Transcript Slide 1

TREATING HYPOTENSION IN THE
PRETERM NEWBORN:
« PERMISSIVE HYPOTENSION »
Keith J Barrington
Ste Justine Hospital, Montreal.
Hypotension in Preterm Infants

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Common practice in the NICU, to treat preterm infants
with a mean arterial blood pressure in mmHg <
gestational age in weeks, regardless of clinical signs,
Many receive a fluid bolus (or 2 or 3 or 4) and then
dopamine.
If the blood pressure remains « low » then
dobutamine is added, and/or hydrocortisone.
Laughon et al: the ELGAN study
Total n
No Treatment
n=249
Proportion of
Infants, %
Gestnl
age,
wk
Any Treatment n
= 1138
P = .001
Vasopressor
Treatment
n = 470
P
.0005
23
85
7
93
52
24
246
10
90
47
25
289
16
84
34
26
338
18
82
32
27
429
27
73
25
Variability in « any » Rx
Center
% Treated Lowest MAP d1 OR
(95% CI)
Adjusted OR
(95% CI)
A
29
28
1
1c
B
46
27
2
(1–4)
3
(1–6)
C
61
20
4
(2–7)
5
(2–10)
D
69
24
5
(3–9)
9
(5–18)
E
80
25
9
(5–20)
33
(14–80)
F
85
24
13
(6–27)
25
(11–56)
G
91
23
24
(11–50)
44
(19–102)
H
92
23
26
(13–52)
54
(25–118)
I
93
23
32
(7–145)
84
(17–404)
J
93
25
34
(15–78)
80
(32–203)
K
94
22
37
(16–82)
58
(24–140)
L
94
23
39
(14–106)
92
(31–275)
M
96
26
65
(19–225)
105
(29–385)
N
98
23
116
(27–504)
299
(65–1383)
Variability in inotrope Rx
Center
% Treated Lowest MAP d1 OR
(95% CI)
Adjusted OR
(95% CI)
A
6
19
1
1c
N
12
20
2
(1–6)
3
(1–9)
F
15
21
3
(1–7)
3
(1–10)
M
18
25
3
(1–9)
4
(2–12)
D
20
22
4
(1–10)
5
(2–14)
B
27
37
6
(2–15)
8
(3–22)
H
32
21
7
(3–17)
12
(5–30)
K
38
21
9
(4–22)
11
(4–27)
C
44
19
12
(4–30)
19
(7–52)
J
46
23
13
(5–31)
25
(10–65)
I
48
25
14
(5–42)
34
(11–107)
E
52
24
16
(6–42)
48
(17–132)
G
60
23
22
(9–54)
35
(14–91)
L
64
24
26
(10–67)
61
(23–165)
IVH frequency among VLBW infants, Synnes
et al 2001
Adjusted Odds Ratios Synnes et al 2001
Further analysis of CNN data
BP<Gestational age,
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48% of <28wk “hypotensive” some time during day 1.
15.9% of “hypotensive” infants had a severe IVH.
13.3% of non-“hypotensive” babies had severe IVH.
Statistically significant (p < 0.05): but not very useful!
After correcting for use of inotropes and SNAP-PE
score → no relation between “hypotension” and IVH:
OR 1.19, p=NS.
Mean BP of preterm infants. Watkins et al
1989.
40
38
10 %ile of mean BP
36
500g
600g
700g
800g
900g
1000g
1100g
1200g
1300g
1400g
1500g
34
32
30
28
26
24
22
20
3
12
24
36
48
60
Age (hrs)
72
84
96
Watkins charts
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Using Watkins charts (10%les) 42,5% of the infants <28
were hypotensive
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More strongly associated with severe IVH (16.5% vs
11.4%):
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Why not 10%? Cross sectional not longitudinal data, rapidly
changing variable
Association disappeared after correction for use of inotropes.
Normotensive infants who received inotropes, (n=150)
more had severe IVH (17.9%) than hypotensive infants
who did not receive inotropes (5.9%).
What is hypotension?

Could define
 Statistically,
according to a predefined percentile
 Physiologically, according to a limit shown to be
associated with poorer outcomes
 Operationally, according to a limit below which
treatment improves outcomes
A physiologic definition: Is hypotension
related to survival or long term outcomes?
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Systematic review of the literature, found 16 studies that
looked carefully at this issue
The answer…
Unclear!
The majority of studies have shown some correlation between
lower BP and poor outcomes BUT
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Many excluded the treated infants from the cohort defining norms
then included them when determining harm...
Impossible to determine a threshold for treatment AND
Systematic biases in many of them:
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For example: same BP used as threshold for all infants (Miall-Allen et al 30
mmHg)
If you use the same threshold for everyone, the more immature babies will be
more likely hypotensive, and they have the worse outcomes
Operational defintion: Is there evidence that
treating hypotension improves outcomes?
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Fluid Boluses compared to no intervention
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Inotrope/Pressors compared to no intervention
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Never studied in hypotensive preterm infants
Steroids compared to no intervention
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Never studied in hypotensive preterm infants
Never studied in hypotensive preterm infants
No level 1 or 2 evidence of benefit, level 3 evidence
of harm
Do we know what to treat it with?
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Dopamine versus dobutamine, 5 trials
 Dopamine
more likely to increase BP than dobutamine
Crystalloid versus colloid, 3 trials.
 FFP versus albumin, 1 trial
 Dopamine versus albumin, 2 trials
 Dopamine versus hydrocortisone,1 trial

All were much too small to show a clinically
important difference
 Commonly NO REPORT of clinically important
outcomes.

Do we know what to treat it with?

Steroids in inotrope and fluid treated infants
compared to no additional treatment
4 very small trials
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Example:
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 Preterm
infants with mean BP < GA, all receiving ≥ 10
mg/kg/min of dopamine after ≥30 mL/kg of normal
saline, randomized to 3 mg/kg/d of hydrocortisone for
5 days.
 Hydrocortisone infants had slightly faster decrease in
dopamine dose, but no clinical differences in outcomes

Conclusion giving one toxin decreases the use of
another toxin!
Why are preterm babies ‘hypotensive’?
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No association with hypovolemia

4 studies with measurements of circulating blood volume and blood
pressure
Plots of blood volume against each of the potential explanatory variables. c-pT, Coreperipheral temperature difference; MAP, mean arterial pressure; PCV, packed cell volume.
Aladangady N et al. Arch Dis Child Fetal Neonatal Ed
2004;89:F344-F347
Figure 3 Scatter plot of mean blood pressure (BP) against superior vena cava (SVC) flow for all
observations. Reference lines represent SVC flow of 41 ml/kg/min and mean BP of 30 mm Hg.
Osborn, D A et al. Arch. Dis. Child. Fetal Neonatal Ed. 2004;89:F168-F173
Copyright ©2004 BMJ Publishing Group Ltd.
Physiological responses to current
common treatments?

Fluid boluses
 appear
to increase left ventricular output but not RVO
 Increase ductal shunt: don’t improve systemic perfusion
 Small transient increase in blood pressure

Dopamine
 Increases
BP, almost entirely by vasoconstriction,
decreasing systemic flow

Steroids
 Increase
pressure slowly, by what hemodynamic
mechanism?
LVO & RVO
Age (h)
SVC (mL/kg/min)
Milrinone (n = 42)
Placebo (n = 48)
P value
3‡
7
78 (51, 107)
70 (48, 92)
86 (67, 107)
75 (51, 94)
.2
.8
10
67 (53, 87)
81 (50, 100)
.5
24
88 (73, 101)
93 (72, 121)
.4
3‡
182 (140, 240)
189 (133, 271)
.9
7
177 (147, 258)
187 (140, 240)
.9
10
189 (146, 258)
187 (133, 243)
.4
24
242 (194, 301)
250 (207, 306)
.7
BP (mm Hg)
3‡
31 ± 6
30 ± 3
.4
HR (beats/min)
7
10
24
3‡
7
10
24
28 ± 5
29 ± 4
34 ± 5
149 ± 16
158 ± 15
157 ± 13
153 ± 13
32 ± 6
32 ± 5
36 ± 6
151 ± 17
145 ± 10
141 ± 12
144 ± 14
.001
.004
.2
.6
.001
.001
.003
PDA diameter 3‡
2 ± 0.9
1.9 ± 0.6
.5
(mm)
1.9 ± 0.7
1.9 ± 0.6
1.7 ± 0.8
1.5 ± 0.6
1.4 ± 0.6
0.9 ± 0.7
.001
.001
.001
RVO (mL/kg/min)
Milrinone
clinical trial
7
10
24
Low dose dopamine and the kidney
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No evidence from neonatal animal models that low
dose dopamine increases renal blood flow
One clinical trial also showed no effect
No evidence of beneficial renal effect of low dose
dopamine in critically ill older children or adults
either! (several systematic reviews)
Pituitary effects of dopamine
Dopamine and thyroid suppression in
the newborn
Filippi L, Cecchi A, Tronchin M, Dani C, Pezzati M, Seminara S, et al. Dopamine
infusion and hypothyroxinaemia in very low birth weight preterm infants. Eur J Pediatr
2004 Jan;163(1):7-13.
Low dose dopamine = Pituitary
dose dopamine
Treatment of Hypotension
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So why do people treat?
« Hypotension impairs cerebral perfusion »
« CBF is pressure passive… »
Of course if you go to your family Doc for a
checkup you aren’t likely to be at significant risk of
brain injury with life long consequences! (But you
are at risk of complications from intervention)
Responses to Questionnaire: Canadian
neonatologists

Criteria for diagnosing hypotension:
 74%
use both BP<GA (or another criterion) and clinical
signs to define hypotension.
 26% use BP alone, (most common, BP<GA)
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Volume 1st-- 97%
Dopamine is 1st drug --92%
Three main patterns of treatment
 volume,
dopamine, steroid (37%)
 volume, dopamine, dobutamine(28%)
 volume, dopamine, epinephrine (16%)
Treatments
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Dopamine: starting dose range 2.5-10 mg/kg/min
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maximum dose 10-30
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Dobutamine: starting dose range 2-10 mg/kg/min
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
maximum dose 10-20
Epinephrine: starting dose 0.01-0.1 mg/kg/min
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The maximum dose for 7 respondents is the initial starting dose for 17
others.
maximum dose 0.3-4.0
Usual corticosteroid = hydrocortisone (98%).
Initial doses varied 0.1–5 mg/kg/dose
Total daily doses range from 0.4-15 mg/kg/day.
Retrospective cohort study
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118 ELBW patients admitted 2000-2003. BP data
were available on 107, 53% of patients had BP <
GA.
18/118 ELBW infants received treatment for
Hypotension:
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11 received only an epinephrine infusion,
4 had only a single fluid bolus (saline 10 ml/kg), and
3 had a fluid bolus followed by epinephrine infusion.
4 other Hypotensive infants received only a blood
transfusion, over 2 hr, as therapy.
Normotensive
Permissive
hypotension
Treated
Hypotension
Number
52
34
18
Birth weight grams,
mean (SD)
828 (144)^
742 (131)
728 (149)
Gestation weeks,
mean (SD)
26.6 (1.6)
26.1 (1.6)
25.2 (1.6)*
Crib II score,
median (range)
11 (7-18)
11 (8-16)
15 (9-16)*
BP @ 6hr mmHg
mean (range)
32 (25-49)^
26(16-62)
22 (14-34)*
BP @ 12hr mmHg
(range)
34 (27-72)^
27(17-35)
22 (12-32)*
BP @18hr mmHg
(range)
33 (26-65)^
30 (20-37)
24 (13-33)*
BP @ 24hr mmHg
(range)
35 (25-54)^
31(22-41)
28 (16-36)*
Antenatal steroid
(%)
71
82
65
Normotensive
Permissive
hypotension
Treated
Hypotension
Number
52
34
18
Necrotizing
enterocolitis,
n (%)
4 (8%)
3 (9%)
2 (11%)
Surgical NEC, n
1
1
1
Isolated GI
perforation, n
2
0
1
IVH 3 or 4, n
2
4
5
Cystic PVL, n
1
0
0
Mortality, n
10
4
13*
Survival without
severe IVH,
cystic PVL,
surgical NEC,
or GI
perforation, n
(%)
40 (77%)
26 (76%)
4* (22%)
Blood Pressure
Hypotension or shock?
DO2/VO2
Conclusion
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
Very little good data to support evidence based guidelines
Do we need to treat Hypotension, or should we be treating
Shock?
Hypotensive babies who are clinically well perfused may not
need any treatment
Babies with poor perfusion do badly, individualizing the
interventions, by measurements of relevant physiologic
endpoints such as blood flow, serum lactate, brain perfusion or
activity etc. may help us to improve care, but this needs to be
proven.
Hypotension in Preterm Infants

What is hypotension?
 No

clear definition
Why do we worry about it?
 Not

Why are babies hypotensive?
 In

general because they have low vascular resistance
Is there evidence that hypotension needs treating?
 Not

clear that we should
really
Do we know what to treat it with?
 No
The HIP trial
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Succesful FP7 application, PI Gene Dempsey,
RCT of 800 infants less than 28 weeks
Masked trial, dopamine or placebo
If max study drug dose reached further treatment
only if signs of poor perfusion
If signs of poor perfusion during treatment, rescue
Primary outcome survival without serious brain injury
Co-primary outcome: survival without
neurodevelopmental impairment to 2 years CA.