By Jean McCaslin, RN, IgCN

Nurses in a variety of settings follow an infusion titration (increasing or decreasing the rate of the dose) when infusing many medications. While it is understood that the use of titration is prudent particularly for first-dosing, there are no established uniform standards in the industry for infusing many medications, including intravenous immunoglobulin (IVIG) and infliximab (brands include Remicade®, Inflectra® and Renflexis®). Titration standards may be developed by individual prescribers, hospital systems, nursing agencies, outpatient infusion centers, or specialty pharmacies, yet each may differ from the other. "As needed" guidelines may also be developed, specifically for when and how to increase or decrease the rate of an infusion during an infusion, based on objective or subjective factors.

Nurses may leave one job for another, or take on a second part-time or per-diem job. It is considered best practice for a nurse to learn the specific policies and procedures for each site of care. Many titration protocols are "one size fits all"; sometimes, a patient-specific approach may be taken. In the home infusion setting, each patient chart should denote titration schedules specific to the patient, as the prescribers originate from a vast number of practice settings.

Key factors in the determination of titration rates and schedules:

• Manufacturer package insert: Contains brand-specific administration instructions, which may include recommended titration steps and maximum rates; based on published clinical trial results submitted to the FDA, as well as post marketing data.
• Weight
• Medical history and risk factors/comorbidities (e.g., age, diabetes, hypertension, clotting history, renal disease, cardiac disease, hepatic disease, neurological conditions, respiratory disorder)
• Dose: low or high, dose per day
• Past history of infusion tolerance
• Individual physician, specialty practice, hospital system or specialty pharmacy orders and protocols

For every patient and each therapy:

• Over time, things may change so it is important to check doctors' orders for each patient before each dose and review the brand, concentration, dose and proposed titration schedule and compare against patient weight.
• Locate and have available the anaphylaxis kit and know the protocol.
• Check pre-medications; anticipate extra time when IV hydration and IV push or IV piggy-backs are ordered. Generally, oral pre-medications should be taken 30 – 60 minutes before primary drug administration.
• Anticipate additional time needed in the event an adverse drug reaction (ADR) occurs and infusion time prolonged; never exceed the maximum infusion rate noted on the titration orders.
• Discuss patient requests for more rapid infusion with the pharmacist since the titration schedule may have been determined based on risk factors. The pharmacist will obtain new orders as necessary.
• Review nursing agency and infusion pharmacy recommendations for decreasing infusion rates when side effects are experienced.
• Typically, analgesics and anti-histamines are prescribed and can be repeated every 4 - 6 hours. When a patient refuses pre-medications, and symptoms arise, encourage patient to reconsider taking them.
• Encourage patient to adequately hydrate before, during, and after infusion. For adults without fluid restriction or comorbidities such as renal disease or congestive heart failure, 64 ounces of water over the course of a day is recommended. When headache is noted, push water-based oral intake; consider Gatorade when not contraindicated.
• Infusion related reactions (IRR) are those that occur during an infusion and thought to be rate-related. IRRs include minor vital signs changes and some mild side effects such as headache, chills, flushing and changes in blood pressure and pulse.
• For IRRs and any ADRs while infusing:
  
  
  • Decrease the infusion rate by half and monitor.
  • If stable, resume the infusion at the reduced rate and titrate as tolerated.
  • If the reaction persists or worsens, hold the infusion until the reaction resolves.
  • For reactions such as headache, chills and flushing, repeat ordered analgesic and anti-histamine premedication(s) if enough time has passed.
  • If stable, resume the infusion at the reduced rate and titrate as tolerated.
• For life-threatening reactions such as urticaria, severe hypotension, angioedema, wheezing, difficulty in breathing or swelling of eyelids or lips, stop infusion, follow anaphylaxis orders and call 911 as necessary. Once the patient is stable, inform the prescriber and NuFACTOR.
• Report to NuFACTOR the inability to increase the rate due to significant, persistent or recurrent side effects. A lower maximum infusion may warrant communication to the nurse (if different) administering the next infusion, pump reprogramming, a new titration sheet and prescription label. If necessary, the pharmacist may suggest interventions, some of which may require physician approval.
• The tolerability of the specific dose, product and titration rates should be assessed post-infusion. Contact NuFACTOR clinical staff to discuss concerns as well as when there are any questions in order to keep open the lines of communication to facilitate optimum patient care.

IVIG

Often, prescriber orders do not include specific administration-related instructions. In the absence of such, the NuFACTOR pharmacist will conduct a patient assessment and determine an appropriate titration schedule. Having pharmacists well-trained on IVIG product differences and expertise in the assessment of IVIG patients is an essential component of the patient experience. These experts must be involved in any IVIG infusion titration protocol. When prudent, individual accommodations must be put in place on a case by case basis

Immune Globulin National Society (IgNS) standards of practice state each IVIG infusion should be administered following a minimum of three dose increments. NuFACTOR recommends 3 - 5 dose increments for first-dosing; these titrations are pre-programmed in the infusion pump prior to shipment and should be reviewed by the nurse. Once IVIG brand and dose tolerance has been established, three dose increments may be used for maintenance infusions; this may require pump reprogramming.

Many nurses have been trained that a dose of 10 gm/hour is prudent for all patients. Some believe a 10% IVIG product should never exceed a certain rate, such as 125 ml/hour and 250 ml/hour for a 5% product. These statements might be true if all patients were created equal! Some nurses may not know clinical trials were performed for each brand and concentration and FDA-approved package insert rates are based on weight and risk of problems such as thromboembolism, renal dysfunction and fluid overload.

The pharmacist works with the prescribing physician to review individual patient metrics, as well as the package inserts for individual IVIG products to determine an infusion plan. It would not be unusual for a 40 gram dose to be infused over 4 hours for a 150 lb., 40 year old patient with no comorbidities but over 7 or 8 hours for the same dose infused in the same patient who has a history of dependent mellitus and pre-renal azotemia.

Another titration rate determination factor is product concentration. The volume of IVIG 10 gm is 100 ml for a 10% product but 200 ml for a 5% product. Because of this difference, maximum infusion rates are lower for 10% products. The extra volume in IVIG 5% provides hydration during the infusion and may be an alternative to separately infusing IV hydration with IVIG 10%. This may be a good option with the current IV fluid shortage caused by last year's hurricane affecting manufacturing plants in Puerto Rico. Conversely, the double volume of IVIG 5% compared to IVIG 10% may not be contraindicated for patients who are fluid restricted or have comorbidities such as renal dysfunction of congestive heart failure.

Any specific nursing agency protocol that is in conflict with a NuFACTOR determined IVIG titration schedule should be directed to NuFACTOR clinical staff for discussion.

Infliximab

Infliximab has been infused in controlled settings for a great many years (Remicade® was FDA approved in 1998). Although it has also been infused in the home setting, it may be new to some clinicians. Two biosimilar infliximab preparations have entered the market (Inflectra® and Renflexis®).

When Remicade® was first approved, a dose titration was specified in the package insert. Sometime later, this recommendation was removed and now the package insert states simply to infuse over at least 2 hours. Some providers, like NuFACTOR, recommend dose titration for each infliximab infusion to enhance patient tolerance. Individual infusion centers and/or physicians may prefer their own long-standing protocols. In absence of a prescriber order, the NuFACTOR pharmacist will determine an appropriate titration schedule.

Infliximab infusion titration schedules may vary in starting rates, incremental rates and incremental times for each rate. The NuFACTOR pharmacist considers past infliximab history and tolerance when determining a titration schedule. NuFACTOR's suggested titration is to initiate the infusing at 25ml/hour for 10 minutes. If tolerated at each step, the rates are increased sequentially to 50 ml/hour x 10 minutes, then 75 ml/hour x 10 minutes, then 125 ml/hour for the remainder of the infusion. Regardless of titration protocol, vital signs must be taken prior to each rate increase.

Some settings may have a "Rapid Remicade" protocol where infliximab is infused faster than the package insert-recommended minimum of 2 hours, typically over one hour. Protocols vary and usually require a certain number of doses to first be administered over the minimum 2 hours with no ADRs (or only mild ones). Some require a specific pre-medication regimen, sometimes including a steroid. Pre-medications may need to be administered as part of the protocol (and not "prn"). NuFACTOR will consider Rapid Remicade with specific orders for patients previously receiving infliximab successfully following the protocol in a controlled setting.

Conclusion

IVIG and infliximab infusions are generally well-tolerated. Many infusion-related side effects are expected, mild, and well controlled with pre-medications, adequate oral hydration, and careful infusion rate adjustments. Although striving for optimal tolerance starts well before the medication is infused, ADRs can still occur. Therefore, it is critical the nurse is knowledgeable of the medications, different products and risk factors, knows and follows titration schedules, possesses astute monitoring skills and takes appropriate action when ADRs occur. Communicating and collaborating with the NuFACTOR pharmacist can result in the best possible patient outcome.