A Preliminary, Single-Center Retrospective Chart Review of Infusion Times of Intravenous Immune Globulin in Kawasaki Disease and Clinical Outcomes

Abstract

OBJECTIVE

Patients diagnosed with Kawasaki disease (KD) are at a high risk of developing coronary artery aneurysms. Intravenous immune globulin (IVIG) given in combination with aspirin is the standard of treatment for the prevention of coronary aneurysm. IVIG is recommended to be administered as a dose of 2 g/kg infused during 10 to 12 hours for the prevention of coronary aneurysms in KD; however, this does not always occur in practice. We aimed to investigate if an infusion time of <10 hours is associated with more coronary artery aneurysms than the recommended infusion time of 10 to 12 hours.

METHODS

Patients with a diagnosis of and treated for KD with IVIG at the University of Chicago Medicine Comer Children's Hospital were identified by drug use reports that included patients who received IVIG between September 2008 and August 2018. Data were collected though chart review and patients were divided into 2 groups based on duration of infusion (<10 hours and 10–12 hours). The primary outcome was the incidence of coronary artery aneurysm. The secondary outcome was the time to defervescence. The safety outcome was the development of renal dysfunction.

RESULTS

A total of 70 patients were screened and 44 were included in the analysis. Coronary aneurysm occurred in 2 of 33 patients (6.0%) in the <10-hour group and no patients in the 10- to 12-hour group (p = 0.558). The median time to defervescence was 0.5 hours in the <10-hour group and 0.95 hours in the 10- to 12-hour group (p = 0.166). The incidence of acute kidney injury was 6% (2 of 33 patients) in the 10-hour group and 9.1% (1 of 11 patients) in the 10- to 12-hour group (p = 0.588).

CONCLUSIONS

All incidences of coronary artery aneurysm occurred in the patients who received IVIG with an infusion time of <10 hours. The incidence of acute kidney injury was numerically higher in the 10- to 12-hour group. Based on the recommendations in the American Heart Association KD guideline, our internal hospital policy, and our results, we recommend the infusion of IVIG be administered at a rate of 10 to 12 hours.

Introduction

Intravenous immune globulin (IVIG), given in conjunction with aspirin, has been the cornerstone therapy for Kawasaki disease (KD) since a trial by Newburger et al¹ showed its effectiveness at a dose of 400 mg/kg for 4 consecutive days in 1986. Numerous trials have been conducted since then and have experimented with different dosages.^2,3 In 1991, Newburger³ compared a dose of 2 g/kg during 10 hours and daily infusions of 400 mg/kg for 4 consecutive days and found the single 2 g/kg dose to be more efficacious and equally safe. However, no clinical trials have been performed to determine if the infusion time of IVIG 2 g/kg causes a clinically significant difference in patient outcomes. In the search for the optimal pharmacotherapeutic treatment plan for KD, we deemed it necessary to undertake this endeavor.

The initial infusion rate of IVIG is 0.5 mL/kg/hr, utilizing a 5 g/50 mL solution .⁴ If the patient does not have a history of adverse infusion-related reactions, no significant risk factors for renal dysfunction or thrombotic complications, and the initial rate is tolerable, the infusion is gradually increased to a maximum rate of 5 mL/kg/hr. In patients at high risk for thrombosis or renal impairment, the infusion rate should not exceed a maximum of 2 mL/kg/hr. However, the recommended infusion time of IVIG in KD is 10 to 12 hours.⁴ This requires a slower maximum infusion rate than the product's labeling suggests. Because of this variation in infusion recommendations, IVIG may not always be ordered or administered within the guideline recommended range for KD, and there is a knowledge gap regarding its impact on efficacy in preventing the incidence of coronary artery aneurysms. The purpose of this study was to evaluate whether or not the infusion time of IVIG made a difference in the overall outcomes associated with treatment of patients with KD.

Methods

This study was a retrospective, cohort, single-center chart review performed at the University of Chicago Medicine Comer Children's Hospital that compared patients who received IVIG 2 g/kg during an infusion time of less than 10 hours and those whose infusion time was 10 to 12 hours. Data were collected and stored via a secure online database (REDCap).

Patients were identified by drug use reports, which included patients who received IVIG from September 1, 2008, to August 31, 2018. Inclusion required a patient to be younger than 18 years, with a diagnosis of typical or atypical KD, and treated with IVIG at the University of Chicago Comer Children's Hospital. Patients were excluded if they received IVIG doses greater than 2.4 g/kg or less than 1.8 g/kg, received IVIG infusions administered during greater than 12 hours, or had a preexisting coronary artery aneurysm.

The primary outcome was the incidence of coronary artery aneurysm, which was objectively diagnosed by an echocardiogram within 3 months after discharge from the hospital. The secondary outcome was the time to defervescence. This was defined as the time from the patient's highest recorded fever during admission to a temperature at or below 38.5°C. The time to defervescence is due to aspirin administration; however, given the lack of standardization of vital checks and the patient presenting to the hospital with a fever, we did not collect the exact timing of aspirin administration. The safety outcome was the development of renal dysfunction as defined by the Pediatric Risk, Injury, Failure, Loss, End Stage Renal Disease (pRIFLE) criteria (Supplemental Table)⁵. We collected all serum creatinine and urine output values within 48 hours after IVIG infusion.

Based on the rates of coronary aneurysm observed in previous studies, we estimated 150 patients would be needed to detect a 15% difference in the incidence of coronary aneurysm between the 2 groups. Our study contained 44 patients and therefore was insufficiently powered to detect a statistically significant difference in this outcome. The Fisher exact test was used for nominal data. Mann-Whitney test was used for continuous data to analyze any differences between the 2 groups.

Results

From September 1, 2008, through August 31, 2018, a total of 70 patients were screened for inclusion. Twenty-six patients were excluded from the study for either incomplete documentation or infusion times greater than 12 hours leaving a total of 44 study patients; 33 patients who received their infusion < 10 hours and 11 patients whose infusion lasted between 10–12 hours. The 2 groups were well matched, except that the <10-hour group was 57.6% male and the 10- to 12-hour group was 27.3% male (Table 1).

Table 1.

Baseline Patient Demographic and Clinical Characteristics

Characteristic*	Less Than 10 hr (n = 33)	10–12 hr (n = 11)
Age, median (range), yr	3 (0.8–8)	2 (0.5–7)
Male sex, n (%)	19 (57.6)	3 (27.3)
Race, n (%)
White	9 (27.3)	4 (36.4)
Black	20 (60.6)	7 (63.6)
Asian/Pacific Islander	1 (3)	0
Other	1 (3)	0
Unknown	2 (6.1)	0
Comorbidities, n (%)
Asthma	2 (6.1)	0
BPD/CLD	1 (3)	0
Immune deficiencies	1 (3)	0
None	29 (87.9)	11 (100)
Time to IVIG initiation, median (range), days	1.33 (0.29–10.07)	1.27 (0.39–6.06)
Tmax, median (range), °C	39.2 (37.1–40)	39.4 (38–40.4)
CRP, median (range), mg/L	84 (5–227)	83 (20–376)
ESR >100 mm/hr, n (%)	8 (24.2)	1 (9.1)
WBC, median (range), 103/μL	13.3 (6.9–28.4)	13.8 (6.6–25.6)
Hemoglobin <10 g/dL, n (%)	8 (24.2)	4 (36.4)
Hematocrit, median (range), %	31.1 (22.6–37.3)	31.2 (27.9–35.5)
Platelets, median (range), 103/μL	345 (97–678)	376 (190–477)
IVIG infusion time, median (range), median (range), hr	7 (5.0–9.9)	10.5 (10–11.9)
IVIG dose, median (range), g/kg	2 (1.85–2.14)	2 (1.88–2.11)
Aspirin TDD, median (range), mg/kg	88 (76.8–93.8)	87.6 (77.3–91.8)
Aspirin HD, n (%)	28 (84.8)	9 (81.8)

BPD, bronchopulmonary dysplasia; CLD, chronic lung disease; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; HD, high dose (80–100 mg/kg/day); IVIG, intravenous immune globulin; TDD, total daily dose; time to IVIG initiation, time from admission to administration on IVIG; T_max, maximum temperature; WBC, white blood cell

^* These lab values were the most recent lab values obtained prior to IVIG initiation.

The primary outcome of coronary aneurysm occurred in 2 of 33 patients (6%) in the <10-hour group and no patients in the 10- to 12-hour group (p = 0.558; Table 2). The median time to defervescence was 0.5 hours in the <10-hour group and 0.95 hours in the 10- to 12-hour group (p = 0.166). The incidence of acute kidney injury (AKI) was 2 of 33 patients (6%) in the 10-hour group and 1 of 11 patients (9.1%) in the 10- to 12-hour group (p = 0.588). The median length of stay was 4 days in the <10-hour group and 3 days in the 10-to 12-hour group (p = 0.702). No patients included in this study received a second dose of IVIG.

Table 2.

Efficacy and Safety Clinical Outcomes

Outcome	Less Than 10 hr (n = 33)	10–12 hr (n = 11)	p value
Coronary artery aneurysm, n	2	0	0.558
Time to defervescence, median, hr	0.5	0.95	0.166
AKI, n	2	1	0.588
Length of stay, median, days	4	3	0.702
Received second dose of IVIG, n	0	0	—

AKI, acute kidney injury, defined by the Pediatric Risk, Injury, Failure, Loss, End Stage Renal Disease (pRIFLE) criteria; IVIG, intravenous immune globulin

Discussion

Patients with a diagnosis of KD who do not receive appropriate therapy are at high risk of developing a coronary artery aneurysm. The use of IVIG at a dose of 2 g/kg is essential in preventing the incidence of coronary aneurysm. In this study, all incidences of coronary artery aneurysm occurred in patients who received IVIG with an infusion time of less than 10 hours. These findings support the guideline recommended infusion time of 10 to 12 hours. However, given the relatively small sample size, we were not sufficiently powered to detect a statistically significant difference in this outcome between the 2 groups. A surprising finding in our study was that only 11 of 44 patients (25%) received the guideline recommended infusion time of 10 to 12 hours.

There was no significant difference in the time to defervescence between the 2 groups in this study. There are several factors that could have influenced this result. One of these factors is that 7 of 44 patients (16%) did not receive high-dose aspirin. Although the efficacy of high-dose (80–100 mg/kg/day) versus moderate-dose (30–50 mg/kg/day) aspirin is controversial in the literature, high-dose aspirin remains the standard of care in the United States. Additionally, aspirin and IVIG had variable start times for each patient, possibly due to delays in preparation of IVIG. We did not collect the precise timing of aspirin administration, so it is unknown if this timing had a significant impact on time to defervescence. Several patients received antipyretic therapy prior to the start of IVIG, which also could have impacted the time to defervescence in the 2 groups. Some patients had received acetaminophen or ibuprofen instead of aspirin, and this could have impacted our results as well. Lastly, the duration of fever prior to initiation of therapy was not collected based on the retrospective nature of this review and lack of consistent precise documentation of when fevers began at home (i.e., presence of fever at home often recorded as days prior to admission rather than exact hour of temperature). Ideally, all of the patients would have initiated treatment during the acute phase of KD; however, we cannot confirm that all patients were treated during this phase.

Although not statistically significant, our results suggest a correlation between IVIG infusion time and the incidence of coronary artery aneurysms. Given the current guidelines for KD already specify 10 to 12 hours as the recommended infusion time based on historical practices and expert opinion, we do not believe that a larger study is necessary to confirm this outcome. However, this may be an opportunity for quality improvement projects aiming to increase consistency with guideline recommendations at our own institutions and at others who see similar protocol deviations.

ABBREVIATIONS

AKI

acute kidney injury

BPD

bronchopulmonary dysplasia

CLD

chronic lung disease

CRP

C-reactive protein

ESR

erythrocyte sedimentation rate

HD

high dose

IVIG

intravenous immune globulin

KD

Kawasaki disease

T_max

maximum temperature

TDD

total daily dose

WBC

white blood cell