Cochrane Database of Systematic Reviews (Reviews) || Vasopressin and its analogues for the treatment of refractory hypotension in neonates

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Vasopressin and its analogues for the treatment of refractory

hypotension in neonates (Review)

Shivanna B, Rios D, Rossano J, Fernandes CJ, Pammi M

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2013, Issue 3

http://www.thecochranelibrary.com

Vasopressin and its analogues for the treatment of refractory hypotension in neonates (Review)

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

http://www.thecochranelibrary.com

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

8DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

8AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

9REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

11CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

13DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

13HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

13CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

13DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

13SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

13INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iVasopressin and its analogues for the treatment of refractory hypotension in neonates (Review)


[Intervention Review]

Vasopressin and its analogues for the treatment of refractoryhypotension in neonates

Binoy Shivanna1, Danielle Rios1 , Joseph Rossano2 , Caraciolo J Fernandes1, Mohan Pammi1

1Section of Neonatology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA. 2The Children’s Hospital of

Philadelphia, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA

Contact address: Mohan Pammi, Section of Neonatology, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza,

Houston, Texas, 77030, USA. [email protected]. [email protected].

Editorial group: Cochrane Neonatal Group.

Publication status and date: New, published in Issue 3, 2013.

Review content assessed as up-to-date: 15 July 2012.

Citation: Shivanna B, Rios D, Rossano J, Fernandes CJ, Pammi M. Vasopressin and its analogues for the treatment

of refractory hypotension in neonates. Cochrane Database of Systematic Reviews 2013, Issue 3. Art. No.: CD009171. DOI:

10.1002/14651858.CD009171.pub2.


A B S T R A C T

Background

Neonatal hypotension that is refractory to volume expansion, catecholamines, or corticosteroids has a mortality of about 50%. Opti-

mization of blood pressure and tissue perfusion in refractory hypotension may be crucial to improve clinical outcomes. Vasopressin, a

neuropeptide hormone, or its analogue terlipressin has been used to treat refractory hypotension in neonates and may be effective.

Objectives

Our primary objective was to evaluate the efficacy and safety of vasopressin and its synthetic analogues (e.g. terlipressin) in decreasing

mortality and adverse neurodevelopmental outcomes, and improving survival in neonates with refractory hypotension. Our secondary

objectives were to determine the effects of vasopressin and its analogues (terlipressin) on improvement in blood pressure, increase in

urine output, decrease in inotrope score, necrotizing enterocolitis (NEC), periventricular leukomalacia, intraventricular hemorrhage,

chronic lung disease, and retinopathy of prematurity (ROP) in neonates with refractory hypotension.

Search methods

We searched the literature in January 2012, using the search strategy recommended by the Cochrane Neonatal Group. We searched

electronic databases (CENTRAL (The Cochrane Library), MEDLINE, CINAHL, EMBASE), abstracts of the Pediatric Academic

Societies, web sites for registered trials at www.clinicaltrials.gov and www.controlled-trials.com and in the reference list of identified

articles.

Selection criteria

Randomized or quasi-randomized trials evaluating vasopressin or its analogues, at any dosage or duration used as an adjunct to standard

therapy (any combination of volume expansion, inotropic agents and corticosteroids) to treat refractory hypotension in neonates.

Data collection and analysis

We followed the standard methods of The Cochrane Collaboration for conducting a systematic review. Two review authors (BS and

MP) independently assessed the titles and abstracts of studies identified by the search strategy for eligibility for inclusion. We obtained

the full text version if eligibility could not be done reliably by title and abstract. We resolved any differences by mutual discussion.

We designed electronic forms for trial inclusion/exclusion, data extraction, and for requesting additional published information from

authors of the original reports.

1Vasopressin and its analogues for the treatment of refractory hypotension in neonates (Review)


mailto:[email protected]

mailto:[email protected]

http://www.clinicaltrials.gov

http://www.controlled-trials.com


Main results

Our search did not identify any completed or ongoing trials that met our inclusion criteria. Three studies that did not include neonates

and one study where the objective was not to treat neonates with refractory hypotension were excluded.

Authors’ conclusions

There is insufficient evidence to recommend or refute the use of vasopressin or its analogues in the treatment of refractory hypotension

in neonates. Well-designed, adequately powered, randomized controlled studies are necessary to address efficacy, optimal dosing, safety

and long-term neurodevelopmental and pulmonary outcomes.

P L A I N L A N G U A G E S U M M A R Y

Vasopressin and its analogues for the treatment of refractory hypotension in neonates

Hypotension or low blood pressure occurs frequently in newborn infants after infection or surgery or in very preterm infants. Sometimes,

the hypotension does not respond to fluids or other drug such as catecholamines or steroids. In those unresponsive infants, vasopressin

may be useful in improving blood pressure and overall survival. We searched the literature for studies that used vasopressin or its

analogue terlipressin in the newborn in the first 28 days of life for unresponsive hypotension. We found no ongoing or completed

studies. Currently there is no evidence to recommend the use of vasopressin or terlipressin, but we recommend that studies be carried

out in the future to study the effectiveness and safety in unresponsive hypotension in newborn infants.

B A C K G R O U N D

Description of the condition

Hypotension is a significant problem in preterm, septic, and post-

surgical neonates. Symptomatic hypotension (hypotension requir-

ing treatment) is associated with significant morbidity. In a case-

control study of 156 extremely low birth weight infants (ELBW,

birth weight less than 1000 g), symptomatic hypotension in the

first 72 hours of life was associated with a severe grade of intraven-

tricular hemorrhage (IVH), higher mortality, increased hearing

loss, and adverse neurodevelopmental outcomes (Fanaroff 2006).

In preterm infants, hypotension may be associated with neonatal

cerebral injury resulting in adverse long-term neurodevelopmental

outcomes (Low 1993; Goldstein 1995).

Normal blood pressure is defined by blood pressure between the 10th and 90th percentiles that are appropriate for postmenstrual age

(Nuntnarumit 1999). The 10th percentile for the mean blood pres-

sure approximately equals the gestational age in the first 48 hours

of life (Hegyi 1994). Impairment of cerebral blood flow and associ-

ated cerebral injury at mean blood pressures of less than 30 mmHg

has been reported, which has prompted some neonatologists to

treat neonates with a mean BP below this threshold (Miall-Allen

1987; Tsuji 2000; Munro 2004). Therapeutic measures for neona-

tal hypotension include volume expansion (bolus of crystalloids

or colloids), inotropic agents (catecholamines: dopamine, dobu-

tamine, epinephrine or rarely norepinephrine) and corticosteroids

(hydrocortisone or dexamethasone) (Pladys 1999; Al-Aweel 2001;

Seri 2001; Dempsey 2006). Strong evidence to support one ther-

apy over the other for the treatment of neonatal hypotension is

lacking. Evidence is insufficient not only regarding the use of

fluid boluses in the treatment of neonatal hypotension, but also

with the type of fluid used (colloid or crystalloid) (Osborn 2004).

Dopamine increases mean blood pressure better than fluid bo-

luses (Osborn 2001) or dobutamine (Subhedar 2003), but it does

not decrease mortality or adverse neurodevelopmental outcomes.

The efficacy of epinephrine (Paradisis 2004) and corticosteroids

(Subhedar 2007) in the treatment of neonatal hypotension in im-

proving the outcomes of mortality or adverse neurodevelopmental

outcomes is yet to be proven.

Refractory hypotension in the newborn is defined as a hypotension

with signs of inadequate perfusion despite volume expansion and

administration of inotropic agents and/or corticosteroids (Sarkar

2007; Baker 2008; Bidegain 2010). Refractory hypotension has an

estimated mortality of about 50% (Bidegain 2010; Meyer 2006a;

Meyer 2006b) and can result in significant morbidity in critically

ill neonates (Meyer 2006b; Rodriguez-Nunez 2006; Leone 2008).

Therefore, optimization of blood pressure and tissue perfusion in

refractory hypotension may be crucial to improve clinical out-

comes.



Description of the intervention

Arginine vasopressin (AVP) is a neuropeptide hormone secreted

by the posterior pituitary that regulates sodium homeostasis and

serum osmolality. AVP is released into the circulation in response

to high plasma osmolality or as a baroreceptor response to hypo-

volemia. In health, AVP secretion is tightly regulated by changes

in serum osmolality. In contrast, the baroreceptor-mediated regu-

lation of AVP secretion is regulated by a fall in blood pressure (>

10%) (Mutlu 2004).

Terlipressin, tri-cycl-lysine-vasopressin, is a synthetic long-acting

analogue of AVP. Terlipressin has a higher affinity for vascular

receptors and similar pharmacodynamic properties compared to

AVP. Terlipressin is a prodrug that is rapidly metabolized by en-

dothelial peptidases to the vasoactive lysine-vasopressin. The half-

life of terlipressin is six hours compared to the short half-life of

AVP (six minutes). The pharmacokinetics of terlipressin suggests

that an intermittent intravenous dosing schedule of every four to

12 hours would be appropriate, as opposed to continuous infusion

of AVP (Pesaturo 2006).

The adverse effects of AVP and terlipressin therapy in human

neonates and infants have not been investigated thoroughly. Liver

necrosis after AVP (Meyer 2006a), and splanchnic, digital and skin

ischemia with terlipressin have been reported (Rodriguez-Nunez

2006; Zeballos 2006).

How the intervention might work

AVP mediates the cardiovascular and renal effects via at least three

known receptor subtypes (V1, V2 and V3). AVP exerts a di-

rect vasoconstrictive effect by acting on the V1 receptors that are

predominantly found on vascular smooth muscle cells and my-

ocardium. V1 receptors are also found on the hepatocytes and

platelets, which may result in platelet aggregation and glycogenol-

ysis during AVP therapy. The receptors are linked to a phospho-

inositol signaling pathway with intracellular calcium acting as a

second messenger (Holmes 2001). Other probable indirect effects

of AVP on vascular smooth muscle cells leading to vasoconstric-

tion include local inhibition of nitric oxide production (Kusano

1997) and inhibition of smooth muscle cell K+-ATP channels

(Wakatsuki 1992). When compared with AVP, terlipressin has a

greater selectivity for the V1 receptor over the V2 receptor (Nilsson

1990). The rationale for using AVP or terlipressin in refractory

hypotension is based on a biphasic response of endogenous AVP in

adults with septic shock, with initial high levels followed by inap-

propriately low levels (Argenziano 1998; Patel 2002). Therefore,

in vasodilatory shock, a relative AVP deficiency exists that may be

corrected by administration of AVP. Currently, AVP and its ana-

logue, terlipressin, are being increasingly used as a rescue therapy

for hypotension refractory to high-dose catecholamine and cor-

ticosteroids in neonates with sepsis (Matok 2004; Matok 2005;

Leone 2008; Bidegain 2010), cardiogenic shock (Meyer 2006b;

Lechner 2007), necrotizing enterocolitis (NEC) (Bidegain 2010),

non-septic shock with acute renal injury (Meyer 2006a), and sys-

temic inflammatory response syndrome following surgery (Filippi

2008). In neonatal studies, dosages of AVP ranged between 0.01

to 0.36 units/kg/hour, and terlipressin from 7 µg/kg twice a day

to 2 µg/kg every four hours. Terlipressin increases the mean blood

pressure by approximately 30% in neonates and infants. The ef-

fect was more pronounced in patients who survived than in those

who died (Matok 2005; Leone 2008).

Why it is important to do this review

Optimal management of refractory hypotension in high-risk

neonates has the potential to improve neonatal outcomes. This re-

view aims to systematically review the literature to investigate the

roles of vasopressin and terlipressin in the treatment of refractory

hypotension in neonates and to identify gaps in knowledge that

will inform future clinical trials.

O B J E C T I V E S

Primary objective

To evaluate the efficacy and safety of vasopressin and its syn-

thetic analogues (e.g. terlipressin) in decreasing mortality and ad-

verse neurodevelopmental outcomes, and improving survival in

neonates with refractory hypotension.

Secondary objectives

To determine the effects of vasopressin and its analogues (terli-

pressin) on improvement in blood pressure, increase in urine out-

put, decrease in inotrope score (Wernovsky 1995; Lechner 2007),

NEC, periventricular leukomalacia (PVL), IVH, chronic lung dis-

ease (CLD), and retinopathy of prematurity (ROP) in neonates

with refractory hypotension.

We planned to analyze the following subgroups if data had been

available.

1. Gestational age:

• term;

• preterm (28 to 37 weeks);

• extremely preterm (less than 28 weeks).

2. Birth weight:

• birth weight more than 2500 g;

• birth weight from 1000 to 2500 g;

• ELBW less than 1000 g.

3. Patient subgroups:



• sepsis;

• post-cardiac surgery;

• NEC.

4. Subgroups of intervention:

• vasopressin;

• terlipressin.

5. Severity of hypotension:

• catecholamine-resistant hypotension;

• catecholamine and steroid-resistant hypotension.

Comparisons

1. Vasopressin and its analogues in the treatment of refractory

hypotension in neonates as an adjunct to standard therapy versus

standard therapy alone (combination of volume expansion,

catecholamines and corticosteroids).


hypotension in neonates as an adjunct to therapy with

catecholamines and corticosteroids versus catecholamine and

corticosteroids.


hypotension in neonates as an adjunct to catecholamines versus

catecholamines alone.


hypotension in neonates as an adjunct to corticosteroids versus

corticosteroids alone.


hypotension in neonates as an adjunct to volume expansion

versus volume expansion alone.

M E T H O D S

Criteria for considering studies for this review

Types of studies

Randomized or quasi-randomized controlled trials, cluster-ran-

domized trials or randomized cross-over trials.

Types of participants

Any neonate (less than 28 days of age), term or preterm, with

refractory hypotension. Refractory hypotension in the newborn

is defined as a hypotension with signs of metabolic and lactic

acidemia despite volume expansion and administration of in-

otropic agents and corticosteroids (Sarkar 2007; Baker 2008;

Bidegain 2010).

Types of interventions

Vasopressin and its analogue terlipressin at any dosage or duration

used as an adjunct to standard therapy to treat refractory hypoten-

sion in neonates.

Standard therapy of neonatal hypotension is any combination of

volume expansion, inotropic agents and corticosteroids.

Types of outcome measures

Primary outcomes

1. Efficacy as measured by any of the following:

i) mortality: ’all-cause mortality’ during hospital stay.

ii) survival at 18 or more months of age.

iii) neurodevelopmental outcome assessed by a validated

test at 18 or more months of age.

Secondary outcomes

i) Increase in mean blood pressure greater than the 10th

percentile for the postmenstrual age (Nuntnarumit 1999) OR

increase in mean blood pressure greater than 30 mm Hg in

preterm infants, irrespective of their postmenstrual age

(Miall-Allen 1987).

ii) Increase in urine output greater than 1 ml/kg/hour

over eight hours.

iii) Decrease in inotrope requirements as determined by

inotrope score. Scores calculated before and after vasopressin

therapy of at least 30 minutes. Inotrope score = dopamine +

dobutamine + epinephrine x 100 + norepinephrine x 100, all

dosages in micrograms per kilogram per minute (Wernovsky

1995; Lechner 2007).

iv) NEC (definite NEC and perforated NEC, Bell’s stage

II or III) (Bell 1978).

v) CLD defined as oxygen requirement at 36 weeks

postmenstrual age (Jobe 2001).

vi) PVL (defined as necrosis of white matter in a

characteristic distribution, i.e., in the white matter dorsal and

lateral to the external angles of lateral ventricles involving

particularly the centrum semi ovale, optic and acoustic radiations

and diagnosed by magnetic resonance imaging (MRI) (Volpe

2008).

vii) IVH- severe grade III or IV (Papile 1978).

viii) ROP stages III and IV (ICROP 1984).

ix) Safety: Monitored for adverse effects of hyponatremia

(serum sodium (Na) less than 130 mEq/L), limb and skin

ischemia (evaluated clinically by mottling or discoloration),

myocardial ischemia (EKG changes or elevation of cardiac

enzymes CPK-MB or troponins).



Search methods for identification of studies

We searched the literature using the search strategy recommended

by the Cochrane Neonatal Group (CNRG), in January 2012 from

the following sources.

1. The Cochrane Central Register of Controlled Trials

(CENTRAL, The Cochrane Library).2. Electronic journal reference databases: MEDLINE (1966 to

present) and PREMEDLINE, EMBASE (1980 to January

2012), CINAHL (1982 to January 2012).

3. We searched for ongoing trials in the following databases at

the following web sites: www.clinicaltrials.gov and

www.controlled-trials.com.

4. We searched abstracts of conferences - proceedings of

Pediatric Academic Societies (American Pediatric Society, Society

for Pediatric Research and European Society for Pediatric

Research) from 1990 from the journal ’Pediatric Research’ and

Abstracts online.

5. We contacted authors who published in this field for

possible unpublished articles.

6. We also searched from the reference list of identified clinical

trials and in the review authors’ personal files.

Search strategy for MEDLINE and PREMEDLINE. We adapted

this strategy to suit EMBASE, CINAHL and the Cochrane Con-

trolled Trials Register.

# 1 explode ’hypotension’ [all subheadings in MIME, MJME]

# 2 explode “shock’

# 3 ‘refractory hypotension”

# 4 “catecholamine refractory hypotension”

# 5 ’hypoperfusion’

# 6 # 1 or # 2 or # 3 or # 4 or # 5

# 7 explode ’infant - newborn’ [all subheadings in MIME, MJME]

# 8 Neonat*

# 9 Newborn*

# 10 # 7 or # 8 or # 9

# 11 # 6 and # 10

# 12 “vasopressin’ or pitressin [all subheadings on MIME, MJME]

# 13 terlipressin or glypressin or glycylpressin or remestyp

# 14 # 12 or # 13

# 15 # 11 and # 14

We did not apply language restriction. We sought randomized,

quasi-randomized trials, cluster-randomized and cross-over trials

from the search results.

Data collection and analysis

We followed the standard methods of The Cochrane Collabora-

tion for conducting a systematic review.

Selection of studies

Two review authors (BS and MP) independently assessed the titles

and abstracts of studies identified by the search strategy for eligi-

bility for inclusion in this review. We obtained the full text version

for assessment, if eligibility could not be assessed reliably by title

and abstract. We resolved any differences by mutual discussion.

We obtained a full text version of all eligible studies for quality

assessment.

Data extraction and management

We designed electronic forms for trial inclusion/exclusion, data

extraction and for requesting additional published information

from authors of the original reports. Two review authors (MP and

BS) performed data extraction independently using specifically

designed electronic spreadsheets. We resolved any differences by

mutual discussion.

Assessment of risk of bias in included studies

There are no included studies in this version of the review. For fu-

ture updates of this review, two review authors will independently

assess the risk of bias for each study when studies for inclusion

are identified, using the criteria outlined in the Cochrane Hand-book for Systematic Reviews of Interventions (Higgins 2011). Any

disagreement will be resolved by discussion with the third review

author (CF).

(1) Sequence generation (checking for possible selection

bias)

If we identify studies that can be included, we will evaluate whether

the method used to generate the allocation sequence was described

in sufficient detail to allow an assessment of whether it should

produce comparable groups. We will assess the methods as:

• low risk (any truly random process, for example, random

number table; computer random number generator);

• high risk (any non-random process, for example, odd or

even date of birth; hospital or clinic record number);

• unclear risk.

(2) Allocation concealment (checking for possible selection

bias)

If we identify studies that can be included, we will evaluate whether

the method used to conceal the allocation sequence was described

in sufficient detail and determine whether intervention allocation

could have been foreseen in advance of, or during recruitment, or

changed after assignment. We will assess the methods as:

• low risk (for example, telephone or central randomization;

consecutively numbered sealed opaque envelopes);

• high risk (open random allocation; unsealed or non-opaque

envelopes, alternation; date of birth);

• unclear risk.



http://www.clinicaltrials.gov



(3) Blinding (checking for possible performance bias)

If we identify studies that can be included, we will describe the

methods used, if any, to blind study participants and personnel

from knowledge of which intervention a participant received. We

will judge studies to be at low risk of bias if they were blinded, or

if we judge that the lack of blinding could not have affected the

results. We will assess blinding separately for different outcomes

or classes of outcomes. We will assess the methods as:

• low risk, high risk or unclear risk for participants;

• low risk, high risk or unclear risk for personnel;

• low risk, high risk or unclear risk for outcome assessors.

(4) Incomplete outcome data (checking for possible attrition

bias through withdrawals, dropouts, protocol deviations)

If we identify studies that can be included, we will evaluate the

completeness of data including attrition and exclusions from the

analysis. We will state whether attrition and exclusions are re-

ported, the numbers included in the analysis at each stage (com-

pared with the total randomized participants), reasons for attrition

or exclusion where reported, and whether missing data are bal-

anced across groups or are related to outcomes. Where sufficient

information is reported, or can be supplied by the trial authors, we

will re-include missing data in the analyses. We will assess methods

as:

• low risk;

• high risk:

• unclear risk.

(5) Selective reporting bias

If we identify studies that can be included, we will investigate the

possibility of selective outcome reporting bias. We will assess the

methods as:

• low risk (where it is clear that all of the study’s pre-specified

outcomes and all expected outcomes of interest to the review

have been reported);

• high risk (where not all the study’s pre-specified outcomes

have been reported; one or more reported primary outcomes were

not pre-specified; outcomes of interest are reported incompletely

and so cannot be used; study fails to include results of a key

outcome that would have been expected to have been reported);

• unclear risk.

(6) Other sources of bias

If we identify studies that can be included, we will describe any

important concerns we had about other possible sources of bias.

We will assess whether each study was free of other problems that

could put it at risk of bias:

• yes;

• no;

• unclear risk.

(7) Overall risk of bias

We will evaluate the studies using all of the above criteria and

make explicit judgements about whether studies are at high risk

of bias. With reference to (1) to (6) above, we will assess the likely

magnitude and direction of the bias and whether we consider it

likely to impact on the findings.

If cross-over or cluster-randomized trials are included in future

updates of the review, then risk of bias will be assessed as outlined

in the Cochrane Handbook for Systematic Reviews of Interventions(Higgins 2011).

Measures of treatment effect

We will perform statistical analyses according to the recommen-

dations of the CNRG when data are available. We will analyze all

infants randomized on ’an intention-to-treat basis’ irrespective of

whether they survived or not, to receive their allocated treatment

completely. We will analyze treatment effects in the individual tri-

als, using The Cochrane Collaboration’s statistical analysis pack-

age, Review Manager 5.1 (RevMan 2011).

We will report risk ratio (RR) and risk difference (RD) with 95%

confidence intervals (CIs) for dichotomous outcomes and mean

differences (MD) for continuous outcomes. With outcomes such

as neurodevelopmental outcomes where different scales may be

used to measure outcomes, we will report standard MD. If there

was a statistically significant reduction in RD then we will calculate

the number needed to treat to benefit (NNTB) or number needed

to harm (NNTH). We will use a fixed-effect model for meta-

analysis.

If cross-over or cluster-randomized trials are included in future

updates of the review, then measures of treatment effect will be

assessed as outlined in the Cochrane Handbook for Systematic Re-views of Interventions (Higgins 2011).

Assessment of heterogeneity

We will assess statistical heterogeneity of treatment effects between

trials using the I 2 statistic (RevMan 2011). We will grade degrees

of heterogeneity as low (greater than 25%), moderate (greater than

50%) or high (greater than 75%). If significant heterogeneity is

noted then we will explore sources of heterogeneity by subgroup

or sensitivity analyses.

Data synthesis

We will use RevMan 5.1 software (RevMan 2011) for statistical

analysis and intend to use a fixed-effect model for meta-analysis

when eligible trials are identified.



Subgroup analysis and investigation of heterogeneity

i) Gestational age: term, preterm (28 to 37 weeks),

extremely preterm (less than 28 weeks).

ii) Birth weight: birth weight greater 2500 g, BW 1000

to 2500 g, ELBW less than 1000 g.

iii) Patient subgroups: sepsis, post-cardiac surgery, NEC.

iv) Subgroups of intervention: vasopressin, terlipressin.

v) Severity of hypotension: catecholamine-resistant

hypotension, catecholamine- and steroid-resistant hypotension.

Comparisons

i) Vasopressin and its analogues in the treatment of

refractory hypotension in neonates as an adjunct to standard

therapy versus standard therapy alone (combination of volume

expansion, catecholamines and corticosteroids).

ii) Vasopressin and its analogues in the treatment of

refractory hypotension in neonates as an adjunct to therapy with

catecholamines and corticosteroids versus catecholamine and

corticosteroids.

iii) Vasopressin and its analogues in the treatment of

refractory hypotension in neonates as an adjunct to

catecholamines versus catecholamines alone.

iv) Vasopressin and its analogues in the treatment of

refractory hypotension in neonates as an adjunct to

corticosteroids versus corticosteroids alone.

v) Vasopressin and its analogues in the treatment of

refractory hypotension in neonates as an adjunct to volume

expansion versus volume expansion alone.

R E S U L T S

Description of studies

See: Characteristics of excluded studies.

Results of the search

We identified three randomized controlled trials of vasopressin

(Baldasso 2009; Choong 2009; Rios 2011) and one on terlipressin

(Yildizdas 2008) in children. None of the studies met our inclusion

criteria. We excluded the studies because there were no neonates

in the study population in three studies (Yildizdas 2008; Baldasso

2009; Choong 2009) and treatment of refractory hypotension was

not the objective of one study (Rios 2011).

Included studies

There are no included studies.

Excluded studies

Baldasso 2009

Baldasso and co-investigators evaluated the effects of prophylactic

low-dose vasopressin to offset the hypotensive effects of sedation

and analgesia in children expected to require mechanical venti-

lation for more than three days. Twenty-four children were ran-

domized to low-dose vasopressin (0.0005 units/kg/min) or nor-

mal saline for a period of 48 hours (12 in each group). Vasopressin

infusion was associated with a higher incidence of hyponatremia,

decrease in urine output and acute increase in blood pressure. Re-

bound hypotension was also noticed after stopping vasopressin.

This study was excluded as neonates were not included.

Choong 2009

Choong and co-investigators randomized 69 children in vasodila-

tory shock in a multicenter, double-blind trial to low-dose vaso-

pressin (0.0005 to 0.002 units/kg/min) or placebo. Data from 65

children (33 received vasopressin and 32 placebo) were analyzed.

There was no significant difference in the primary outcome of

time to vasoactive-free hemodynamic stability or the secondary

outcomes of mortality (a trend towards increased mortality in the

vasopressin group), organ failure-free days, length of critical care

unit stay or adverse events. This study was excluded as neonates

were not included.

Yildizdas 2008

Yildizdas and co investigators randomized 58 children (age range

one to 156 months) with catecholamine-resistant septic shock to

receive either terlipressin (n = 30) or additional catecholamines (n

= 28). Terlipressin was administered as intravenous bolus doses of

20 micrograms/kg every six hours if necessary (mean arterial blood

pressure was lower than 2 SD (standard deviation)) for a maximum

of 96 hours. A combination of at least two catecholamines were

administered to all patients in both groups. The outcomes assessed

were mean arterial pressure, heart rate, PaO2/FiO2 ratio, duration

of mechanical ventilation, blood urea nitrogen, creatinine, alanine

aminotransferase, aspartate aminotransferase, urine output, cuta-

neous and extremity ischemia findings, length of stay, and mor-

tality. Terlipressin improved mean blood pressure and oxygena-

tion 30 minutes after each terlipressin treatment but not mortal-

ity rate, urine output, or the duration of mechanical ventilation.

Terlipressin use was not associated with any adverse events in this

study. This study was excluded as neonates were not included.

Rios 2011

Rios and co-investigators, in a double-blind randomized con-

trolled trial at a single center (Texas Children’s Hospital) are inves-

tigating the role of vasopressin compared with dopamine for the

treatment of low blood pressure in ELBW infants. ELBW infants

with a birth weight of < 1001 g and/or gestational age of < 29

weeks, who have hypotension in the first 24 hours of life will be

randomized to either a continuous infusion of vasopressin at low,

moderate or high doses (0.01 to 0.04 units/kg/hour) or dopamine

at low, moderate or high doses (5 to 20 mcg/kg/minute), titrated

to target an optimal mean blood pressure value. Outcomes that



will be evaluated are achievement of optimal mean blood pressure

(primary), ’all-cause mortality’, heart rate, serum lactate, sodium

and glucose levels, urine output, ischemic changes, feeding in-

tolerance, necrotizing enterocolitis (NEC), intestinal perforation,

severity of lung disease, symptomatic patent ductus arteriosus, se-

vere retinopathy of prematurity (ROP), chronic lung disease, in-

traventricular hemorrhage, periventricular leukomalacia, and neu-

rodevelopmental outcomes. The study started enrolling in March

2011 is expected to complete recruitment in 2013. This study was

excluded as the objective of this study was not to treat neonates

with refractory hypotension.

Risk of bias in included studies

We did not identify any eligible studies for inclusion.

Effects of interventions

We did not identify any eligible studies for inclusion.

D I S C U S S I O N

We did not identify any completed or ongoing studies that met

our inclusion criteria that randomized neonates with refractory

shock to vasopressin or its analogues. We identified and excluded

three randomized controlled studies in children but not neonates

(Yildizdas 2008; Baldasso 2009; Choong 2009) and one ongoing

randomized controlled study in neonates where the objective was

not to treat neonates with refractory hypotension (Rios 2011).

The randomized controlled trial (Yildizdas 2008) that included

children with an age range of one to 156 months suggests that

terlipressin can be safely used to increase the mean blood pressure

in children with catecholamine-resistant septic shock. Limitations

of this study include small sample size and risk of performance

bias as the investigators were not blinded to the intervention. Even

though terlipressin increased the mean blood pressure, improved

oxygenation, and decreased the length of pediatric intensive care

unit stay, it had no effects on mortality.

Challenges in summarizing data on vasopressin or terlipressin

therapy in neonates include variations in the dose and duration

of therapy and the heterogeneous study population in terms of

gestational age and underlying disease. Absence of randomized

controlled trials complicates unbiased assessment of clinical out-

comes including adverse effects. The evidence for the use of va-

sopressin and terlipressin in neonates is limited to case reports

(Matok 2004; Filippi 2008; Stathopoulos 2011) and case se-

ries (Matok 2005; Meyer 2006a; Meyer 2006b; Lechner 2007;

Leone 2008; Mastropietro 2008; Bidegain 2010; Ikegami 2010;

Rodriguez-Nunez 2010;Filippi 2011; Alten 2012). Vasopressin

and terlipressin were predominantly used to rescue neonates with

catecholamine-resistant and catecholamine- and corticosteroid-re-

sistant hypotension caused by sepsis (Matok 2004; Matok 2005;

Meyer 2006b; Bidegain 2010; Rodriguez-Nunez 2010; Filippi

2011), NEC (Bidegain 2010), post cardiac surgery (Lechner

2007; Mastropietro 2008; Alten 2012), systemic inflammatory re-

sponse syndrome (Filippi 2008), refractory pulmonary hyperten-

sion (Filippi 2011; Stathopoulos 2011), and acute kidney injury

(Meyer 2006a). The observations from the above studies suggest

that vasopressin and its analogue, terlipressin, can effectively in-

crease mean blood pressure both in extremely preterm and term

neonates with catecholamine-resistant shock.

Vasopressin or terlipressin-mediated increase in mean blood pres-

sure has not shown to be accompanied by improved survival or in-

creased end-organ perfusion. It is possible that vasopressin or ter-

lipressin were administered to rescue severely moribund neonates

late in the disease process. A trend towards increased mortality was

observed in children on low-dose vasopressin despite excluding

children who were terminally ill or who lacked commitment to life

support (Choong 2009). Vasopressin did not consistently improve

markers of end-organ perfusion, such as serum lactate, creatinine

or urine output and the effects were variable (Matok 2004; Matok

2005; Meyer 2006a; Lechner 2007; Filippi 2008; Mastropietro

2008; Bidegain 2010; Filippi 2011; Alten 2012). The ability of

terlipressin and vasopressin to decrease the inotrope score (Lechner

2007; Mastropietro 2008) and the need for catecholamines

(Matok 2005; Lechner 2007; Filippi 2008; Mastropietro 2008;

Bidegain 2010; Rodriguez-Nunez 2010; Filippi 2011) have been

reported. If this is found to be true in well-designed studies, vaso-

pressin or terlipressin can decrease the side-effects associated with

high-dose catecholamine therapy, such as arrhythmias, increased

myocardial oxygen consumption, and severe vasoconstriction.

Adverse effects of vasopressin and terlipressin have been re-

ported in some neonatal studies and include hyponatremia (Filippi

2011; Stathopoulos 2011; Alten 2012), cutaneous/limb ischemia

(Rodriguez-Nunez 2010), and liver necrosis (Meyer 2006a). Va-

sopressin or terlipressin use in neonates has not been associated

with NEC (Matok 2004; Meyer 2006a; Alten 2012). The safety

of vasopressin and its analogues needs to be assessed in prospective

randomized controlled studies in neonates. Given the limited ex-

perience with the use of vasopressin and its analogues in neonates,

it is not surprising that we could not find studies evaluating the

effects of vasopressin or terlipressin on the neurodevelopmental

outcomes, chronic lung disease, grade III or IV intraventricular

hemorrhage, periventricular leukomalacia, and ROP. Further re-

search is needed to clarify the role of vasopressin and its analogues

in neonatal refractory hypotension.

A U T H O R S ’ C O N C L U S I O N S



Implications for practice

There is insufficient evidence to recommend or refute the use

of vasopressin or its analogue, terlipressin, in the safe and effec-

tive treatment of refractory hypotension in neonates. Importantly,

there is no information about the long-term neurodevelopmental

or pulmonary outcomes of neonates treated with vasopressin or

terlipressin.

Implications for research

Well-designed , adequately powered, randomized controlled stud-

ies are necessary to clarify the role of vasopressin and its analogues

in neonatal refractory hypotension. Specifically, studies should ad-

dress the efficacy, safety, indications for their use, timing of ther-

apy, optimal dosing, impact of treatment on major morbidities in

preterm infants such as necrotizing enterocolitis, intraventricular

hemorrhage, periventricular leukomalacia, retinopathy of prema-

turity, and especially long-term neurodevelopmental, pulmonary

outcomes and survival.

R E F E R E N C E S

References to studies excluded from this review

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Baldasso E, Garcia PC, Piva JP, Branco RG, Tasker RC. Pilot

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Choong 2009 {published data only}

Choong K, Bohn D, Fraser DD, Gaboury I, Hutchison JS,

Joffe AR, et al.Vasopressin in pediatric vasodilatory shock: a

multicenter randomized controlled trial. American Journal

of Respiratory and Critical Care Medicine 2009;180(7):

632–9.

Rios 2011 {unpublished data only}

Rios DR, Gest AL. Study of dopamine versus vasopressin

for treatment of low blood pressure in low birth weight

infants. ClinicalTrials.gov 2011:NCT01318278.

Yildizdas 2008 {published data only}

Yildizdas D, Yapicioglu H, Celik U, Sertdemir Y, Alhan E.

Terlipressin as a rescue therapy for catecholamine-resistant

septic shock in children. Intensive Care Medicine 2008;34

(3):511–7.

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C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Baldasso 2009 Neonates were not included in the study

Choong 2009 Neonates were not included in the study

Rios 2011 The objective of this study was not to treat neonates with refractory hypotension

Yildizdas 2008 Neonates were not included in the study



D A T A A N D A N A L Y S E S

This review has no analyses.

H I S T O R Y

Protocol first published: Issue 6, 2011

Review first published: Issue 3, 2013

Date Event Description

29 October 2008 New citation required and minor changes Converted to new review format.

C O N T R I B U T I O N S O F A U T H O R S

BS and PM carried out the search, identified eligible articles and wrote the review

CF and DR assisted with the search, commented on the review and incorporated comments.

JR commented on the review and helped incorporate comments.

D E C L A R A T I O N S O F I N T E R E S T

None known.

S O U R C E S O F S U P P O R T

Internal sources

• No sources of support supplied

External sources

• Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health,

Department of Health and Human Services, USA.

Editorial support of the Cochrane Neonatal Review Group has been funded with Federal funds from the Eunice Kennedy Shriver

National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human

Services, USA, under Contract No. HHSN275201100016C.



I N D E X T E R M S

Medical Subject Headings (MeSH)

Hypotension [∗drug therapy]; Infant, Newborn; Lypressin [analogs & derivatives; therapeutic use]; Vasoconstrictor Agents [∗ therapeutic

use]; Vasopressins [∗therapeutic use]

MeSH check words

Humans



Documents

Cochrane Database of Systematic Reviews (Reviews) || Vasopressin and its analogues for the treatment of refractory hypotension in neonates