Incidence and aetiology:

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Leona Barrett
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1 A pilot randomised cross-over double blinded controlled efficacy study of Octreotide versus hyoscine hydrobromide in controlling respiratory secretions at the end of life Katherine Clark, David Currow, Meera Agar, Belinda Fazekas, Amy Abernethy. Dept of Palliative and Supportive Services, Flinders University. Incidence and aetiology: Observational studies have estimated respiratory secretions at end of life occurs in up to 90% of unconscious dying patients. Pathophysiology - due to oscillatory movements of accumulated bronchial mucosa and salivary secretions. Bennett 1996 &2002, Hughes 1996, Power 1992, Watts, T.

2 Current standard therapy: Use of antimuscarinics extrapolated from evidence of efficacy in reducing bronchial secretions during intubation and bronchoscopy. Both bronchial and salivary mucosa have muscarinic receptors. The comparative studies have been non randomised - efficacy to reduce noisy secretions between 35-79% reported. Potentially distressing anticholinergic effects - agitation, urinary retention, hallucinations impossible to assess. Bennett 2002, Wildiers 2002, Hughes 2000, Back 2001 Rationale for Octreotide: Somatostatin receptors have widespread distribution including lung, and salivary glands. Clinical observation that patients being treated with octreotide for other reasons had less distressing respiratory secretions. Infrequent immediate side effects. dosing schedules - less frequent (q8 - q12h). Reubi 1990, Lamberts 1996, Dean 2001, Mercadante 1994

3 Why do we need to study? Frequent problem. Pharmacological therapy is often in setting where caregivers are distressed rather than person dying. Limited evidence for efficacy, dose, duration of response, or side effect profile. Need evidence of efficacy and minimise harm Primary objective: To test the feasibility of an early advanced consent process. To pilot subcutaneous octreotide in controlling subjective (nurse rated) intensity of terminal respiratory secretions.

4 Secondary objectives: Subjective intensity of secretions as reported by a family member Duration of effect of medications in relief of subjective intensity of secretions. Side effects - nausea/vomiting, erythema at the injection site. Method: Setting and Participants Approval by the local Institutional Research and Ethics Committee. Participants were recruited 15 bed palliative care inpatient unit in South Australia. Participants had to be able and willing to provide informed consent prior to entering the terminal phase of illness.

5 Methods: Setting and Participants Inclusion criteria: within 72 hours of admission. expected to progress into the terminal phase of illness during the admission (modified Palliative care prognostic scale) Written informed consent patient and family/caregiver. No known sensitivity to study medications. Exclusion criteria: if they were not willing to discuss potential death. relatives would not also provide consent. currently taking or had known hypersensitivity to either of the study medications. family or clinical factors impeding informed consent or participation. Intervention randomised to 200mcg octreotide followed by 400mcg hyoscine hydrobromide or vice versa. Both medications were made up to 2ml volume in identical syringes, with order of injections indicated and administered by subcutaneous injection.

6 Study Protocol If the patient entered the terminal phase of their illness, respiratory secretions became noisy, and the secretions were assessed by the nurse caring for them as requiring pharmacological intervention, then the study protocol was invoked. A questionnaire was designed to document the nurses assessment of: intensity of secretions, level of patient comfort, level of consciousness, general hydration status, state of skin at the site of injection. Study Protocol cont. The questionnaire was completed at each injection and monitoring time-point (30 min, 1 hr, 4 hr, 6 hr). If family were present they were also asked to rate secretion intensity. If further treatment was required the second pre-prepared syringe was administered.

7 Study Protocol If adequate control was obtained by only one injection, the patient was monitored for six hours and then considered to have completed the trial and then reverted to standard care. If further intervention was required, the duration after the initial intervention was recorded and the second injection administered. After this second injection, the patient assessment continued at 1/2 hour, 1 hour, 4 hours, and 6 hours. Primary Outcome: intensity of secretions as assessed by the inpatient hospice nurse using a four - point categorical scale: absent, mild, moderate, severe.

8 Patient demographics: Patient ID Age Gender Female Female Male Male Male Male Female Male Male Male order Octreotide/Hyoscine Hyoscine Hyoscine/Octreotide Hyoscine/Octreotide Octreotide/Hyoscine Octreotide/Hyoscine Octreotide/Hyoscine Hyoscine/Octreotide Octreotide/Hyoscine Hyoscine/Octreotide

9 Results - medication administration Octreotide - hysocine: 5/5 received both medication. The median time to administration of hyoscine was three hours (range 1-6) after octreotide administration.. Hysocine - octreotide: 4/5 received both medications. The median time to administration of octreotide was three hours (range 1-8) after hyoscine administration Results - secretion scores: Baseline secretion scores: Mild n = 1 moderate n = 7 Severe n = 2 Only four patients (2 in each arm) had improvement of two categories of intensity over time period of study. This change occurred in wide ranging time frame: from one hour after first dose of medication to 6 hours after administration of second medication.

10 Scores at one hour after administration of first medication: Octreotide as first medication: the intensity of secretions were unchanged from baseline in four patients. and reduced by one intensity level for one patient (from moderate to mild intensity). Hyoscine as first medication: the intensity of secretions were unchanged from baseline in three patients. one worsened from moderate to severe. and one reduced for moderate to mild intensity. Intensity score: 1 = no secretions, 2 mild secretions, 3 = moderate secretions, 4 = severe secretions. The time point where line ends is administration of second medication.

Intensity score: 1 = no secretions, 2 mild secretions, 3 = moderate secretions, 4 = severe secretions. The time point where line ends is administration of second medication.

11 Intensity score: 1 = no secretions, 2 mild secretions, 3 = moderate secretions, 4 = severe secretions. The time point where line ends is administration of second medication. Scores after administration of second medication: hyoscine as their second medication: three had unchanged intensity of secretions (moderate or severe rating). two patients had a reduction from moderate to mild intensity at one hour after administration. Octreotide as the second medication: one reduced from severe to mild intensity. two reduced from moderate to mild, and one worsened to severe.

12 Results: family rating Assess next of kin s response to the intervention: limited by NOK not being present. Family member present often changed. Results: LOC and hydration Level of consciousness at baseline: Four patients were anxious or agitated, three patients had a sluggish response, three patients no response. The last oral fluid consumed was: < 12 hours n = hours n = 2 > 24 hours prior n =5. parenteral fluids (both > 12 hours previously) n = 2

13 Adverse events and death: Adverse events: no reports of vomiting, erythema at injection site n = 1, 6 hr time-point (octreotide arm). Death: n =2 died during the study period, four and eight hours after administration of first medication. The other eight patients were monitored for between 8 and 10 hours, and were still alive at the completion of the study period. Discussion Highlights the willingness of people to participate in which they believe will improve subsequent quality of care offered. no significant clinically meaningful trends in benefit in either arm, in the order, dose or schedule used for this study. Consent and recruitment was labour intensive process.

14 Limitations: Variability in initiation of treatment - differing between individual practitioners. Natural history of respiratory secretions not well described. Though cross over study 5 half lives prior to second drug not used - due to short life expectancy in this clinical setting. Further research: Early versus late intervention. Consider loading dose. Parallel arm study, with one agent per patient. Consideration of emerging literature that respiratory secretions are not uniformly distressing - both positive and negative interpretations found. Wee 2006

Death rattle: critical review and research agenda

Support Care Cancer (2014) 22:571 575 DOI 10.1007/s00520-013-2047-5 REVIEW ARTICLE Death rattle: critical review and research agenda Sebastiano Mercadamte Received: 19 September 2013 /Accepted: 31 October