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A nurse-led accelerated procedure for infliximab infusion is well tolerated and effective in patients with inflammatory bowel disease

Digestive and Liver Disease, 5, 47, pages 372 - 377



Shorter infusions of infliximab for inflammatory bowel disease seem to be as tolerated as standard procedures and nurses may be able to manage them safely.


To test tolerability and effectiveness of a fast nurse-led infusion procedure and the related patients’ satisfaction.


We retrospectively compared three different regimens adopted in our outpatient infusion unit from 2010 to 2013: Group 1, a standard procedure with two-hour infusions, preceded by hydrocortisone medication (87 patients, 311 infusions); Group 2, a similar regimen without physician supervision (130 patients, 464 infusions); Group 3, a one-hour nurse-led procedure without routine premedication (176 patients, 1356 infusions). Disease characteristics, infusion reactions, infusions per month and patients’ satisfaction were recorded.


There were significantly fewer infusion reactions in Group 3 than Group 1 (2.2% versus 5.8% respectively;p = 0.001). The only significant risk factor for side effects was premedication (odds ratio 4.71, 95% confidence interval 2.21–10.02,p < 0.001) which was related to the presence of previous side effects. Number of infusions per month increased by 27% (83 versus 61,p < 0.001) without increasing nurses’ workload and patients were satisfied.


Our fast nurse-led procedure was well tolerated, effective and satisfactory for patients.

Keywords: Cost-benefit, Infusion reactions.

1. Introduction

Tumour necrosis factor α (TNFα) is now recognized as one of the key inflammatory cytokines involved in chronic conditions such as inflammatory bowel diseases (IBD). Infliximab is a chimeric antibody against human TNFα that has proved effective in both Crohn's disease and ulcerative colitis[1], [2], and [3]. Scheduled administrations are now preferred with a view to maintaining remission [4] , and the drug is usually administered over a 2-hour period followed by one hour of clinical observation [5] .

Medication, and anti-TNFα medication in particular, accounts for the main healthcare costs relating to patients with IBD, while productivity losses due to absence from work account for 16–39% of the total social costs of these conditions [6] . In a recent study comparing the costs of biological drugs for luminal Crohn's disease, significantly lower costs were associated with the use of adalimumab and this was due mainly to the costs associated with the administration of infliximab [7] . The time spent monitoring the infusion accounts for 8.7% of the total cost of using this drug [8] .

Faster infusions, lasting one hour or thirty minutes, with or without post-infusion monitoring, have recently been proposed for patients who tolerate the standard procedure well, and they have proved safe in adults[9], [10], and [11]and children [12] . Such shorter infusion times can also be managed safely at dedicated units by nurses specifically trained to handle biological infusions[13], [14], and [15].

A recent meta-analysis on the use of shorter infliximab administration times in patients with IBD, rheumatological diseases or psoriasis emphasized the differences in the design of previous studies. Indeed much heterogeneity exists in administration protocols, use of premedication, infliximab dosage, and types of infusion reactions considered [16] . To date, there have been no cohort studies on nurse-led protocols involving shorter infusion times, without routine premedication and with variable doses of infliximab. The aim of the present study was therefore to test the effectiveness and tolerability of this protocol, and the related patients’ satisfaction. Given the increasing usage of infliximab to treat IBD, such a protocol could substantially reduce healthcare costs, lower the impact of drug administration on the increasingly limited hospital resources, and improve patients’ quality of life.

2. Materials and methods

This was a single-centre retrospective cohort study on IBD patients treated with infliximab on a scheduled maintenance basis from June 2010 to December 2013 at the Unit of Gastroenterology, Department of Surgical, Oncological and Gastroenterological Sciences, at the Padua University and General Hospital. All infusions were administered at our outpatient infusion unit manned by two dedicated nurses, a medical registrar and a gastroenterologist in a supervisory role. To avoid missing infusions nurses phoned the patients missing an infusion to re-schedule. Follow-up visits were planned at the discretion of the physician at the outpatient clinic.

The change in the administration procedure was developed from 2010 to 2013 by the head of the IBD unit in agreement with the head of the Gastroenterology unit and in accordance to the revision of European public assessment report (EPAR) for infliximab (available online at European Medicines Agency website), which allowed shortened infusions of the drug. The aim of the change was to meet the increasing requests of infliximab treatment and to accomplish a reduction of the time spent in hospital demanded by patients.

Information was recorded at each infusion on each patient's diagnosis, the extent and behaviour of their disease, the number of infliximab infusions they had received, and concomitant therapies. All infusion reactions were recorded, as were doctor's visits and changes made to the infusion protocol. All patients were taught to monitor changes in their state of health and to report any adverse reactions between sessions. During infusions, they were monitored for any onset of symptoms and vital signs were checked before and after the infusion.

The study was notified to the local ethical committee (“Comitato Etico per la Sperimentazione Clinica della provincia di Padova”) on September 2014 according to the Italian law “Determinazione AIFA 20 marzo 2008” for non-interventional studies.

2.1. Infusion procedure and patient selection

Patients treated with infliximab from June 1st to December 31st 2010 formed a first group (Group 1) treated using the standard physician-led procedure, which consisted of a two-hour infusion preceded by premedication with hydrocortisone and followed by clinical observation for two hours during the induction phase, and one hour during the maintenance phase.

A second group (Group 2) comprised patients treated from June 1st to December 31st 2011, who followed a nurse-led procedure in the maintenance phase. Patients were assessed by the nurse before the infusion using a specific questionnaire designed to identify any contraindications (signs and symptoms of infections experienced during the previous few days). The infusion regimen was the same as for Group 1 and the nurse monitored vital parameters during and at the end of the infusion. The physician remained on call.

In Group 1 and Group 2 inclusion/exclusion criteria were the same for infliximab prescription.

Patients treated from January 1st 2012 to June 30th 2013 formed a third study group (Group 3) that followed a one-hour nurse-led procedure. According to the EPAR summary patients were eligible if they had no history of severe infusion reactions and if they had received stable doses of the drug in recent infusions. This protocol was never used during the induction period and only started with the fifth infusion. Premedication was not given routinely, but only if a patient had experienced a prior infusion reaction or had taken a holiday from therapy.

While all the patients in Group 1 were assessed by the physician before and during the infusion according to the protocol, the patients in the two groups treated with nurse-led procedures were seen by the physician only on demand (if warranted by the answers given in the questionnaire administered to patients before each infusion or in the event of suspected or documented acute reactions during an infusion).

Before starting the nurse-led protocol, nurses were given specific training on the whole strategy of biological administrations to improve their awareness. Drug pharmacology, dosing and scheduled treatment strategies were explained, and nurses were taught to recognize and treat any adverse event.

2.2. Definition and management of infusion reactions

Acute infusion reactions were defined as any adverse experience that occurred during or within one hour after an infliximab infusion. They were classified as mild (headache, mild fever, erythema, paraesthesia, nausea, pruritus), moderate (chest pain, mild dyspnoea, palpitations, urticaria, mild hypotension or hypertension, fever) or severe (severe hypotension or hypertension, dyspnoea with laryngospasm, anaphylactic shock).

Nurses were trained to manage infusion reactions with the aid of a protocol summarized in Appendix A .

Patients were instructed to report any delayed infusion reactions, defined as arthralgia, myalgia, fever or rash, occurring between 1 and 14 days after the infliximab infusion.

2.3. Effectiveness analysis

We traced the total number of infusions performed in our unit per month in the three different time periods since the increased need for infusions prompted the monitoring of the unit's performance.

We also assessed the impact on nurses’ workload given their central role in the new procedure. The weekly working time of the two nurses in our infusion unit has been recorded as a full-time equivalent (FTE).

2.4. Patients’ satisfaction questionnaires

For administrative purposes a patient satisfaction questionnaire was developed and randomly administered to assess the impact of the new fast nurse-led procedure on quality of life and health perception. Specific items were investigated using Likert and rating scales, with questions concerning how the accelerated infusion interfered with their daily activities (occupation, family or spare time), the safety of the nurse-led protocol, and the patient's relationship with his gastroenterologist. Data were collected anonymously.

2.5. Statistical analysis

All statistical tests were performed using the SPSS 13.0 statistical software package for Windows (SPSS Inc.). Descriptive statistics were used for population and subgroup characteristics; Chi square and Kruskal–Wallis tests were used to assess any differences among the three groups. The threshold for significance was set at 0.05. The Chi square test was also used to assess any differences in the occurrence of infusion reactions and in the medical assessments between the three groups of patients. Post hoc analysis with Bonferroni's method was used for multiple comparisons, setting the level of significance at 0.0167. A binary logistic regression model for multiple variables was used to identify any risk factors related to infusion reactions. Odds ratios (OR) and 95% confidence intervals (CI) were calculated. The Mann–WhitneyU-test was used to compare the number of infusions performed per year at our unit.

3. Results

In all, 2131 infusions were administered to 395 patients enrolled in the three groups, i.e. 87 in Group 1, 130 in Group 2, and 178 in Group 3, who received a total of 311, 464 and 1356 infusions, respectively. All 87 patients in Group 1 were also included in Group 2, while only 112 patients in Group 2 were also involved in Group 3. None of the patients missed any infusion.

The three groups were similar for what concerns gender, age, disease duration and diagnosis while the proportion of patients taking immunomodulators was lower in Group 1. Patients’ characteristics are summarized in Table 1 .

Table 1 Characteristics of the patients by group. Group 1: standard infusion; Group 2: two-hour nurse-led infusion; Group 3: one-hour nurse-led infusion.

  Group 1 Group 2 Group 3 p
Patients (n) 87 130 178
Median age (years, IR) 41 (33–47) 40 (30–46) 42 (35–48) 0.259
Males (n, %) 52 (59.8) 75 (57.7) 109 (61.2) 0.822
Median Disease duration (years, IR) 10 (5–14) 10 (5–13) 10 (5–13) 0.549
Crohn's disease (n, %) 55 (63.2) 86 (66.1) 108 (60. 7) 0.616
Immunomodulator use (n, %) 3 (3.4) 17 (13.1) 26 (14.6) 0.024

IR, interquartile range.

The induction infusions amounted to 38/311 (12.22%) in Group 1, and 68/464 (14.66%) in Group 2; there were none in Group 3 because the one-hour infusion protocol could only be adopted from a patient's fifth infusion onwards. Table 2 shows the characteristics of all the infusions administered (dosage, premedication and concomitant immunomodulators).

Table 2 Characteristics of the infusions administered. Group 1: standard infusion; Group 2: two-hour nurse-led infusion; Group 3: one-hour nurse-led infusion.

  Group 1 Group 2 Group 3 p
Infusions (n) 311 464 1356
10 mg/kg (n, %) 3 (0.96) 29 (6.25) 112 (8.26) <0.001
Steroid premedication (n, %) 311 (100) 464 (100) 380 (28.02) n.a.
Immunomodulator use (n, %) 10 (3.22) 65 (14.00) 165 (12.17) <0.001

n.a., not applicable.

There were 18 infusion reactions recorded in Group 1: 10 acute (8 mild and 2 moderate) and 8 delayed. Among the patients with mild reactions, one developed diffuse erythema with pruritus during three different infusions despite premedication, one had facial erythema, three had diffuse pruritus, and one had erythema at the infusion site; only one of the patients experiencing mild reactions was taking concomitant immunomodulators (methotrexate). Moderate reactions occurred twice in the same patient, who complained of mild dyspnoea, which regressed after the infusion was discontinued and antihistamines were administered; he was not taking immunomodulators. During the days after the infusion, five patients developed skin rash, two arthralgia and one fever; no immunomodulator usage was reported. The rate of infusion reactions in Group 1 was 3.22/100 infusions for acute reactions, and 2.57/100 infusions for delayed reactions.

In Group 2 there were 14 infusion reactions: 3 acute (2 mild and one moderate) and 11 delayed. The two mild reactions (erythema) occurred in the same patient. The moderate reaction (urticaria) responded to antihistamine treatment. Among the delayed reactions, there were 3 cases of skin rash, 8 of arthralgia, and one of fever a few days after the infusion; two patients experiencing arthralgia were taking immunomodulators (azathioprine and methotrexate). The rate of infusion reactions in Group 2 was 0.65/100 infusions for acute reactions, and 2.37/100 infusions for delayed reactions.

Group 3 experienced 30 infusion reactions: 19 were acute (10 mild and 9 moderate), and 11 were delayed. Five patients developed erythema (one of them twice) and 4 suffered from pruritus. Four patients had mild dyspnoea, one had chest pain, and one had palpitations during four different infusions. All the moderate reactions were overcome by discontinuing the infusion and administering antihistamines. Three patients experienced delayed reactions: two had skin rash (which occurred after five different infusions in one patient) and one arthralgia and skin rash after five different infusions. None of the patients in Group 3 who experienced an infusion reaction was taking immunomodulators. The rate of infusion reactions inGroup 3was 1.4/100 infusions for acute reactions, and 0.81/100 infusions for delayed reactions.

No severe reactions were reported in the three groups during the study period. Discontinuation of infliximab therapy due to infusion reactions occurred in Group 1 after the second episode of dyspnoea in the same patient, in Group 2 after a severe skin rash as a delayed reaction and in Group 3 after four moderate reactions (chest pain, 2 cases of dyspnoea and after the recurrence of palpitation in the same patient).

A significant difference emerged between the three groups in the rate of total infusion reactions (p = 0.003, Fig. 1 ). After performing post hoc analysis for multiple comparisons, Group 3 had a significantly lower rate of infusion reactions than Group 1 (2.2% versus 5.8%, respectively;p = 0.001), while the differences between Group 2 and 3 (p = 0.330), and between Group 1 and 2 (p = 0.057) were not statistically significant.


Fig. 1 Infusion reactions. Group 1: standard infusion; Group 2: two-hour nurse-led infusion; Group 3: one-hour nurse-led infusion.p = 0.003.

Possible risk factors for the onset of infusion reactions were investigated using a multivariate analysis. A binary logistic regression model was designed, considering patient's age, gender, disease diagnosis, disease duration, cumulative number of infusions received, infliximab dosage, interval since last infusion, premedication with steroids, and concomitant immunomodulators as covariates ( Table 3 ). This model was only applied to the 1356 infusions in Group 3 because all patients in the other two groups had received premedication with steroids. The final model identified one risk factor (premedication: OR 4.706; 95% CI 2.211–10.018), and one protective factor (cumulative number of infusions received: OR 0.950; 95% CI 0.909–0.992), albeit with a rather weak association for the latter.

Table 3 Multivariate analysis of possible risk factors for infusion reactions using binary logistic regression.

  All variables included Final model
  p p OR 95.0% CI for OR
        Lower Upper
Age (years) 0.332      
Gender 0.941      
Diagnosis (UC, CD) 0.829      
Disease duration (years) 0.594      
Cumulative number of infusions 0.017 0.021 0.950 0.909 0.992
Infliximab dosage (5, 10 mg/kg) 0.946      
Interval since last infusion (weeks) 0.082      
Steroid premedication <0.001 <0.001 4.706 2.211 10.018
Immunomodulator use 0.995      

UC, ulcerative colitis; CD, Crohn's disease; CI, confidence interval; OR, odds ratio.

No significant differences emerged in the need for medical assessment before the infusions between Group 2 and 3 (8.6% versus 6.5% respectively,p = 0.121), while the physician was called in significantly more often in Group 2 compared to Group 3 during the infusions (3.8% versus 1.1% respectively,p < 0.001).

The new procedure enabled significantly more infusions to be scheduled each month, with a 27% increase from 2010–2011 to 2013 (median 61, IR 55–66 versus 83, IR 71–93;p < 0.001). Meanwhile, the nurses’ workload did not increase since the FTE of the two nurses remained the same (one working as 1 FTE and one as 0.5 FTE).

The patient satisfaction questionnaire was randomly administered to 75 patients in Group 3 who had experience of the standard infusion protocol to ascertain their opinion of the nurse-led shorter protocol. Seventy patients returned the questionnaire (93%) and 91% of them said the new infusion protocol enabled them to spend less time in hospital; 49% of patients said they would spend the time they saved on their daily activities (work/school), 29% said they would spend the time they saved with their families and nearly one in two felt that their relatives would benefit from the accelerated protocol (49%).

As concerns tolerability, 71% of the patients judged the new protocol to be just as safe as the physician-led alternative, and 17% of them even judged it to be safer. The patients’ relationship with the physician nonetheless remained very good: 79% of the patients felt comfortable with the idea of seeing the doctor only if necessary and at scheduled follow-up visits, and in 99% of cases their perception of their state of health was unchanged.

4. Discussion

The rate of infusion reactions in patients following the standard infusion procedure (Group 1) is comparable with the findings of other studies[11] and [17]. We found a significantly lower incidence of infusion reactions with the one-hour, nurse-led protocol, as also reported elsewhere[11] and [13]. The authors of the previous studies attributed this result to a selection bias, given that only patients with a proven tolerance of the standard infusions were eligible for the faster infusion protocols. On the other hand, our findings indicate that the infusion time could be shortened even for patients with previous mild or moderate reactions, providing they were given premedication with steroids before the infusion. Another potential selection bias in our study could relate to the exclusion of the first four infusions (in the induction phase) since the fast protocol adopted forGroup 3began with the fifth. Infusion reactions are known to be more common during a patient's first few infusions, possibly due to hypersensitivity to the chimeric protein or to the development of anti-infliximab antibodies [5] . We used a multivariate analysis to investigate specific risk factors for the onset of infusion reactions and the binary logistic regression model confirmed the cumulative number of infusions received by a given patient as a slightly protective factor. This means that having excluded the first four infusions from our analysis may have lowered the rate of infusion reactions (although the induction infusions account for only a small proportion of the total infusions administered to patients inGroups 1and2).

Several studies have reported a relationship between anti-infliximab antibodies and infusion reactions. A recent meta-analysis found the presence of these antibodies associated with a higher risk of acute, but not delayed infusion reactions [18] . The concomitant use of immunomodulators has consequently been recommended to contain the rate of these reactions[19] and [20], but current data on their efficacy are conflicting[10], [13], [16], and [21]. Our multivariate analysis indicated that the concomitant use of immunomodulators is not a protective factor, though only a small proportion of the patients in our sample were taking these drugs.

Another factor identified by our multivariate analysis – as a risk factor – was premedication with steroids. This may reflect the confounding effect of administering premedication to patients who had already experienced a mild infusion reaction in the past or who had been on holiday from the treatment since their last infusion. On the other hand, our multivariate analysis indicated that having temporarily suspended the scheduled maintenance treatments did not influence the onset of infusion reactions: patients with an interval between infusions of more than ten weeks carried the same risk as patients receiving monthly infusions. Similar results were reported by Rutgeerts et al. and by Domènech et al.[4] and [22], who found that resuming infliximab infusions even after longer intervals did not affect the rate of infusion reactions.

The significant risk seen in patients taking premedication therefore probably related more to an individual predisposition to infusion reactions than to the premedication per se, since several of our patients experienced more than one reaction with both the standard and the shorter infusion protocols. Premedication with steroids did not emerge as a protective factor in other studies either[5], [13], and [16], and a randomized controlled trial demonstrated that they reduced anti-infliximab antibody levels but they did not significantly affect their formation or the rate of infusion reactions [23] .

Age, gender, diagnosis, disease duration, and infliximab dosage did not emerge as significantly influencing the risk of infusion reactions. The lack of any significant correlation between high dosage (10 mg/kg) and infusion reactions seems to make a dose-effect relationship less likely. Although less than 10% of the infusions administered inGroup 3involved a dose of 10 mg/kg, their number is still comparable with the figure in the study by Babouri et al. [15] .

Our study revealed a lower incidence of infusion reactions in the nurse-led one-hour infusion group, which was also confirmed by the lesser need to consult a physician during the infusions administered in Group 3 than in Group 2. The only factors influencing the risk of adverse reactions seemed to be cumulative exposure to the drug and a history of infusion reactions, suggesting a role for an individual predisposition due to interaction between the drug and the immune system of certain patients.

As for the impact on healthcare resources, shorter infusion protocols coincided with a significant reduction in costs - of up to 37% per infusion[5], [16], and [24]. Van Assche et al. reported that premedication significantly lengthened the time patients spent at the outpatients unit to receive one-hour infusions [10] . We focused instead on the number of infusions administered per month at our unit, and found that the new, faster protocol enabled a 27% increase. It also saved the health care staff's time, both physicians’ and nurses’, since more patients could be managed without increasing the number of nurses or their working time dedicated to infliximab administration. Indeed, shortening the infusion time is not the only difference between the fast nurse-led procedure and the standard regimens: routine premedication was abolished, post-infusion monitoring was shortened and the absence of a routine physician evaluation reduced the time of patients’ initial assessment and discard. Likewise, Saxena et al. recently found that 30-minutes infusions decreased direct cost of nursing by 51% per infusion [25] .

As infliximab is increasingly used in several inflammatory conditions, the role of nurses in its administration becomes crucial. Training them on how to instruct and support patients, administer the treatment, and manage any side effects is fundamental to ensure a high quality of care. Our patient satisfaction questionnaires indicated that patients felt safe with the nurse-led regimen, and their relationship with the gastroenterologist did not change. They reported being satisfied with the shorter infusion times because this meant spending less time in hospital, and consequently fewer absences from work, more spare time, and even advantage for their relatives. A greater degree of patient satisfaction could positively affect patients’ adherence to the treatment, thereby further reducing the healthcare costs. In fact, non-adherence is reported for as many as 25–35% of patients with Crohn's disease treated with infliximab, and it is associated with higher medical costs and hospitalization rates[26] and [27].

In conclusion, the nurse-led one-hour procedure considered in this study proved well-tolerated, more convenient for patients, and useful for the purpose of saving and better allocating healthcare resources.

Conflict of interest

None declared.


We would like to thank nurses Anna Carlà and Paola Migliolaro for their precious collaboration in this work.

Appendix A. Supplementary data

The following are the supplementary data to this article:


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a Department of Surgical, Gastroenterological and Oncological Sciences, Azienda Ospedaliera – Università di Padova, Padua, Italy

b Clinical Research Unit, Azienda Ospedaliera – Università di Padova, Padua, Italy

lowast Corresponding author at: Divisione di Gastroenterologia, Dipartimento di Scienze Chirurgiche, Oncologiche e Gastroenterologiche, Azienda Ospedaliera – Università di Padova, Via Giustiniani 2, 35128 Padova, Italy. Tel.: +39 0498212893; fax: +39 0498760820.