What is the data for maximum fluid rates for papaverine containing fluids in pediatrics patients?

Comment by InpharmD Researcher

There is a paucity of data evaluating maximum papaverine-containing fluid infusion rates in the pediatric population. Two identified studies evaluated the use of papaverine for peripheral arterial catheter patency in pediatric patients, with no defined infusion rates (see Tables 1 and 2). Expert opinion recommends an infusion rate of ≤1 mL/hour for papaverine-containing solutions, however, clinical evidence to support this recommendation could not be identified.

Background

Papaverine, an opium alkaloid, is a potent vasodilator and antispasmodic commonly used for the management of vascular spasms or cardiac extrasystole either as an intravenous (IV) bolus or intramuscular injection in adult patients. Although clinical evidence for papaverine use is limited in pediatric populations, a 2008 review of papaverine discussed the pharmacology, dosing, and evidence for use in peripheral arterial lines for neonatal treatment. Papaverine continuous IV infusions have been utilized to manage peripheral arterial catheter (PAC) patency, reducing catheter failure risk and increasing the duration of catheter function; catheter failure is associated with vasospasm events, resulting in an inability to draw blood or drip from PAC. Despite the overall clinical benefit for catheter retention, papaverine use in premature infants within the first few days following birth should be administered with caution as these patients are at a heightened risk for intraventricular hemorrhage. Papaverine infusion is recommended to be administered as an admixture of 30 mg/mL papaverine, 250 mL of standard peripheral line solution (0.9% or 0.45% normal saline), and sodium heparin 1 U/mL. For the prevention of vasospasm, papaverine solution is recommended to be infused at a rate of ≤1 mL/hour. Significantly, evidence for a defined infusion rate was not provided by the study authors. Admixture recommendations are derived from studies conducted by Heulitt et al. and Griffin et al. Please refer to Tables 1 and 2, for further details. [1]

A 2016 study retrospectively analyzed 14 extremely low birth weight (ELBW) neonates who developed skin discoloration subsequent to peripheral arterial catheterization. The primary intervention involved the use of intra-arterial papaverine, specifically at a dose of 1 mg/kg diluted with saline (1 mg:1 mL) and infused over 5-10 minutes before the arterial line removal. Following this, nitroglycerin (NTG) patches were applied to further assist in vasodilation. Skin discoloration, which was indicative of either vasospasm or thromboembolism, was the focal point of assessment. Notably, out of the 14 neonates, 11 received papaverine (gestational age 26-31 weeks; weight 0.56-0.98 kg), and all showed recovery. In 6 cases, normal skin color reappeared within 4 hours, and in the remaining 5, normalization occurred over a few days without residual damage. Three neonates could not receive papaverine due to arterial line blockages. Of these, two achieved spontaneous recovery, while one progressed to gangrene of the fingers. The report highlights the potential utility of papaverine in mitigating ischemic complications associated with peripheral arterial catheterization in ELBW neonates. However, limitations included the study’s retrospective design, the absence of a control group, the use of an additional intervention (NTG patch), and a relatively small sample size. Although these findings suggest the efficacy of papaverine in preventing ischemic injury, they underscore the need for well-controlled studies to substantiate the observed outcomes. It should also be noted that these results were only presented as an abstract and may not be comprehensive. [2]

References:

[1] Bell SG. Use of a papaverine solution in peripheral arterial lines. Neonatal Netw. 2008;27(1):65-66. doi:10.1891/0730-0832.27.1.65
[2] Panigrahy N, Kumar PP, Chirla DK, Vennapusa SR. Papaverine for Ischemia Following Peripheral Arterial Catheterization in Neonates. Indian Pediatr. 2016;53(2):169.

Relevant Prescribing Information

DOSAGE AND ADMINISTRATION
Papaverine Hydrochloride may be administered intravenously or intramuscularly. The intravenous route is recommended when an immediate effect is desired, but the drug must be injected slowly over the course of 1 or 2 minutes to avoid uncomfortable or alarming side effects.
Parenteral administration of papaverine hydrochloride in doses of 1 to 4 mL is repeated every 3 hours as indicated. In the treatment of cardiac extrasystoles, 2 doses may be given 10 minutes apart. [3]

References:

[3] Papaverine hydrochloride. Package insert. Oryza Pharmaceuticals Inc.; 2023.

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

What is the data for maximum fluid rates for papaverine containing fluids in pediatrics patients?

Level of evidence

D - Case reports or unreliable data  Read more→



Please see Tables 1-2 for your response.


 

Double-blind, randomized, controlled trial of papaverine-containing infusions to prevent failure of arterial catheters in pediatric patients

Design

Prospective, double-blind, randomized, controlled trial

N= 239

Objective

To test the efficacy of the continuous infusion of papaverine-containing fluids into peripheral arterial catheters for reducing the risk of catheter failure

Study Groups

Placebo (n= 124)

Papaverine (n= 115)

Inclusion Criteria

Children aged 3 weeks to 18 years with an indwelling arterial catheter inserted for critical care and admitted to the pediatric intensive care unit (ICU)

Exclusion Criteria

Hepatic failure, complete atrioventricular block

Methods

Patients were randomized into four strata based on weight (<10 kg or ≥10 kg) and shock status (presence of circulatory shock, shock, or without shock). Patients received arterial catheter infusions of 0.9% or 0.45% sodium chloride, containing 1 U/mL sodium heparin, with or without papaverine (60mg/500mL). The composition of the infusions was only known to the pediatric ICU pharmacist and was not made available to the investigators. If the patient had more than one catheter inserted, only the first catheter was studied. 

Catheter failure was defined as the inability to draw blood from the catheter or the loss of waveform; once patients exhibited one or both criteria, the catheter was removed. 

Duration

April 18, 1989 to April 3, 1990

Outcome Measures

Primary: Catheter failure

Baseline Characteristics

 

Placebo (n= 124)

Papaverine (n= 115)

 

Age, years (IQR)

1.6 (0.4-4.9) 1.8 (0.6-5.5)  

Female

50 54  

Weight, kg (IQR)

10.4 (5.5-17.8)  12.3 (5.7-17.6)   

Total blood draws

Draws per day

17 (9-31)

6.7 (5-8.7)

17 (10-30)

6.7 (4.7-8.3)

 

Diagnosed with shock

23 15  

Shock risk factors (IQR)

Poor capillary refill

Systolic BP, mmHg

Diastolic BP, mmHg

Urine <1 mL/kg/hour

 

12

91 (78-110)

50 (42-61)

19

 

13

94 (85-119)

50 (41-60)

11

 

Vasoactive drugs

Dobutamine

Dopamine

Nitroprusside†

 

27

14

23

 

36

17

36

 

Treatment with NMB

34 30  

Treatment with pressors (before catheter)

15 20  

Primary diagnosis

Complex heart disease

Simple heart disease

Respiratory failure

Sepsis

Other

 

40

15

19

8

18

 

47

21

10

8

14

 

Catheter site

Radial artery

Other arterial sites

 

85

15

 

83

17

 

Previous puncture at site

36 32  

Previous catheter at site

3 6  

Type of pump

Pressure bag

Pressure box

Infusion pump

 

81

9

10

 

85

11

4

 

†Nitroprusside use was significantly higher in the papaverine group than placebo (p= 0.04). 

Abbreviations: IQR, interquartile range; BP, blood pressure; NMB, neuromuscular blockade

Results

Endpoint

Placebo (n= 124)

Papaverine (n= 115)

p-value

Catheter failure

27 (22%)

8 (7%)

0.02

Following a multivariate analysis, papaverine use was significantly associated with reduced risk of catheter failure in patients treated with papaverine when compared to controls (risk ratio 0.45; 95% confidence limit 0.2 to 1; p= 0.05). 

Adverse Events

Common Adverse Events: Vomiting (3 patients in papaverine group vs. 3 patients in placebo group), change in mental status (2 patients in the papaverine group vs. 2 patients in the placebo group), and facial flushing (1 patient in the placebo group); adverse effects were not considered papaverine-induced. 

Study Author Conclusions

Infusion of papaverine-containing fluids into arterial catheters reduces the risk of catheter failure and should reduce patient discomfort. These benefits appear to be realized without drug toxicity or side effects. In patients in whom prolonged arterial catheterization is anticipated, papaverine-containing infusions should be considered. 

InpharmD Researcher Critique

As this study was reported in 1993, clinical data should be interpreted with caution. Study authors concluded the benefit of papaverine use for the prevention of arterial catheter failure in children >3 weeks, but did not disclose infusion rates of papaverine during administration, limiting the generalizability of this study, as maximum infusion rates were not identified. 



References:

Heulitt MJ, Farrington EA, O'Shea TM, Stoltzman SM, Srubar NB, Levin DL. Double-blind, randomized, controlled trial of papaverine-containing infusions to prevent failure of arterial catheters in pediatric patients. Crit Care Med. 1993;21(6):825-829. doi:10.1097/00003246-199306000-00008

 

Papaverine Prolongs Patency of Peripheral Arterial Catheters in Neonates

Design

Prospective, randomized, placebo-controlled, masked trial

N= 141; 180 catheters

Objective

To test the hypothesis that the continuous infusion of papaverine-containing solutions in peripheral arterial catheters would decrease the catheter failure rate and increase the functional duration of the catheter in neonates

Study Groups

Papaverine (n= 70; 82 catheters)

Placebo (n= 71; 98 catheters)

Inclusion Criteria

Infants admitted to a neonatal intensive care unit, indwelling peripheral arterial catheter

Exclusion Criteria

Parents unavailable or not approached, parents refused consent, extracorporeal membrane oxygenation, intraventricular hemorrhage (IVH), infants not randomized by pharmacy, already given papaverine

Methods

Study patients were randomized to receive arterial catheter infusion solutions of 0.9% or 0.45% sodium chloride with 1.0 U/mL sodium heparin, with or without papaverine (30 mg/250 mL), all prepared by the pharmacy. Investigators and medical personnel were blinded to patient assignments.

Duration

Enrollment: August 1995 to August 2002

Outcome Measures

Hemorrahge, reasons for catheter removal, catheter duration

Baseline Characteristics

 

Papaverine (n= 70; 82 catheters)

Placebo (n= 71; 98 catheters)

 

Age at insertion, days (IQR)

11 (3-19) 12 (7-25)   

Gestational age, weeks (IQR)

27 (25-36) 27 (24-34)  

Birth weight, grams (IQR)

952 (692-2670) 910 (655-2150)  

Male

40 44  

Total number of draws (IQR)

51 (28-93) 52 (25-83)  

Attempts at placement, n

1

2

>2

Unkown

 

43

19

14

 

47

18

21

12 

 

Dopamine, n

30 39  

Dobutamine, n

7 8  

IQR, interquartile range

Results

Endpoint

Papaverine (n= 70; 82 catheters)

Placebo (n= 71; 98 catheters)

p-value

# studies before treatment

41 45  

Status before treatment, n

No hemorrhage

Grade 1

Grade 2

Grade 3

Grade 4

Periventricular bleed

 

30

4

3

3

1

1

 

35

2

5

3

2

 

# studies after treatment, n

54 50  

Status after treatment

No hemorrhage

Grade 1

Grade 2

Grade 3

Grade 4

Periventricular bleed

 

35

8

2

8*

1

 

35

3*

8

2

2

 

Reason for removal of arterial catheters

Catheter failure

Elective removal

Accidental removal

Death

 

40 (49%)

34 (41%)

6 (7%)

2 (2%) 

 

56 (57%)

28 (29%) 

8 (8%)

6 (6%)

0.25

-

-

-

-   

Catheter duration, days (IQR)

16.6 (9.5-24.3) 12 (6.1-18.2) 0.023

*Indicates 1 infant in the papaverine group who had periventricular hemorrhage in addition to grade 3 IVH and 1 infant in the placebo group who had periventricular hemorrhage in addition to grade 1 IVH.

Adverse Events

There was no evidence of hepatic toxicity caused by papaverine.

Study Author Conclusions

The continuous infusion of papaverine-containing fluids prolongs the patency of peripheral arterial catheters in neonates. In this small number of infants, we found no difference in the incidence of IVH or hepatic toxicity.

InpharmD Researcher Critique

This study did not describe the infusion rate of papaverine, making it difficult to draw conclusions on appropriate maximum infusion rates.

References:

Griffin MP, Siadaty MS. Papaverine prolongs patency of peripheral arterial catheters in neonates. J Pediatr. 2005;146(1):62-65. doi:10.1016/j.jpeds.2004.08.050