Defining Persistent Total Parenteral Nutrition Use in Patients with Neurologic Impairment

Introduction

Patients with neurologic impairment (NI) often lack the oromotor capacity to safely ingest food. Many receive some or all of their nutrition through a gastric or jejunal tube. Parents of patients with NI identify gastrointestinal (GI) symptoms (abdominal pain, retching, and vomiting) as one of the most common distressing problems associated with central nervous system impairment.^1,2 There can be identifiable, common sources of the aforementioned pain, such as gastroesophageal reflux (GER), esophagitis, constipation, GI distension due to overfeeding, central neuropathic pain, and visceral hyperalgesia, although symptoms may persist even after optimizing treatment.^3–7 This leads to a diagnosis of recurrent or persistent feeding intolerance secondary to GI dysfunction^5,8 and caregiver concern for refractive pain and suffering. In turn, families and their medical teams may then consider permanent total parenteral nutrition (TPN) or end-of-life care to mitigate the pain.

Providing nutrition to a child is important to families, and making treatment decisions surrounding feeding intolerance and GI symptoms is stressful. ⁵ While feeding intolerance in patients with NI is well documented in the literature,^{2,4–6,8–11} the clinical progression—from the need for intermittent bowel rest and initiation of treatments targeted at neuropathic GI pain, to extended periods of time requiring parenteral fluid and nutrition—has not been well characterized. Particularly, the incidence of patients with NI and long-term feeding intolerance is not known. Our study analyzed characteristics of patients with NI at risk for persistent feeding intolerance, as well as their hospitalizations and mortality outcomes.

Our primary aim was to determine the incidence of persistent TPN use, defined in this study as the inability to wean from TPN back to enteral autonomy, in this population of patients with NI. There are a multitude of indications for TPN usage, including to promote healing in fistulas involving the GI tract, for nutritional support during sepsis or burn injury, and for supportive use in the perioperative period or in chronically nutritionally deficient patients. ¹² Because many patients with NI may be hospitalized with one or more of these diagnoses, as well as for other unknown sources of pain, we chose the permanent inability to wean from TPN as our primary endpoint. ⁵

Secondary objectives included determining mortality rate, frequency of hospitalizations, time to TPN initiation, and to describe symptoms of functional feeding intolerance that precede persistent TPN use.

Materials and Methods

This study took place in a university-affiliated pediatric tertiary care hospital with a Complex Health Care (CHC) Program, which provides interdisciplinary medical care for patients with complex chronic medical problems, including neurodevelopmental disabilities. Institutional Review Board (IRB) approval was obtained for the study. Patients enrolled in the CHC Program from 2011 to October 1, 2015 who were 0–40 years of age at the time of the first CHC visit were eligible for inclusion in the study. This age range was chosen because the CHC Program follows patients starting in childhood and continues to provide care through adulthood, although the majority of adult patients are considered “young adults.” In addition, this study aimed to describe a spectrum of feeding intolerance, so it was important to include an age range that encompassed both pediatric and young adult ages.

Severe neurological impairment is now defined as “a group of disorders of the CNS which arise in childhood, resulting in motor impairment, cognitive impairment, and medical complexity, where much assistance is required with activities of daily living. The impairment is permanent but can be progressive or static.” ¹³

All patients included in the study had a ICD-9 and CPT codes consistent with both NI and utilizing a surgical feeding tube (Tables 1 and 2). In addition, patients must have attended at least one clinic visit with a Registered Dietitian on the interdisciplinary CHC team, as they evaluate each patient's specific nutritional requirements through documentation of estimated energy requirement, weight trajectory, and create a personalized feeding plan.

Patients were excluded from the study if they had short bowel syndrome, determined by use of specific ICD-9 codes, or if they had received care in the Intestinal Rehabilitation Center, which provides multidisciplinary care for patients affected by conditions like gastroschisis, Hirschsprung disease, inflammatory bowel disease, and short bowel syndrome. These patients were excluded from the study as these entities are already associated in enteral failure, and we sought identification and description of persistent feeding intolerance distinct from these known etiologies.

After the eligible patients were identified, a retrospective chart review was performed. Initial patient characteristics at the time of entry into the study were analyzed, including age at initial visit, weight, gender, and race. All hospital admissions longer than 24 hours were reviewed for diagnoses, feeding intolerance necessitating temporary feed cessation, and TPN initiation.

Results

The eligible patient population included 208 patients, of which 168 were admitted to the inpatient service. We limited the analysis to these patients. Table 3 describes the patient characteristics for all patients and the admitted patients. Admitted patients were 59% male and 58% white. The median age at initial visit was 8.5 years (IQR: 2.5–15.5).

The median number of admissions per patient was four (IQR: 2, 7) (Table 4). Within the cohort, 125 patients required at least one admission with an unplanned full bowel rest, and 37 patients required at least one admission with unplanned partial bowel rest. The median number of admissions for a patient with bowel rest was five (IQR: 3, 10), while the median number of admissions for a patient requiring partial bowel rest was eight (IQR: 4, 15). The length of stay (LOS) for hospitalizations of patients in the cohort ranged from 1 to 173 hospital days, with the average LOS of 7.3 days. TPN was initiated 53 times during hospitalization in 26 unique patients with average time-to-TPN initiation of two years from CHC enrollment. Twenty-eight patients (14%) died. The median age at death was 12 years (IQR: 6.5, 20.5) and 61% were male.

The multivariate logistic regression models (Fig. 1) show associations with the outcomes of TPN initiation, bowel rest, and mortality. The total number of admissions was significantly associated with an increased OR for TPN initiation (OR: 1.15; 95% CI: 1.07–1.24) and bowel rest (OR: 2.26; 95% CI: 1.64–3.12). However, the total number of hospitalizations had a decreased association with mortality (OR: 0.86; 95% CI: 0.75–0.99). In addition, TPN initiation was significantly associated with an increased OR of mortality (OR: 3.72; 95% CI: 1.10–12.5) and bowel rest (OR: 3.52; 95% CI: 0.91–13.7) had an increased association, but was not statistically significant.

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FIG. 1.

Adjusted odds ratio (95% confidence interval) of TPN initiation, bowel rest, and mortality. TPN, total parenteral nutrition.

As shown in Table 5, opioids, including oxycodone, morphine, hydromorphone, fentanyl, hydrocodone, and methadone, were the most common administered medications in patients who were admitted (n = 136, 96% patients), compared to gabapentin (n = 34, 24% patients) and clonidine (n = 40, 28% patients). Patients requiring TPN initiation more commonly received gabapentin (n = 9, 25% patients), clonidine (n = 10, 38%), and opioids (n = 26, 100% patients) compared to patients who required only bowel rest.

Patient diagnoses during hospitalizations, identified by admission and final ICD-9 and ICD-10 diagnosis codes, also showed associations with the outcomes of TPN initiation and bowel rest (Fig. 1). TPN initiation was significantly associated with the presence of diseases of the circulatory system during hospitalizations (OR: 13.8; 95% CI: 4.25–44.6). Bowel rest was significantly associated with the presence of infectious diseases during hospitalizations (OR: 4.27; 95% CI: 1.07–17.1). TPN initiation was significantly associated with the presence of nervous system diseases during hospitalizations (OR: 4.2; 95% CI: 1.08–16.5). Diagnosis codes involving cerebral palsy were removed during this part of the analysis, as a diagnosis of cerebral palsy was part of the inclusion criteria for the study and was present for every patient. Finally, TPN initiation was significantly associated with the presence of GI diseases during hospitalizations (OR: 4.34; 95% CI: 1.01–18.6).

Discussion

Although feeding intolerance in patients with NI is well documented in the literature^{2,4–6,8–11} and GI symptoms have been identified as one of the three most common problems associated with CNS impairment,^1,2 the clinical progression to persistent TPN use has not previously been well characterized. Developing an understanding of the progression to persistent feeding intolerance is important for informing conversations about symptom progression, prognostication, and creating a care plan that aligns with a patient's and family's values and preferences.

We performed a retrospective chart review on hospitalizations from a cohort of patients with NI utilizing a surgical feeding tube, who were patients from a CHC clinic. Using these data, we were able to describe the incidence of persistent TPN use in this patient population at our institution. Using TPN initiation as a marker for persistent feeding intolerance, 15% of the cohort experienced persistent feeding intolerance after a mean time of two years since initial CHC evaluation. Six patients (3.5%) reached persistent TPN use, meaning that they were unable to be successfully weaned from TPN by the final hospitalization during the study period, and four of those patients died.

These results suggest that if a patient does become TPN-dependent, this may become a risk factor for mortality. A previous study of 12 children with NI presenting with status dystonicus and feeding-related pain showed that all 12 children had multiple episodes, during which pausing enteral feeds improved pain symptoms and restarting enteral feeds lead to recurrence of pain. ¹⁴ Seven patients in the study required initiation of TPN, and three of those patients remained on TPN for greater than six months. Those results show a higher rate of TPN utilization, although the study was limited to patients presenting with GI-related symptoms at time of entry into the study.

In our study, the total number of admissions had a significant association with an increased OR for TPN and bowel rest. A prior cross sectional, multicenter study showed that the patients with severe cerebral palsy and the presence of a feeding tube had increased use of health care resources, including hospitalizations, emergency room visits, outpatient physician appointments, and missed days from school or other programs. ¹⁵ In a study surveying caregivers of patients with significant cognitive impairment, pain related to the GI tract was found to be a significant concern, with its intensity rated 7.5 out of 10. ⁵ Patients often undergo multiple evaluations to determine the cause and manage symptoms, and bowel rest or TPN may be part of the management while determining etiology. Based on these prior results and our findings, we propose that as patients develop more poorly controlled GI symptoms due to feeding intolerance, these drive more frequent hospitalizations.

The total number of hospitalizations had a decreased OR for mortality. One possible theory is that patients who had increased scheduled admissions for procedures were more connected in the health care system and had increased resources, leading to a longer time to death. All hospitalizations greater than 24 hours were included in the study, including planned hospitalizations for procedures, as well as hospitalizations unrelated to GI symptoms. In future studies, it would be helpful to consider only hospitalizations involving feeding intolerance or other GI symptoms.

TPN initiation was also associated with increased frequency of medications commonly used in the treatment of neuropathic causes of GI pain, including gabapentin, clonidine, and opioids. We propose that the increased frequency of administration of medications in patients requiring TPN may indicate that, despite treatment of neuropathic GI pain, persistent symptoms may continue, signifying progression of feeding intolerance. Visceral hyperalgesia and central neuropathic pain are well-recognized causes of neuropathic GI pain and may result in improvement of symptoms when treated with medications targeted at these etiologies.^4,5,7,16

Recently, there has been more published literature highlighting the importance of performing risk assessments on patients with pain related to an altered neurologic system and maximizing treatment targeting this pain, as well as treating other reversible triggers, such as GI distension and overfeeding. ⁷ Chronic pain in children with SNI has been more recently described, including chronic GI pain that deserves greater attention in future studies of persistent feeding intolerance.^5,7 Medication trials, identifying triggers, bowel rest, and consideration of TPN initiation are all important components of a patient's care plan when treating recurrent pain episodes.

Finally, TPN initiation was significantly associated with the presence of several affected organ systems, including circulatory, digestive, infectious disease, and the nervous system. Further chart review revealed that the circulatory system diagnoses seem to be more related to manifestations of sepsis and complications of intravenous catheters, rather than a primary cardiac etiology. The association between TPN initiation and infectious disease issues, however, may be more directly related. Patients with NI who have a surgical feeding tube are at risk for infectious complications, such as aspiration pneumonia and site infections, ¹ in addition to primary infections that can lead to abdominal pain, including gastroenteritis, urinary tract infections, and Helicobacter pylori infections. ⁵

The abdominal pain and retching lead to the final association between nervous system disorders and TPN initiation. Patients who have more severe NI have more GI-related pain and have a more extreme experience of pain, both of which are associated with feeding intolerance.^3,5 Patients with more severe NI are at increased risk for overestimation of caloric needs leading to GI tract distension and pain.^4,5 These patients often require fewer calories than typical patients due to decreased movement, decreased muscle mass, and lower baseline body temperature, resulting in overall lower metabolism. ⁵ In addition, patients with more severe NI are at higher risk for overestimation of caloric requirements than other patients with cerebral palsy who have more ability to move independently, especially during the aging process with functional decline over a period of months to years. ⁵

Overestimation of caloric needs is common and has become a recognized trigger of overdistension of the GI tract resulting in feeding intolerance in recent years.^4,5 It is important to accurately track caloric intake and identify patients who may be receiving excessive nutrition, especially as functional status and mobility changes over time. There is also a strong neurologic component of this feeding intolerance and GI-related pain, stemming from a combination of increased excitability in the CNS, autonomic dysfunction, and increased sensitization to pain from repeated triggers over time.^3,5,8,14 Based on our results and the previously studied evidence, we propose that having a more complicated neurologic condition is a risk factor for recurrent GI-related pain and may lead to the need to initiate TPN if identifiable triggers are able to be reversed and feeding intolerance still persists.

In addition, bowel rest and TPN initiation were both associated with an increased OR of mortality. Patients with more severe NI and a feeding tube have higher utilization of health care resources and have overall worse health outcomes. ¹⁵ It is also known that many patients with NI have recurrent and refractory GI symptoms, despite numerous evaluations and medical interventions. ⁵ We suspect that persistent feeding intolerance and the progression to persistent TPN use is suspected to be related to an irreversible decline. This decline may be, in part, the result of long-standing changes in GI tract function, dysmotility, difficult-to-treat symptoms (GER, esophagitis, constipation), and increased sensitization to pain, as well as likely related to overall functional and physiologic decline.^1–3,5 This evidence aligns with our results as well. We propose that feeding intolerance, necessitating bowel rest, and the need for TPN initiation, may be risk factors for mortality in patients with NI.

This study has several limitations that may have affected the results. First, the sample size was relatively small and limited to a single institution. The small cohort of patients contributed to wide CIs associated with the data. Also, the retrospective nature of the study allowed only the use of ORs, rather than relative risk. We were limited to recognizing associations to the endpoints rather than causations among the variables.

One of the associations included identifying specific triggers leading GI pain, such as overestimation of caloric requirements. The risk of overestimating caloric needs has been suggested in more recent publications that were not available in the dates of the retrospective review. ⁵ Each patient in the study was established with a registered dietitian on the CHC interdisciplinary team, which helped ensure evaluation of individualized feeding plans were considered for each patient. Due to variations in documentation at the time of data collection, it was not possible to consistently track caloric estimates during each episode of feeding intolerance and during each hospitalization.

In addition, many of the deaths did not take place in the hospital, and documentation about the events leading up out-of-hospital deaths was limited. The lack of documentation led to difficulty in identifying physical signs, such as edema, indicating a patient may be nearing the end-of-life, GI symptoms occurring around the time of death, and if they may have played a role in the patient's death.

Finally, due to differences in documentation and initial workup of patients during hospitalizations, it was not clear if all patients presented exclusively with irritability and pain as the driver to implement bowel rest, or if certain patients presented with functional ileus as well. Multicenter prospective studies that define the population, including level of intellectual and motor disability, follow a standardized workup and treatment approach, including chronic pain assessment, as well as documentation of caloric estimates with each episode of feeding intolerance, would help clarify and resolve these limitations.

This study has future implications, which may increase opportunities for palliative care involvement. While prospective studies are required, this study provides provisional considerations regarding the clinical trajectory of a patient at risk for persistent TPN use that aids primary and palliative care teams' determination of when to refer to palliative care. It also fosters conversation around the implication of recurrent feeding intolerance and persistent TPN use.

Conclusions

Our study demonstrates that patients with NI and a surgical feeding tube are at risk for persistent TPN use, despite optimization of medications targeted at neuropathic GI pain. In addition, TPN and bowel rest were found to have a positive association with mortality. Thus, prospective studies are needed to further characterize relationships between persistent TPN use, hospitalizations, and mortality. Including this information when discussing the possibility of TPN initiation with families may be helpful in the context of benefits and burdens of treatment, as well as prognosis. Ultimately, it is important to understand persistent feeding intolerance in patients with NI to create a care plan that aligns with a patient's and family's values and preferences.