What is the optimal dose and route of Vitamin K for treatment of prolonged INR in the setting of presumed DIC in pediatric patients?

Comment by InpharmD Researcher

There is a lack of data on pediatric vitamin K treatment for DIC. Only two retrospective studies were identified, both used a wide range of phytonadione dosing. As such, no optimal vitamin K dose or route for pediatric DIC can be established.
Background

A retrospective, single-center study presented as a poster abstract evaluated the use of vitamin K administration for coagulopathy in critically ill pediatric patients. A total of 75 patients (age range, 3 days to 17 years) received vitamin K therapy. The most common admission diagnoses were infection or sepsis (56%) and trauma (23%). The most common risk factors for coagulopathy were suspected vitamin K deficiency secondary to antimicrobials and NPO status (85%), followed by sepsis/septic shock (53%). Despite an elevated INR, most patients (83%) did not show active bleeding. There was wide variability in vitamin K dosing (0.18 ± 0.14 mg/kg/dose). Decreases in INR were observed in 62% of cases after vitamin K administration; however, 11% showed an increase in INR and the remaining cases did not have a post-administration INR recorded. No adverse events attributed to vitamin K were documented, irrespective of dose. Whether INR normalized was not reported, and neither was the route of administration. Additionally, there was no mention of other medication or blood product administration. While not exclusively for disseminated intravascular coagulopathy, this small study suggests vitamin K administration is safe and effective in decreasing elevated INR in critically ill pediatric patients. [1]

References:

[1] Koshel C, Greenberg P, Siu A. Vitamin K for correction of laboratory-defined coagulopathy in critically ill children. Crit Care Med . 2017;46(1):875. doi:10.1097/01.ccm.0000528884.30642.ac

Literature Review

A search of the published medical literature revealed 1 study investigating the researchable question:

What is the optimal dose and route of Vitamin K for treatment of prolonged INR in the setting of presumed DIC in pediatric patients?

Please see Table 1 for your response.


 

Effect of Phytonadione on Correction of Coagulopathy in Pediatric Patients With Septic Shock

Design

Retrospective, single-center, observational study

= 156

Objective

To evaluate phytonadione in children with septic shock with disseminated intravascular coagulopathy (DIC)

Study Groups

No follow-up INR (n= 10)

Follow-up INR ≤1.2 (n= 66)

Follow-up INR >1.2 (n= 80)

Inclusion Criteria

Children aged <18 years; admitted to a pediatric intensive care unit or cardiac intensive care unit; diagnosis of septic shock; received IV phytonadione

Exclusion Criteria

Patients who received phytonadione via oral, intramuscular, or subcutaneous route; received warfarin; received chronic phytonadione (including with total parenteral nutrition) prior to coagulopathy; had chronic liver or hematologic disease

Methods

This was a retrospective chart review of children admitted to the pediatric intensive care unit or cardiac intensive care unit at a single tertiary care academic center in Oklahoma. There was no standardized dosing protocol for phytonadione for sepsis-induced DIC.

Patients had an INR collected within 24 hours prior to IV phytonadione, during therapy, and up to 24 hours post-administration. When multiple INRs were collected, the closest value to 24 hours post-dose was used for this analysis. For patients who received more than 1 course of phytonadione for septic shock during the study period, only their initial course was included.

Duration

October 1, 2013 to August 31, 2020

Follow-up: up to 24 hours post-phytonadione

Outcome Measures

Primary: number of patients who achieved a normalized INR (defined as an INR ≤1.2)

Secondary: INR change, phytonadione dosing regimens

Baseline Characteristics

 

No follow-up INR (n= 10)

Follow-up INR ≤1.2 (n= 66)

Follow-up INR >1.2 (n= 80)

p-value

Age, years (IQR)

9.4 (0.93–14.6) 5.33 (0.92–11.5) 3.56 (0.38–12.7) 0.45

Male

50% 51.5% 60% 0.30

Weight, kg (IQR)

31.9 (6.82–58.3) 17.5 (8–41.8) 14.15 (4.8–37.4) 0.28

PRISM III score (IQR)

12.5 (4.25–19.5) 11 (7-19) 15 (6-23) 0.26

Active bleeding

0 12.1% 5% 0.12

Medications

Anticoagulation*

Vasopressors

 

10%

50%

 

3%

57.6%

 

8.8%

71.3%

 

0.18

0.08

ECMO

0 4.5% 3.8% 1.0

Mortality

20% 7.6% 1.3% 0.22

ECMO: extracorporeal membrane oxygenation; IQR: interquartile range; PRISM III: Pediatric Risk of Mortality III

*enoxaparin or heparin

Results

Endpoint

No follow-up INR (n= 10)

Follow-up INR ≤1.2 (n= 66)

Follow-up INR >1.2 (n= 80)

p-value

Total number of phytonadione doses (IQR)

2 (1-3) 3 (2-3) 3 (2-3) 0.58

Phytonadione dosage

Initial dose, mg

Initial dose, mg/kg

Cumulative dose, mg

Cumulative dose, mg/kg

 

2.8 (1.3–5.0)

0.15 (0.09–0.30)

6.75 (3.00–10.00)

0.19 (0.12–0.57)

 

1.0 (1.0–5.0)

0.12 (0.05–0.23)

3.00 (2.50–10.00)

0.27 (0.12–0.60)

 

1.0 (1.0–2.75)

0.13 (0.05–0.26)

3.00 (2.00–8.50)

0.30 (0.11–0.79)

 

0.56

0.50

0.60

0.47

Received blood products

Fresh frozen plasma

Cryoprecipitate

Both

 

50%

0

0

 

42.4%

15.2%

10.6%

 

62.5%

12.3%

11.3%

 

0.02

0.65

0.90

Only 42.3% of pediatric patients achieved a normalized INR following phytonadione therapy.

Overall, 55.8% of patients received either fresh frozen plasma or cryoprecipitate in addition to phytonadione for sepsis-induced coagulopathy; 10.3% received both. Two additional patients received prothrombin complex concentrate in addition to blood products.

There was a significantly higher median (IQR) baseline INR in patients who received cryoprecipitate and/or fresh frozen plasma with phytonadione versus phytonadione alone (1.9 [IQR, 1.6–2.5] vs 1.7 [IQR, 1.5–2.0]; p= 0.03). There was no significant difference in cumulative phytonadione dose, but patients who received blood products received more doses of phytonadione than patients who received phytonadione alone (p= 0.005).

The overall mean change in INR from baseline with each phytonadione dose ranged from −0.18 to −0.55, with the largest reduction seen after the 2nd dose.

Per a logistic regression analysis, baseline INR, fresh frozen plasma, cryoprecipitate, vasopressors, PRISM III score, or cumulative phytonadione dose were not associated with achieving a normalized INR.

Adverse Events

Not evaluated

Study Author Conclusions

Less than half of patients achieved a normalized INR. The median cumulative dose of phytonadione and receipt of FFP or cryoprecipitate was not associated with an increased odds of a normalized INR. Future studies are needed to further explore phytonadione use in children with sepsis-induced coagulopathy.

InpharmD Researcher Critique

Limitations of this study include the small sample size and single-center aspect. Additionally, 10 courses had no follow-up INR reported. The retrospective nature of the study also allows for reporting errors and confounding variables. Adverse events were not collected due to difficulties in differentiating documentation of active bleeding or adverse events attributed to phytonadione.

No dosing protocol was used, which also may have varied the results. However, a logistic regression model found cumulative phytonadione dose was not associated with a normalized INR. Similarly, the timing of INR after phytonadione administration was not uniform.



References:

Stephens K, Miller JL, Harkin M, Neely SB, Haws L, Johnson PN. Effect of Phytonadione on Correction of Coagulopathy in Pediatric Patients With Septic Shock. J Pediatr Pharmacol Ther. 2023;28(5):423-429. doi:10.5863/1551-6776-28.5.423