Abstract
Objectives:
About 16,000 infants die in the neonatal intensive care unit (NICU) each year with many experiencing invasive medical treatments and high number of symptoms.1 To inform better management, we characterized diagnoses, symptoms, and patterns of care among infants who died in the NICU.
Method:
Retrospective electronic medical record (EMR) review of 476 infants who died following admission to a large regional level IV NICU in the United States over a 10-year period. Demographic, symptom, diagnosis, treatment, and end-of-life characteristics were extracted.
Results:
About half of infants were male (55.9%, n = 266), average gestational age was 31.3 weeks (standard deviation [SD] = 6.5), and average age at death was 40.1 days (SD = 84.5; median = 12; range: 0–835). Race was documented for 65% of infants, and most were White (67.0%). One-third of infants (n = 138) were seen by fetal medicine. Most infants experienced pain through both the month and week before death (79.6%), however, infants with necrotizing enterocolitis had more symptoms in the week before death. Based on EMR, infants had more symptoms, and received more medical interventions and comfort measures during the week before death compared with the month prior. Only 35% (n = 166) received a palliative care referral.
Conclusions:
Although the medical profiles of infants who die in the NICU are complex, the overall number of symptoms was less than in older pediatric populations. For infants at high risk of mortality rate, providers should assess for common symptoms over time. To manage symptoms as effectively as possible, both timely and continuous communication with parents and early referral to palliative care are recommended.
Keywords: critically ill infants, end of life, NICU, symptoms
Introduction
Despite improved survival, roughly 16,000 of the half-million infants admitted annually to the neonatal intensive care unit (NICU) die.1,2 Moreover, these infants may undergo numerous procedures,3,4 and experience symptoms that can be challenging for the health care team to assess and manage.5 Infant symptom experiences, especially near end of life (EOL), have not been well-described, and clinical assessment tools are limited. This is concerning because symptoms are distressing for parents and can influence care decisions.6,7
Characterizing the EOL in infants is a priority in pediatric palliative care.2,3,8–14 Most symptom research has focused on older children with cancer, relying heavily on medical charts or proxy reports.15–18 Types of medications to manage symptoms in infants are also not well understood,19 with the exception of opioids for pain.9 Thus, a retrospective review of the various characteristics of infants who died in an NICU over a 10-year period was undertaken. We focused on identifying characteristics (e.g., treatment, symptoms) necessary to improve the care of critically ill infants. We hypothesized that the number of symptoms, medications, and medical interventions would increase from the month to the week before death and that lack of further treatment benefit would be documented late for most infants.
Methods
Setting
The palliative care team at the study site includes physicians, nurse practitioners, social workers, and chaplains. It provides the full complement of palliative care services 24 hours/seven days a week, including the ability to provide bedside EOL care medication and decisional support. A trigger list of severe conditions impacting infants to increase palliative care consultation within the NICU was fully implemented in 2015 (Table 1).
Table 1.
Trigger List for Pediatric Palliative Care Referral in the Neonatal Intensive Care Unit
| Diagnosis | ICD 9 codes |
|---|---|
| Trisomy 13 | 758.1 |
| Trisomy 18 | 758.2 |
| Renal agenesis | 753.0 |
| Bilateral polycystic kidney disease | 753.12, 753.13, 753.14 |
| Anencephaly | 740.0 |
ICD 9, International Classification of Diseases, ninth revision.
Data collection
Following Institutional Review Board approval, a retrospective review of electronic medical records (EMR) was conducted between July 2009 and June 2019 in a Midwestern level IV NICU that serves as a regional referral and surgical center for outborn infants, with roughly 900 admissions annually. Data were extracted for 476 infants admitted to, and who died in, the NICU by trained research assistants using an extraction form developed for the study. Consent was not required from parents of infant decedents.
Medical variables
For each infant, demographic, illness, treatment, and EOL characteristics were extracted.
Demographic information
Date of birth, gestational age, sex, race/ethnicity, date of NICU admission and death, and location of death were extracted. Race/ethnicity were originally collected by mother self-report. Primary diagnosis at birth was categorized as the reason for admission, whereas diagnoses at death were categorized using death certificates. All infants died in the hospital, with most dying in the NICU.
Treatment characteristics
Symptoms, medications, medical interventions, and comfort measures were assessed using physicians' progress notes and nursing flow sheets. Comparisons were made between the week (up to six days before death) and month before death (four weeks before death [or date of birth, if infant lived less than four weeks] through the seventh day before death). These time frames were chosen as the last month represents a time when infants could be potential survivors and the last week captures either a time of decompensation or when their nonsurvivor status became clearer.
Common symptoms were extracted (e.g., pain, respiratory difficulty).7 Pain and agitation were assessed by the NICU staff using the Neonatal Pain, Agitation, and Sedation Scale (N-PASS) for infants younger than two months,20,21 and the Face, Leg, Activity, Cry, Consolability Scale (FLACC) for infants older than two months.22 Pain was categorized as scores exceeding zero on the irritability, facial expression, or extremities tone subscales of the N-PASS, or on the face, legs, or activity subscales of the FLACC. Scores exceeding zero on the behavior state section of the N-PASS or the consolability section of the FLACC indicated agitation. Pain was considered present during the week and/or month before death if infant scores exceeded zero at least once in the corresponding time frame. Comfort measures included repositioning, nesting (providing boundaries for the infant to touch and brace against), holding, skin-to-skin care, and hand containment (gentle but secure hands placed on the infant's head/body).
EOL characteristics
Documentation of palliative care referrals, allow natural death (AND) orders, code events, lack of further treatment benefit, and withdrawal of life sustaining treatment was extracted.
Statistical analysis
Descriptive statistics were examined for study variables. For infants surviving more than six days (68%, n = 326), paired samples t-tests (α = 0.05, two-tailed) compared symptoms, medications, medical interventions, and comfort measures documented during the month and week before death. One-way analysis of variances (ANOVAs) compared infants based on primary diagnoses. McNemar tests (α = 0.05, two-tailed) compared the presence of specific symptoms and medication classes administered during the month and week before death (n = 289–312). Independent samples t-tests (α = 0.05, two-tailed) and chi-square tests compared infants based on referral to palliative care and admission before or after implementation of the trigger list.
Results
Demographic information
All demographic information is reported in Table 2, and common diagnoses at birth and death are reported in Table 3. Infants who lived less than one week (n = 150) had a significantly longer gestational age (mean [M] = 32.4 weeks, SD = 6.3) than infants who lived more than six days (M = 30.8 weeks, SD = 6.5; t = −2.4, p = 0.02, d = 0.24).
Table 2.
Demographic Information
| Infants older than six days n = 326 n (%) or M (SD) | Infants younger than seven days n = 150 n (%) or M (SD) | All infants n = 476 n (%) or M (SD) | |
|---|---|---|---|
| Sex | |||
| Male | 185 (56.7) | 81 (54.0) | 266 (55.9) |
| Female | 141 (43.3) | 69 (46.0) | 210 (44.1) |
| Race/ethnicity | |||
| Asian | 4 (1.2) | 3 (2.0) | 7 (1.5) |
| Black/African American | 51 (15.6) | 14 (9.3) | 65 (13.7) |
| White | 146 (44.8) | 61 (40.7) | 207 (43.5) |
| Multiracial | 16 (4.9) | 2 (1.3) | 18 (3.8) |
| Hispanic/Latinx | 6 (1.8) | 3 (2.0) | 9 (1.9) |
| Non-Hispanic/Latinx | 232 (71.2) | 93 (62.0) | 325 (68.3) |
| Unknown racea | 104 (31.9) | 68 (45.3) | 172 (36.1) |
| Unknown ethnicitya | 93 (28.5) | 56 (37.3) | 149 (31.3) |
| Gestational age (weeks) | 30.8 (6.5) | 32.4 (6.3) | 31.3 (6.5) |
| Age at death (days; 0–835) | 57.2 (97.4) | 2.8 (1.9) | 40.1 (84.5) |
| Seen by fetal medicineb | 100 (30.7) | 38 (25.3) | 138 (29.0) |
| No. of comorbid conditionsc | 2.3 (1.6) | 2.1 (1.6) | 2.2 (1.6) |
Race was not documented in the medical chart of 165 infants. Ethnicity was not documented in the medical chart of 147 infants.
Infants were seen by fetal medicine for potential complications at birth.
Comorbid conditions refer to secondary diagnoses present on the death certificate other than the primary death diagnosis.
M, mean; SD, standard deviation.
Table 3.
Primary Diagnoses at Birth and at Death
| Infants older than six days n = 326 n (%) or M (SD) | Infants younger than seven days n = 150 n (%) or M (SD) | All infants n = 476 n (%) or M (SD) | |
|---|---|---|---|
| Birth | |||
| Prematurity | 115 (35.3) | 48 (32.0) | 163 (34.2) |
| Respiratorya | 81 (24.8) | 43 (28.7) | 124 (26.1) |
| Congenital/genetic | 51 (15.6) | 27 (18.0) | 78 (16.3) |
| Cardiac | 33 (10.1) | 9 (6.0) | 42 (8.8) |
| Neurologic | 17 (5.2) | 16 (10.7) | 33 (6.9) |
| Other conditions | 25 (7.7) | 11 (7.3) | 36 (7.4) |
| Death | |||
| Respiratory | 64 (19.6) | 38 (25.3) | 102 (21.4) |
| Cardiac | 68 (20.9) | 25 (16.7) | 93 (19.5) |
| Neurologic | 35 (10.7) | 23 (15.3) | 58 (12.2) |
| Congenital/genetic | 33 (10.1) | 20 (13.3) | 53 (11.1) |
| Necrotizing enterocolitis | 43 (13.2) | 5 (3.3) | 48 (10.1). |
| Sepsis | 33 (10.1) | 9 (6.0) | 42 (8.8) |
| Other conditions | 42 (12.9) | 39 (26.0) | 81 (8.2) |
Note: respiratory conditions also included bronchopulmonary dysplasia. Cardiac conditions also included congenital heart disease. Neurologic conditions also included intraventricular hemorrhage. Other conditions at birth included: sepsis, NEC cyanosis, intrauterine growth restriction, metabolic acidosis, and four charts missing data. Other conditions at death included: prematurity, hydrops fetalis, metabolic acidosis, anasarca, shock, coagulopathy, complications associated with ileal perforation, complications from a metabolic/mitochondrial disorder, nonketotic hyperglycinemia, pulmonary thromboembolism, and organ failure.
Three infants did not have a diagnosis at birth but were later diagnosed with bronchopulmonary dysplasia. For the purpose of analyses, these infants were considered to have a respiratory diagnosis.
NEC, necrotizing enterocolitis.
Treatment characteristics
The frequency of symptoms during the week and month before death is in Table 4. Compared with the month before death, infants had more symptoms in the week prior (Table 5). A smaller proportion of infants experienced pain (p = 0.045) only in the week (4.8%) versus only in the month before death (9.7%). Yet, most infants experienced pain throughout both the month and week before death (79.6%; n = 230). In addition, a larger proportion of infants experienced abdominal distension (p = 0.006) in only the week (21.9%) versus only the month before death (12.3%). A one-way ANOVA (F(7,461) = 4.8, p < 0.001) demonstrated a significant difference between death diagnoses.
Table 4.
Frequency of Symptoms and Comfort Measures as Documented in the Medical Chart
| Month prior (n = 326) n (%) | Week prior (n = 476) n (%) | McNemar test p | |
|---|---|---|---|
| Symptoms** | |||
| Respiratory difficulty | 304 (93.3) | 461 (96.8) | 1.00a |
| Unstable vital signs | 297 (91.1) | 465 (97.7) | 0.06a |
| Pain | 258 (79.1) | 375 (78.8) | 0.045 |
| Agitation | 229 (70.2) | 335 (70.4) | 1.00 |
| Abdominal distension | 124 (38.0) | 219 (46.0) | 0.01 |
| Lethargy | 96 (29.4) | 175 (36.8) | 0.84 |
| Feeding intolerance | 77 (23.6) | 87 (18.3) | 0.63 |
| Seizures | 50 (15.3) | 86 (18.1) | 0.63 |
| Comfort measures** | |||
| Repositioning/nesting | 283 (86.8) | 437 (91.8) | 0.73a |
| Decreased sensory stimulation | 264 (81.0) | 394 (82.8) | 1.00 |
| Distractions | 174 (53.4) | 159 (33.4) | <0.001 |
| Holding/kangaroo | 142 (43.6) | 344 (72.3) | <0.001 |
| Neutral thermal environment | 115 (35.3) | 120 (25.2) | 0.22 |
| Lightweight clothing/bedding | 99 (30.4) | 80 (16.8) | 0.01 |
| Other | 121 (37.1) | 162 (34.0) | — |
Note: other comfort measures included, but were not limited to, touch, clustered care, pillow support, adjusted clothing/bedding, and promoted sleep/rest. Bolded p-values are significant.
Indicates exact p-values. All other values should be assumed to be asymptotic.
Indicates t-test p-value of <0.001.
Table 5.
Paired and Independent Samples t-Tests
| n | Month prior M (SD) | Week prior M (SD) | Palliative referral M (SD) | No referral M (SD) | t | p | |
|---|---|---|---|---|---|---|---|
| Paired t-tests | |||||||
| Symptoms | 326 | 4.4 (1.6) | 4.8 (1.2) | −3.8 | <0.001 | ||
| Medications | 310 | 12.2 (7.2) | 11.8 (6.2) | 0.88 | 0.38 | ||
| Interventions | 326 | 5.5 (1.6) | 5.7 (1.3) | −1.99 | 0.048 | ||
| Comfort measures | 326 | 3.3 (1.7) | 3.6 (1.2) | −3.68 | <0.001 | ||
| Independent t-tests (greater than six days) | |||||||
| Ma symptoms | 325 | 4.8 (1.4) | 4.1 (1.7) | 3.91 | <0.001 | ||
| M medications | 310 | 12.6 (7.2) | 11.8 (7.2) | 1.02 | 0.31 | ||
| M interventions | 325 | 5.4 (1.4) | 5.5 (1.8) | −0.46 | 0.64 | ||
| M comfort measures | 325 | 3.8 (1.5) | 3.0 (1.8) | 4.52 | <0.001 | ||
| Wb symptoms | 325 | 4.6 (1.2) | 4.9 (1.2) | −2.08 | 0.04 | ||
| W medications | 323 | 10.9 (7.4) | 12.4 (5.1) | −1.91 | 0.06 | ||
| W interventions | 325 | 5.1 (1.3) | 6.1 (1.1) | −6.69 | <0.001 | ||
| W comfort measures | 325 | 3.8 (1.2) | 3.5 (1.2) | 1.81 | 0.07 | ||
| Age at death, days (log) | 325 | 86.6 (136.8) | 35.1 (39.9) | 4.23 | <0.001 | ||
| Independent t-tests (less than seven days) | |||||||
| W symptoms | 148 | 4.6 (1.4) | 4.2 (1.3) | 1.30 | 0.20 | ||
| W medications | 148 | 10.3 (5.7) | 10.3 (4.1) | 0.02 | 0.99 | ||
| W interventions | 148 | 5.1 (1.6) | 5.4 (1.3) | −1.06 | 0.29 | ||
| W comfort measures | 148 | 2.5 (1.0) | 2.3 (1.1) | 0.72 | 0.48 | ||
| Age at death | 148 | 3.0 (1.7) | 2.7 (2.0) | 0.68 | 0.50 | ||
Note: bolded p-values are significant.
M = month before death.
W = week before death.
A Tukey post hoc test showed that infants with necrotizing enterocolitis (NEC) had more symptoms in the week before death than those with neurologic (p < 0.001), cardiac (p < 0.001), respiratory (p < 0.001), congenital and/or genetic (p = 0.01), and premature diagnoses (p = 0.004).
Medications and medical interventions are detailed in Table 6. For infants who lived more than six days, the number of medications during the month before death was similar to the week prior (Table 5). A greater proportion of infants received benzodiazepines (26.5% vs. 10.3%, p < 0.001), steroids (20.4% vs. 12%, p = 0.01), opioids (26.6% vs. 3.5%, p < 0.001), and vasopressors (27.1% vs. 12.3%, p < 0.001) only in the week versus only the month before death. In addition, a smaller proportion of infants were administered nonsteroidal anti-inflammatory drugs (NSAIDs; 1.6% vs. 11.7%, p < 0.001), acetaminophen (7.1% vs. 12.7%, p = 0.04), sucrose (4.5% vs. 20.6%, p < 0.001), and antibiotics (4.5% vs. 16.4%, p < 0.001) only in the week versus only the month before death.
Table 6.
Frequency of Medications and Medical Interventions as Documented in the Medical Chart
| Month prior (n = 326) n (%) | Week prior (n = 476) n (%) | McNemar test p | |
|---|---|---|---|
| Medication types | |||
| Antibiotic | 282 (86.5) | 396 (83.2) | <0.001 |
| Opioid | 219 (67.2) | 440 (92.4) | <0.001 |
| Benzodiazepine | 167 (51.2) | 302 (63.5) | <0.001 |
| Diuretic | 162 (49.7) | 177 (37.2) | 0.56 |
| Vasopressor | 158 (48.5) | 340 (71.4) | <0.001 |
| Steroid | 140 (42.9) | 261 (54.9) | 0.01 |
| Sucrose | 129 (39.6) | 138 (29.0) | <0.001 |
| Pulmonary inhaled | 94 (28.8) | 89 (18.7) | 0.06 |
| Antiepileptic | 80 (24.5) | 109 (22.9) | 0.48 |
| Acetaminophen | 65 (19.9) | 56 (11.8) | 0.04 |
| Gastrointestinal | 59 (18.1) | 53 (11.2) | 0.12 |
| NSAID | 52 (16.0) | 32 (6.7) | <0.001 |
| Vasodilator | 32 (9.8) | 44 (9.2) | 1.00 |
| Antispasmodic | 2 (0.6) | 9 (1.9) | 0.29a |
| Other | 285 (87.4) | 394 (82.8) | — |
| Medical interventions* | |||
| Common | |||
| Suction | 290 (89.0) | 433 (91.0) | 0.74 |
| Ventilator | 277 (85.0) | 436 (91.6) | 0.14 |
| PICC, CVC, UVC | 277 (85.0) | 412 (86.6) | 0.02 |
| TPN, intralipid | 253 (77.6) | 338 (71.0) | <0.001 |
| Feeding tube | 250 (76.7) | 359 (75.4) | 0.50 |
| Peripheral intravenous line | 219 (67.2) | 348 (73.1) | 0.66 |
| CPAP | 114 (35.0) | 126 (26.5) | <0.001 |
| Surgical | |||
| Gastrostomy tube | 28 (8.6) | 30 (6.3) | 0.69a |
| Tracheostomy | 26 (8.0) | 39 (8.2) | 0.63a |
| Surgery for NEC | 10 (3.1) | 60 (12.6) | <0.001 |
| Colostomy, ileostomy | 15 (4.6) | 20 (4.2) | 0.38a |
| ECMO | 11 (3.3) | 21 (4.4) | 1.00a |
| Ventriculoperitoneal shunt | 11 (3.3) | 12 (2.5) | 1.00a |
| PDA surgery | 9 (2.8) | 9 (1.9) | 0.77a |
Note: week before death = six days before death through date of death; month before death = four weeks before death—or date of birth if infant lived less than four weeks—through the first day of the last week of life. Bolded p-values are significant.
Indicates exact p-values. All other values should be assumed to be asymptotic.
Indicates t-test p-value of <0.05.
CPAP, continuous positive airway pressure; CVC, central venous catheter; ECMO, extracorporeal membrane oxygenation; NEC, necrotizing enterocolitis; NSAID, nonsteroidal anti-inflammatory drug; PDA, patent ductus arteriosus; PICC, peripherally inserted central catheter; TPN, total parenteral nutrition; UVC, umbilical venous catheter.
Medical interventions during the week before death were greater compared with the month prior (Table 5). A smaller proportion of infants had a PICC (2.6% vs. 7.1%, p = 0.02), CPAP (4.5% vs. 14.7%, p < 0.001), and TPN (3.5% vs. 11.6%, p < 0.001) only in the week before death versus only the month prior. A greater proportion of infants had surgery for NEC (13.3% vs. 2.3%, p < 0.001) only in the week versus only the month before death. A one-way ANOVA (F(5,463) = 2.9, p = 0.01) demonstrated a significant difference between birth diagnoses: infants with respiratory diagnoses received more medical interventions in the week before death than those with neurologic diagnoses (p = 0.02).
Lastly, more comfort measures were provided in the week before death compared with the month prior (Table 5). A smaller proportion of infants received distractions (7.1% vs. 18.6%, p < 0.001) and lightweight clothing/bedding (3.8% vs. 11.4%, p = 0.01) only in the week versus only the month before death. A greater proportion of infants were held (30.9% vs. 8.2%, p < 0.001) only in the week versus only the month before death.
EOL characteristics
EOL characteristics are provided in Table 7. Proportionally less infants with a premature or respiratory birth diagnosis were referred to palliative care than expected, while more infants with a congenital and/or genetic birth diagnoses were referred than expected [X2(5, n = 467) = 15.1, p = 0.01]. For infants who lived more than six days, those referred to palliative care had more symptoms and were provided more comfort measures in the month before death, and had less symptoms and were provided less medical interventions in the week prior than infants not referred. Referred infants also lived significantly longer than those not referred (Table 5). A higher proportion of infants referred to palliative care than nonreferred infants had an AND order at the time of death, and died due to respiratory causes or congenital and/or genetic conditions.
Table 7.
End-of-Life Characteristics
| Infants older than six days n = 326 n (%) or M (SD) | Infants younger than seven days n = 150 n (%) or M (SD) | All infants n = 476 n (%) or M (SD) | |
|---|---|---|---|
| Life-sustaining treatment discontinued | 262 (80.4) | 108 (72.0) | 370 (77.7) |
| Code activated at death | 53 (16.3) | 33 (22.0) | 86 (18.1) |
| Died in NICU | 295 (90.5) | 147 (98.0) | 442 (92.9) |
| Transferred before death | 29 (8.9) | 3 (2.0) | 32 (6.7) |
| Physician notea | 277 (85.0) | 127 (84.7) | 404 (85.1) |
| Physician note on date of death | 79 (24.2) | 65 (51.2) | 144 (35.6) |
| AND order | 182 (55.8) | 62 (41.3) | 244 (51.3) |
| Palliative care referral | 134 (41.1) | 32 (21.3) | 166 (34.9) |
| Date of physician note (days before death) | 13.1 (32.2) | 0.98 (1.3) | 9.3 (27.3) |
| Date of AND order (days before death) | 8.2 (26.7) | 0.6 (0.7) | 6.3 (23.3) |
| Date of palliative care referral (days after admission) | 41.2 (81.4) | 1.5 (1.3) | 33.4 (74.6) |
| Date of palliative care referral (days before death) | 32.8 (63.9) | 1.5 (1.3) | 26.6 (58.7) |
Physician note = a physician documented that further treatment may not have benefit. These documentations appeared in note templates that are specifically designed to accompany Do Not Resuscitate and AND orders.
AND, allow natural death; NICU, neonatal intensive care unit.
A lower proportion of infants referred to palliative care than nonreferred infants died following a code, and due to sepsis, or NEC (Table 8). Infants who lived less than one week did not differ in age at death, symptoms, medications, medical interventions, or comfort measures based on palliative care referral or not (Table 5). A higher proportion of infants referred to palliative care than nonreferred infants had an AND order at death, had a physician document that further treatment may not have benefit, and died due to organ failure or congenital and/or genetic conditions. A lower proportion of infants referred to palliative care than nonreferred infants died following a code (Table 8).
Table 8.
Chi-Square Comparisons of Infants Referred and Not Referred to Palliative Care
| n | Referred, n (%) | Not referred, n (%) | X2 | df | p | |
|---|---|---|---|---|---|---|
| Infants older than six days | ||||||
| AND order | 323 | 103 (31.9) | 79 (24.5) | 40.9 | 1 | <0.001 |
| Physician notea | 322 | 118 (36.6) | 159 (49.4) | 2.1 | 1 | 0.15 |
| Code activated at time of death | 317 | 12 (3.8) | 41 (12.9) | 9.2 | 1 | 0.002 |
| Life-sustaining therapy withheld | 317 | 112 (35.3) | 150 (47.3) | 1.3 | 1 | 0.26 |
| Respiratory death diagnosis | 320 | 37 (11.6) | 26 (8.1) | 10.3 | 1 | 0.001 |
| Cardiac death diagnosis | 320 | 27 (8.4) | 41 (12.8) | 0.1 | 1 | 0.82 |
| Congenital and/or genetic death diagnosis | 320 | 24 (7.5) | 9 (2.8) | 15.4 | 1 | <0.001 |
| Premature death diagnosis*,b | 320 | 0 (0) | 3 (0.9) | — | — | 0.27 |
| Sepsis death diagnosis | 320 | 5 (1.6) | 28 (8.8) | 10.1 | 1 | 0.001 |
| NEC death diagnosis | 320 | 6 (1.9) | 37 (11.6) | 15.0 | 1 | <0.001 |
| Neurologic death diagnosis | 325 | 17 (5.2) | 18 (5.5) | 0.9 | 1 | 0.35 |
| Organ failure death diagnosis | 320 | 6 (1.9) | 9 (2.8) | 0.006 | 1 | 0.94 |
| Infants younger than seven days | ||||||
| AND order | 146 | 24 (16.4) | 38 (26.0) | 17.8 | 1 | <0.001 |
| Physician note* | 148 | 31 (20.9) | 95 (64.2) | — | — | 0.046 |
| Code activated at time of death | 144 | 3 (2.1) | 30 (20.8) | 4.3 | 1 | 0.04 |
| Life-sustaining therapy withheld | 144 | 26 (18.1) | 82 (56.9) | 1.6 | 1 | 0.20 |
| Respiratory death diagnosis | 148 | 9 (6.1) | 29 (19.6) | 0.1 | 1 | 0.72 |
| Cardiac death diagnosis | 148 | 3 (2.0) | 22 (14.9) | 1.6 | 1 | 0.20 |
| Neurologic death diagnosis* | 148 | 4 (2.7) | 19 (12.8) | — | — | 0.78 |
| Premature death diagnosis* | 148 | 0 (0) | 2 (1.4) | — | — | 0.61 |
| Congenital and/or genetic death diagnoses* | 148 | 8 (5.4) | 12 (8.1) | — | — | 0.04 |
| Sepsis death diagnosis* | 148 | 0 (0) | 9 (6.1) | — | — | 0.21 |
| NEC death diagnosis* | 148 | 0 (0) | 5 (3.4) | — | — | 0.59 |
| Organ failure death diagnosis* | 148 | 6 (4.1) | 7 (4.7) | — | — | 0.04 |
Note: all chi square p-values are asymptotic. Bolded p-values are significant.
Fisher's exact test: exact two-tailed probability.
Physician note = a physician documented that further treatment may not have benefit. These documentations appeared in note templates that are specifically designed to accompany Do Not Resuscitate and AND orders.
Premature death diagnosis refers to infants who were extremely premature, and no other cause of death was listed on the death certificate.
About half of infants (55.3%, n = 263) were admitted in or before 2014, before the full implementation of the trigger list. The proportion of infants referred to palliative care in 2015–2019 was significantly greater than before 2015, X2(1, n = 473) = 47.6, p < 0.001. There were no differences in symptom number, withdrawal of life support, or resuscitation orders between infants who were referred before or after trigger list implementation. However, infants referred afterward (M = 12.6, SD = 7.2, n = 164) received more medications in the week before death than infants referred beforehand (M = 7.3, SD = 5.4, t = 4.83, p < 0.001, d = 0.83).
Discussion
We characterized the diagnoses, symptoms, medications, medical interventions, comfort measures, palliative care referrals, and physician orders related to infants in the week and month before death in a large level IV NICU. Although infants who died over the 10-year period had a variety of admitting diagnoses, comorbid conditions, and causes of death, several commonalities were identified. Two-thirds of the sample survived for a week or more after birth and received medications and other interventions to support and stabilize their condition.
Illness and treatment characteristics
Infants experienced an average of four to five symptoms, which significantly increased from the month before death to the week prior. Infants with NEC had more symptoms in the week before death than all of the other diagnoses reported, and a greater proportion had NEC surgery in the week before death than in the month prior. Infants who die following NEC surgery are likely very sick and may be in septic shock, and thus, it could be anticipated that these infants may have increased symptoms. Furthermore, overall, pain decreased and abdominal distension increased in the week before death in infants who lived longer than one week.
However, this number of symptoms is considerably less than that reported in older pediatric populations.23 For example, older children who die of cancer or other conditions experience about 11 symptoms in the week before death.17 It is unclear if this difference in number of symptoms is due to variability in the assessment and care of infants, lack of validated symptom assessment tools (other than pain) for infants, informant effects, types of health conditions, or true developmental differences in the symptom experience. Although the cause is likely multifactorial, it is important to note that symptoms can have important implications for satisfaction with care, recall of the infant's EOL, and family grief experiences.24,25 For example, one study found that parents who recalled more symptoms during the last week of their infant's life, also perceived that their infant suffered more.7
Thus, improvements in symptom assessment of critically ill infants are needed, not just for the benefit of the infant, but also for caregivers.
As noted, pain was documented for most infants, and opioids were the medications used most frequently during the week before death. This finding is noteworthy given other studies have indicated that witnessing the infant's pain was a source of distress and affected parent perceptions of their child's suffering and quality of life.24,26 This is also consistent with parents of children with cancer.27 Unfortunately, we could not determine whether interventions increased symptoms in infants, necessitating pain management or sedation, or whether symptoms increased as they declined in health, thereby requiring more opioid use. Treatment efficacy could also not be determined. The finding that medication use was not significantly different between the month and week before death is likely due to the limited numbers of medications available to treat infants.
Depending on the symptoms exhibited by the infant, a combination of pharmacologic and nonpharmacolgic approaches can be utilized to optimize symptom control.28 Comfort measures may be difficult to extract from the EMR as nurses utilize these techniques during routine care and may not document every occurrence.
EOL characteristics
Although survival has improved, infants born extremely premature or with congenital and/or genetic complications continue to experience a higher risk of mortality rate.1,29 Curative treatments often continue until it is clear the infant will not survive, yet infants often experience pain and other symptoms during this time. Palliative care can help infants live more comfortably with their condition and the effects of subsequent therapies. Only one-third of infants received palliative care referrals, frequently initiated on the last day of life. However, palliative care referrals increased after an automatic trigger list including life-threatening diagnoses was implemented. More infants with a congenital and/or genetic birth diagnosis were referred to palliative care, and a higher proportion of referred infants died from congenital/genetic causes than infants who were not referred to palliative care. AND orders and discussions regarding lack of further treatment benefit were frequently documented late and often on the day of death.
Palliative care referrals were associated with more comfort measures in the month before death, fewer medical interventions and symptoms in the week prior, having an AND, and living longer. This mirrors research with both adults and children experiencing cancer indicating that early palliative care consultation can have positive effects on symptom management, patient survival, and quality of life.30,31
Parents often choose concurrent goals of continuing curative treatment to extend life while optimizing quality of life.32,33 During the week before death, use of medical interventions was significantly greater than in the month prior. These findings suggest that attempts were still being made to ensure infant survival and may reflect time-limited trials of intensive care with recognition that if no improvement occurs, withdrawal of life-sustaining treatments may be in the best interest of the infant. This is consistent with literature in both infants and other populations suggesting that it is difficult for family members and health care providers to curtail treatment.14,23,34,35 A common reason palliative care or EOL discussions may not occur is because clinicians do not feel the family is ready or willing to engage in these conversations.36 However, parents may not know that these discussions should be taking place, or they may be waiting for the clinicians to initiate them.36
While parental readiness is important, there is currently not a clear model for assessing the correct timing for conversations. Therefore, incorporating advance care planning discussions into the continuous care of families is recommended.37 This allows for early and ongoing responses to parental needs that arise as their awareness and acceptance of the infant's situation changes throughout the illness trajectory. Parents desire complete and honest information that is delivered with compassion and measured so as to not overwhelm them.38 A personalized approach that incorporates the family's values and goals is also helpful.39,40 Thus, offering more opportunities for training and specific guidelines for engaging in difficult conversations have proven beneficial.41 There may be multiple contributing factors that still need to be determined, and so, it is important that research further investigates decision making in the NICU.
Limitations
This retrospective study utilized EMR data collected for clinical, rather than research, purposes.42 Some data are incomplete, especially for symptoms that are more subjective in nature (e.g., agitation). In addition, the documented date of terminal condition may not be a reliable indicator of when the physician became aware that the infant would likely not survive. Alternate indicators such as timing of palliative care referral or physician self-report may be better measures. Furthermore, charting by exception may lead to missing symptom documentation, and thus, inferences are difficult to assume (e.g., observed symptoms may not be documented). Moreover, data were from one, Midwestern NICU. Although this NICU is one of the largest in the country, infant EOL experiences may not generalize to other regions or institutions. Race/ethnicity were not consistently recorded, and so, differences across minoritized groups that may have unique experiences and known health disparities both with usual clinical care43–46 and at EOL could not be explored.47–50
While the race/ethnicity data were collected through parent report across the study time frame, they were inconsistently documented in the medical record. Recording of these data in the medical record improved over time. Future studies should include prospective, multisite collaborations to characterize the experiences of diverse families.
Conclusion
Our study described diagnoses, symptoms, and care patterns common to EOL in the NICU. Understandably, each patient requires a unique approach as clinicians and families work to determine the best course of action until it becomes clear that the infant will not survive. There is a distinct symptom pattern in infant death compared with death in older children. Clinicians will benefit from the knowledge of the most common diagnoses and symptoms that characterize critically ill infants dying in the NICU to offer timely and targeted comfort measures, enhanced communication skills, and referral for palliation. This study showed associations between palliative care referral, symptom control, and documented advanced care planning. This study reinforces that palliative care referral augments symptom management.
Further studies are needed to better establish the best timing for palliative care consultation in the NICU, along with those diagnoses most appropriate for referral. However, it is increasingly clear that palliative care involvement is paramount to optimize the quality of an infant's life when sadly death is likely.
Acknowledgments
We thank the following individuals for their time and effort devoted to assistance with data collection/data entry on the project: Stephanie D. Sealschott, PhD, RN, Kayla Thomsen, BSN, RN, Cristy Yang Gao, BSN, RN, Hannah Richey, BSN, and John (Gage) Boyer.
Authors' Contributions
C.A.F.: conceptualization (lead); funding acquisition (equal); project administration (lead), methodology (lead); supervision (equal); writing—original draft (lead); and writing—review and editing (equal). A.E.B.: conceptualization (supporting); funding acquisition (equal); methodology (supporting); supervision (equal); writing—original draft (supporting); and writing—review and editing (equal). D.G.: investigation (equal); formal analysis (lead); and writing—review and editing (equal). A.M.W.: investigation (equal); formal analysis (supporting); and writing—review and editing (equal). L.H.: conceptualization (supporting) and writing—review and editing (equal). N.C.: investigation (equal) and writing—review and editing (equal). E.L.M.: investigation (equal); formal analysis (supporting); and writing—review and editing (equal). M.C.K.: investigation (equal); formal analysis (supporting); and writing—review and editing (equal). L.D.N.: conceptualization (supporting); methodology (supporting); and writing—review and editing (equal). C.A.G.: conceptualization (supporting); funding acquisition (supporting); methodology (supporting); supervision (equal); and writing—review and editing (equal).
All authors approved the final article as submitted and agree to be accountable for all aspects of the work.
Data Availability
Data from this study are not publicly available, however, deidentified data could be made available by the PI upon request under a data use agreement.
Funding Information
This study was supported by the Clinical and Translational Research Intramural Funding Program at The Abigail Wexner Research Institute at Nationwide Children's Hospital (grant number: 20051014). This funding source had no role in the design and conduct of the study.
Author Disclosure Statement
No competing financial interests exist.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data from this study are not publicly available, however, deidentified data could be made available by the PI upon request under a data use agreement.