In adults with septic shock, there is strong evidence that
dopamine is associated with increased mortality and adverse
events (7, 8). Similarly, Ventura et al (17) found a significant
increase in mortality in children who received dopamine, in a
much shorter period of time than who received epinephrine.
The current study lacked sufficient sample size to demonstrate
significant difference in mortality.
Rhythm disturbances were also observed in both the groups;
more in the dopamine (9.7%) than the epinephrine (3.4%)
group. However, they were not severe enough to warrant
withdrawal from the study. De Backer et al (8) had observed
that the use of dopamine was associated with increased risk
of arrhythmic events than norepinephrine; they hypothesized
that this was probably due to increased occurrence of cardiac
ischemic events with dopamine. They supported this hypoth-
esis with subgroup analysis, which showed that dopamine was
associated with significant increase in mortality than norepi-
nephrine in adults with cardiogenic shock. Since our study
included children with cold hypotensive septic shock sugges-
tive of significant myocardial dysfunction, dopamine as com-
pared to epinephrine could have further worsened myocardial
dysfunction.
The concern that epinephrine may induce lactic acido-
sis was not substantiated by our study. On the contrary, lac-
tate clearance was similar in both the groups. Trend analysis
also did not reveal any significant difference between the two
groups. This could probably be due to improvement in cardiac
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Online Clinical Investigations
index and microcirculation with epinephrine in the dose range
0.1–0.3 μg/kg/min.
The mortality in our study was nearly 52%, in spite of adher-
ence to ACCM guidelines. It is likely that greater severity of illness,
more severe organ dysfunction, and failure to achieve resolution
of shock within 6 hours of enrolment among nonsurvivors con-
tributed to increased mortality in the study cohort. Resolution
of shock within 6 hours was achieved in only 48.3% children
in epinephrine group and only 29% of children in dopamine
group. In an almost similar patient population, Sankar et al (18)
observed a mortality of 42% in fluid-refractory pediatric septic
shock in spite of more than 90% adherence to ACCM guidelines.
It appears that achieving therapeutic end points in fluid-refrac-
tory cold hypotensive shock is difficult and can lead to increased
mortality if end points are not achieved within 6 hours.
Though this study was a pilot trial, the study had sufficient
power to demonstrate a significantly early resolution of shock with
use of epinephrine as compared to dopamine as the first-line vaso-
active agent in hypotensive cold septic shock, with no difference in
incidence and profile of adverse events. However, there are limita-
tions to our study. Our main limitation is a small sample size, which
may have affected the effect size of short-term benefits such as early
resolution of shock and improved organ functions at 72 hours,
translating into long-term outcomes including as 28-day mortal-
ity. Also, a majority of the children enrolled in our study had com-
munity-acquired sepsis, and therefore the study results may not be
applicable to children with hospital-acquired sepsis. The increased
proportion of children with community-acquired sepsis is due to
the fact that the most of hospital-acquired septic shock in children
are diagnosed early in stage of warm shock, whereas children with
community-acquired septic shock commonly present late in cold
shock and require fluids and inotropic agents (19). Our study was
not pragmatic as there were several exclusion criteria. The reason
we excluded children with heart disease, severe acute malnutri-
tion, and immunosuppression was the fact that these conditions
can alter the response of myocardium and vascular response to the
test drugs (20–22). We were also unable to measure quantitatively
effect of test drugs on cardiac index and systemic vascular resis-
tance using cardiac output monitors.
In summary, our study shows that epinephrine when used
as first-line vasoactive agent achieves early resolution of fluid-
refractory cold hypotensive shock in children as compared to
dopamine and is relatively safe. The future role of dopamine in
pediatric septic shock needs to be investigated, in light of the
results of this study. Our study also provides rationale for well-
planned multicenter studies to evaluate benefit of epinephrine
as first-line vasoactive agent in fluid-refractory hypotensive
cold shock in terms of mortality.
ACKNOWLEDGMENTS
We thank Prof. Pratibha Singhi for critical review of the article.
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