Open Access

Peripherally inserted central catheters (PICCs) have evolved since their inception in the early 1970s and are used with increasing frequency for pediatric inpatients and outpatients.^1-3 Emerging literature, including a meta-analysis of international observational studies,⁴ reports PICC failure (complications necessitating premature removal) occurs in up to 30% of PICCs, most commonly due to infection, thrombosis, occlusion, and fracture.^4-7 Raffini et al.⁷ report the increasing incidence of pediatric PICC-related thrombosis increases morbidity and mortality⁸ and negatively impacts future vessel health and preservation.⁹

PICCs have progressed from relatively simple, silicone-based catheters with an external clamp to chemically engineered polyurethane with pressure-activated valves placed at the proximal or distal catheter hub with the intent to reduce occlusion.¹⁰ Further modernization of PICC material occurred with the incorporation of antithrombogenic (AT) material (Endexo^®). These PICCs are designed to contain a nonstick polymer, which is designed to reduce the adherence of blood components (platelets and clotting factors) and inhibit thrombus formation (and hence prevent deep vein thrombosis andocclusion, as well as inhibit microbial biofilm attachment [and subsequent infection]).¹¹

In addition to new materials, other aspects of this PICC design have been the addition of a pressure-activated safety valve (PASV^®) built into the proximal hub. Pressure-activated valve technology promises to prevent catheter occlusion by reducing blood reflux into the PICC; the valve opens with pressure during infusion and aspiration and remains closed with normal venous pressure, circumventing the need for clinicians to manually clamp the PICC and reducing human error and the potential for thrombosis, occlusion, and fracture development.¹² Hoffer et al.¹³ reported half as many occlusions of valved PICCs (3.3%) compared with nonvalved or clamped PICCs (7.1%); although not statistically significant (P = .10), perhaps due to the small sample, overall complications, including occlusion and infection, were significantly lessened with the valved PICC (35% vs 79%; P = .02). Comparatively, Pittiruti et al.¹⁴ conducted a trial of 2 types of valved PICCs with an open-ended, nonvalved PICC and found no reduction in PICC occlusion or catheter malfunction.

Today, PICC use is common for patients who require short-to-medium intravenous therapy. PICCs are increasingly recognized for their significant complications, including thrombosis and infection.¹⁵ Novel PICC technology, including the incorporation of AT material such as Endexo^® and PASV^®, may reduce complications; however, the clinical efficacy, cost-effectiveness, and acceptability of these innovations have not been tested through randomized trials in pediatric patients. In accordance with Medical Research Council guidelines¹⁶ for developing interventions, we pilot tested the feasibility of the BioFlo^® PICC, including intervention acceptability, compliance, recruitment, and initial estimates of effect, in anticipation of a subsequent full-scale efficacy randomized controlled trial. Our secondary aim was to compare the effectiveness of the BioFlo^® PICC with Endexo^® and PASV^® technology in reducing PICC complications and failure.

METHODS

Design

We undertook a pilot randomized controlled trial comparing the standard polyurethane PICC (with external clamp) with the BioFlo^® PICC (with internal valve) in preventing catheter failure in pediatric patients. The study was prospectively registered with the Australian Clinical Trials Registry (ACTRN12615001290583), and the research protocol was published.¹⁷

Study Setting

The study commenced in March 2016 at the Lady Cilento Children’s Hospital in South Brisbane, Australia, a tertiary-level, specialist, pediatric teaching hospital in Queensland, Australia, providing full-spectrum health services to children and young people from birth to 18 years of age. Recruitment, including data collection, was completed in November 2016.

Sample

The target sample size was 110 participants, 50 participants per group plus 10% for potential attrition, as determined by standard pilot trial sample size recommendations.¹⁸ With ethics approval, the sample size was later increased to 150 participants in order to adequately pilot a microbiological substudy method (published separately).¹⁷ Participants were consecutively recruited if they met the inclusion criteria: PICC insertion, age <18 years, predicted hospital stay >24 hours, single-lumen PICC, and written informed consent by an English-speaking, legal parent or guardian. Patients were excluded if they had a current (<48 hours) blood stream infection (BSI), vessel size <2 mm, could not speak English without an interpreter, required a multilumen PICC, or were previously enrolled in the study.

 

Interventions

Participants were randomized to receive either of the following PICCs: (1) standard care: Cook™ polyurethane, turbo-ject, power-injectable PICC (Cook Medical, Bloomington, IN) or (2) comparison: BioFlo^® polyurethane with Endexo^® technology (AngioDynamics Inc, Queensbury, NY).

Outcomes

The primary outcome was feasibility of a full-efficacy trial established by composite analysis of the elements of eligibility (>70% of patients will be eligible), recruitment (>70% of patients will agree to enroll), retention and attrition (<15% of participants are lost to follow-up or withdraw from the study), protocol adherence (>80% of participants receive their allocated, randomly assigned study product), missing data (<10% of data are missed during data collection), parent and healthcare staff satisfaction, and PICC failure effect size estimates to allow sample size calculations.^18,19 PICC failure was defined as the following complications associated with PICC removal: (1) catheter-associated BSI,^8,20-22 (2) local site infection,²² (3) venous thrombosis,²³ (4) occlusion,^24,25 (5) PICC fracture, or (6) PICC dislodgement.^25,26 Parents (or caregivers) and healthcare staff were asked to rate their level of confidence with the study product and ease of PICC removal by using a 0 to 100 numeric rating scale (NRS) of increasing confidence and/or ease. These data were collected at the time of PICC removal. Operators were also asked to rate their levels of satisfaction with the insertion equipment and ease of PICC insertion immediately upon completion of the insertion procedure (both 0-100 NRS of increasing satisfaction and/or ease). Secondary outcomes included individual PICC complications (eg, occlusion) occurring at any time point during the PICC dwell (including at removal), adverse events, pain, redness at the insertion site, and overall PICC dwell.

Study Procedures

The research nurse (ReN) screened operating theater lists for patients, obtained written informed consent, and initiated the randomization. Randomization was computer generated, and web based via Griffith University (https://www151.griffith.edu.au/random) to ensure allocation concealment until study entry. Patients were randomly assigned in a 1:1 ratio with computer-generated and randomly varied block sizes of 2 and 4. Data were collected by the ReN on the day of insertion, at day 1 postinsertion, then every 2 to 3 days thereafter so that PICCs were checked at least twice per week until study completion. Participants were included in the trial until 12 weeks post-PICC insertion, study withdrawal or PICC removal (whichever came first), with an additional 48 hours follow-up for infection outcomes. Patient review was face to face during the inpatient stay, with discharged patients’ follow-up occurring via outpatient clinics, hospital-in-the-home service, or telephone.

Data collection was via Research Electronic Data Capture (http://project-redcap.org/). The ReN collected data on primary and secondary outcomes by using the predefined criteria. Demographic and clinical data were collected to assess the success of randomization, describe the participant group, and display characteristics known to increase the risk of PICC complication and thrombosis. A blinded radiologist and infectious disease specialist reviewed and diagnosed thrombosis of deep veins and catheter-associated BSI outcomes, respectively.

PICC Procedures

Extensive prestudy education for 2 months prior to trial commencement was provided to all clinicians involved with the insertion and care of PICCs, including the study products. PICCs were inserted in an operating theater environment by a qualified consultant pediatric anesthetist, a senior anesthetic registrar or fellow in an approved anesthetic training program, or pediatric vascular access nurse practitioner. Ultrasound guidance was used to assess a patient’s vasculature and puncture the vessel. The operator chose the PICC size on the basis of clinical judgment of vessel size and patient needs and then inserted the allocated PICC.²⁷ Preferred PICC tip location was the cavoatrial junction. All PICC tip positions were confirmed with a chest x-ray before use.

Postinsertion, PICCs were managed by local interdisciplinary clinicians in accordance with local practice guidelines.^27-31 PICC care and management includes the use of 2% chlorhexidine gluconate in 70% alcohol for site antisepsis and neutral displacement needleless connectors (TUTA Pulse; Medical Australia Limited, Lidcombe, New South Wales, Australia); normal saline was used to flush after medication administration, and if the device was not in use for 6 hours or longer, heparin is instilled with securement via bordered polyurethane dressing (Tegaderm 1616; 3M, St Paul, Minnesota) and a sutureless securement device (Statlock VPPCSP; Bard, Georgia).

Statistical Analyses

Data were exported to Stata 15³² for cleaning and analysis. Data cleaning of outlying figures and missing and implausible data was undertaken prior to analysis. Missing data were not imputed. The PICC was the unit of measurement, and all randomly assigned patients were analyzed on an intention-to-treat basis.³³ Descriptive statistics (frequencies and percentages) were used to ascertain the primary outcome of feasibility for the larger trial. Incidence rates (per 1,000 catheter days) and rate ratios, including 95% confidence intervals (CIs), were calculated. The comparability of groups at baseline was described across demographic, clinical, and device characteristics. Kaplan-Meier survival curves (with log-rank tests) were used to compare PICC failure between study groups over time. Associations between baseline characteristics and failure were described by calculating hazard ratios (HRs). Univariable Cox regression was performed only due to the relatively low number of outcomes. P values of <.05 were considered statistically significant.

 

Ethics

The Children’s Health Service District, Queensland (Human Research Ethics Committee/15/QRCH/164), and Griffith University (2016/077) Human Research Ethics Committees provided ethics and governance approval. Informed consent was obtained from parents or legal guardians, with children providing youth assent if they were 7 years or older, dependent upon cognitive ability.

RESULTS

Participant and PICC Characteristics

Participant and PICC characteristics are described in Table 1. The majority of participant and PICC characteristics were balanced between intervention groups. The mean patient age was 7.3 years (standard deviation 5.0; range 0-18). PICC insertion was most commonly for a respiratory diagnosis (n = 98; 65%). Most PICCs were placed in the basilica vein (n = 115; 79%), with insertion being successful on the first attempt (n = 125; 86%). There was some imbalance (>10% absolute difference between groups) in nurse practitioner and registrar insertions (standard care 35% and 23% vs BioFlo^® 51% and 8%, respectively) and patients with leucocytes <1000 µl (standard care 10% vs BioFlo^® 22%). Optimal PICC tip location at the cavoatrial junction was higher with BioFlo^® than standard care, although this difference was <10%.

Feasibility Outcomes

As shown in Figure 1, the majority of feasibility criteria were met, with 94% of 188 screened patients being eligible to participate and 97% of eligible patients consenting to enroll. Of 150 patients randomly assigned, 4 (1 in standard care and 3 in BioFlo^®) were unable to have a PICC inserted or the procedure was cancelled. Demographic data only were collected for these 4 patients. No participants were lost to follow-up, and no primary outcome data were missing. Staff satisfaction with insertion kit and ease of insertion, ease of removal of the PICC, and parental confidence in the PICC product were similar across both groups (Table 2).

PICC Failure and Complications

In total, 24 of 146 participants (16%) experienced PICC failure. There were 16 (22%) failures of standard care PICCs and 8 (11%) failures of BioFlo^® PICCs. This corresponded to incident rates of 12.6 and 7.3 per 1000 catheter days (incident rate ratio 0.58; 95% CI, 0.21-1.43; P = .172; Table 2). Failure was most commonly from thrombosis (n = 5; 7%) or occlusion (n = 5; 7%) in the standard care group, with lower incidences in the BioFlo^® group (n = 2 [3%] and n = 1 [1%], respectively). Figure 2 displays survival from PICC failure.

Considering the entire PICC dwell, of the 74 standard care patients, 49 (66%) had no complications, 9 (12%) had complications during the dwell but none at removal, 2 (3%) had no complications during the dwell but had a complication (ie, failure) at removal, and 14 (19%) had complications during the dwell and at removal. For the 72 BioFlo^® patients, 61 (85%) had no PICC complications, 3 (4%) had complications during the dwell but none at removal, 4 (5.5%) had no complications during the dwell but had a complication (ie, failure) at removal, and 4 (5.5%) had complications during the dwell and at removal.

More than twice as many standard care patients as BioFlo^® patients had a complication during the PICC dwell, and this difference was statistically significant (25 of 74, 34% vs 11 of 72, 15%; P = .009; Table 2). These results are consistent with the Kaplan-Meier curve, which shows longer complication-free survival with BioFlo^® (Figure 2A and 2B). The median BioFlo^® dwell was 1 day longer (13.8 vs 12.9 days), and the median time to first complication was one day later (4.0 BioFlo^® vs 3.0 standard care; Table 2).

As per supplementary Table 1, univariate Cox regression identified PICC failure as significantly associated with tip placement in the proximal superior vena cava (SVC) compared to the SVC–right atrium junction (HR 2.61; 95% CI, 1.17-5.82; P = .024). Reduced risk of PICC failure was significantly associated with any infusion during the dwell (continuous fluid infusion, P = .007; continuous antibiotic, P = .042; or intermittent infusion, P = .046) compared to no infusion. Other variables potentially influencing the risk of failure included PICC insertion by nurse specialist compared to consultant anesthetist (HR 2.61; 95% CI, 0.85-5.44) or registrar (HR 1.97; 95% CI, 0.57-6.77). These differences were not statistically significant; however, baseline imbalance between study groups for this variable and the feasibility design preclude absolute conclusions.

DISCUSSION

This is the first pilot feasibility trial of new PICC materials and valve design incorporated in the BioFlo^® PICC in the pediatric population. The trial incorporated best practice for randomized trials, including using a concurrent control group, centralized and concealed randomization, predetermined feasibility criteria, and a registered and published trial protocol.¹⁷ As in other studies,^15,24,34 PICC failure and complication prevalence was unacceptably high for this essential device. Standard care PICCs failed twice as often as the new BioFlo^® PICCs (22% vs 11%), which is a clinically important difference. As researchers in a pilot study, we did not expect to detect statistically significant differences; however, we found that overall complications during the dwell occurred significantly more with the standard care than BioFlo^® PICCs (P = .009).

 

BioFlo^® PICC material offers a major advancement in PICC material through the incorporation of AT technologies into catheter materials, such as PICCs. Endexo^® is a low molecular–weight, fluoro-oligomeric additive that self-locates to the top few nanometers of the material surface. When added to power-injectable polyurethane, the additive results in a strong but passive, nonstick, fluorinated surface in the base PICC material. This inhibits platelet adhesion, suppresses protein procoagulant conformation, and thereby reduces thrombus formation in medical devices. Additionally, Endexo^® is not a catheter coating; rather, it is incorporated within the polyurethane of the PICC, thereby ensuring these AT properties are present on the internal, external, and cut surfaces of the PICC. If this technology can reduce complication during treatment and reduce failure from infection, thrombosis, occlusion, fracture, and dislodgement, it will improve patient outcomes considerably and lower health system costs. Previous studies investigating valve technology in PICC design to reduce occlusion have been inconclusive.^12-14,35,36 Occlusion (both partial and complete) was less frequent in our study with the BioFlo^® group (n = 3; 4%) compared to the standard care group (n = 6; 8%). The results of this pilot study suggest that either the Endexo^® material or PASV^® technology has a positive association with occlusion reduction during PICC treatment.

Thrombosis was the primary failure type for the standard care PICCs, comprising one-third of failures. All but one patient with radiologically confirmed thrombosis required the removal of the PICC prior to completion of treatment. The decision to remove the PICC or retain and treat conservatively remained with the treating team. Raffini et al.⁷ found thrombosis to increase in patients with one or more coexisting chronic medical condition. Slightly more standard care than BioFlo^® patients were free of such comorbidities (25% vs 16%), yet standard care patients still had the higher number of thromboses (7% vs 3%). Morgenthaler and Rodriguez³⁷ reported vascular access-associated thrombosis in pediatrics to be less common than in adults but higher in medically complex children. Worryingly, Menendez et al.³⁸ reported pediatric thrombosis to be largely asymptomatic, so the true incidence in our study is likely higher because only radiologically confirmed thromboses were recorded.

Occlusion (partial or complete) was the predominant complication across the study, being associated with one-third of all failures. When occlusion complications during the dwell (some of which were resolved with treatment), in addition to those causing failure, were considered, this number was even greater. Occlusion complications are prevalent and costly. Smith et al.²⁴ reported that occlusion was the most common reason for PICC removal and the most likely complication to delay treatment. Both the BioFlo^® and standard care PICCs are pressure rated with good tensile strength; however, fracture occurred in 4% (n = 3) of standard care PICCs compared to no fractures in BioFlo^® PICCs. Although the numbers are small, it may suggest a superior tensile strength of the BioFlo^® material.

This study reinforces previously published results^24,38 that PICC tip position is important and can influence complications, such as occlusion and thrombosis. In addition, we found a significant association with failure when PICCs did not have a continuous infusion. These findings reinforce the need for optimal tip location at insertion and ongoing flushing and maintenance of PICCs not used for infusions.

Limitations of this study include the small sample size, which was not designed to detect statistical differences in the primary outcome between groups. Despite randomization, there were slight imbalances at baseline for inserter type and leukocyte count, although these were not significantly associated with PICC failure in the Cox regression (data not shown), and thus were unlikely to influence findings. Additionally, a difference of <10% was associated with PICC tip position, favoring the BioFlo^® group. PICC tip position outside the cavoatrial junction was positively associated with failure; therefore, the effect of tip positioning on outcomes is difficult to ascertain given the small sample size and feasibility nature of the study. Further study is warranted to further explore this effect. The population sampled was pediatric medical and surgical inpatients with a vessel size >2 mm attending the operating theater suite for PICC insertion, thereby limiting the study’s generalizability to adults and other populations, including neonates and those with PICCs inserted in the pediatric intensive care unit. The study could not be blinded because study products had to be visible to the clinical and research staff. However, it is unlikely that staff would intentionally sabotage PICCs to bias the study. Blinding was possible for the assessment of blood culture and ultrasound reports to diagnose infection and thrombosis. Strengths of this study included 100% protocol adherence, and no patients were lost to follow-up.

 

CONCLUSION

These results confirm that PICC failure is unacceptably high and suggest that the innovative BioFlo^® PICC material and design holds promise to improve PICC outcomes by reducing complications and overall PICC failure. Trials of this technology are feasible, safe, and acceptable to healthcare staff and parents. Further trials are required, including in other patient populations, to definitively identify clinical, cost-effective methods to prevent PICC failure and improve reliability during treatment.

Acknowledgments

The authors thank the children and parents of Lady Cilento Children’s Hospital for participating in this important research. A special thank you goes to the nurses within the Vascular Assessment and Management Service and to Karen Turner, Julieta Woosley, and Anna Dean for their efforts in data collecting and ensuring protocol adherence.

Disclosure

Griffith University has received unrestricted, investigator-initiated research or educational grants to support the research of T. K., A. J. U., and C. R. M. from product manufacturers 3M, Adhezion Inc, AngioDynamics, Bard Medical, Baxter, B. Braun Medical Inc, Becton Dickinson, CareFusion, Centurion Medical Products, Cook Medical, Entrotech, FloMedical, ICU Medical Inc, Medical Australia Limited, Medtronic, Smiths Medical, and Teleflex. Griffith University has received consultancy payments on behalf of C. R. M., A. J. U., and T. K. from manufacturers 3M, AngioDynamics, Bard Medical, B. Braun Medical Inc, Becton Dickinson, CareFusion, Mayo Healthcare Inc, ResQDevices, and Smiths Medical. AngioDynamics (the BioFlo^® PICC manufacturer) provided partial funds to undertake this research via an unrestricted donation to Griffith University (but not the study authors). Queensland Health provided in-kind support to fund the remainder of the trial. The funders had no role in the study design, collection, analysis, or interpretation of the data, writing of the report, or decision to submit the article for publication.

Peripherally inserted central catheters (PICCs) have evolved since their inception in the early 1970s and are used with increasing frequency for pediatric inpatients and outpatients.^1-3 Emerging literature, including a meta-analysis of international observational studies,⁴ reports PICC failure (complications necessitating premature removal) occurs in up to 30% of PICCs, most commonly due to infection, thrombosis, occlusion, and fracture.^4-7 Raffini et al.⁷ report the increasing incidence of pediatric PICC-related thrombosis increases morbidity and mortality⁸ and negatively impacts future vessel health and preservation.⁹

PICCs have progressed from relatively simple, silicone-based catheters with an external clamp to chemically engineered polyurethane with pressure-activated valves placed at the proximal or distal catheter hub with the intent to reduce occlusion.¹⁰ Further modernization of PICC material occurred with the incorporation of antithrombogenic (AT) material (Endexo^®). These PICCs are designed to contain a nonstick polymer, which is designed to reduce the adherence of blood components (platelets and clotting factors) and inhibit thrombus formation (and hence prevent deep vein thrombosis andocclusion, as well as inhibit microbial biofilm attachment [and subsequent infection]).¹¹

In addition to new materials, other aspects of this PICC design have been the addition of a pressure-activated safety valve (PASV^®) built into the proximal hub. Pressure-activated valve technology promises to prevent catheter occlusion by reducing blood reflux into the PICC; the valve opens with pressure during infusion and aspiration and remains closed with normal venous pressure, circumventing the need for clinicians to manually clamp the PICC and reducing human error and the potential for thrombosis, occlusion, and fracture development.¹² Hoffer et al.¹³ reported half as many occlusions of valved PICCs (3.3%) compared with nonvalved or clamped PICCs (7.1%); although not statistically significant (P = .10), perhaps due to the small sample, overall complications, including occlusion and infection, were significantly lessened with the valved PICC (35% vs 79%; P = .02). Comparatively, Pittiruti et al.¹⁴ conducted a trial of 2 types of valved PICCs with an open-ended, nonvalved PICC and found no reduction in PICC occlusion or catheter malfunction.

Today, PICC use is common for patients who require short-to-medium intravenous therapy. PICCs are increasingly recognized for their significant complications, including thrombosis and infection.¹⁵ Novel PICC technology, including the incorporation of AT material such as Endexo^® and PASV^®, may reduce complications; however, the clinical efficacy, cost-effectiveness, and acceptability of these innovations have not been tested through randomized trials in pediatric patients. In accordance with Medical Research Council guidelines¹⁶ for developing interventions, we pilot tested the feasibility of the BioFlo^® PICC, including intervention acceptability, compliance, recruitment, and initial estimates of effect, in anticipation of a subsequent full-scale efficacy randomized controlled trial. Our secondary aim was to compare the effectiveness of the BioFlo^® PICC with Endexo^® and PASV^® technology in reducing PICC complications and failure.

METHODS

Design

We undertook a pilot randomized controlled trial comparing the standard polyurethane PICC (with external clamp) with the BioFlo^® PICC (with internal valve) in preventing catheter failure in pediatric patients. The study was prospectively registered with the Australian Clinical Trials Registry (ACTRN12615001290583), and the research protocol was published.¹⁷

Study Setting

The study commenced in March 2016 at the Lady Cilento Children’s Hospital in South Brisbane, Australia, a tertiary-level, specialist, pediatric teaching hospital in Queensland, Australia, providing full-spectrum health services to children and young people from birth to 18 years of age. Recruitment, including data collection, was completed in November 2016.

Sample

The target sample size was 110 participants, 50 participants per group plus 10% for potential attrition, as determined by standard pilot trial sample size recommendations.¹⁸ With ethics approval, the sample size was later increased to 150 participants in order to adequately pilot a microbiological substudy method (published separately).¹⁷ Participants were consecutively recruited if they met the inclusion criteria: PICC insertion, age <18 years, predicted hospital stay >24 hours, single-lumen PICC, and written informed consent by an English-speaking, legal parent or guardian. Patients were excluded if they had a current (<48 hours) blood stream infection (BSI), vessel size <2 mm, could not speak English without an interpreter, required a multilumen PICC, or were previously enrolled in the study.

 

Interventions

Participants were randomized to receive either of the following PICCs: (1) standard care: Cook™ polyurethane, turbo-ject, power-injectable PICC (Cook Medical, Bloomington, IN) or (2) comparison: BioFlo^® polyurethane with Endexo^® technology (AngioDynamics Inc, Queensbury, NY).

Outcomes

The primary outcome was feasibility of a full-efficacy trial established by composite analysis of the elements of eligibility (>70% of patients will be eligible), recruitment (>70% of patients will agree to enroll), retention and attrition (<15% of participants are lost to follow-up or withdraw from the study), protocol adherence (>80% of participants receive their allocated, randomly assigned study product), missing data (<10% of data are missed during data collection), parent and healthcare staff satisfaction, and PICC failure effect size estimates to allow sample size calculations.^18,19 PICC failure was defined as the following complications associated with PICC removal: (1) catheter-associated BSI,^8,20-22 (2) local site infection,²² (3) venous thrombosis,²³ (4) occlusion,^24,25 (5) PICC fracture, or (6) PICC dislodgement.^25,26 Parents (or caregivers) and healthcare staff were asked to rate their level of confidence with the study product and ease of PICC removal by using a 0 to 100 numeric rating scale (NRS) of increasing confidence and/or ease. These data were collected at the time of PICC removal. Operators were also asked to rate their levels of satisfaction with the insertion equipment and ease of PICC insertion immediately upon completion of the insertion procedure (both 0-100 NRS of increasing satisfaction and/or ease). Secondary outcomes included individual PICC complications (eg, occlusion) occurring at any time point during the PICC dwell (including at removal), adverse events, pain, redness at the insertion site, and overall PICC dwell.

Study Procedures

The research nurse (ReN) screened operating theater lists for patients, obtained written informed consent, and initiated the randomization. Randomization was computer generated, and web based via Griffith University (https://www151.griffith.edu.au/random) to ensure allocation concealment until study entry. Patients were randomly assigned in a 1:1 ratio with computer-generated and randomly varied block sizes of 2 and 4. Data were collected by the ReN on the day of insertion, at day 1 postinsertion, then every 2 to 3 days thereafter so that PICCs were checked at least twice per week until study completion. Participants were included in the trial until 12 weeks post-PICC insertion, study withdrawal or PICC removal (whichever came first), with an additional 48 hours follow-up for infection outcomes. Patient review was face to face during the inpatient stay, with discharged patients’ follow-up occurring via outpatient clinics, hospital-in-the-home service, or telephone.

Data collection was via Research Electronic Data Capture (http://project-redcap.org/). The ReN collected data on primary and secondary outcomes by using the predefined criteria. Demographic and clinical data were collected to assess the success of randomization, describe the participant group, and display characteristics known to increase the risk of PICC complication and thrombosis. A blinded radiologist and infectious disease specialist reviewed and diagnosed thrombosis of deep veins and catheter-associated BSI outcomes, respectively.

PICC Procedures

Extensive prestudy education for 2 months prior to trial commencement was provided to all clinicians involved with the insertion and care of PICCs, including the study products. PICCs were inserted in an operating theater environment by a qualified consultant pediatric anesthetist, a senior anesthetic registrar or fellow in an approved anesthetic training program, or pediatric vascular access nurse practitioner. Ultrasound guidance was used to assess a patient’s vasculature and puncture the vessel. The operator chose the PICC size on the basis of clinical judgment of vessel size and patient needs and then inserted the allocated PICC.²⁷ Preferred PICC tip location was the cavoatrial junction. All PICC tip positions were confirmed with a chest x-ray before use.

Postinsertion, PICCs were managed by local interdisciplinary clinicians in accordance with local practice guidelines.^27-31 PICC care and management includes the use of 2% chlorhexidine gluconate in 70% alcohol for site antisepsis and neutral displacement needleless connectors (TUTA Pulse; Medical Australia Limited, Lidcombe, New South Wales, Australia); normal saline was used to flush after medication administration, and if the device was not in use for 6 hours or longer, heparin is instilled with securement via bordered polyurethane dressing (Tegaderm 1616; 3M, St Paul, Minnesota) and a sutureless securement device (Statlock VPPCSP; Bard, Georgia).

Statistical Analyses

Data were exported to Stata 15³² for cleaning and analysis. Data cleaning of outlying figures and missing and implausible data was undertaken prior to analysis. Missing data were not imputed. The PICC was the unit of measurement, and all randomly assigned patients were analyzed on an intention-to-treat basis.³³ Descriptive statistics (frequencies and percentages) were used to ascertain the primary outcome of feasibility for the larger trial. Incidence rates (per 1,000 catheter days) and rate ratios, including 95% confidence intervals (CIs), were calculated. The comparability of groups at baseline was described across demographic, clinical, and device characteristics. Kaplan-Meier survival curves (with log-rank tests) were used to compare PICC failure between study groups over time. Associations between baseline characteristics and failure were described by calculating hazard ratios (HRs). Univariable Cox regression was performed only due to the relatively low number of outcomes. P values of <.05 were considered statistically significant.

 

Ethics

The Children’s Health Service District, Queensland (Human Research Ethics Committee/15/QRCH/164), and Griffith University (2016/077) Human Research Ethics Committees provided ethics and governance approval. Informed consent was obtained from parents or legal guardians, with children providing youth assent if they were 7 years or older, dependent upon cognitive ability.

RESULTS

Participant and PICC Characteristics

Participant and PICC characteristics are described in Table 1. The majority of participant and PICC characteristics were balanced between intervention groups. The mean patient age was 7.3 years (standard deviation 5.0; range 0-18). PICC insertion was most commonly for a respiratory diagnosis (n = 98; 65%). Most PICCs were placed in the basilica vein (n = 115; 79%), with insertion being successful on the first attempt (n = 125; 86%). There was some imbalance (>10% absolute difference between groups) in nurse practitioner and registrar insertions (standard care 35% and 23% vs BioFlo^® 51% and 8%, respectively) and patients with leucocytes <1000 µl (standard care 10% vs BioFlo^® 22%). Optimal PICC tip location at the cavoatrial junction was higher with BioFlo^® than standard care, although this difference was <10%.

Feasibility Outcomes

As shown in Figure 1, the majority of feasibility criteria were met, with 94% of 188 screened patients being eligible to participate and 97% of eligible patients consenting to enroll. Of 150 patients randomly assigned, 4 (1 in standard care and 3 in BioFlo^®) were unable to have a PICC inserted or the procedure was cancelled. Demographic data only were collected for these 4 patients. No participants were lost to follow-up, and no primary outcome data were missing. Staff satisfaction with insertion kit and ease of insertion, ease of removal of the PICC, and parental confidence in the PICC product were similar across both groups (Table 2).

PICC Failure and Complications

In total, 24 of 146 participants (16%) experienced PICC failure. There were 16 (22%) failures of standard care PICCs and 8 (11%) failures of BioFlo^® PICCs. This corresponded to incident rates of 12.6 and 7.3 per 1000 catheter days (incident rate ratio 0.58; 95% CI, 0.21-1.43; P = .172; Table 2). Failure was most commonly from thrombosis (n = 5; 7%) or occlusion (n = 5; 7%) in the standard care group, with lower incidences in the BioFlo^® group (n = 2 [3%] and n = 1 [1%], respectively). Figure 2 displays survival from PICC failure.

Considering the entire PICC dwell, of the 74 standard care patients, 49 (66%) had no complications, 9 (12%) had complications during the dwell but none at removal, 2 (3%) had no complications during the dwell but had a complication (ie, failure) at removal, and 14 (19%) had complications during the dwell and at removal. For the 72 BioFlo^® patients, 61 (85%) had no PICC complications, 3 (4%) had complications during the dwell but none at removal, 4 (5.5%) had no complications during the dwell but had a complication (ie, failure) at removal, and 4 (5.5%) had complications during the dwell and at removal.

More than twice as many standard care patients as BioFlo^® patients had a complication during the PICC dwell, and this difference was statistically significant (25 of 74, 34% vs 11 of 72, 15%; P = .009; Table 2). These results are consistent with the Kaplan-Meier curve, which shows longer complication-free survival with BioFlo^® (Figure 2A and 2B). The median BioFlo^® dwell was 1 day longer (13.8 vs 12.9 days), and the median time to first complication was one day later (4.0 BioFlo^® vs 3.0 standard care; Table 2).

As per supplementary Table 1, univariate Cox regression identified PICC failure as significantly associated with tip placement in the proximal superior vena cava (SVC) compared to the SVC–right atrium junction (HR 2.61; 95% CI, 1.17-5.82; P = .024). Reduced risk of PICC failure was significantly associated with any infusion during the dwell (continuous fluid infusion, P = .007; continuous antibiotic, P = .042; or intermittent infusion, P = .046) compared to no infusion. Other variables potentially influencing the risk of failure included PICC insertion by nurse specialist compared to consultant anesthetist (HR 2.61; 95% CI, 0.85-5.44) or registrar (HR 1.97; 95% CI, 0.57-6.77). These differences were not statistically significant; however, baseline imbalance between study groups for this variable and the feasibility design preclude absolute conclusions.

DISCUSSION

This is the first pilot feasibility trial of new PICC materials and valve design incorporated in the BioFlo^® PICC in the pediatric population. The trial incorporated best practice for randomized trials, including using a concurrent control group, centralized and concealed randomization, predetermined feasibility criteria, and a registered and published trial protocol.¹⁷ As in other studies,^15,24,34 PICC failure and complication prevalence was unacceptably high for this essential device. Standard care PICCs failed twice as often as the new BioFlo^® PICCs (22% vs 11%), which is a clinically important difference. As researchers in a pilot study, we did not expect to detect statistically significant differences; however, we found that overall complications during the dwell occurred significantly more with the standard care than BioFlo^® PICCs (P = .009).

 

BioFlo^® PICC material offers a major advancement in PICC material through the incorporation of AT technologies into catheter materials, such as PICCs. Endexo^® is a low molecular–weight, fluoro-oligomeric additive that self-locates to the top few nanometers of the material surface. When added to power-injectable polyurethane, the additive results in a strong but passive, nonstick, fluorinated surface in the base PICC material. This inhibits platelet adhesion, suppresses protein procoagulant conformation, and thereby reduces thrombus formation in medical devices. Additionally, Endexo^® is not a catheter coating; rather, it is incorporated within the polyurethane of the PICC, thereby ensuring these AT properties are present on the internal, external, and cut surfaces of the PICC. If this technology can reduce complication during treatment and reduce failure from infection, thrombosis, occlusion, fracture, and dislodgement, it will improve patient outcomes considerably and lower health system costs. Previous studies investigating valve technology in PICC design to reduce occlusion have been inconclusive.^12-14,35,36 Occlusion (both partial and complete) was less frequent in our study with the BioFlo^® group (n = 3; 4%) compared to the standard care group (n = 6; 8%). The results of this pilot study suggest that either the Endexo^® material or PASV^® technology has a positive association with occlusion reduction during PICC treatment.

Thrombosis was the primary failure type for the standard care PICCs, comprising one-third of failures. All but one patient with radiologically confirmed thrombosis required the removal of the PICC prior to completion of treatment. The decision to remove the PICC or retain and treat conservatively remained with the treating team. Raffini et al.⁷ found thrombosis to increase in patients with one or more coexisting chronic medical condition. Slightly more standard care than BioFlo^® patients were free of such comorbidities (25% vs 16%), yet standard care patients still had the higher number of thromboses (7% vs 3%). Morgenthaler and Rodriguez³⁷ reported vascular access-associated thrombosis in pediatrics to be less common than in adults but higher in medically complex children. Worryingly, Menendez et al.³⁸ reported pediatric thrombosis to be largely asymptomatic, so the true incidence in our study is likely higher because only radiologically confirmed thromboses were recorded.

Occlusion (partial or complete) was the predominant complication across the study, being associated with one-third of all failures. When occlusion complications during the dwell (some of which were resolved with treatment), in addition to those causing failure, were considered, this number was even greater. Occlusion complications are prevalent and costly. Smith et al.²⁴ reported that occlusion was the most common reason for PICC removal and the most likely complication to delay treatment. Both the BioFlo^® and standard care PICCs are pressure rated with good tensile strength; however, fracture occurred in 4% (n = 3) of standard care PICCs compared to no fractures in BioFlo^® PICCs. Although the numbers are small, it may suggest a superior tensile strength of the BioFlo^® material.

This study reinforces previously published results^24,38 that PICC tip position is important and can influence complications, such as occlusion and thrombosis. In addition, we found a significant association with failure when PICCs did not have a continuous infusion. These findings reinforce the need for optimal tip location at insertion and ongoing flushing and maintenance of PICCs not used for infusions.

Limitations of this study include the small sample size, which was not designed to detect statistical differences in the primary outcome between groups. Despite randomization, there were slight imbalances at baseline for inserter type and leukocyte count, although these were not significantly associated with PICC failure in the Cox regression (data not shown), and thus were unlikely to influence findings. Additionally, a difference of <10% was associated with PICC tip position, favoring the BioFlo^® group. PICC tip position outside the cavoatrial junction was positively associated with failure; therefore, the effect of tip positioning on outcomes is difficult to ascertain given the small sample size and feasibility nature of the study. Further study is warranted to further explore this effect. The population sampled was pediatric medical and surgical inpatients with a vessel size >2 mm attending the operating theater suite for PICC insertion, thereby limiting the study’s generalizability to adults and other populations, including neonates and those with PICCs inserted in the pediatric intensive care unit. The study could not be blinded because study products had to be visible to the clinical and research staff. However, it is unlikely that staff would intentionally sabotage PICCs to bias the study. Blinding was possible for the assessment of blood culture and ultrasound reports to diagnose infection and thrombosis. Strengths of this study included 100% protocol adherence, and no patients were lost to follow-up.

 

CONCLUSION

These results confirm that PICC failure is unacceptably high and suggest that the innovative BioFlo^® PICC material and design holds promise to improve PICC outcomes by reducing complications and overall PICC failure. Trials of this technology are feasible, safe, and acceptable to healthcare staff and parents. Further trials are required, including in other patient populations, to definitively identify clinical, cost-effective methods to prevent PICC failure and improve reliability during treatment.

Acknowledgments

The authors thank the children and parents of Lady Cilento Children’s Hospital for participating in this important research. A special thank you goes to the nurses within the Vascular Assessment and Management Service and to Karen Turner, Julieta Woosley, and Anna Dean for their efforts in data collecting and ensuring protocol adherence.

Disclosure

Griffith University has received unrestricted, investigator-initiated research or educational grants to support the research of T. K., A. J. U., and C. R. M. from product manufacturers 3M, Adhezion Inc, AngioDynamics, Bard Medical, Baxter, B. Braun Medical Inc, Becton Dickinson, CareFusion, Centurion Medical Products, Cook Medical, Entrotech, FloMedical, ICU Medical Inc, Medical Australia Limited, Medtronic, Smiths Medical, and Teleflex. Griffith University has received consultancy payments on behalf of C. R. M., A. J. U., and T. K. from manufacturers 3M, AngioDynamics, Bard Medical, B. Braun Medical Inc, Becton Dickinson, CareFusion, Mayo Healthcare Inc, ResQDevices, and Smiths Medical. AngioDynamics (the BioFlo^® PICC manufacturer) provided partial funds to undertake this research via an unrestricted donation to Griffith University (but not the study authors). Queensland Health provided in-kind support to fund the remainder of the trial. The funders had no role in the study design, collection, analysis, or interpretation of the data, writing of the report, or decision to submit the article for publication.

Peripherally inserted central catheters (PICCs) have evolved since their inception in the early 1970s and are used with increasing frequency for pediatric inpatients and outpatients.^1-3 Emerging literature, including a meta-analysis of international observational studies,⁴ reports PICC failure (complications necessitating premature removal) occurs in up to 30% of PICCs, most commonly due to infection, thrombosis, occlusion, and fracture.^4-7 Raffini et al.⁷ report the increasing incidence of pediatric PICC-related thrombosis increases morbidity and mortality⁸ and negatively impacts future vessel health and preservation.⁹

PICCs have progressed from relatively simple, silicone-based catheters with an external clamp to chemically engineered polyurethane with pressure-activated valves placed at the proximal or distal catheter hub with the intent to reduce occlusion.¹⁰ Further modernization of PICC material occurred with the incorporation of antithrombogenic (AT) material (Endexo^®). These PICCs are designed to contain a nonstick polymer, which is designed to reduce the adherence of blood components (platelets and clotting factors) and inhibit thrombus formation (and hence prevent deep vein thrombosis andocclusion, as well as inhibit microbial biofilm attachment [and subsequent infection]).¹¹

In addition to new materials, other aspects of this PICC design have been the addition of a pressure-activated safety valve (PASV^®) built into the proximal hub. Pressure-activated valve technology promises to prevent catheter occlusion by reducing blood reflux into the PICC; the valve opens with pressure during infusion and aspiration and remains closed with normal venous pressure, circumventing the need for clinicians to manually clamp the PICC and reducing human error and the potential for thrombosis, occlusion, and fracture development.¹² Hoffer et al.¹³ reported half as many occlusions of valved PICCs (3.3%) compared with nonvalved or clamped PICCs (7.1%); although not statistically significant (P = .10), perhaps due to the small sample, overall complications, including occlusion and infection, were significantly lessened with the valved PICC (35% vs 79%; P = .02). Comparatively, Pittiruti et al.¹⁴ conducted a trial of 2 types of valved PICCs with an open-ended, nonvalved PICC and found no reduction in PICC occlusion or catheter malfunction.

Today, PICC use is common for patients who require short-to-medium intravenous therapy. PICCs are increasingly recognized for their significant complications, including thrombosis and infection.¹⁵ Novel PICC technology, including the incorporation of AT material such as Endexo^® and PASV^®, may reduce complications; however, the clinical efficacy, cost-effectiveness, and acceptability of these innovations have not been tested through randomized trials in pediatric patients. In accordance with Medical Research Council guidelines¹⁶ for developing interventions, we pilot tested the feasibility of the BioFlo^® PICC, including intervention acceptability, compliance, recruitment, and initial estimates of effect, in anticipation of a subsequent full-scale efficacy randomized controlled trial. Our secondary aim was to compare the effectiveness of the BioFlo^® PICC with Endexo^® and PASV^® technology in reducing PICC complications and failure.

METHODS

Design

We undertook a pilot randomized controlled trial comparing the standard polyurethane PICC (with external clamp) with the BioFlo^® PICC (with internal valve) in preventing catheter failure in pediatric patients. The study was prospectively registered with the Australian Clinical Trials Registry (ACTRN12615001290583), and the research protocol was published.¹⁷

Study Setting

The study commenced in March 2016 at the Lady Cilento Children’s Hospital in South Brisbane, Australia, a tertiary-level, specialist, pediatric teaching hospital in Queensland, Australia, providing full-spectrum health services to children and young people from birth to 18 years of age. Recruitment, including data collection, was completed in November 2016.

Sample

The target sample size was 110 participants, 50 participants per group plus 10% for potential attrition, as determined by standard pilot trial sample size recommendations.¹⁸ With ethics approval, the sample size was later increased to 150 participants in order to adequately pilot a microbiological substudy method (published separately).¹⁷ Participants were consecutively recruited if they met the inclusion criteria: PICC insertion, age <18 years, predicted hospital stay >24 hours, single-lumen PICC, and written informed consent by an English-speaking, legal parent or guardian. Patients were excluded if they had a current (<48 hours) blood stream infection (BSI), vessel size <2 mm, could not speak English without an interpreter, required a multilumen PICC, or were previously enrolled in the study.

 

Interventions

Participants were randomized to receive either of the following PICCs: (1) standard care: Cook™ polyurethane, turbo-ject, power-injectable PICC (Cook Medical, Bloomington, IN) or (2) comparison: BioFlo^® polyurethane with Endexo^® technology (AngioDynamics Inc, Queensbury, NY).

Outcomes

The primary outcome was feasibility of a full-efficacy trial established by composite analysis of the elements of eligibility (>70% of patients will be eligible), recruitment (>70% of patients will agree to enroll), retention and attrition (<15% of participants are lost to follow-up or withdraw from the study), protocol adherence (>80% of participants receive their allocated, randomly assigned study product), missing data (<10% of data are missed during data collection), parent and healthcare staff satisfaction, and PICC failure effect size estimates to allow sample size calculations.^18,19 PICC failure was defined as the following complications associated with PICC removal: (1) catheter-associated BSI,^8,20-22 (2) local site infection,²² (3) venous thrombosis,²³ (4) occlusion,^24,25 (5) PICC fracture, or (6) PICC dislodgement.^25,26 Parents (or caregivers) and healthcare staff were asked to rate their level of confidence with the study product and ease of PICC removal by using a 0 to 100 numeric rating scale (NRS) of increasing confidence and/or ease. These data were collected at the time of PICC removal. Operators were also asked to rate their levels of satisfaction with the insertion equipment and ease of PICC insertion immediately upon completion of the insertion procedure (both 0-100 NRS of increasing satisfaction and/or ease). Secondary outcomes included individual PICC complications (eg, occlusion) occurring at any time point during the PICC dwell (including at removal), adverse events, pain, redness at the insertion site, and overall PICC dwell.

Study Procedures

The research nurse (ReN) screened operating theater lists for patients, obtained written informed consent, and initiated the randomization. Randomization was computer generated, and web based via Griffith University (https://www151.griffith.edu.au/random) to ensure allocation concealment until study entry. Patients were randomly assigned in a 1:1 ratio with computer-generated and randomly varied block sizes of 2 and 4. Data were collected by the ReN on the day of insertion, at day 1 postinsertion, then every 2 to 3 days thereafter so that PICCs were checked at least twice per week until study completion. Participants were included in the trial until 12 weeks post-PICC insertion, study withdrawal or PICC removal (whichever came first), with an additional 48 hours follow-up for infection outcomes. Patient review was face to face during the inpatient stay, with discharged patients’ follow-up occurring via outpatient clinics, hospital-in-the-home service, or telephone.

Data collection was via Research Electronic Data Capture (http://project-redcap.org/). The ReN collected data on primary and secondary outcomes by using the predefined criteria. Demographic and clinical data were collected to assess the success of randomization, describe the participant group, and display characteristics known to increase the risk of PICC complication and thrombosis. A blinded radiologist and infectious disease specialist reviewed and diagnosed thrombosis of deep veins and catheter-associated BSI outcomes, respectively.

PICC Procedures

Extensive prestudy education for 2 months prior to trial commencement was provided to all clinicians involved with the insertion and care of PICCs, including the study products. PICCs were inserted in an operating theater environment by a qualified consultant pediatric anesthetist, a senior anesthetic registrar or fellow in an approved anesthetic training program, or pediatric vascular access nurse practitioner. Ultrasound guidance was used to assess a patient’s vasculature and puncture the vessel. The operator chose the PICC size on the basis of clinical judgment of vessel size and patient needs and then inserted the allocated PICC.²⁷ Preferred PICC tip location was the cavoatrial junction. All PICC tip positions were confirmed with a chest x-ray before use.

Postinsertion, PICCs were managed by local interdisciplinary clinicians in accordance with local practice guidelines.^27-31 PICC care and management includes the use of 2% chlorhexidine gluconate in 70% alcohol for site antisepsis and neutral displacement needleless connectors (TUTA Pulse; Medical Australia Limited, Lidcombe, New South Wales, Australia); normal saline was used to flush after medication administration, and if the device was not in use for 6 hours or longer, heparin is instilled with securement via bordered polyurethane dressing (Tegaderm 1616; 3M, St Paul, Minnesota) and a sutureless securement device (Statlock VPPCSP; Bard, Georgia).

Statistical Analyses

Data were exported to Stata 15³² for cleaning and analysis. Data cleaning of outlying figures and missing and implausible data was undertaken prior to analysis. Missing data were not imputed. The PICC was the unit of measurement, and all randomly assigned patients were analyzed on an intention-to-treat basis.³³ Descriptive statistics (frequencies and percentages) were used to ascertain the primary outcome of feasibility for the larger trial. Incidence rates (per 1,000 catheter days) and rate ratios, including 95% confidence intervals (CIs), were calculated. The comparability of groups at baseline was described across demographic, clinical, and device characteristics. Kaplan-Meier survival curves (with log-rank tests) were used to compare PICC failure between study groups over time. Associations between baseline characteristics and failure were described by calculating hazard ratios (HRs). Univariable Cox regression was performed only due to the relatively low number of outcomes. P values of <.05 were considered statistically significant.

 

Ethics

The Children’s Health Service District, Queensland (Human Research Ethics Committee/15/QRCH/164), and Griffith University (2016/077) Human Research Ethics Committees provided ethics and governance approval. Informed consent was obtained from parents or legal guardians, with children providing youth assent if they were 7 years or older, dependent upon cognitive ability.

RESULTS

Participant and PICC Characteristics

Participant and PICC characteristics are described in Table 1. The majority of participant and PICC characteristics were balanced between intervention groups. The mean patient age was 7.3 years (standard deviation 5.0; range 0-18). PICC insertion was most commonly for a respiratory diagnosis (n = 98; 65%). Most PICCs were placed in the basilica vein (n = 115; 79%), with insertion being successful on the first attempt (n = 125; 86%). There was some imbalance (>10% absolute difference between groups) in nurse practitioner and registrar insertions (standard care 35% and 23% vs BioFlo^® 51% and 8%, respectively) and patients with leucocytes <1000 µl (standard care 10% vs BioFlo^® 22%). Optimal PICC tip location at the cavoatrial junction was higher with BioFlo^® than standard care, although this difference was <10%.

Feasibility Outcomes

As shown in Figure 1, the majority of feasibility criteria were met, with 94% of 188 screened patients being eligible to participate and 97% of eligible patients consenting to enroll. Of 150 patients randomly assigned, 4 (1 in standard care and 3 in BioFlo^®) were unable to have a PICC inserted or the procedure was cancelled. Demographic data only were collected for these 4 patients. No participants were lost to follow-up, and no primary outcome data were missing. Staff satisfaction with insertion kit and ease of insertion, ease of removal of the PICC, and parental confidence in the PICC product were similar across both groups (Table 2).

PICC Failure and Complications

In total, 24 of 146 participants (16%) experienced PICC failure. There were 16 (22%) failures of standard care PICCs and 8 (11%) failures of BioFlo^® PICCs. This corresponded to incident rates of 12.6 and 7.3 per 1000 catheter days (incident rate ratio 0.58; 95% CI, 0.21-1.43; P = .172; Table 2). Failure was most commonly from thrombosis (n = 5; 7%) or occlusion (n = 5; 7%) in the standard care group, with lower incidences in the BioFlo^® group (n = 2 [3%] and n = 1 [1%], respectively). Figure 2 displays survival from PICC failure.

Considering the entire PICC dwell, of the 74 standard care patients, 49 (66%) had no complications, 9 (12%) had complications during the dwell but none at removal, 2 (3%) had no complications during the dwell but had a complication (ie, failure) at removal, and 14 (19%) had complications during the dwell and at removal. For the 72 BioFlo^® patients, 61 (85%) had no PICC complications, 3 (4%) had complications during the dwell but none at removal, 4 (5.5%) had no complications during the dwell but had a complication (ie, failure) at removal, and 4 (5.5%) had complications during the dwell and at removal.

More than twice as many standard care patients as BioFlo^® patients had a complication during the PICC dwell, and this difference was statistically significant (25 of 74, 34% vs 11 of 72, 15%; P = .009; Table 2). These results are consistent with the Kaplan-Meier curve, which shows longer complication-free survival with BioFlo^® (Figure 2A and 2B). The median BioFlo^® dwell was 1 day longer (13.8 vs 12.9 days), and the median time to first complication was one day later (4.0 BioFlo^® vs 3.0 standard care; Table 2).

As per supplementary Table 1, univariate Cox regression identified PICC failure as significantly associated with tip placement in the proximal superior vena cava (SVC) compared to the SVC–right atrium junction (HR 2.61; 95% CI, 1.17-5.82; P = .024). Reduced risk of PICC failure was significantly associated with any infusion during the dwell (continuous fluid infusion, P = .007; continuous antibiotic, P = .042; or intermittent infusion, P = .046) compared to no infusion. Other variables potentially influencing the risk of failure included PICC insertion by nurse specialist compared to consultant anesthetist (HR 2.61; 95% CI, 0.85-5.44) or registrar (HR 1.97; 95% CI, 0.57-6.77). These differences were not statistically significant; however, baseline imbalance between study groups for this variable and the feasibility design preclude absolute conclusions.

DISCUSSION

This is the first pilot feasibility trial of new PICC materials and valve design incorporated in the BioFlo^® PICC in the pediatric population. The trial incorporated best practice for randomized trials, including using a concurrent control group, centralized and concealed randomization, predetermined feasibility criteria, and a registered and published trial protocol.¹⁷ As in other studies,^15,24,34 PICC failure and complication prevalence was unacceptably high for this essential device. Standard care PICCs failed twice as often as the new BioFlo^® PICCs (22% vs 11%), which is a clinically important difference. As researchers in a pilot study, we did not expect to detect statistically significant differences; however, we found that overall complications during the dwell occurred significantly more with the standard care than BioFlo^® PICCs (P = .009).

 

BioFlo^® PICC material offers a major advancement in PICC material through the incorporation of AT technologies into catheter materials, such as PICCs. Endexo^® is a low molecular–weight, fluoro-oligomeric additive that self-locates to the top few nanometers of the material surface. When added to power-injectable polyurethane, the additive results in a strong but passive, nonstick, fluorinated surface in the base PICC material. This inhibits platelet adhesion, suppresses protein procoagulant conformation, and thereby reduces thrombus formation in medical devices. Additionally, Endexo^® is not a catheter coating; rather, it is incorporated within the polyurethane of the PICC, thereby ensuring these AT properties are present on the internal, external, and cut surfaces of the PICC. If this technology can reduce complication during treatment and reduce failure from infection, thrombosis, occlusion, fracture, and dislodgement, it will improve patient outcomes considerably and lower health system costs. Previous studies investigating valve technology in PICC design to reduce occlusion have been inconclusive.^12-14,35,36 Occlusion (both partial and complete) was less frequent in our study with the BioFlo^® group (n = 3; 4%) compared to the standard care group (n = 6; 8%). The results of this pilot study suggest that either the Endexo^® material or PASV^® technology has a positive association with occlusion reduction during PICC treatment.

Thrombosis was the primary failure type for the standard care PICCs, comprising one-third of failures. All but one patient with radiologically confirmed thrombosis required the removal of the PICC prior to completion of treatment. The decision to remove the PICC or retain and treat conservatively remained with the treating team. Raffini et al.⁷ found thrombosis to increase in patients with one or more coexisting chronic medical condition. Slightly more standard care than BioFlo^® patients were free of such comorbidities (25% vs 16%), yet standard care patients still had the higher number of thromboses (7% vs 3%). Morgenthaler and Rodriguez³⁷ reported vascular access-associated thrombosis in pediatrics to be less common than in adults but higher in medically complex children. Worryingly, Menendez et al.³⁸ reported pediatric thrombosis to be largely asymptomatic, so the true incidence in our study is likely higher because only radiologically confirmed thromboses were recorded.

Occlusion (partial or complete) was the predominant complication across the study, being associated with one-third of all failures. When occlusion complications during the dwell (some of which were resolved with treatment), in addition to those causing failure, were considered, this number was even greater. Occlusion complications are prevalent and costly. Smith et al.²⁴ reported that occlusion was the most common reason for PICC removal and the most likely complication to delay treatment. Both the BioFlo^® and standard care PICCs are pressure rated with good tensile strength; however, fracture occurred in 4% (n = 3) of standard care PICCs compared to no fractures in BioFlo^® PICCs. Although the numbers are small, it may suggest a superior tensile strength of the BioFlo^® material.

This study reinforces previously published results^24,38 that PICC tip position is important and can influence complications, such as occlusion and thrombosis. In addition, we found a significant association with failure when PICCs did not have a continuous infusion. These findings reinforce the need for optimal tip location at insertion and ongoing flushing and maintenance of PICCs not used for infusions.

Limitations of this study include the small sample size, which was not designed to detect statistical differences in the primary outcome between groups. Despite randomization, there were slight imbalances at baseline for inserter type and leukocyte count, although these were not significantly associated with PICC failure in the Cox regression (data not shown), and thus were unlikely to influence findings. Additionally, a difference of <10% was associated with PICC tip position, favoring the BioFlo^® group. PICC tip position outside the cavoatrial junction was positively associated with failure; therefore, the effect of tip positioning on outcomes is difficult to ascertain given the small sample size and feasibility nature of the study. Further study is warranted to further explore this effect. The population sampled was pediatric medical and surgical inpatients with a vessel size >2 mm attending the operating theater suite for PICC insertion, thereby limiting the study’s generalizability to adults and other populations, including neonates and those with PICCs inserted in the pediatric intensive care unit. The study could not be blinded because study products had to be visible to the clinical and research staff. However, it is unlikely that staff would intentionally sabotage PICCs to bias the study. Blinding was possible for the assessment of blood culture and ultrasound reports to diagnose infection and thrombosis. Strengths of this study included 100% protocol adherence, and no patients were lost to follow-up.

 

CONCLUSION

These results confirm that PICC failure is unacceptably high and suggest that the innovative BioFlo^® PICC material and design holds promise to improve PICC outcomes by reducing complications and overall PICC failure. Trials of this technology are feasible, safe, and acceptable to healthcare staff and parents. Further trials are required, including in other patient populations, to definitively identify clinical, cost-effective methods to prevent PICC failure and improve reliability during treatment.

Acknowledgments

The authors thank the children and parents of Lady Cilento Children’s Hospital for participating in this important research. A special thank you goes to the nurses within the Vascular Assessment and Management Service and to Karen Turner, Julieta Woosley, and Anna Dean for their efforts in data collecting and ensuring protocol adherence.

Disclosure

Griffith University has received unrestricted, investigator-initiated research or educational grants to support the research of T. K., A. J. U., and C. R. M. from product manufacturers 3M, Adhezion Inc, AngioDynamics, Bard Medical, Baxter, B. Braun Medical Inc, Becton Dickinson, CareFusion, Centurion Medical Products, Cook Medical, Entrotech, FloMedical, ICU Medical Inc, Medical Australia Limited, Medtronic, Smiths Medical, and Teleflex. Griffith University has received consultancy payments on behalf of C. R. M., A. J. U., and T. K. from manufacturers 3M, AngioDynamics, Bard Medical, B. Braun Medical Inc, Becton Dickinson, CareFusion, Mayo Healthcare Inc, ResQDevices, and Smiths Medical. AngioDynamics (the BioFlo^® PICC manufacturer) provided partial funds to undertake this research via an unrestricted donation to Griffith University (but not the study authors). Queensland Health provided in-kind support to fund the remainder of the trial. The funders had no role in the study design, collection, analysis, or interpretation of the data, writing of the report, or decision to submit the article for publication.

After discharge from the hospital, patients have a significantly elevated risk for adverse events, including emergency department use, hospital readmission, and death. More than 1 in 3 patients discharged from the hospital require acute care in the month after hospital discharge, and more than 1 in 6 require readmission, with readmission diagnoses frequently differing from those of the preceding hospitalization.^1-4 This heightened susceptibility to adverse events persists beyond 30 days but levels off by 7 weeks after discharge, suggesting that the period of increased risk is transient and dynamic.⁵

The term posthospital syndrome (PHS) describes this period of vulnerability to major adverse events following hospitalization.⁶ In addition to increased risk for readmission and mortality, patients in this period often show evidence of generalized dysfunction with new cognitive impairment, mobility disability, or functional decline.^7-12 To date, the etiology of this vulnerability is neither well understood nor effectively addressed by transitional care interventions.¹³

One hypothesis to explain PHS is that stressors associated with the experience of hospitalization contribute to transient multisystem dysfunction that induces susceptibility to a broad range of medical maladies. These stressors include frequent sleep disruption, noxious sounds, painful stimuli, mobility restrictions, and poor nutrition.¹² The stress hypothesis as a cause of PHS is therefore based, in large part, on evidence about allostasis and the deleterious effects of allostatic overload.

Allostasis defines a system functioning within normal stress-response parameters to promote adaptation and survival.¹⁴ In allostasis, the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic and parasympathetic branches of the autonomic nervous system (ANS) exist in homeostatic balance and respond to environmental stimuli within a range of healthy physiologic parameters. The hallmark of a system in allostasis is the ability to rapidly activate, then successfully deactivate, a stress response once the stressor (ie, threat) has resolved.^14,15 To promote survival and potentiate “fight or flight” mechanisms, an appropriate stress response necessarily impacts multiple physiologic systems that result in hemodynamic augmentation and gluconeogenesis to support the anticipated action of large muscle groups, heightened vigilance and memory capabilities to improve rapid decision-making, and enhancement of innate and adaptive immune capabilities to prepare for wound repair and infection defense.^14-16 The stress response is subsequently terminated by negative feedback mechanisms of glucocorticoids as well as a shift of the ANS from sympathetic to parasympathetic tone.^17,18

Extended or repetitive stress exposure, however, leads to dysregulation of allostatic mechanisms responsible for stress adaptation and hinders an efficient and effective stress response. After extended stress exposure, baseline (ie, resting) HPA activity resets, causing a disruption of normal diurnal cortisol rhythm and an increase in total cortisol concentration. Moreover, in response to stress, HPA and ANS system excitation becomes impaired, and negative feedback properties are undermined.^14,15 This maladaptive state, known as allostatic overload, disrupts the finely tuned mechanisms that are the foundation of mind-body balance and yields pathophysiologic consequences to multiple organ systems. Downstream ramifications of allostatic overload include cognitive deterioration, cardiovascular and immune system dysfunction, and functional decline.^14,15,19

Although a stress response is an expected and necessary aspect of acute illness that promotes survival, the central thesis of this work is that additional environmental and social stressors inherent in hospitalization may unnecessarily compound stress and increase the risk of HPA axis dysfunction, allostatic overload, and subsequent multisystem dysfunction, predisposing individuals to adverse outcomes after hospital discharge. Based on data from both human subjects and animal models, we present a possible pathophysiologic mechanism for the postdischarge vulnerability of PHS, encourage critical contemplation of traditional hospitalization, and suggest interventions that might improve outcomes.

POSTHOSPITAL SYNDROME

Posthospital syndrome (PHS) describes a transient period of vulnerability after hospitalization during which patients are at elevated risk for adverse events from a broad range of conditions. In support of this characterization, epidemiologic data have demonstrated high rates of adverse outcomes following hospitalization. For example, data have shown that more than 1 in 6 older adults is readmitted to the hospital within 30 days of discharge.²⁰ Death is also common in this first month, during which rates of postdischarge mortality may exceed initial inpatient mortality.^21,22 Elevated vulnerability after hospitalization is not restricted to older adults, as readmission risk among younger patients 18 to 64 years of age may be even higher for selected conditions, such as heart failure.^3,23

Vulnerability after hospitalization is broad. In patients over age 65 initially admitted for heart failure or acute myocardial infarction, only 35% and 10% of readmissions are for recurrent heart failure or reinfarction, respectively.¹ Nearly half of readmissions are for noncardiovascular causes.¹ Similarly, following hospitalization for pneumonia, more than 60 percent of readmissions are for nonpulmonary etiologies. Moreover, the risk for all these causes of readmission is much higher than baseline risk, indicating an extended period of lack of resilience to many types of illness.²⁴ These patterns of broad susceptibility also extend to younger adults hospitalized with common medical conditions.³

Accumulating evidence suggests that hospitalized patients face functional decline, debility, and risk for adverse events despite resolution of the presenting illness, implying perhaps that the hospital environment itself is hazardous to patients’ health. In 1993, Creditor hypothesized that the “hazards of hospitalization,” including enforced bed-rest, sensory deprivation, social isolation, and malnutrition lead to a “cascade of dependency” in which a collection of small insults to multiple organ systems precipitates loss of function and debility despite cure or resolution of presenting illness.¹² Covinsky (2011) later defined hospitalization-associated disability as an iatrogenic hospital-related “disorder” characterized by new impairments in abilities to perform basic activities of daily living such as bathing, feeding, toileting, dressing, transferring, and walking at the time of hospital discharge.¹¹ Others have described a postintensive-care syndrome (PICS),²⁵ characterized by cognitive, psychiatric, and physical impairments acquired during hospitalization for critical illness that persist postdischarge and increase the long-term risk for adverse outcomes, including elevated mortality rates,^26,27 readmission rates,²⁸ and physical disabilities.²⁹ Similar to the “hazards of hospitalization,” PICS is thought to be related to common experiences of ICU stays, including mobility restriction, sensory deprivation, sleep disruption, sedation, malnutrition, and polypharmacy.^30-33

Taken together, these data suggest that adverse health consequences attributable to hospitalization extend across the spectrum of age, presenting disease severity, and hospital treatment location. As detailed below, the PHS hypothesis is rooted in a mechanistic understanding of the role of exogenous stressors in producing physiologic dysregulation and subsequent adverse health effects across multiple organ systems.

Nature of Stress in the Hospital

Compounding the stress of acute illness, hospitalized patients are routinely and repetitively exposed to a wide variety of environmental stressors that may have downstream adverse consequences (Table 1). In the absence of overt clinical manifestations of harm, the possible subclinical physiologic dysfunction generated by the following stress exposures may increase patients’ susceptibility to the manifestations of PHS.

Sleep Disruption

Sleep disruptions trigger potent stress responses,^34,35 yet they are common occurrences during hospitalization. In surveys, about half of patients report poor sleep quality during hospitalization that persists for many months after discharge.³⁶ In a simulated hospital setting, test subjects exposed to typical hospital sounds (paging system, machine alarms, etc.) experienced significant sleep-wake cycle abnormalities.³⁷ Although no work has yet focused specifically on the physiologic consequences of sleep disruption and stress in hospitalized patients, in healthy humans, mild sleep disruption has clear effects on allostasis by disrupting HPA activity, raising cortisol levels, diminishing parasympathetic tone, and impairing cognitive performance.^{18,34,35,38,39}

Malnourishment

Malnourishment in hospitalized patients is common, with one-fifth of hospitalized patients receiving nothing per mouth or clear liquid diets for more than 3 continuous days,⁴⁰ and one-fifth of hospitalized elderly patients receiving less than half of their calculated nutrition requirements.⁴¹ Although the relationship between food restriction, cortisol levels, and postdischarge outcomes has not been fully explored, in healthy humans, meal anticipation, meal withdrawal (withholding an expected meal), and self-reported dietary restraint are known to generate stress responses.^42,43 Furthermore, malnourishment during hospitalization is associated with increased 90-day and 1-year mortality after discharge,⁴⁴ adding malnourishment to the list of plausible components of hospital-related stress.

Mobility Restriction

Physical activity counterbalances stress responses and minimizes downstream consequences of allostatic load,¹⁵ yet mobility limitations via physical and chemical restraints are common in hospitalized patients, particularly among the elderly.^45-47 Many patients are tethered to devices that make ambulation hazardous, such as urinary catheters and infusion pumps. Even without physical or chemical restraints or a limited mobility order, patients may be hesitant to leave the room so as not to miss transport to a diagnostic study or an unscheduled physician’s visit. Indeed, mobility limitations of hospitalized patients increase the risk for adverse events after discharge, while interventions designed to encourage mobility are associated with improved postdischarge outcomes.^47,48

Other Stressors

Other hospital-related aversive stimuli are less commonly quantified, but clearly exist. According to surveys of hospitalized patients, sources of emotional stress include social isolation; loss of autonomy and privacy; fear of serious illness; lack of control over activities of daily living; lack of clear communication between treatment team and patients; and death of a patient roommate.^49,50 Furthermore, consider the physical discomfort and emotional distress of patients with urinary incontinence awaiting assistance for a diaper or bedding change or the pain of repetitive blood draws or other invasive testing. Although individualized, the subjective discomfort and emotional distress associated with these experiences undoubtedly contribute to the stress of hospitalization.

 

IMPACT OF ALLOSTATIC OVERLOAD ON PHYSIOLOGIC FUNCTION

Animal Models of Stress

Laboratory techniques reminiscent of the numerous environmental stressors associated with hospitalization have been used to reliably trigger allostatic overload in healthy young animals.⁵¹ These techniques include sequential exposure to aversive stimuli, including food and water deprivation, continuous overnight illumination, paired housing with known and unknown cagemates, mobility restriction, soiled cage conditions, and continuous noise. All of these techniques have been shown to cause HPA axis and ANS dysfunction, allostatic overload, and subsequent stress-mediated consequences to multiple organ systems.^19,52-54 Given the remarkable similarity of these protocols to common experiences during hospitalization, animal models of stress may be useful in understanding the spectrum of maladaptive consequences experienced by patients within the hospital (Figure 1).

These animal models of stress have resulted in a number of instructive findings. For example, in rodents, extended stress exposure induces structural and functional remodeling of neuronal networks that precipitate learning and memory, working memory, and attention impairments.^55-57 These exposures also result in cardiovascular abnormalities, including dyslipidemia, progressive atherosclerosis,^58,59 and enhanced inflammatory cytokine expression,⁶⁰ all of which increase both atherosclerotic burden and susceptibility to plaque rupture, leading to elevated risk for major cardiovascular adverse events. Moreover, these extended stress exposures in animals increase susceptibility to both bacterial and viral infections and increase their severity.^16,61 This outcome appears to be driven by a stress-induced elevation of glucocorticoid levels, decreased leukocyte proliferation, altered leukocyte trafficking, and a transition to a proinflammatory cytokine environment.^{16, 61} Allostatic overload has also been shown to contribute to metabolic dysregulation involving insulin resistance, persistence of hyperglycemia, dyslipidemia, catabolism of lean muscle, and visceral adipose tissue deposition.^62-64 In addition to cardiovascular, immune, and metabolic consequences of allostatic overload, the spectrum of physiologic dysfunction in animal models is broad and includes mood disorder symptoms,⁶⁵ intestinal barrier abnormalities,⁶⁶ airway reactivity exacerbation,⁶⁷ and enhanced tumor growth.⁶⁸

Although the majority of this research highlights the multisystem effects of variable stress exposure in healthy animals, preliminary evidence suggests that aged or diseased animals subjected to additional stressors display a heightened inflammatory cytokine response that contributes to exaggerated sickness behavior and greater and prolonged cognitive deficits.⁶⁹ Future studies exploring the consequences of extended stress exposure in animals with existing disease or debility may therefore more closely simulate the experience of hospitalized patients and perhaps further our understanding of PHS.

Hospitalized Patients

While no intervention studies have examined the effects of potential hospital stressors on the development of allostatic overload, there is evidence from small studies that dysregulated stress responses during hospitalization are associated with adverse events. For example, high serum cortisol, catecholamine, and proinflammatory cytokine levels during hospitalization have individually been associated with the development of cognitive dysfunction,^70-72 increased risk of cardiovascular events such as myocardial infarction and stroke in the year following discharge,^73-76 and the development of wound infections after discharge.⁷⁷ Moreover, elevated plasma glucose during admission for myocardial infarction in patients with or without diabetes has been associated with greater in-hospital and 1-year mortality,⁷⁸ with a similar relationship seen between elevated plasma glucose and survival after admission for stroke⁷⁹ and pneumonia.⁸⁰ Furthermore, in addition to atherothrombosis, stress may contribute to the risk for venous thromboembolism,⁸¹ resulting in readmissions for deep vein thrombosis or pulmonary embolism posthospitalization. Although potentially surrogate markers of illness acuity, a handful of studies have shown that these stress biomarkers are actually only weakly correlated with,⁸² or independent of,^72,76 disease severity. As discussed in detail below, future studies utilizing a summative measure of multisystem physiologic dysfunction as opposed to individual biomarkers may more accurately reflect the cumulative stress effects of hospitalization and subsequent risk for adverse events.

Additional Considerations

Elderly patients, in particular, may have heightened susceptibility to the consequences of allostatic overload due to common geriatric issues such as multimorbidity and frailty. Patients with chronic diseases display both baseline HPA axis abnormalities as well as dysregulated stress responses and may therefore be more vulnerable to hospitalization-related stress. For example, when subjected to psychosocial stress, patients with chronic conditions such as diabetes, heart failure, or atherosclerosis demonstrate elevated cortisol levels, increased circulating markers of inflammation, as well as prolonged hemodynamic recovery after stress resolution compared with normal controls.^83-85 Additionally, frailty may affect an individual’s susceptibility to exogenous stress. Indeed, frailty identified on hospital admission increases the risk for adverse outcomes during hospitalization and postdischarge.⁸⁶ Although the specific etiology of this relationship is unclear, persons with frailty are known to have elevated levels of cortisol and other inflammatory markers,^87,88 which may contribute to adverse outcomes in the face of additional stressors.

 

IMPLICATIONS AND NEXT STEPS

A large body of evidence stretching from bench to bedside suggests that environmental stressors associated with hospitalization are toxic. Understanding PHS within the context of hospital-induced allostatic overload presents a unifying theory for the interrelated multisystem dysfunction and increased susceptibility to adverse events that patients experience after discharge (Figure 2). Furthermore, it defines a potential pathophysiological mechanism for the cognitive impairment, elevated cardiovascular risk, immune system dysfunction, metabolic derangements, and functional decline associated with PHS. Additionally, this theory highlights environmental interventions to limit PHS development and suggests mechanisms to promote stress resilience. Although it is difficult to disentangle the consequences of the endogenous stress triggered by an acute illness from the exogenous stressors related to hospitalization, it is likely that the 2 simultaneous exposures compound risk for stress system dysregulation and allostatic overload. Moreover, hospitalized patients with preexisting HPA axis dysfunction at baseline from chronic disease or advancing age may be even more susceptible to these adverse outcomes. If this hypothesis is true, a reduction in PHS would require mitigation of the modifiable environmental stressors encountered by patients during hospitalization. Directed efforts to diminish ambient noise, limit nighttime disruptions, thoughtfully plan procedures, consider ongoing nutritional status, and promote opportunities for patients to exert some control over their environment may diminish the burden of extrinsic stressors encountered by all patients in the hospital and improve outcomes after discharge.

Hospitals are increasingly recognizing the importance of improving patients’ experience of hospitalization by reducing exposure to potential toxicities. For example, many hospitals are now attempting to reduce sleep disturbances and sleep latency through reduced nighttime noise and light levels, fewer nighttime interruptions for vital signs checks and medication administration, and commonsensical interventions like massages, herbal teas, and warm milk prior to bedtime.⁸⁹ Likewise, intensive care units are targeting environmental and physical stressors with a multifaceted approach to decrease sedative use, promote healthy sleep cycles, and encourage exercise and ambulation even in those patients who are mechanically ventilated.³⁰ Another promising development has been the increase of Hospital at Home programs. In these programs, patients who meet the criteria for inpatient admission are instead comprehensively managed at home for their acute illness through a multidisciplinary effort between physicians, nurses, social workers, physical therapists, and others. Patients hospitalized at home report higher levels of satisfaction and have modest functional gains, improved health-related quality of life, and decreased risk of mortality at 6 months compared with hospitalized patients.^90,91 With some admitting diagnoses (eg, heart failure), hospitalization at home may be associated with decreased readmission risk.⁹² Although not yet investigated on a physiologic level, perhaps the benefits of hospital at home are partially due to the dramatic difference in exposure to environmental stressors.

A tool that quantifies hospital-associated stress may help health providers appreciate the experience of patients and better target interventions to aspects of their structure and process that contribute to allostatic overload. Importantly, allostatic overload cannot be identified by one biomarker of stress but instead requires evidence of dysregulation across inflammatory, neuroendocrine, hormonal, and cardiometabolic systems. Future studies to address the burden of stress faced by hospitalized patients should consider a summative measure of multisystem dysregulation as opposed to isolated assessments of individual biomarkers. Allostatic load has previously been operationalized as the summation of a variety of hemodynamic, hormonal, and metabolic factors, including blood pressure, lipid profile, glycosylated hemoglobin, cortisol, catecholamine levels, and inflammatory markers.⁹³ To develop a hospital-associated allostatic load index, models should ideally be adjusted for acute illness severity, patient-reported stress, and capacity for stress resilience. This tool could then be used to quantify hospitalization-related allostatic load and identify those at greatest risk for adverse events after discharge, as well as measure the effectiveness of strategic environmental interventions (Table 2). A natural first experiment may be a comparison of the allostatic load of hospitalized patients versus those hospitalized at home.

The risk of adverse outcomes after discharge is likely a function of the vulnerability of the patient and the degree to which the patient’s healthcare team and social support network mitigates this vulnerability. That is, there is a risk that a person struggles in the postdischarge period and, in many circumstances, a strong healthcare team and social network can identify health problems early and prevent them from progressing to the point that they require hospitalization.^13,94-96 There are also hospital occurrences, outside of allostatic load, that can lead to complications that lengthen the stay, weaken the patient, and directly contribute to subsequent vulnerability.^94,97 Our contention is that the allostatic load of hospitalization, which may also vary by patient depending on the circumstances of hospitalization, is just one contributor, albeit potentially an important one, to vulnerability to medical problems after discharge.

In conclusion, a plausible etiology of PHS is the maladaptive mind-body consequences of common stressors during hospitalization that compound the stress of acute illness and produce allostatic overload. This stress-induced dysfunction potentially contributes to a spectrum of generalized disease susceptibility and risk of adverse outcomes after discharge. Focused efforts to diminish patient exposure to hospital-related stressors during and after hospitalization might diminish the presence or severity of PHS. Viewing PHS from this perspective enables the development of hypothesis-driven risk-prediction models, encourages critical contemplation of traditional hospitalization, and suggests that targeted environmental interventions may significantly reduce adverse outcomes.

 

After discharge from the hospital, patients have a significantly elevated risk for adverse events, including emergency department use, hospital readmission, and death. More than 1 in 3 patients discharged from the hospital require acute care in the month after hospital discharge, and more than 1 in 6 require readmission, with readmission diagnoses frequently differing from those of the preceding hospitalization.^1-4 This heightened susceptibility to adverse events persists beyond 30 days but levels off by 7 weeks after discharge, suggesting that the period of increased risk is transient and dynamic.⁵

The term posthospital syndrome (PHS) describes this period of vulnerability to major adverse events following hospitalization.⁶ In addition to increased risk for readmission and mortality, patients in this period often show evidence of generalized dysfunction with new cognitive impairment, mobility disability, or functional decline.^7-12 To date, the etiology of this vulnerability is neither well understood nor effectively addressed by transitional care interventions.¹³

One hypothesis to explain PHS is that stressors associated with the experience of hospitalization contribute to transient multisystem dysfunction that induces susceptibility to a broad range of medical maladies. These stressors include frequent sleep disruption, noxious sounds, painful stimuli, mobility restrictions, and poor nutrition.¹² The stress hypothesis as a cause of PHS is therefore based, in large part, on evidence about allostasis and the deleterious effects of allostatic overload.

Allostasis defines a system functioning within normal stress-response parameters to promote adaptation and survival.¹⁴ In allostasis, the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic and parasympathetic branches of the autonomic nervous system (ANS) exist in homeostatic balance and respond to environmental stimuli within a range of healthy physiologic parameters. The hallmark of a system in allostasis is the ability to rapidly activate, then successfully deactivate, a stress response once the stressor (ie, threat) has resolved.^14,15 To promote survival and potentiate “fight or flight” mechanisms, an appropriate stress response necessarily impacts multiple physiologic systems that result in hemodynamic augmentation and gluconeogenesis to support the anticipated action of large muscle groups, heightened vigilance and memory capabilities to improve rapid decision-making, and enhancement of innate and adaptive immune capabilities to prepare for wound repair and infection defense.^14-16 The stress response is subsequently terminated by negative feedback mechanisms of glucocorticoids as well as a shift of the ANS from sympathetic to parasympathetic tone.^17,18

Extended or repetitive stress exposure, however, leads to dysregulation of allostatic mechanisms responsible for stress adaptation and hinders an efficient and effective stress response. After extended stress exposure, baseline (ie, resting) HPA activity resets, causing a disruption of normal diurnal cortisol rhythm and an increase in total cortisol concentration. Moreover, in response to stress, HPA and ANS system excitation becomes impaired, and negative feedback properties are undermined.^14,15 This maladaptive state, known as allostatic overload, disrupts the finely tuned mechanisms that are the foundation of mind-body balance and yields pathophysiologic consequences to multiple organ systems. Downstream ramifications of allostatic overload include cognitive deterioration, cardiovascular and immune system dysfunction, and functional decline.^14,15,19

Although a stress response is an expected and necessary aspect of acute illness that promotes survival, the central thesis of this work is that additional environmental and social stressors inherent in hospitalization may unnecessarily compound stress and increase the risk of HPA axis dysfunction, allostatic overload, and subsequent multisystem dysfunction, predisposing individuals to adverse outcomes after hospital discharge. Based on data from both human subjects and animal models, we present a possible pathophysiologic mechanism for the postdischarge vulnerability of PHS, encourage critical contemplation of traditional hospitalization, and suggest interventions that might improve outcomes.

POSTHOSPITAL SYNDROME

Posthospital syndrome (PHS) describes a transient period of vulnerability after hospitalization during which patients are at elevated risk for adverse events from a broad range of conditions. In support of this characterization, epidemiologic data have demonstrated high rates of adverse outcomes following hospitalization. For example, data have shown that more than 1 in 6 older adults is readmitted to the hospital within 30 days of discharge.²⁰ Death is also common in this first month, during which rates of postdischarge mortality may exceed initial inpatient mortality.^21,22 Elevated vulnerability after hospitalization is not restricted to older adults, as readmission risk among younger patients 18 to 64 years of age may be even higher for selected conditions, such as heart failure.^3,23

Vulnerability after hospitalization is broad. In patients over age 65 initially admitted for heart failure or acute myocardial infarction, only 35% and 10% of readmissions are for recurrent heart failure or reinfarction, respectively.¹ Nearly half of readmissions are for noncardiovascular causes.¹ Similarly, following hospitalization for pneumonia, more than 60 percent of readmissions are for nonpulmonary etiologies. Moreover, the risk for all these causes of readmission is much higher than baseline risk, indicating an extended period of lack of resilience to many types of illness.²⁴ These patterns of broad susceptibility also extend to younger adults hospitalized with common medical conditions.³

Accumulating evidence suggests that hospitalized patients face functional decline, debility, and risk for adverse events despite resolution of the presenting illness, implying perhaps that the hospital environment itself is hazardous to patients’ health. In 1993, Creditor hypothesized that the “hazards of hospitalization,” including enforced bed-rest, sensory deprivation, social isolation, and malnutrition lead to a “cascade of dependency” in which a collection of small insults to multiple organ systems precipitates loss of function and debility despite cure or resolution of presenting illness.¹² Covinsky (2011) later defined hospitalization-associated disability as an iatrogenic hospital-related “disorder” characterized by new impairments in abilities to perform basic activities of daily living such as bathing, feeding, toileting, dressing, transferring, and walking at the time of hospital discharge.¹¹ Others have described a postintensive-care syndrome (PICS),²⁵ characterized by cognitive, psychiatric, and physical impairments acquired during hospitalization for critical illness that persist postdischarge and increase the long-term risk for adverse outcomes, including elevated mortality rates,^26,27 readmission rates,²⁸ and physical disabilities.²⁹ Similar to the “hazards of hospitalization,” PICS is thought to be related to common experiences of ICU stays, including mobility restriction, sensory deprivation, sleep disruption, sedation, malnutrition, and polypharmacy.^30-33

Taken together, these data suggest that adverse health consequences attributable to hospitalization extend across the spectrum of age, presenting disease severity, and hospital treatment location. As detailed below, the PHS hypothesis is rooted in a mechanistic understanding of the role of exogenous stressors in producing physiologic dysregulation and subsequent adverse health effects across multiple organ systems.

Nature of Stress in the Hospital

Compounding the stress of acute illness, hospitalized patients are routinely and repetitively exposed to a wide variety of environmental stressors that may have downstream adverse consequences (Table 1). In the absence of overt clinical manifestations of harm, the possible subclinical physiologic dysfunction generated by the following stress exposures may increase patients’ susceptibility to the manifestations of PHS.

Sleep Disruption

Sleep disruptions trigger potent stress responses,^34,35 yet they are common occurrences during hospitalization. In surveys, about half of patients report poor sleep quality during hospitalization that persists for many months after discharge.³⁶ In a simulated hospital setting, test subjects exposed to typical hospital sounds (paging system, machine alarms, etc.) experienced significant sleep-wake cycle abnormalities.³⁷ Although no work has yet focused specifically on the physiologic consequences of sleep disruption and stress in hospitalized patients, in healthy humans, mild sleep disruption has clear effects on allostasis by disrupting HPA activity, raising cortisol levels, diminishing parasympathetic tone, and impairing cognitive performance.^{18,34,35,38,39}

Malnourishment

Malnourishment in hospitalized patients is common, with one-fifth of hospitalized patients receiving nothing per mouth or clear liquid diets for more than 3 continuous days,⁴⁰ and one-fifth of hospitalized elderly patients receiving less than half of their calculated nutrition requirements.⁴¹ Although the relationship between food restriction, cortisol levels, and postdischarge outcomes has not been fully explored, in healthy humans, meal anticipation, meal withdrawal (withholding an expected meal), and self-reported dietary restraint are known to generate stress responses.^42,43 Furthermore, malnourishment during hospitalization is associated with increased 90-day and 1-year mortality after discharge,⁴⁴ adding malnourishment to the list of plausible components of hospital-related stress.

Mobility Restriction

Physical activity counterbalances stress responses and minimizes downstream consequences of allostatic load,¹⁵ yet mobility limitations via physical and chemical restraints are common in hospitalized patients, particularly among the elderly.^45-47 Many patients are tethered to devices that make ambulation hazardous, such as urinary catheters and infusion pumps. Even without physical or chemical restraints or a limited mobility order, patients may be hesitant to leave the room so as not to miss transport to a diagnostic study or an unscheduled physician’s visit. Indeed, mobility limitations of hospitalized patients increase the risk for adverse events after discharge, while interventions designed to encourage mobility are associated with improved postdischarge outcomes.^47,48

Other Stressors

Other hospital-related aversive stimuli are less commonly quantified, but clearly exist. According to surveys of hospitalized patients, sources of emotional stress include social isolation; loss of autonomy and privacy; fear of serious illness; lack of control over activities of daily living; lack of clear communication between treatment team and patients; and death of a patient roommate.^49,50 Furthermore, consider the physical discomfort and emotional distress of patients with urinary incontinence awaiting assistance for a diaper or bedding change or the pain of repetitive blood draws or other invasive testing. Although individualized, the subjective discomfort and emotional distress associated with these experiences undoubtedly contribute to the stress of hospitalization.

 

IMPACT OF ALLOSTATIC OVERLOAD ON PHYSIOLOGIC FUNCTION

Animal Models of Stress

Laboratory techniques reminiscent of the numerous environmental stressors associated with hospitalization have been used to reliably trigger allostatic overload in healthy young animals.⁵¹ These techniques include sequential exposure to aversive stimuli, including food and water deprivation, continuous overnight illumination, paired housing with known and unknown cagemates, mobility restriction, soiled cage conditions, and continuous noise. All of these techniques have been shown to cause HPA axis and ANS dysfunction, allostatic overload, and subsequent stress-mediated consequences to multiple organ systems.^19,52-54 Given the remarkable similarity of these protocols to common experiences during hospitalization, animal models of stress may be useful in understanding the spectrum of maladaptive consequences experienced by patients within the hospital (Figure 1).

These animal models of stress have resulted in a number of instructive findings. For example, in rodents, extended stress exposure induces structural and functional remodeling of neuronal networks that precipitate learning and memory, working memory, and attention impairments.^55-57 These exposures also result in cardiovascular abnormalities, including dyslipidemia, progressive atherosclerosis,^58,59 and enhanced inflammatory cytokine expression,⁶⁰ all of which increase both atherosclerotic burden and susceptibility to plaque rupture, leading to elevated risk for major cardiovascular adverse events. Moreover, these extended stress exposures in animals increase susceptibility to both bacterial and viral infections and increase their severity.^16,61 This outcome appears to be driven by a stress-induced elevation of glucocorticoid levels, decreased leukocyte proliferation, altered leukocyte trafficking, and a transition to a proinflammatory cytokine environment.^{16, 61} Allostatic overload has also been shown to contribute to metabolic dysregulation involving insulin resistance, persistence of hyperglycemia, dyslipidemia, catabolism of lean muscle, and visceral adipose tissue deposition.^62-64 In addition to cardiovascular, immune, and metabolic consequences of allostatic overload, the spectrum of physiologic dysfunction in animal models is broad and includes mood disorder symptoms,⁶⁵ intestinal barrier abnormalities,⁶⁶ airway reactivity exacerbation,⁶⁷ and enhanced tumor growth.⁶⁸

Although the majority of this research highlights the multisystem effects of variable stress exposure in healthy animals, preliminary evidence suggests that aged or diseased animals subjected to additional stressors display a heightened inflammatory cytokine response that contributes to exaggerated sickness behavior and greater and prolonged cognitive deficits.⁶⁹ Future studies exploring the consequences of extended stress exposure in animals with existing disease or debility may therefore more closely simulate the experience of hospitalized patients and perhaps further our understanding of PHS.

Hospitalized Patients

While no intervention studies have examined the effects of potential hospital stressors on the development of allostatic overload, there is evidence from small studies that dysregulated stress responses during hospitalization are associated with adverse events. For example, high serum cortisol, catecholamine, and proinflammatory cytokine levels during hospitalization have individually been associated with the development of cognitive dysfunction,^70-72 increased risk of cardiovascular events such as myocardial infarction and stroke in the year following discharge,^73-76 and the development of wound infections after discharge.⁷⁷ Moreover, elevated plasma glucose during admission for myocardial infarction in patients with or without diabetes has been associated with greater in-hospital and 1-year mortality,⁷⁸ with a similar relationship seen between elevated plasma glucose and survival after admission for stroke⁷⁹ and pneumonia.⁸⁰ Furthermore, in addition to atherothrombosis, stress may contribute to the risk for venous thromboembolism,⁸¹ resulting in readmissions for deep vein thrombosis or pulmonary embolism posthospitalization. Although potentially surrogate markers of illness acuity, a handful of studies have shown that these stress biomarkers are actually only weakly correlated with,⁸² or independent of,^72,76 disease severity. As discussed in detail below, future studies utilizing a summative measure of multisystem physiologic dysfunction as opposed to individual biomarkers may more accurately reflect the cumulative stress effects of hospitalization and subsequent risk for adverse events.

Additional Considerations

Elderly patients, in particular, may have heightened susceptibility to the consequences of allostatic overload due to common geriatric issues such as multimorbidity and frailty. Patients with chronic diseases display both baseline HPA axis abnormalities as well as dysregulated stress responses and may therefore be more vulnerable to hospitalization-related stress. For example, when subjected to psychosocial stress, patients with chronic conditions such as diabetes, heart failure, or atherosclerosis demonstrate elevated cortisol levels, increased circulating markers of inflammation, as well as prolonged hemodynamic recovery after stress resolution compared with normal controls.^83-85 Additionally, frailty may affect an individual’s susceptibility to exogenous stress. Indeed, frailty identified on hospital admission increases the risk for adverse outcomes during hospitalization and postdischarge.⁸⁶ Although the specific etiology of this relationship is unclear, persons with frailty are known to have elevated levels of cortisol and other inflammatory markers,^87,88 which may contribute to adverse outcomes in the face of additional stressors.

 

IMPLICATIONS AND NEXT STEPS

A large body of evidence stretching from bench to bedside suggests that environmental stressors associated with hospitalization are toxic. Understanding PHS within the context of hospital-induced allostatic overload presents a unifying theory for the interrelated multisystem dysfunction and increased susceptibility to adverse events that patients experience after discharge (Figure 2). Furthermore, it defines a potential pathophysiological mechanism for the cognitive impairment, elevated cardiovascular risk, immune system dysfunction, metabolic derangements, and functional decline associated with PHS. Additionally, this theory highlights environmental interventions to limit PHS development and suggests mechanisms to promote stress resilience. Although it is difficult to disentangle the consequences of the endogenous stress triggered by an acute illness from the exogenous stressors related to hospitalization, it is likely that the 2 simultaneous exposures compound risk for stress system dysregulation and allostatic overload. Moreover, hospitalized patients with preexisting HPA axis dysfunction at baseline from chronic disease or advancing age may be even more susceptible to these adverse outcomes. If this hypothesis is true, a reduction in PHS would require mitigation of the modifiable environmental stressors encountered by patients during hospitalization. Directed efforts to diminish ambient noise, limit nighttime disruptions, thoughtfully plan procedures, consider ongoing nutritional status, and promote opportunities for patients to exert some control over their environment may diminish the burden of extrinsic stressors encountered by all patients in the hospital and improve outcomes after discharge.

Hospitals are increasingly recognizing the importance of improving patients’ experience of hospitalization by reducing exposure to potential toxicities. For example, many hospitals are now attempting to reduce sleep disturbances and sleep latency through reduced nighttime noise and light levels, fewer nighttime interruptions for vital signs checks and medication administration, and commonsensical interventions like massages, herbal teas, and warm milk prior to bedtime.⁸⁹ Likewise, intensive care units are targeting environmental and physical stressors with a multifaceted approach to decrease sedative use, promote healthy sleep cycles, and encourage exercise and ambulation even in those patients who are mechanically ventilated.³⁰ Another promising development has been the increase of Hospital at Home programs. In these programs, patients who meet the criteria for inpatient admission are instead comprehensively managed at home for their acute illness through a multidisciplinary effort between physicians, nurses, social workers, physical therapists, and others. Patients hospitalized at home report higher levels of satisfaction and have modest functional gains, improved health-related quality of life, and decreased risk of mortality at 6 months compared with hospitalized patients.^90,91 With some admitting diagnoses (eg, heart failure), hospitalization at home may be associated with decreased readmission risk.⁹² Although not yet investigated on a physiologic level, perhaps the benefits of hospital at home are partially due to the dramatic difference in exposure to environmental stressors.

A tool that quantifies hospital-associated stress may help health providers appreciate the experience of patients and better target interventions to aspects of their structure and process that contribute to allostatic overload. Importantly, allostatic overload cannot be identified by one biomarker of stress but instead requires evidence of dysregulation across inflammatory, neuroendocrine, hormonal, and cardiometabolic systems. Future studies to address the burden of stress faced by hospitalized patients should consider a summative measure of multisystem dysregulation as opposed to isolated assessments of individual biomarkers. Allostatic load has previously been operationalized as the summation of a variety of hemodynamic, hormonal, and metabolic factors, including blood pressure, lipid profile, glycosylated hemoglobin, cortisol, catecholamine levels, and inflammatory markers.⁹³ To develop a hospital-associated allostatic load index, models should ideally be adjusted for acute illness severity, patient-reported stress, and capacity for stress resilience. This tool could then be used to quantify hospitalization-related allostatic load and identify those at greatest risk for adverse events after discharge, as well as measure the effectiveness of strategic environmental interventions (Table 2). A natural first experiment may be a comparison of the allostatic load of hospitalized patients versus those hospitalized at home.

The risk of adverse outcomes after discharge is likely a function of the vulnerability of the patient and the degree to which the patient’s healthcare team and social support network mitigates this vulnerability. That is, there is a risk that a person struggles in the postdischarge period and, in many circumstances, a strong healthcare team and social network can identify health problems early and prevent them from progressing to the point that they require hospitalization.^13,94-96 There are also hospital occurrences, outside of allostatic load, that can lead to complications that lengthen the stay, weaken the patient, and directly contribute to subsequent vulnerability.^94,97 Our contention is that the allostatic load of hospitalization, which may also vary by patient depending on the circumstances of hospitalization, is just one contributor, albeit potentially an important one, to vulnerability to medical problems after discharge.

In conclusion, a plausible etiology of PHS is the maladaptive mind-body consequences of common stressors during hospitalization that compound the stress of acute illness and produce allostatic overload. This stress-induced dysfunction potentially contributes to a spectrum of generalized disease susceptibility and risk of adverse outcomes after discharge. Focused efforts to diminish patient exposure to hospital-related stressors during and after hospitalization might diminish the presence or severity of PHS. Viewing PHS from this perspective enables the development of hypothesis-driven risk-prediction models, encourages critical contemplation of traditional hospitalization, and suggests that targeted environmental interventions may significantly reduce adverse outcomes.

 

After discharge from the hospital, patients have a significantly elevated risk for adverse events, including emergency department use, hospital readmission, and death. More than 1 in 3 patients discharged from the hospital require acute care in the month after hospital discharge, and more than 1 in 6 require readmission, with readmission diagnoses frequently differing from those of the preceding hospitalization.^1-4 This heightened susceptibility to adverse events persists beyond 30 days but levels off by 7 weeks after discharge, suggesting that the period of increased risk is transient and dynamic.⁵

The term posthospital syndrome (PHS) describes this period of vulnerability to major adverse events following hospitalization.⁶ In addition to increased risk for readmission and mortality, patients in this period often show evidence of generalized dysfunction with new cognitive impairment, mobility disability, or functional decline.^7-12 To date, the etiology of this vulnerability is neither well understood nor effectively addressed by transitional care interventions.¹³

One hypothesis to explain PHS is that stressors associated with the experience of hospitalization contribute to transient multisystem dysfunction that induces susceptibility to a broad range of medical maladies. These stressors include frequent sleep disruption, noxious sounds, painful stimuli, mobility restrictions, and poor nutrition.¹² The stress hypothesis as a cause of PHS is therefore based, in large part, on evidence about allostasis and the deleterious effects of allostatic overload.

Allostasis defines a system functioning within normal stress-response parameters to promote adaptation and survival.¹⁴ In allostasis, the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic and parasympathetic branches of the autonomic nervous system (ANS) exist in homeostatic balance and respond to environmental stimuli within a range of healthy physiologic parameters. The hallmark of a system in allostasis is the ability to rapidly activate, then successfully deactivate, a stress response once the stressor (ie, threat) has resolved.^14,15 To promote survival and potentiate “fight or flight” mechanisms, an appropriate stress response necessarily impacts multiple physiologic systems that result in hemodynamic augmentation and gluconeogenesis to support the anticipated action of large muscle groups, heightened vigilance and memory capabilities to improve rapid decision-making, and enhancement of innate and adaptive immune capabilities to prepare for wound repair and infection defense.^14-16 The stress response is subsequently terminated by negative feedback mechanisms of glucocorticoids as well as a shift of the ANS from sympathetic to parasympathetic tone.^17,18

Extended or repetitive stress exposure, however, leads to dysregulation of allostatic mechanisms responsible for stress adaptation and hinders an efficient and effective stress response. After extended stress exposure, baseline (ie, resting) HPA activity resets, causing a disruption of normal diurnal cortisol rhythm and an increase in total cortisol concentration. Moreover, in response to stress, HPA and ANS system excitation becomes impaired, and negative feedback properties are undermined.^14,15 This maladaptive state, known as allostatic overload, disrupts the finely tuned mechanisms that are the foundation of mind-body balance and yields pathophysiologic consequences to multiple organ systems. Downstream ramifications of allostatic overload include cognitive deterioration, cardiovascular and immune system dysfunction, and functional decline.^14,15,19

Although a stress response is an expected and necessary aspect of acute illness that promotes survival, the central thesis of this work is that additional environmental and social stressors inherent in hospitalization may unnecessarily compound stress and increase the risk of HPA axis dysfunction, allostatic overload, and subsequent multisystem dysfunction, predisposing individuals to adverse outcomes after hospital discharge. Based on data from both human subjects and animal models, we present a possible pathophysiologic mechanism for the postdischarge vulnerability of PHS, encourage critical contemplation of traditional hospitalization, and suggest interventions that might improve outcomes.

POSTHOSPITAL SYNDROME

Posthospital syndrome (PHS) describes a transient period of vulnerability after hospitalization during which patients are at elevated risk for adverse events from a broad range of conditions. In support of this characterization, epidemiologic data have demonstrated high rates of adverse outcomes following hospitalization. For example, data have shown that more than 1 in 6 older adults is readmitted to the hospital within 30 days of discharge.²⁰ Death is also common in this first month, during which rates of postdischarge mortality may exceed initial inpatient mortality.^21,22 Elevated vulnerability after hospitalization is not restricted to older adults, as readmission risk among younger patients 18 to 64 years of age may be even higher for selected conditions, such as heart failure.^3,23

Vulnerability after hospitalization is broad. In patients over age 65 initially admitted for heart failure or acute myocardial infarction, only 35% and 10% of readmissions are for recurrent heart failure or reinfarction, respectively.¹ Nearly half of readmissions are for noncardiovascular causes.¹ Similarly, following hospitalization for pneumonia, more than 60 percent of readmissions are for nonpulmonary etiologies. Moreover, the risk for all these causes of readmission is much higher than baseline risk, indicating an extended period of lack of resilience to many types of illness.²⁴ These patterns of broad susceptibility also extend to younger adults hospitalized with common medical conditions.³

Accumulating evidence suggests that hospitalized patients face functional decline, debility, and risk for adverse events despite resolution of the presenting illness, implying perhaps that the hospital environment itself is hazardous to patients’ health. In 1993, Creditor hypothesized that the “hazards of hospitalization,” including enforced bed-rest, sensory deprivation, social isolation, and malnutrition lead to a “cascade of dependency” in which a collection of small insults to multiple organ systems precipitates loss of function and debility despite cure or resolution of presenting illness.¹² Covinsky (2011) later defined hospitalization-associated disability as an iatrogenic hospital-related “disorder” characterized by new impairments in abilities to perform basic activities of daily living such as bathing, feeding, toileting, dressing, transferring, and walking at the time of hospital discharge.¹¹ Others have described a postintensive-care syndrome (PICS),²⁵ characterized by cognitive, psychiatric, and physical impairments acquired during hospitalization for critical illness that persist postdischarge and increase the long-term risk for adverse outcomes, including elevated mortality rates,^26,27 readmission rates,²⁸ and physical disabilities.²⁹ Similar to the “hazards of hospitalization,” PICS is thought to be related to common experiences of ICU stays, including mobility restriction, sensory deprivation, sleep disruption, sedation, malnutrition, and polypharmacy.^30-33

Taken together, these data suggest that adverse health consequences attributable to hospitalization extend across the spectrum of age, presenting disease severity, and hospital treatment location. As detailed below, the PHS hypothesis is rooted in a mechanistic understanding of the role of exogenous stressors in producing physiologic dysregulation and subsequent adverse health effects across multiple organ systems.

Nature of Stress in the Hospital

Compounding the stress of acute illness, hospitalized patients are routinely and repetitively exposed to a wide variety of environmental stressors that may have downstream adverse consequences (Table 1). In the absence of overt clinical manifestations of harm, the possible subclinical physiologic dysfunction generated by the following stress exposures may increase patients’ susceptibility to the manifestations of PHS.

Sleep Disruption

Sleep disruptions trigger potent stress responses,^34,35 yet they are common occurrences during hospitalization. In surveys, about half of patients report poor sleep quality during hospitalization that persists for many months after discharge.³⁶ In a simulated hospital setting, test subjects exposed to typical hospital sounds (paging system, machine alarms, etc.) experienced significant sleep-wake cycle abnormalities.³⁷ Although no work has yet focused specifically on the physiologic consequences of sleep disruption and stress in hospitalized patients, in healthy humans, mild sleep disruption has clear effects on allostasis by disrupting HPA activity, raising cortisol levels, diminishing parasympathetic tone, and impairing cognitive performance.^{18,34,35,38,39}

Malnourishment

Malnourishment in hospitalized patients is common, with one-fifth of hospitalized patients receiving nothing per mouth or clear liquid diets for more than 3 continuous days,⁴⁰ and one-fifth of hospitalized elderly patients receiving less than half of their calculated nutrition requirements.⁴¹ Although the relationship between food restriction, cortisol levels, and postdischarge outcomes has not been fully explored, in healthy humans, meal anticipation, meal withdrawal (withholding an expected meal), and self-reported dietary restraint are known to generate stress responses.^42,43 Furthermore, malnourishment during hospitalization is associated with increased 90-day and 1-year mortality after discharge,⁴⁴ adding malnourishment to the list of plausible components of hospital-related stress.

Mobility Restriction

Physical activity counterbalances stress responses and minimizes downstream consequences of allostatic load,¹⁵ yet mobility limitations via physical and chemical restraints are common in hospitalized patients, particularly among the elderly.^45-47 Many patients are tethered to devices that make ambulation hazardous, such as urinary catheters and infusion pumps. Even without physical or chemical restraints or a limited mobility order, patients may be hesitant to leave the room so as not to miss transport to a diagnostic study or an unscheduled physician’s visit. Indeed, mobility limitations of hospitalized patients increase the risk for adverse events after discharge, while interventions designed to encourage mobility are associated with improved postdischarge outcomes.^47,48

Other Stressors

Other hospital-related aversive stimuli are less commonly quantified, but clearly exist. According to surveys of hospitalized patients, sources of emotional stress include social isolation; loss of autonomy and privacy; fear of serious illness; lack of control over activities of daily living; lack of clear communication between treatment team and patients; and death of a patient roommate.^49,50 Furthermore, consider the physical discomfort and emotional distress of patients with urinary incontinence awaiting assistance for a diaper or bedding change or the pain of repetitive blood draws or other invasive testing. Although individualized, the subjective discomfort and emotional distress associated with these experiences undoubtedly contribute to the stress of hospitalization.

 

IMPACT OF ALLOSTATIC OVERLOAD ON PHYSIOLOGIC FUNCTION

Animal Models of Stress

Laboratory techniques reminiscent of the numerous environmental stressors associated with hospitalization have been used to reliably trigger allostatic overload in healthy young animals.⁵¹ These techniques include sequential exposure to aversive stimuli, including food and water deprivation, continuous overnight illumination, paired housing with known and unknown cagemates, mobility restriction, soiled cage conditions, and continuous noise. All of these techniques have been shown to cause HPA axis and ANS dysfunction, allostatic overload, and subsequent stress-mediated consequences to multiple organ systems.^19,52-54 Given the remarkable similarity of these protocols to common experiences during hospitalization, animal models of stress may be useful in understanding the spectrum of maladaptive consequences experienced by patients within the hospital (Figure 1).

These animal models of stress have resulted in a number of instructive findings. For example, in rodents, extended stress exposure induces structural and functional remodeling of neuronal networks that precipitate learning and memory, working memory, and attention impairments.^55-57 These exposures also result in cardiovascular abnormalities, including dyslipidemia, progressive atherosclerosis,^58,59 and enhanced inflammatory cytokine expression,⁶⁰ all of which increase both atherosclerotic burden and susceptibility to plaque rupture, leading to elevated risk for major cardiovascular adverse events. Moreover, these extended stress exposures in animals increase susceptibility to both bacterial and viral infections and increase their severity.^16,61 This outcome appears to be driven by a stress-induced elevation of glucocorticoid levels, decreased leukocyte proliferation, altered leukocyte trafficking, and a transition to a proinflammatory cytokine environment.^{16, 61} Allostatic overload has also been shown to contribute to metabolic dysregulation involving insulin resistance, persistence of hyperglycemia, dyslipidemia, catabolism of lean muscle, and visceral adipose tissue deposition.^62-64 In addition to cardiovascular, immune, and metabolic consequences of allostatic overload, the spectrum of physiologic dysfunction in animal models is broad and includes mood disorder symptoms,⁶⁵ intestinal barrier abnormalities,⁶⁶ airway reactivity exacerbation,⁶⁷ and enhanced tumor growth.⁶⁸

Although the majority of this research highlights the multisystem effects of variable stress exposure in healthy animals, preliminary evidence suggests that aged or diseased animals subjected to additional stressors display a heightened inflammatory cytokine response that contributes to exaggerated sickness behavior and greater and prolonged cognitive deficits.⁶⁹ Future studies exploring the consequences of extended stress exposure in animals with existing disease or debility may therefore more closely simulate the experience of hospitalized patients and perhaps further our understanding of PHS.

Hospitalized Patients

While no intervention studies have examined the effects of potential hospital stressors on the development of allostatic overload, there is evidence from small studies that dysregulated stress responses during hospitalization are associated with adverse events. For example, high serum cortisol, catecholamine, and proinflammatory cytokine levels during hospitalization have individually been associated with the development of cognitive dysfunction,^70-72 increased risk of cardiovascular events such as myocardial infarction and stroke in the year following discharge,^73-76 and the development of wound infections after discharge.⁷⁷ Moreover, elevated plasma glucose during admission for myocardial infarction in patients with or without diabetes has been associated with greater in-hospital and 1-year mortality,⁷⁸ with a similar relationship seen between elevated plasma glucose and survival after admission for stroke⁷⁹ and pneumonia.⁸⁰ Furthermore, in addition to atherothrombosis, stress may contribute to the risk for venous thromboembolism,⁸¹ resulting in readmissions for deep vein thrombosis or pulmonary embolism posthospitalization. Although potentially surrogate markers of illness acuity, a handful of studies have shown that these stress biomarkers are actually only weakly correlated with,⁸² or independent of,^72,76 disease severity. As discussed in detail below, future studies utilizing a summative measure of multisystem physiologic dysfunction as opposed to individual biomarkers may more accurately reflect the cumulative stress effects of hospitalization and subsequent risk for adverse events.

Additional Considerations

Elderly patients, in particular, may have heightened susceptibility to the consequences of allostatic overload due to common geriatric issues such as multimorbidity and frailty. Patients with chronic diseases display both baseline HPA axis abnormalities as well as dysregulated stress responses and may therefore be more vulnerable to hospitalization-related stress. For example, when subjected to psychosocial stress, patients with chronic conditions such as diabetes, heart failure, or atherosclerosis demonstrate elevated cortisol levels, increased circulating markers of inflammation, as well as prolonged hemodynamic recovery after stress resolution compared with normal controls.^83-85 Additionally, frailty may affect an individual’s susceptibility to exogenous stress. Indeed, frailty identified on hospital admission increases the risk for adverse outcomes during hospitalization and postdischarge.⁸⁶ Although the specific etiology of this relationship is unclear, persons with frailty are known to have elevated levels of cortisol and other inflammatory markers,^87,88 which may contribute to adverse outcomes in the face of additional stressors.

 

IMPLICATIONS AND NEXT STEPS

A large body of evidence stretching from bench to bedside suggests that environmental stressors associated with hospitalization are toxic. Understanding PHS within the context of hospital-induced allostatic overload presents a unifying theory for the interrelated multisystem dysfunction and increased susceptibility to adverse events that patients experience after discharge (Figure 2). Furthermore, it defines a potential pathophysiological mechanism for the cognitive impairment, elevated cardiovascular risk, immune system dysfunction, metabolic derangements, and functional decline associated with PHS. Additionally, this theory highlights environmental interventions to limit PHS development and suggests mechanisms to promote stress resilience. Although it is difficult to disentangle the consequences of the endogenous stress triggered by an acute illness from the exogenous stressors related to hospitalization, it is likely that the 2 simultaneous exposures compound risk for stress system dysregulation and allostatic overload. Moreover, hospitalized patients with preexisting HPA axis dysfunction at baseline from chronic disease or advancing age may be even more susceptible to these adverse outcomes. If this hypothesis is true, a reduction in PHS would require mitigation of the modifiable environmental stressors encountered by patients during hospitalization. Directed efforts to diminish ambient noise, limit nighttime disruptions, thoughtfully plan procedures, consider ongoing nutritional status, and promote opportunities for patients to exert some control over their environment may diminish the burden of extrinsic stressors encountered by all patients in the hospital and improve outcomes after discharge.

Hospitals are increasingly recognizing the importance of improving patients’ experience of hospitalization by reducing exposure to potential toxicities. For example, many hospitals are now attempting to reduce sleep disturbances and sleep latency through reduced nighttime noise and light levels, fewer nighttime interruptions for vital signs checks and medication administration, and commonsensical interventions like massages, herbal teas, and warm milk prior to bedtime.⁸⁹ Likewise, intensive care units are targeting environmental and physical stressors with a multifaceted approach to decrease sedative use, promote healthy sleep cycles, and encourage exercise and ambulation even in those patients who are mechanically ventilated.³⁰ Another promising development has been the increase of Hospital at Home programs. In these programs, patients who meet the criteria for inpatient admission are instead comprehensively managed at home for their acute illness through a multidisciplinary effort between physicians, nurses, social workers, physical therapists, and others. Patients hospitalized at home report higher levels of satisfaction and have modest functional gains, improved health-related quality of life, and decreased risk of mortality at 6 months compared with hospitalized patients.^90,91 With some admitting diagnoses (eg, heart failure), hospitalization at home may be associated with decreased readmission risk.⁹² Although not yet investigated on a physiologic level, perhaps the benefits of hospital at home are partially due to the dramatic difference in exposure to environmental stressors.

A tool that quantifies hospital-associated stress may help health providers appreciate the experience of patients and better target interventions to aspects of their structure and process that contribute to allostatic overload. Importantly, allostatic overload cannot be identified by one biomarker of stress but instead requires evidence of dysregulation across inflammatory, neuroendocrine, hormonal, and cardiometabolic systems. Future studies to address the burden of stress faced by hospitalized patients should consider a summative measure of multisystem dysregulation as opposed to isolated assessments of individual biomarkers. Allostatic load has previously been operationalized as the summation of a variety of hemodynamic, hormonal, and metabolic factors, including blood pressure, lipid profile, glycosylated hemoglobin, cortisol, catecholamine levels, and inflammatory markers.⁹³ To develop a hospital-associated allostatic load index, models should ideally be adjusted for acute illness severity, patient-reported stress, and capacity for stress resilience. This tool could then be used to quantify hospitalization-related allostatic load and identify those at greatest risk for adverse events after discharge, as well as measure the effectiveness of strategic environmental interventions (Table 2). A natural first experiment may be a comparison of the allostatic load of hospitalized patients versus those hospitalized at home.

The risk of adverse outcomes after discharge is likely a function of the vulnerability of the patient and the degree to which the patient’s healthcare team and social support network mitigates this vulnerability. That is, there is a risk that a person struggles in the postdischarge period and, in many circumstances, a strong healthcare team and social network can identify health problems early and prevent them from progressing to the point that they require hospitalization.^13,94-96 There are also hospital occurrences, outside of allostatic load, that can lead to complications that lengthen the stay, weaken the patient, and directly contribute to subsequent vulnerability.^94,97 Our contention is that the allostatic load of hospitalization, which may also vary by patient depending on the circumstances of hospitalization, is just one contributor, albeit potentially an important one, to vulnerability to medical problems after discharge.

In conclusion, a plausible etiology of PHS is the maladaptive mind-body consequences of common stressors during hospitalization that compound the stress of acute illness and produce allostatic overload. This stress-induced dysfunction potentially contributes to a spectrum of generalized disease susceptibility and risk of adverse outcomes after discharge. Focused efforts to diminish patient exposure to hospital-related stressors during and after hospitalization might diminish the presence or severity of PHS. Viewing PHS from this perspective enables the development of hypothesis-driven risk-prediction models, encourages critical contemplation of traditional hospitalization, and suggests that targeted environmental interventions may significantly reduce adverse outcomes.