Biologic therapy, also referred to as biologics, include the use of agents derived from biological sources or of agents that affect biological responses. Primarily, these are products derived from the mammalian genome (Alexander et al, 2010). Infliximab (IFX) is a chimeric (ie part murine, part human) monoclonal antibody that binds with high affinity and specificity to tumour necrosis factor-α, a potent proinflammatory cytokine, to neutralize its biological activity. The overall incidence of infusion reactions to IFX is 6.1%, according to previous research (Cheifetz et al, 2003). The exact mechanism and cause for the infusion reactions related to biologic agents are unknown and often believed to be non-Immunoglobulin E(IgE) mediated. The types, severity and manifestations of infusion reactions vary among biologic agents, but have some commonality. These include symptoms, including dizziness, headaches, and chest tightness, or signs such as rash or hypotension (Alexander et al, 2010).
The introduction of newer monoclonal antibodies to the market, without manufacturer recommended vital signs assessment and monitoring parameters, as well as clinical experience with IFX and other monoclonal antibodies, led to a review of collected infusion data to determine if evidence and literature support the practice of scheduled vital signs assessment during IFX infusions for the detection of infusion reactions.
Infliximab is a top-selling drug used widely in patients with rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, psoriatic arthritis, and plaque psoriasis – the Health Canada approved clinical indications. The drug is administered under Health Canada's imposed manufacturer's guidance.
Background
Privately owned and operated infusion clinics began to appear in the early 2000s, when a number of IFX clinical trials ended and some hospitals could no longer provide services to these patients. In subsequent years, the number of private infusion clinics grew significantly and these clinics now administer a wide variety of specialty infusion and injection therapies as well as other services.
Setting
The infusion clinics providing this data are privately owned and operated, and work under contract to provide infusion services for a variety of specialty medications for a number of manufacturers. The clinics are generally located in medical office buildings near urgent care facilities, and are equipped to deal with any infusion reactions that may occur. Infusion nurses may be Registered Nurses or Licensed Practical Nurses, depending on the scope of practice within their province, their experience, and training, as well as the patient population being served and contract requirements. All infusion nurses receive both standardized online and hands-on training on each therapy administered at their clinic, infusion reaction detection, monitoring, and management, and a physician trained in the recognition and management of infusion reactions is available for nurse consultation at all times.
Patient population
Patients served in community infusion clinics can range in age from pediatric to elderly, depending on the contracts for a particular clinic and community needs. The infusion clinics often work closely with local hospitals and pediatric centres to ensure the provided services meet their standards and expectations and follow similar guidelines for care. The clinics accept both first dose patients as well as patients who have been on therapy long term.
Patients may or may not be ordered premedications (such as acetaminophen, diphenhydramine, and hydrocortisone) pre-infusion, at the discretion of their prescribing physician.
Infusion therapy protocol
Standard IFX infusions are two hours in length, as per the manufacturer standardized recommended protocol. The standardized recommended protocol includes specific recommendations for premedication based on patient history of reactions, as well as the required frequency of vital signs assessment, infusion start rate, and titration rate, and the management of infusion reactions. Premedications are administered as ordered by the prescribing physician. Vital signs (blood pressure, pulse, respirations and temperature) are assessed and documented pre-infusion for a baseline, then every 30 minutes during the infusion, as well as post infusion, prior to discharge, amounting to at minimum five vital signs checks during a two-hour infusion. The infusion rate is slowly titrated up according to a standardized protocol, and all care provided is documented according to standardized protocols.
Shortened IFX infusions are one hour in length and are typically for rheumatoid arthritis patients that have completed their first three infusions without any reactions and must adhere to the standardized manufacturer recommended protocol for shortened infusions. Vital signs for shortened infusions are assessed pre-infusion for baseline, midway through the infusion at the 30-minute mark, and at the end of the infusion.
The frequent and potentially unnecessary scheduled vital signs checks can amount to a significant amount of nursing resources over time, especially in major hospitals and community infusion centres with a large volume of patients. See Table 1.
Table 1. Potential impact on nursing resources
| Current standard IFX infusion protocol | Suggested protocol |
|---|---|
| 5 vital signs checks per infusion | 1 vital signs check pre-infusion then prn |
|
|
| Nursing time: 8,997 hours/year | Nursing time: 1,799 hours/year |
| Potential savings: 7,198 hours/year (based on 35,988 Standard IFX infusions per year) | |
Adverse event reporting
By contract with the manufacturer, any IFX infusion reactions are considered an adverse event and must be reported to the manufacturer immediately, using an official manufacturer provided Adverse Event Report. This document is the official record of the infusion reaction and is completed by the infusion nurse the same day as the infusion reaction occurs and is submitted to management, as well as the manufacturer for review and submission to Health Canada. These infusion reactions are also documented in the daily infusion clinic log and other patient chart documentation as needed. To ensure compliance with Health Canada regulations and contractual requirements for adverse event reporting, extensive report tracking, reconciliation, and chart audits are performed bi-monthly by internal audit processes and annually or biannually by external audit specialists contracted by the manufacturer.
Methods
This study was performed with data collected from 57 Canadian infusion centres owned and operated by the largest, privately owned infusion clinic network in Canada. The geographic distribution of clinics providing data for this study spans from Edmonton, Alberta, to St John's, Newfoundland.
Infusion reaction data and patient records for all 35,988 IFX infusions administered in 2017 were reviewed. Of 101 infusion reaction cases recorded by the infusion nurses in 2017, seven cases were excluded from this review due to incomplete records, and four cases were excluded due to the reaction occurring post infusion. The remaining 90 cases of infusion reactions that occurred during the infusion were selected for further review and analysis for this paper, consisting of 77 unique patients, some of which had multiple reactions in 2017. Patient demographics, including gender, ages, and primary indications for treatment, varied and are detailed in Table 2.
Table 2. Demographics of 2017 Infusion Reaction Cases Reviewed
| Gender | Total sample |
|---|---|
| Unique patients | 77 |
| Male | 45% (35) |
| Female | 55% (42) |
| Age (years) | |
| Median | 46 |
| 14–17 | 3 |
| 18–24 | 9 |
| 25–34 | 20 |
| 35–44 | 15 |
| 45–54 | 9 |
| 55–64 | 12 |
| 65+ | 9 |
| Primary indication | |
| Ankylosing spondylitis | 5 |
| Crohn's Disease | 47 |
| Other | 2 |
| Psoriasis | 2 |
| Rheumatoid arthritis | 3 |
| Ulcerative colitis | 18 |
| Premedicated | |
| Yes | 54 |
| No | 23 |
| Infusion protocol used | |
| Pediatric (2 hours) | 6 |
| Shortened (1 hour) | 13 |
| Standard (2 hours) | 55 |
| Long (4+ hours)* | 3 |
| Total number of infusions patients received prior to experiencing a reaction in 2017** | 31 |
| Median number of infusions | |
| 1–3 | 15 |
| 4–10 | 20 |
| 11+ | 55 |
| Patients with more than 1 infusion reaction in 2017 data set | 8 |
| Patients with a history of infusion reactions in 2016 data set | 5 |
Counts of previous infusions for a small number of patients are approximate, as on occasion patients may receive a few doses of IFX in hospital or another facility without clear records upon transfer. Patient records from initial referral onward were reviewed closely to make all attempts to calculate accurate previous infusion counts. As all IFX patients are treated according to a standardized schedule, including loading doses, this could be calculated
In accordance with the terminology and language used in the official Recommended Standard Protocols provided by the manufacturer, the type of reaction is defined by a symptom list, see Table 3.
Table 3. Manufacturer provided categories of infusion reaction symptoms
| Type of reaction | Mild | Moderate | Severe |
|---|---|---|---|
| Symptoms | DiaphoresisDizzinessFlushingHeadacheNauseaPalpitationsElevated temperature | Chest discomfort (eg tightening, pressure)Hypo/hypertension (≥20 points SBP)Shortness of breathPalpitationsUrticaria | Chest discomfort (eg tightening, pressure)Elevated temperature with rigoursFlushingSignificant hypo/hypertension (≥40 points SBP)Shortness of breath with wheezingStridor |
Source: Janssen BioAdvance, 2018
For each of the 90 selected cases, the official Adverse Event Report of the infusion reaction was reviewed to ensure the case was an infusion reaction symptom as defined by the manufacturer, see Table 3. Each case was then reviewed to determine if the infusion reaction was detected by vital signs assessment. In cases where the Adverse Event Report was unclear as to the exact sequence of events, additional documentation was acquired from the clinic, such as Post Infusion Reports, Infusion Worksheets, Infusion Reaction Notes, and Nursing Progress Notes.
Support and approval for this study was obtained.
Results
Of the 90 complete records reviewed, no infusion reactions (0) were detected by vital signs assessment.
In the cases reviewed, the infusion reaction was detected either by visual observation by the nurse (the patient appeared diaphoretic, flushed, etc., upon visual assessment), or by the patient alerting the nurse they were feeling unwell (reporting symptoms such as headache, nausea, chest discomfort, etc), see Table 4. In three cases, it was unclear in the documentation whether the patient or nurse noticed the first symptoms. In 77% of cases, it was documented that the patient noticed and signaled the first symptom of the infusion reaction to the infusion nurse(s).
Table 4. Results
| How the initial reaction was signaled | |
| Nurse observation | 18 |
| Patient report | 69 |
| Unclear | 3 |
| Classification of initial reaction symptom according to manufacturer definitions (Table 3) | |
| n | 90 |
| mild | 34 |
| moderate | 53 |
| severe | 3 |
| Initial symptom of reaction | |
| Difficulty breathing or chest discomfort | 19 |
| Flushing, diaphoresis | 26 |
| Headache, dizziness | 17 |
| Nausea | 13 |
| Urticaria | 24 |
| Other | 5 |
Discussion
While scheduled vital signs are a mainstay of nursing care across many fields of practice, including infusion therapy, there is little evidence in literature indicating an optimal frequency or clinical benefit for scheduled vital signs assessment during an IFX infusion. Many nursing texts and sources defer to agency policy for monitoring recommendations. Infusion Nurses Society (INS)'s recommendation is to assess vital signs pre-infusion for baseline, then as indicated during the infusion (Gorski et al, 2016). The Canadian Vascular Access Association (CVAA) recommends monitoring vital signs prior to and during, infusion (Canadian Vascular Access Association, 2019) but neither INS nor CVAA recommends a specific frequency. This study was undertaken to attempt to determine the utility of scheduled vital signs monitoring in the detection of infusion reactions to IFX.
More specific to IFX infusions, two articles examining the utility of vital signs monitoring during IFX infusions concluded that acute infusion reactions were not associated with any significant changes in heart rate, systolic blood pressure, or temperature when comparing baseline vitals to those taken prior to the reaction (de Vries et al, 2009; Gold et al, 2018).
An expert panel literature review came to the consensus that aside from a baseline set of vital signs to determine eligibility for infusion, scheduled vital signs during IFX infusions is not of any value in predicting or recognizing acute infusion reactions and should only be performed in case of an acute infusion reaction (de Vries et al, 2011).
It should be taken into consideration in any discussion of nursing resources and IFX infusions that while there are standard premedication recommendations available for these patients, in practice patient orders can vary significantly by prescriber. Some prescribers include premedication orders for all new patients regardless of infusion reaction history, and some include premedications only if an infusion reaction occurs. Premedication orders require extra resources and nursing time, and impact patient risk.
From a clinic management standpoint, a change to standard IFX infusion vital signs monitoring protocol has the potential to yield significant savings in terms of nursing time, allowing nurses to put more time into patient education and support, or other valuable activities (see Table 1). In early March 2020, during the COVID-19 pandemic, to reduce close contact with patients and protect clinic staff, a temporary policy was put in place to reduce scheduled vital signs monitoring frequency. This policy reduced the frequency of vital signs assessment during IFX infusions to a pre-infusion baseline then subsequent checks only as needed. This policy, in addition to other COVID-19 related policy changes, was intended to protect patients and infusion nurses through physical distancing requirements. The reduced vital signs policy allowed infusion nurses to use a verbal/visual check of each patient during their infusion at each interval when vital signs would normally have been rechecked. This temporary change in policy was well-received by manufacturers, patients, and nurses. Anecdotally, patients have reported the reduced vital signs assessment frequency, along with other COVID-19 related safety precautions, reduced their anxiety about their health and safety in the clinic during the pandemic; nurses reported the policy change created a quieter, calmer clinic environment during a high-stress time for all healthcare workers. This requires further study.
Suggestions for practice consideration include the following:
- Mandatory patient education on infusion reaction symptoms and how to alert the nurse when they occur
- Regular and documented visual or verbal checks of the patient during the infusion
- Base facility infusion monitoring protocols on infusion reaction data and research.
Conclusion
According to the infusion reaction records reviewed, scheduled vital signs did not detect any infusion reactions. All recorded infusion reactions were detected either by a visual assessment of the patient by the nurse, or reported by the patient.
Strengths of this study include:
- A large number of patients and infusions
- Extensive electronic patient, infusion and reaction data
- A standardized infusion protocol, which includes standardized premedication, infusion titration rates, and vital sign assessment frequency
- A standardized infusion reaction protocol that clearly outlines infusion reaction symptoms and medical directives on specific medications to administer, and actions to take for each category of symptoms
- A robust and mandatory system for adverse event reporting, including regular internal and external auditing and reconciliation mechanisms
- Standardized education on infusion reaction recognition, management, and reporting across all infusion clinic staff.
Limitations of this review are that the private infusion clinic networks have nurses and pharmacists who specialize in monoclonal antibodies and other specialized therapies, and have strict requirements for training and annual retraining on protocols to be used for infusion, reaction management, and other relevant topics. Nurse training, support, and oversight may vary from a hospital or independently operated clinic.
Another limitation is that of 97 reactions reviewed, 7% (7/97) had to be excluded due to incomplete records.