What are the recommendations for hydration for patients on IV acyclovir?

Comment by InpharmD Researcher

Available guidance regarding an optimized hydration strategy to prevent acyclovir-induced nephrotoxicity among the patients receiving IV acyclovir is scarce and limited to retrospective studies. Available evidence suggests renal function indicators in acyclovir-treated patients vary according to hydration volume. As such, there is no consensus on an adequate hydration protocol or rate to prevent acyclovir-induced nephrotoxicity. One study diluted all doses in 250 mL of NS or D5W and infused acyclovir over 2 hours to prevent renal dysfunction (see Tables 2 and 3), but the rates of supplemental IV fluids were not specified.

Background

A recent 2022 retrospective cohort study included patients who received intravenous (IV) acyclovir to evaluate the incidence of induced-nephrotoxicity associated with acyclovir as well as the predisposing risk factors. Eligible patients received acyclovir (5-10 mg/kg/dose every 8 to 24 h) dosed based on their renal function infused over one hour while maintaining adequate hydration. The patients were treated for an average duration of approximately five days and 80.9% of the patients received IV hydration. Based on the results of the study, the incidence of acyclovir induced-nephrotoxicity was 20.1%; older age, longer duration of treatment, and concomitant vancomycin use were proposed as potential risk factors for acute kidney injury (AKI). Unfortunately, information on IV hydration protocol was not specified. [1]

A 2016 prospective cohort study emphasized the importance of IV hydration for the prevention of acyclovir-induced nephrotoxicity without specifying a preferred hydration method. In this study, 10.3% of patients with elevated creatinine were reported to be dehydrated, which was specified as a subjective variable identified by decreased skin turgor, dry mouth, sunken eyes, concentrated urine, and delayed capillary refill. [2]

Limited retrospective studies (see Tables 1-2) revealed renal function indicators in acyclovir-treated patients varied according to hydration volume. One study diluted all doses in 250 mL of NS or D5W and administered over 2 hours to prevent renal dysfunction. However, given the scarcity of data on IV hydration methods for patients receiving IV acyclovir, higher quality studies on the appropriate hydration of patients, especially those with predisposing factors for induced nephrotoxicity are warranted. [1], [2], [3], [4]

A 2020 poster presentation described a retrospective cohort study that sought to evaluate hydration during IV acyclovir therapy and its association with AKI. The primary outcome of the study was the association between hydration rates and AKI, defined as an increase in serum creatinine (SCr) of at least 0.3 mg/dL within 48 hours. Correlation between AKI and hydration was determined to be the secondary outcome. Seventeen of 78 total patients (21.8%) developed AKI, and 9 (52.9%) of these patients were given at least 1 mL/kg/hr of IV fluids over the course of IV acyclovir therapy. Final results for the study have not yet been published, but preliminary results again reinforce that inadequate IV fluid may contribute to AKI during IV acyclovir therapy. [5]

A recent 2024 single-center, retrospective cross-sectional study aimed to evaluate the prevalence of acyclovir-induced AKI while characterizing the utilization of IV fluids during therapy. Patients (N= 150; among which 32 [21%] had developed AKI) who received ≥ 48 hours consecutive hours of IV acyclovir were hydrated with an order panel including continuous IV isotonic crystalloids. Utilizing the order panel was associated with a significantly more daily fluids administration (1,817 mL vs. 1,267 mL; p= 0.005). Of note, the rate of AKI was not significantly different between patients with ≥ 2 L/day or ≥ 1L/gram of acyclovir/day. Although this study aimed to provide insight into characterizing adequate hydration during acyclovir therapy, identifying an optimized fluid requirement to avoid acyclovir-induced AKI necessitates further evaluations. Caution is warranted in interpretation as only the abstract was available for scrutiny. [6]

References:

[1] Al-Alawi AM, Al-Maqbali JS, Al-Adawi M, Al-Jabri A, Falhammar H. Incidence, patterns, risk factors and clinical outcomes of intravenous acyclovir induced nephrotoxicity. Saudi Pharm J. 2022 Jun;30(6):874-877. doi: 10.1016/j.jsps.2022.03.013. Epub 2022 Mar 26. PMID: 35812148; PMCID: PMC9257855.
[2] Richelsen RKB, Jensen SB, Nielsen H. Incidence and predictors of intravenous acyclovir-induced nephrotoxicity. Eur J Clin Microbiol Infect Dis. 2018;37(10):1965-1971. doi:10.1007/s10096-018-3332-5
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4777587/

[3] Dubrofsky L, Kerzner RS, Delaunay C, Kolenda C, Pepin J, Schwartz BC. Interdisciplinary Systems-Based Intervention to Improve IV Hydration during Parenteral Administration of Acyclovir. Can J Hosp Pharm. 2016 Jan-Feb;69(1):7-13. doi: 10.4212/cjhp.v69i1.1517. PMID: 26985083; PMCID: PMC4777587.
[4] Kim S, Byun Y. Comparison of renal function indicators according to hydration volume in patients receiving intravenous acyclovir with CNS infection. Biol Res Nurs. 2015;17(1):55-61. doi:10.1177/1099800414531483
[5] American College of Clinical Pharmacy (ACCP). Virtual Poster Symposium. Evaluation of hydration and acute kidney injury with intravenous acyclovir at a large academic medical center. May 26, 2020. Accessed July 22, 2022. https://accp.confex.com/accp/2020vp/meetingapp.cgi/Paper/54264
[6] Brochu J, Hodges S, Kantharia S, Jones M, August B. 517: characterizing fluid hydration practices among patients receiving intravenous acyclovir therapy. Critical Care Medicine. 2024;52(1):S232-S232. doi:10.1097/01.ccm.0001000244.53154.bb
Relevant Prescribing Information

PRECAUTIONS
General
Precipitation of acyclovir crystals in renal tubules can occur if the maximum solubility of free acyclovir (2.5 mg/mL at 37°C in water) is exceeded or if the drug is administered by bolus injection. Ensuing renal tubular damage can produce acute renal failure. [7]

Abnormal renal function (decreased creatinine clearance) can occur as a result of acyclovir administration and depends on the state of the patient's hydration, other treatments, and the rate of drug administration. Concomitant use of other nephrotoxic drugs, pre-existing renal disease, and dehydration make further renal impairment with acyclovir more likely. [7]

Administration of acyclovir by intravenous infusion must be accompanied by adequate hydration. [7]

References:

[7] Acyclovir (acyclovir sodium injection, solution). Prescribing Information. Slate Run Pharmaceuticals, LLC; 2024.
Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

What are the recommendations for hydration for patients on IV acyclovir?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-3 for your response.

 

Comparison of Renal Function Indicators According to Hydration Volume in Patients Receiving Intravenous Acyclovir with CNS Infection

Design

Single-center, retrospective chart review

N= 216

Objective

To compare the changes in renal function indicators as a function of hydration volume in patients treated with acyclovir for suspected herpes simplex virus (HSV) infection

Study Groups

<2 L (n= 100)

>2 L (n= 76)

No hydration (n= 40)

Inclusion Criteria

Suspected CNS infection with HSV requiring hospital admission; administered intravenous (IV) acyclovir infusion (10 mg/kg over 1 hr, repeated every 8 hr); normal baseline levels of renal function indicators before IV infusion therapy; no changes in the hydration volume during IV acyclovir infusion therapy by the end of the therapy

Exclusion Criteria

Use of additional antiviral or antibiotic medications besides acyclovir; abnormal levels of renal function indicators before IV infusion therapy; history of kidney or metabolic diseases; use of medications that affect the levels of renal function indicators

Methods

Data obtained from the eligible patients' chart review were used to determine and compare the levels of renal function indicators before administration of acyclovir and after 3 days of acyclovir administration. Based on the daily IV isotonic fluid hydration volume, the patients were categorized into three groups: patients without hydration, patients with hydration volumes lower than 2 L/day, and patients with hydration volumes of 2 L/day or more.

Duration

January 2007 through December 2012

Follow-up: 3 days

Outcome Measures

 Renal function indicators including serum creatinine (sCr), blood urea nitrogen (BUN), estimated glomerular filtration rate (eGFR), uric acid levels, and urine pH after 3 days of treatment

Baseline Characteristics

  

<2 L (n= 100)

>2 L (n= 76)

 No hydration (n= 40)  

Age, years

39.88 ± 13.44

40.56 ± 9.11

38.43 ± 13.89

  

Male

49.26% 30.15%  20.59%  

Length of hospitalization, days

 16.55 ± 8.91

16.41 ± 11.40

17.55 ± 10.03

  

Duration of IV acyclovir treatment, days

 11.02 ± 3.58

10.32 ± 5.28

 9.33 ± 4.01   

Hydration solution

0.9% Normal saline

5% Dextrose saline

5% Dextrose

 

77%

13%

10%

 

56.58%

32.89%

10.53%

 

-

-

-

  

Renal function indicators

sCr, mg/dl

BUN, mg/dl

eGFR, ml/min

 

0.84 ± 0.18

13.79 ± 3.83

87.26 ± 29.97

 

0.79 ± 0.18

13.63 ± 5.32

107.40 ± 28.36

 

0.73 ± 0.13

11.25 ± 4.99

104.50 ± 17.07

  

No statistically significant difference between the groups.

Results

Endpoint

 <2 L (n= 100)

>2 L (n= 76)

No hydration (n= 40)

p-value

Renal function indicators

sCr, mg/dl

BUN, mg/dl

eGFR, ml/min

 

1.70 ± 0.35

22.14 ± 7.95

59.66 ± 10.25 

 

0.87 ± 0.17

11.38 ± 4.19

89.35 ± 26.14

 

2.22 ± 0.51

28.33 ± 0.57

53.03 ± 3.05

 

< 0.001

<0.001

<0.001 

Serum uric acid levels and urine pH values were normal in all three groups after 3 days of treatment with IV acyclovir.

Adverse Events

N/A

Study Author Conclusions

Renal function indicators in acyclovir-treated patients varied according to hydration volume. Health care providers should consider whether the hydration volume in each patient receiving intravenous acyclovir is sufficient for preventing nephropathy.

InpharmD Researcher Critique

In addition to its retrospective nature and potential for selection bias, the results of the study were solely based on surrogate outcomes (renal function indicators). Further prospective studies to establish standardized clinical guidelines for early detection of renal insufficiency and to minimize complications in patients with suspected HSV infections are warranted.



References:

Kim S, Byun Y. Comparison of renal function indicators according to hydration volume in patients receiving intravenous acyclovir with CNS infection. Biol Res Nurs. 2015;17(1):55-61. doi:10.1177/1099800414531483

 

Interdisciplinary Systems-Based Intervention to Improve IV Hydration during Parenteral Administration of Acyclovir

Design

Single-center, pre-post, retrospective analysis

N= 84

Objective

To explore the effectiveness of the study institution’s inter-disciplinary quality improvement intervention in increasing the dilution of acyclovir before IV administration

Study Groups

Pre-intervention (n= 44)

Post-intervention (n= 40)

Inclusion Criteria

Aged >18 years old, seen in the emergency department or admitted to a ward, received at least one IV dose of acyclovir at the study institution

Exclusion Criteria

Received treatment in the month of December 2013 (immediately after protocol implementation)

Methods

This was a pre-post study evaluating the effects of implementing a protocol to prevent acyclovir-induced acute kidney injury (AKI) at a single center in Quebec, Canada. Prior to the protocol implementation, acyclovir was usually prepared in a 100 mL back of diluent; however, the protocol mandated acyclovir be administered in at least 250 mL of diluent at a maximum rate of 125 mL/h. The 250 mL bag target was chosen after a discussion with healthcare professionals at the institution. The full protocol can be found in Table 3.

Duration

Pre-intervention period: 6 months (May 31 to November 30, 2013)

Post-intervention period: 6 months (January 1 to June 30, 2014)

Outcome Measures

Primary: volume in which each acyclovir dose was delivered

Secondary: hourly rate of fluid administration, the frequency of an increase in hourly hydration rate, and the incidence of acute kidney injury

Baseline Characteristics

  

Pre-intervention (n= 44)

Post-intervention (n= 40)

 p-value

Median age, years (IQR)

 66.5 (38.0–76.5) 57.0 (38.0–76.5) 0.16

Male

45%  48% 0.85

Median baseline creatinine, μmol/L (IQR)

eGFR, mL/min/1.73 m2  

eGFR < 30 mL/min/1.73 m2

84 (61–137)

78 ± 41

5/41 (12%)

77.5 (54–93)

93 ± 41

1/39 (3%)

0.21

0.12

0.10

Median duration of acyclovir therapy, h (IQR)

 46.5 (12–100.5) 58.75 (31.5–97) 0.41

IQR, interquartile range; eGFR, estimated glomerular filtration rate

Results

Endpoint

Pre-intervention (n= 44)

Post-intervention (n= 40)

p-value

Median dilution volume per dose of acyclovir, mL

 100 250 < 0.001

Median rate of IV hydration, mL/h (IQR)

 100 (80–150) 100 (100–150) 0.19

Rate of IV hydration increased at acyclovir initiation

n= 37

41%

n= 39

56%

 0.17

Drug-induced AKI (30% increase in SCr)

n= 38

18%

n= 38

21%

 0.77

Doubling of serum creatinine

n= 38

13%

n= 38

0

 0.021

Adverse Events

Not studied

Study Author Conclusions

In this study, an easily implemented intervention significantly increased the volume of IV fluid administered to patients receiving acyclovir. Adequately powered prospective studies are suggested to investigate the effectiveness of this intervention on the clinically relevant incidence of acyclovir-induced nephrotoxicity.

InpharmD Researcher Critique

Due to the retrospective design, this study was subject to selection bias and the potential for misclassification of outcome measures. Given the limited number of patients before the intervention, it was not possible to conduct power calculations and adjust the sample size accordingly. Additionally, the type and rate of supplemental IV fluids were not reported.



References:

Dubrofsky L, Kerzner RS, Delaunay C, Kolenda C, Pepin J, Schwartz BC. Interdisciplinary Systems-Based Intervention to Improve IV Hydration during Parenteral Administration of Acyclovir. Can J Hosp Pharm. 2016 Jan-Feb;69(1):7-13. doi: 10.4212/cjhp.v69i1.1517. PMID: 26985083; PMCID: PMC4777587.

 

Parenteral Acyclovir Intravenous Administration Protocol from a Single-center Retrospective Study

Usual dosage

5-10 mg/kg intravenous q8h (doses >10 mg/kg to 15 mg/kg may be used with Infectious Diseases consult)

Renal dose adjustment

CrCl (mL/min)

% or recommended dose

Dosing interval, hours

> 50

 100% 8

26-50

 100% 12

11-25

 100% 24

0-10

 50% 24

Administration

To help prevent renal dysfunction, all doses should be diluted in 250 mL of NS or D5W and run over 2 hours.

Acyclovir should never be administered as an IV push or via subcutaneous or intramuscular routes.

Administration in a larger volume over a longer period of time is recommended.

Adequate Hydration

Hydration is recommended to be initiated 1-2 hours prior to starting the treatment. 

Particular attention should be paid to patients at risk of fluid overload (e.g. congestive heart failure, cirrhosis).

 

References:

Adapted from supplementary information:
Dubrofsky L, Kerzner RS, Delaunay C, Kolenda C, Pepin J, Schwartz BC. Interdisciplinary Systems-Based Intervention to Improve IV Hydration during Parenteral Administration of Acyclovir. Can J Hosp Pharm. 2016 Jan-Feb;69(1):7-13. doi: 10.4212/cjhp.v69i1.1517. PMID: 26985083; PMCID: PMC4777587.