To determine the efficacy of pharmacological treatment on nonspecific fatigue in palliative care, including patients with advanced cancer and other chronic conditions associated with fatigue.

Databases searched were EMBASE, PsychLit, CENTRAL, and MEDLINE. Reference lists of identified articles were reviewed for inclusion, and textbooks were handsearched. Conference proceedings of the American Society of Clinical Oncology (ASCO) from 2000 to 2008 and the 2005 meeting of the European Cancer Conference were included in the search.

An extensive listing of keywords and specific search methods per database are provided in the article.

Studies were included in the review if

• They were randomized, controlled trials
• The primary outcome was fatigue or related terms, such as asthenia
• Participants were 18 years or older
• The study included evaluation of the effect of pharmacologic treatment of fatigue with psychostimulants, amantadine, corticosteroids, donazepine, and antidepressants if used for the treatment of fatigue. 

Studies were excluded if they studied megestrol or focused on physiologic deficiencies, such as lack of hemoglobin and use of erythropoietin.

Initial searching provided 2,000 titles. Of those, 22 met the inclusion criteria. They included data from 11 drugs:  amantadine (6), pemoline (3), methylphenidate (3), dexamphetamine (2), paroxetine (2), acetyl-L-carnitine (2), testosterone (2), fluoxetine (1), donepezil (1), modafinil (1), and acetylsalicylic acid (1). If two or more studies of the same medication could be analyzed in the same subpopulation of patients, meta-analysis was performed. Meta-analysis was performed for amantadine, pemoline, methylphenidate, and modafinil.

• The final sample of 22 studies included 1,632 patients.
• Studies were performed in patients with multiple sclerosis (MS) (10), HIV (4), cancer (6), postpolio (1), and endstage chronic obstructive pulmonary disease (COPD) (1).

Most studies showed some beneficial effect; however, a substantial similar placebo effect was often observed.

Amantadine

• Meta-analysis was conducted for three (n = 154) studies comparing amantadine to placebo in patients with MS.
• Standard mean difference (SMD) favored amantadine (SMD = 1.68; 95% confidence interval [CI] [1.24,1.92]; Z = 12.76; p < 0.00001).
• No statistically significant heterogeneity existed.
• Study samples were generally small, and several methodologic weaknesses were seen.

Pemoline

• Pemoline was used in three studies on MS.
• Meta-analysis demonstrated no benefit (SMD = –0.11; 95% CI [–0.42, 0.2]; Z = 0.71; p = 0.48).
• There was significant heterogeneity among the studies.

Methylphenidate

• Two studies in patients with cancer were included.
• There was a slightly superior effect compared to placebo (SMD = 0.49; 95% CI [0.15, 0.83]; Z = 2.86; p = 0.004).
• There was significant heterogeneity.

Dextroamphetamine

• Two studies compared the drug to placebo in patients with cancer. No significant benefits were seen.

Paroxetine

• There were no significant effects demonstrated in one study in patients with COPD and one in patients with cancer.

Testosterone

• No significant effects were demonstrated in studies on HIV.

Acetyl-L-carnitine

• No significant effects were shown in one study on cancer and one on MS.

Modafinil

• Meta-analysis in two studies on MS showed no significant effect.

Donepezil

• One study in 142 patients with cancer showed no benefit compared to placebo.

Other

• Fluoxetine was inferior to testosterone in one study on HIV.
• Acetylsalicylic acid was associated with relief of fatigue compared to placebo in one study on MS.

Methylphenidate and amantadine showed promise for reducing fatigue in patients with advanced disease. Amantadine has not been studied in patients with cancer-related fatigue, but it has been shown to be effective in patients with MS. The meta-analysis included only a few studies and the evidence was weak, pointing to the need for additional research in this area. It is not clear whether amantadine would be useful for patients with cancer, as this has not been studied.

The analysis was performed only in palliative care populations and did not include studies of methylphenidate in patients with cancer during active treatment, which also have shown some efficacy. However, side effects included insomnia, anorexia, behavior change, and vertigo in studies reviewed with methylphenidate. In addition, although statistically significant, effect sizes were small. These findings suggest that use in patients with cancer, who also may experience anorexia and sleep disorders from other causes, has potential benefits that would need to be balanced with potential adverse effects. Carnitine, acetylsalicylic acid, and modafinil have been used in a few studies with positive results. These drugs warrant additional investigation to confirm efficacy in different patient populations with fatigue.

To record mucositis and dysphagia toxicity and level of anesthesia for patients receiving MuGard, Caphosol, or Episil in comparison to standard care

Patients undergoing concurrent radiotherapy and chemotherapy for locally advanced head and neck cancer were audited for eight weeks during treatment. Patients were sequentially given either the standard oral care regimen of aspirin, glycerin, and sucralfate and Gelclair^® or one of the other products. Patients were assessed weekly during four weeks of radiotherapy and for four weeks after completion. All patients received the same protocol approach for analgesia.

• N = 104  
• AGE: Not reported
• MALES: Not reported, FEMALES: Not reported
• KEY DISEASE CHARACTERISTICS: All had squamous cell head and neck cancer, most were of the oropharynx. All were receiving concurrent carboplatin or cetuximab. Radiotherapy was 55 Gy in 20 fractions over 25 days.

• SITE: Single site 
• SETTING TYPE: Outpatient 
• LOCATION: United Kingdom

PHASE OF CARE: Active antitumor treatment

Observational

Common Terminology Criteria for Adverse Events v3

No differences were seen between groups in average grade of dysphagia or analgesia use. No differences were seen between those receiving radiotherapy with intensity-modulated radiation therapy or conformal radiotherapy.

• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Unintended interventions or applicable interventions not described that would influence results
• A much larger group of patients was in the standard care group. No information is provided about general oral care, and frequency of use of any of the oral agents is not described. Adherence varied considerably across groups, with the largest adherence to the standard care regimen.

This study had numerous design limitations and provides little supportive evidence for any of the approaches used for prevention and management of oral mucositis or associated pain.

To examine the effect of decreased intake of insoluble dietary fiber and lactose on acute gastrointestinal (GI) side effects and other aspects of health-related quality of life (QOL) in patients with localized prostate cancer receiving radiotherapy (either brachytherapy or proton therapy)

Patients in the intervention group were instructed to avoid foods high in insoluble dietary fiber and lactose and to consume foods higher in soluble fibers and low in lactose beginning at baseline and continuing for 24 months past the completion of radiotherapy. Patients in the standard care group were instructed to continue their normal diet during this time period. Data was collected at four time points: prior to randomization and initiation of radiotherapy, after four weeks of treatment, one week after radiotherapy completion, and two months after completion of radiotherapy.

• The study consisted of 113 patients, with 55 in the intervention group and 58 in the standard care group.
• Median age was 66 years with a range of 50–77 years.
• The sample was 100% male.
• All patients had localized prostate cancer.
• Patients were excluded from the study if they had received prior radiation therapy to the pelvic/bowel area, had been diagnosed with inflammatory bowel disease, had cognitive dysfunction, had long-term hospitalization, or were unable to speak or understand Swedish.

This was a single-site, outpatient study conducted in Uppsala, Sweden.

Patients were undergoing multiple phases of care.

This was a randomized controlled trial.

• The European Organization for Research and Treatment of Cancer (EORTC) Core Questionnaire (EORTC QLQ-C30) and Prostate Module (EORTC QLQ-PR25) were used to assess factors such as constipation, diarrhea, limitations on activities of daily living, and unintentional leaking of stools.
• The Gastrointestinal Side Effects Questionnaire (GISEQ), a study-specific questionnaire, was used to assess how bothered patients are by GI side effects.
• A scale indicating adherence to dietary instruction (lower score = better compliance) was developed from a Food Frequency Questionnaire (FFQ).

Both the intervention group and the standard care groups followed dietary instructions as indicated by an interaction effect between randomization and time in the FFQ scores (p ˂ 0.001).  The dietary intervention had no statistically significant effect on GI side effects or other aspects of QOL, although bowel symptoms were lower in the intervention group.

The dietary intervention of decreased intake of insoluble dietary fibers and lactose did not have an effect on acute GI side effects in patients with localized prostate cancer undergoing radiotherapy (either brachytherapy or proton therapy).

• Key sample group differences could have influenced results.
• Comorbidities of pulmonary disease, cardiovascular disease, rheumatic disease, obesity, older age, and a history of smoking were more common among the patients in the intervention group. The authors sited references indicating that patients with comorbidities and older patients are more likely to develop GI toxicity. These group differences could have impeded the effect of the intervention.

Although this study did not show that a diet with reduced intake of insoluble dietary fiber and lactose had a significant effect on GI side effects, it did show a tendency toward lower prevalence of bowel symptoms in the intervention group during radiotherapy, which suggests the intervention may have had a positive effect. Controlling for health status in future studies might lead to a different outcome. Also, patients in this study had localized prostate cancer where a small part of the rectum was in the field of irradiation. Future research should evaluate the effect of the diet intervention in patients with lymph node positive disease, which would involve a larger bowel volume in the radiation field and increase the possibility of GI toxicity.

To evaluate the efficacy of palonosetron in the clinical practice setting

Patients were given premedication with 0.25 mg palonosetron on day one of each chemotherapy cycle. All patients were prescribed standard antiemetics as recommended in Multinational Association of Supportive Care in Cancer (MASCC) and American Society of Clinical Oncology (ASCO) guidelines. Patients completed questionnaires to document satisfaction with control of nausea and emesis in the acute and delayed phases.

• The study consisted of 135 participants.
• Age of patients was not provided.
• The majority of patients were female (67%).
• Patients had a variety of cancer diagnoses, with the most frequently being breast, lung, and ovarian; 67% of patients had metastatic disease.
• The majority of patients were receiving cisplatin, carboplatin, anthracyclines, 5-floururacil, or cyclophosphamide.
• One-fifth of patients reported anticipatory nausea, and 19% of patients were chemotherapy naïve.
• Patients were receiving either moderately or highly emetogenic treatments.

The study was conducted in multiple outpatient settings in Austria.

All patients were in active treatment.

This was a prospective trial.

• Patients reported their satisfaction with antiemetic control on a four-point Likert-type scale.
• Complete response (CR) was defined a lack of emesis and no rescue medications used on days 1–5 of chemotherapy.

• The overall CR rate was 68%, with 87% on day 1, and 72% on days 2–5.
• Response rates were highest in males (82%), those age 50 or older (70%–73%), and those who were chemotherapy naïve (73%) (p < 0.05).
• Subgroup analysis showed that the CR rate also was lower in patients who received highly emetogenic therapy.
• Nausea was highest on days 2 and 3. Palonsetron side effects including vertigo and dyspepsia were reported by 1.5% of patients.

Palonosetron was found to be effective for prevention of chemotherapy-induced nausea and vomiting (CINV) and to provide a significant contribution to the antiemetic armamentarium.

• An appropriate control group was not included.
• Actual measurement of nausea was not provided.
• Method of measurement of emesis episodes or use of rescue medications was not described.

Findings support the effectiveness of palonosetron in management of CINV. Effectiveness in managing nausea, rather than just emesis, is not clear.

To evaluate the safety and efficacy of human intestinal trefoil factor (rh/TF) oral spray for the treatment and prevention of chemotherapy-induced oral mucositis.

Patients who had at least grade 2 oral mucositis after the first course of chemotherapy were randomized to receive placebo spray, low-dose rh/TF (10 mg/ml) spray, or high-dose rh/TF (80 mg/ml) spray. Patients had to fully recover from the mucositis prior to study entry. Patients were instructed to administer three puffs to the oral mucosa eight times daily for 14 days, beginning on the first day of the second chemotherapy cycle. Patients were to refrain from oral intake for 15 minutes after dosing.

• The sample consisted of 99 participants.
• Mean patient age was 58.7 years (SD = 9.1 years) in the placebo group, 62.1 years (SD = 8.9 years) in the low-dose group, and 56 years (SD = 7.9 years) in the high-dose group.
• The sample was composed of 58.6% females and 41.4% males.
• All patients had colon cancer and were receiving chemotherapy based on fluorouracil (5-FU). Of all participants, 85% had had prior radiotherapy; 97% had had leucovorin also.

• Multisite
• Outpatient setting
• Russia

Randomized double-blind placebo-controlled trial

World Health Organization grading system for oral mucositis

• Of all participants, 48.5% developed recurrent oral mucositis.
• Treatment with low-dose rh/TF and high-dose rf/TF, respectively, produced an 81.2% and a 75.1% reduction in WHO grade 2 or higher mucositis (p < 0.002). The proportion of patients with grade 0 mucositis was 60% in the low-dose group, 69.7% in the high-dose group, and 33.3% in the placebo group.
• Patient self-assessment reported higher frequency of mouth and throat soreness with placebo (p < 0.05) between days 6 and 11.
• Analgesic use was infrequent and not significantly different among groups.
• The safety profile of rh/TF was similar to that of placebo.

Topical administration of rh/TF was safe and effective in ameliorating symptoms of chemotherapy-induced oral mucositis.

• The sample had a small sample size, with fewer than 100 participants.
• The study was of limited duration, lasting through only one additional course of chemotherapy with 5-FU. Efficacy in the longer term and in other patient populations, with other chemotherapeutic regimens, is unknown.

The study suggests that rh/TF is a promising approach for the prevention and management of oral mucositis. Its ease of use and safety profile makes rh/TF a practical treatment. Authors did not discuss cost, which may be a consideration. Further study in other patient groups is warranted.

To summarize the evidence around the use of radiotherapy, standard-dose chemotherapy, and high-dose chemotherapy with or without total body irradiation plus hematopoietic stem cell transplantation (HSCT) for the management of mucositis

• Databases searched were the Multinational Association of Supportive Care in Cancer (MASCC)/International Society of Oral Oncology (ISOO).
• Evidence was evaluated based on the American Society of Clinical Oncology (ASCO) Levels of Evidence (I-V) and Grades of Recommendation (A-D). Statements without grading were considered justified standard clinical practice by the expert authors and the European Society for Medical Oncology (ESMO) faculty.

• Institutions should develop oral care protocols based on clinical practice and interdisciplinary involvement. Staff and patient education are essential. Basic oral care should include saline mouth rinses 4–6 times per day and use of a soft toothbrush replaced on a regular basis. 
• Patient-controlled analgesic (PCA) with morphine is recommended for the treatment of pain in patients with oral mucositis undergoing HSCT.
• Regular oral pain assessment and topical anesthetics can provide short-term pain relief. 
• Chlorhexidine rinses are not recommended to treat established mucositis but may be an option to enhance treatment of oral infection.
• Benzydamine oral rinse is recommended for prevention of mucositis in patients with head and neck cancer receiving radiotherapy.
• For prevention of mucositis in patients receiving standard-dose chemotherapy,
  • Oral cryotherapy for 30 minutes is recommended in patients receiving fluorouracil (5-FU).
  • Keratinocyte growth factor-1 (palifermin) 40 mcg/kg per day for three days may be useful in patients receiving bolus 5-FU plus leucovorin.
• For prevention of mucositis in patients receiving high-dose chemotherapy with or without total body irradiation plus HSCT, the following are recommended.
  • Palifermin 60 mcg/kg per day for three days prior to transplant and three days post-transplant
  • Cryotherapy in high-dose melphalan
  • Low-level laser therapy (LLLT) before HSCT

The primary author was the principal investigator on the National Institutes of Health (NIH) R13 Conference Grant that provided partial support for the symposium “Oral Complications of Emerging Cancer Therapies,” 14-15 April 2009, Bethesda, MD, USA. Production of a Journal of the National Cancer Institute (JNCI) Monograph for conference publications was supported by an unrestricted educational grant form Biovirum, which owned palifermin at the time of the publication. Peterson also is a member of the Scientific Advisory Board and a paid consultant for the GI Co., Inc, which is responsible for the development of recombinant intestinal trefoil factor, for which the phase II study is cited in the references.

The mucositis guidelines reported contain few changes from the previous two versions of the ESMO Clinical Practice Guidelines. With the 2009 MASCC/ISCO Mucositis Study Group in June 2009, it was decided that no new guidelines were warranted based on the current published literature. Progress has been made in the understanding of molecular basis of mucositis. Evidence-based, cancer-specific identification of risk factors and management of mucositis depend on clinical research so that approval of new drugs and devices will be possible.

• Glutamine (Saforis, MGI Pharma) was administered at 2.5 g per 5 ml, three times per day, for a total daily dose of 7.5 g. Treatment began on the first day of chemotherapy and continued for 14 days after the last dose in patients who did not develop oral mucositis or until 5 days after resolution of oral mucositis. Glutamine was orally swished for 30 seconds, then swallowed.
• Oral hygiene consisted of gently brushing teeth twice per day, 30 minutes or more after each study drug treatment, with a soft toothbrush and fluoride toothpaste. Daily flossing and alcohol-free fluoride rinse was recommended.
• All patients were treated with 200 mg oral acyclovir twice per day.

• Patients were eligible for the study if they
  • Were age 18 or older.
  • Had European Cooperative Oncology Group (ECOG) scores of 2 or less.
  • Had histopathologically confirmed breast cancer to be treated with anthracycline-based chemotherapy.
  • Experienced World Health Organization (WHO) grade 2 or higher mucositis during the first cycle of chemotherapy.
  • Were scheduled to receive at least two more cycles without dose reduction.
• In cycle 1, 163 patients received glutamine and 163 received placebo.
• In cycle 2, 150 patients received glutamine and 155 received placebo.

The study was conducted in Russia.

This was a randomized, double-blind, placebo-controlled, crossover, phase III trial.

• Oral mucositis was measured with regard to incidence, severity, ability to eat solid food, and pain.
• The WHO scale and Oral Mucositis Assessment Scale (OMAS) were used.

• Some nausea was reported.
• In treatment cycle 1, incidence of WHO grade 2 or higher was 38.7% in the treatment group and 49.7% in the placebo group (p = 0.026).
• Incidence of grade 3 or higher was 1.2% in the treatment group versus 6.7% in the control group (p = 0.005).
• Ability to eat solid food was 97.5% in the treatment group versus 91.9% in the control group (p = 0.039).
• No differences were observed in oral pain intensity or difficulty swallowing.
• In treatment cycle 2, incidence of WHO grade 2 or higher oral mucositis among patients in the placebo group was significantly lower than cycle 1 (31.9 versus 49.7; p = 0.0269); this was considered to be a carryover effect.

Glutamine is easy to use, has a favorable safety profile, and is low in cost. The total daily dose was within the range of dietary glutamine consumed by an adult on a high-protein diet (about 8 g per day). This treatment should be tested in higher intensity chemotherapy regimens.

To summarize the oral and gastrointestinal mucositis guidelines developed by the Mucositis Study Group of Multinational Association of Supportive Care in Cancer (MASCC)/International Society of Oral Oncology (ISOO) for patients receiving high-dose chemotherapy, standard-dose chemotherapy, radiation therapy, and combination chemotherapy/radiation therapy

The resource type is guidelines. The process of development was not explained.

Patients were undergoing the active treatment phase of care.

This study has clinical applicability for the following.

• High-dose (HD) head and neck radiation
• Hematopoietic stem cell transplant (HSCT)
• Standard multicycle chemotherapy
   

This report contains few changes compared to previous versions published in 2008 and 2010. The oral mucositis (OM) guidelines are as follows.

• Basic oral care and good clinical practice
  • ​Multidisciplinary development and evaluation of oral care protocols that include frequent use of nonmedicated oral rinses (e.g., saline mouth rinses 4–6 times per day) is recommended. Patient and staff education in the use of such protocols is recommended.
  • Alcohol-based mouth rinses should be avoided.
  • Interdisciplinary development of systemic oral care protocols is suggested. The protocol should include the use of a soft toothbrush that is replaced on a regular basis.
  • Patient-controlled analgesia with morphine is recommended as the treatment of choice for OM pain in patients undergoing HSCT. Regular oral pain assessment using validated instruments for self-reporting is essential.
  • All patients should be screened for nutritional risk, and early enteral nutrition should be started if patients cannot swallow.
  • Topical anesthesia can provide short-term pain relief for OM on an empiric basis.
• ​Prevention of OM associated with radiotherapy (RT)
  • ​Use of midline radiation blocks and three-dimensional RT to reduce mucosal injury is recommended.
  • Benzydamine oral rinse for prevention of radiation-induced mucositis in patients with head and neck cancer receiving moderate-dose RT is recommended. (This is not available in the United States.) 
  • Chlorhexidine is not recommended for patients with head and neck cancer.
  • Antimicrobial lozenges are not recommended
• ​Prevention of OM for patients receiving standard-dose (SD) chemotherapy
  • ​Oral cryotherapy recommended for prevention of OM in patients receiving bolus 5-FU and reduction of OM with bolus edatrexate.
  • Including granulocyte-colony stimulating factor (G-CSF) in Taxotere^®, Adriamycin, cyclophosphamide (TAC) breast cancer regimens has been associated with significant reduction in toxicities, including OM.
  • IV acyclovir and its analogs are not recommended to prevent OM in SD chemotherapy. However, antivirals may be indicated to treat viral infections that may coexist with OM.
  • IV palifermin in solid tumors needs additional research.
• Prevention of OM in patients receiving HD chemotherapy with or without total body irradiation (TBI) plus HSCT
  • Palifermin is recommended.
  • Oral cryotherapy is recommended with HD melphalan.
  • Topical pentoxifylline is not recommended.
  • Granulocyte macrophage-colony stimulating factor (GM-CSF) mouthwashes are not suggested.
  • Low-level laser therapy (LLLT) is suggested to reduce OM and pain associated with OM, if available.
• Treatment of OM associated with RT
  • Oral sucralfate is not recommended.
• Treatment of OM with SD chemotherapy
  • Chlorhexidine oral rinses are not recommended.
  • Approved devices for OM, including Gelclair^®, Caphasol^TM, and Biotene^®, have a limited research evidence base but are safe and may offer some benefit for some patients.

Other recommendations are listed in the article for gastrointestinal mucositis prevention and treatment.

• Few changes were made from previously published guidelines.
• Revisions to these guidelines are expected in the next 2–5 years because of newer technology, better understanding of the clinical impact of OM, molecular pathobiology, and emerging targeted cancer therapy.
• Oncology nurses should recommend evidence-based management for prevention and treatment of OM because some therapies may be expensive and have not been proven effective. For example, “magic mouthwash” continues to be prescribed without evidence to support its use.    
• Consistent oral care with bland rinses continues to be recommended, is easy to use, and is inexpensive.

To evaluate the impact of antifungal prophylaxis in patients with hematologic cancers

Retrospective analysis of medical records was used to compare invasive fungal infection outcomes among patients who received prophylactic posaconazole and a historical cohort treated prior to the implementation of standard prophylaxis. Prophylaxis was used in high-risk patients.

• N = 200 (100 historical controls)
• MEAN AGE = 51 years
• AGE RANGE = 18–77 years
• MALES: 50%        
• FEMALES: 50%
• KEY DISEASE CHARACTERISTICS: Patients had acute myeloid leukemia or myelodysplastic syndromes or received hematopoietic cell transplantation 

• SITE: Single site 
• SETTING TYPE: Multiple settings 
• LOCATION: Germany

• PHASE OF CARE: Active antitumor treatment

• Retrospective, descriptive with historical control comparison

• Aspergillus testing
• Weekly stool samples and mouth swabs
• European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria for possible, probable, or proven invasive fungal disease (IFD)

Mean duration of posaconazole prophylaxis was 21.7 days. Comparisons showed that 43% of controls had no IFD, compared to 72% of those with prophylaxis. Possible IFD was seen in 43% of controls and 24% of those on posaconazole.  Probable IFD was 7% in controls, compared to 4% of those getting prophylaxis. No cases of IFD were proven among patients receiving prophylaxis, compared to 7% of controls with proven IFD. Forty-one percent of those on prophylaxis required antifungal therapy, compared to 91% of controls.

Findings showed that routine posaconazole prophylaxis in high-risk patients was associated with substantial reduction in the incidence of IFD and treatment with antifungal therapy.

• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Other limitations/explanation: The definition of high-risk used for the intervention was not specifically described.

Findings support the routine use of antifungal prophylaxis in high-risk patients with cancer.

To document the characteristics of do-not-intubate (DNI) patients on high-flow nasal cannula (HFNC)—Optiflow™—including underlying disease, HFNC FiO2/flows, breathing frequency, oxygen saturation (pre and post HFNC), escalation to noninvasive ventilation (NIV), and hospital mortality for participants

Based on chart review, HFNC therapy was usually started at previous FiO2 and at a flow of 35 L per minute, with flow titrated as tolerated to 45–50 L per minute. FiO2 was ultimately titrated to maintain SaO2 greater than 90%, or according to specific clinical orders. Average changes in oxygen saturation and breathing frequency before and after HFNC were compared. Arterial blood gases were available for all participants at baseline but with variable availability after HFNC. Data were analyzed using closest values prior to HFNC and about one hour after starting HFNC (participants served as their own control).

• N = 50   
• MEAN AGE = 73 years
• AGE RANGE = 27–96 years
• MALES: 50%, FEMALES: 50% 
• CURRENT TREATMENT: Not applicable
• KEY DISEASE CHARACTERISTICS: Participant diagnoses include pulmonary fibrosis (PF) (n = 15), pneumonia (n = 15), chronic obstructive pulmonary disease (COPD) (n = 12), cancer (n = 7), hematologic malignancy (n = 7), congestive heart failure (CHF) (n = 3), pulmonary embolism (n = 2), sepsis (n = 2), alveolar hemorrhage (n = 1), and myocardial infarction (n = 1).
• OTHER KEY SAMPLE CHARACTERISTICS: Subjects were included if they had do-not-resusitate (DNR)/DNI status, clinical evidence of respiratory distress (e.g., dyspnea, tachypnea), hypoxemia, and mild or compensated hypercapnia (PaCO2 less than or equal to 65; pH greater than 7.28). Participants were excluded if they were on comfort care or if no indication for progress to NIV was evident.

• SITE: Single site   
• SETTING TYPE: Inpatient    
• LOCATION: Medical or medical-surgical intensive care unit (ICU) of two hospitals of the Mayo Clinic in Rochester, MN

• PHASE OF CARE: Multiple phases of care
• APPLICATIONS: Palliative care 

• Retrospective study

• PaO2
• SaO2
• PaCO2
• pH
• FiO2
• Breaths per minute

• Hospital mortality for participants was 60% (30 out of 50) ranging from 33.3% in COPD and CHF patients to 73.3% in patients with PF.
• Breathing frequency decreased from 30.6 to 24.7 breaths per minute on HFNC (p < 0.001).
• Mean oxygen saturation improved from 89.1% to 94.7% (p <  0.001).
• Nine out of 50 (18%) participants escalated to NIV, and 41 of 50 participants (82%) were maintained on HFNC until improvement or withdrawal of support. Of the nine patients who escalated to NIV, six (67%) died versus death in 24 of 41 (58%) who did not receive NIV (p = 0.72). Of the nine participants who escalated to NIV, the six had PF, two had COPD, and one had sepsis.
• Median duration of use of HFNC was 30 hours (mean = 41.9 hours, range = 2–144 hours).
• HFNC was well-tolerated with no documented nasal bleeding or facial skin breakdown.

HFNC reduced hypoxemic respiratory failure in patients with DNI, as well as the need for NIV. HFNC is, therefore, an effective, tolerable, and safe alternative to noninvasive intubation for patients with DNI with hypoxemic respiratory failure.

• Small sample (< 100)
• Risk of bias (no random assignment)
• Retrospective analysis of data was from a single institution. The mixture of diagnoses allowed for only small samples for generalization. Participants with severe acidosis and hypercapnia were excluded. The timing of baseline arterial blood gases varied prior to ICU admission or transfer and was relative to HFNC initiation. Participants all were managed in the ICU, so no comparison of management on the ward was available. Sample was notably very ill as evidenced by overall hospital mortality and may, therefore, have some influence on the generizability of the data.

HFNC has the ability to generate a low level of positive airway pressure with the mouth closed and sufficiently provides oxygenation for patients with hypoxemic respiratory failure.