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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 sisted even at 6 hours (48.3% vs 29%; p = 0.184). Children in
as first-line vasoactive therapy in achieving resolution of shock in epinephrine group had lower Sequential Organ Function Assess-
fluid-refractory hypotensive cold septic shock. ment score on day 3 (8 vs 12; p = 0.05) and more organ failure–
Design: Double-blind, pilot, randomized controlled study. free days (24 vs 20 d; p  =  0.022). No significant difference in
Setting: Pediatric emergency and ICU of a tertiary care teaching adverse events (16.1% vs 13.8%; p = 0.80) and mortality (58.1%
hospital. vs 48.3%; p = 0.605) was observed between the two groups.
Patients: Consecutive children 3 months to 12 years old, with Conclusion: Epinephrine is more effective than dopamine in
fluid-refractory hypotensive septic shock, were enrolled between achieving resolution of fluid-refractory hypotensive cold shock
July 2013 and December 2014. within the first hour of resuscitation and improving organ func-
Intervention: Enrolled children were randomized to receive either tions. (Pediatr Crit Care Med 2016; 17:e502–e512)
dopamine (in incremental doses, 10 to 15 to 20 μg/kg/min) Key Words: children; dopamine; epinephrine; fluid-refractory
or epinephrine (0.1 to 0.2 to 0.3 μg/kg/min) till end points of septic shock; septic shock
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

S
shock within first hour of resuscitation. The study was registered eptic shock is a leading cause of mortality and mor-
(CTRI/2014/02/004393) and was approved by institute ethics bidity among children in developed and developing
committee. countries. Mortality ranging 10–50% is observed in
Measurements and Main Results: We enrolled 29 children in epi- developed countries and up to 80% in developing countries
nephrine group and 31 in dopamine group. Resolution of shock (1–4). Guidelines and recommendations for the management
within first hour was achieved in greater proportion of children of pediatric septic shock have been published since 2002 by the
receiving epinephrine (n = 12; 41%) than dopamine (n = 4; 13%) American College of Critical Care Medicine (ACCM)-Pediat-
(odds ratio, 4.8; 95% CI, 1.3–17.2; p  =  0.019); the trend per- ric Advanced Life Support and were updated in 2007 (5). The
Surviving Sepsis Campaign 2012 guidelines endorse dopamine
*See also p. 1099. as first-line vasoactive agent in fluid-refractory septic shock
All authors: Division of Pediatric Intensive and Emergency Care, Depart- (6). This recommendation is based more on the knowledge
ment of Pediatrics, Advanced Pediatrics Centre, Post Graduate Institute of pharmacologic effects of dopamine rather than any strong
of Medical Education and Research, Chandigarh, India.
clinical evidence. Dopamine has a dose-dependent agonist
This work was performed at Advanced Pediatrics Centre, Post Graduate
Institute of Medical Education and research, Chandigarh, India. effects on dopaminergic and adrenergic (α and β) receptors.
Supplemental digital content is available for this article. Direct URL cita- In the general dosing range of 5–10 μg/kg/min, dopamine is
tions appear in the printed text and are provided in the HTML and PDF inotropic via β-adrenergic stimulation; in the dosing range ~
versions of this article on the journal’s website (http://journals.lww.com/ 10–15 μg/kg/min, in addition to predominant inotropic effect,
pccmjournal).
dopamine has a mild vasopressor effect via α1-adrenergic
Supported, in part, by the departmental fund.
stimulation; and in the doses more than 15 μg/kg/min, it is
The authors have disclosed that they do not have any potential conflicts
of interest. predominantly a vasopressor (via α1-adrenergic effect) with
For information regarding this article, E-mail: sunit.singhi@gmail.com minimal inotropic action (7).
Copyright © 2016 by the Society of Critical Care Medicine and the World There is no clinical trial that has demonstrated unequivocal
Federation of Pediatric Intensive and Critical Care Societies benefit of dopamine on outcomes of pediatric septic shock in
DOI: 10.1097/PCC.0000000000000954 any of the above dose range. Furthermore, in adults with septic

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shock, dopamine has been observed to increase mortality and Children were excluded if they had any of the follow-
occurrence of arrhythmias when compared with norepineph- ing: preexisting heart disease or rhythm disturbance, on
rine (7, 8). Dopamine infusion in septic shock reduces release vasoactive agent infusion at the time of screening, raised
of prolactin, increases oxidative stress, and suppresses proin- intracranial pressure, known immune compromised state,
flammatory cytokine production and increases anti-inflam- and severe acute malnutrition. Written informed con-
matory cytokine production, causing immunosuppression sent was obtained from the parents prior to enrollment.
(9). Dopamine also suppresses secretion of growth hormone The study was registered in Clinical Trial Registry of India
and thyroid hormone (10). In young children and infants, (CTRI/2014/02/004393) and was approved by institute eth-
dopamine response may be unpredictable because of recep- ics committee. Since this was a pilot study, a convenient sam-
tor insensitivity to dopamine or catecholamine depletion in ple of 60 children was enrolled.
decompensated hypotensive septic shock (11). This may lead
to the usage of increased infusion dosages to attain similar Randomization
effects (10–15 μg/kg/min for enhancing inotropic action and Subjects were randomly assigned to two groups. Group I received
> 15 μg/kg/min for vasopressor action) (11). Epinephrine, on dopamine infusion (10–20 μg/kg/min) and placebo, and group
the other hand, has the advantage of predictable response and II received epinephrine infusion (0.1–0.3 μg/kg/min) and pla-
increasing mean arterial pressure and cardiac output, in the cebo. Randomization sequence was generated using computer-
absence of immunosuppression (12). At lower infusion doses ized random generator in variable blocks of 2, 4, and 8, by an
(0.05–0.2 μg/kg/min), epinephrine provides predominantly independent biostatistician who was not involved in the study.
inotropic support via β1 receptor stimulation and modest The biostatistician prepared serially numbered, sealed, identical
vasodilatation via β2 receptor stimulation. At doses more opaque envelopes containing the random numbers as per the
than 0.2 μg/kg/min, epinephrine leads to increase in systemic allocation sequence. All sealed envelopes were placed with the
vascular resistance by causing peripheral vasoconstriction due nurse in charge of pediatric emergency. The randomization was
to α1 receptor stimulation along with β1-mediated inotropic done only after informed consent from the parents.
action (12). Though epinephrine may increase serum lac- The nurse in charge prepared the test drug and placebo solu-
tate and impair gut perfusion in adult septic shock patients tions for infusion in 5 mL syringes and distributed those to the
(13, 14), it has not been shown to have adverse effects in when staff nurse of the treating team after putting study labels. The
used for pediatric septic shock. We have therefore compared labels had random allocation number with a suffix “A” or “B.”
efficacy of dopamine and epinephrine as first-line vasoactive “A” contained either epinephrine (if randomized into group I)
therapy in children with fluid-refractory hypotensive cold or placebo (if randomized into group II), and “B” contained
septic shock. Since the focus of the study was on early initia- either dopamine (if randomized into group II) or placebo (if
tion of an agent that had potent inotropic action with mini- randomized into group I). The concentration and volume of
mal effect on systemic vascular resistance in a hypotensive the trial drugs and number of syringes supplied were based on
septic child, we compared dopamine infusion dosage ranging the body weight of the child.
from 10 to 20 μg/kg/min with epinephrine infusion dosage The treating pediatricians and the investigators were blinded
ranging from 0.1 to 0.3 μg/kg/min. 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.
METHODS
Participants Study Interventions
All children between 3 months and 12 years in fluid-refractory Infusions A and B were started simultaneously at the rate of
hypotensive cold septic shock admitted to pediatric emergency 0.5 mL/hr via infusion pumps through separate peripheral
or PICU of a tertiary care referral center between July 2013 and catheters and were shifted to a central line as soon as the
December 2014 were eligible for inclusion in the study. “Septic line was established. The rate of infusion A was increased
shock” was diagnosed in presence of signs of sepsis with cardio- by 0.5 mL/hr after every 10 minutes to a maximum of
vascular dysfunction. “Cardiovascular dysfunction” was defined 1.5 mL/hr till resolution of shock. Infusion B was increased
as presence of “either” hypotension (systolic blood pressure < fifth simultaneously with A by 0.25 mL/hr every 10 minutes
percentile: < 70 mm Hg in infants; 70 + [age in years × 2] after to a maximum of 1.0 mL/hr till resolution of shock. This
1 yr of age) “or” two or more signs of poor perfusion—namely, delivered dopamine in increments of 5 μg/kg/min, from
decreased pulse volume (weak or absent radial or dorsalis pedis 10 up to 20 μg/kg/min, and epinephrine in increments of
pulse), capillary refill more than 2 seconds, central (rectal or oral)- 0.1 μg/kg/min, from 0.1 μg/kg up to 0.3 μg/kg/min, at
to-peripheral (skin-toe) temperature gap greater than 3°C, mottled intervals of 10 minutes, (Fig. 1). If the child remained in
or cool extremities, and oliguria (< 1.0 mL/kg/hr), unexplained hypotensive shock with maximal infusion rate of test drugs
metabolic acidosis or increased lactate (> 2 mmol/L). “Fluid- and adequate fluid resuscitation, open-label epinephrine
refractory hypotensive cold septic shock” was defined as persistence (0.1–0.3 μg/kg/min) was added and titrated (in addition
of hypotension and signs of poor perfusion in spite of resuscitation to continued infusion of test drugs) in line with “surviving
with infusion of at least 40 mL/kg of isotonic saline bolus. sepsis campaign” guidelines.

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

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

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

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