Symptom
Management
Reviews
EBM in Hospice and Palliative Care
Katrina Hoffman FNP, ACHPN
Samaritan Evergreen Hospice
Albany, OR
OHA PPE- September, 2015
• Review of the current literature
•
•
•
Cochrane Database
EBM and Essential Evidence Plus
Journal Reviews
• Classification/Definition of Symptom:
• Opioid Induced Neurotoxicity (OIN), Hiccups, Terminal Secretions,
Terminal Delirium
• Pathophysiology
• Assessment
• Treatment
• PEER DISCUSSION
OBJECTIVES
• Review of the current literature
•
•
•
Cochrane Database
EBM and Essential Evidence Plus
Journal Reviews
• Classification/Definition of Symptom:
• Opioid Induced Neurotoxicity (OIN), Hiccups, Terminal Secretions,
Terminal Delirium
• Pathophysiology
• Assessment
• Treatment
• PEER DISCUSSION
OBJECTIVES
Databases
• Essential Evidence Plus
• Essential Evidence Plus features over 13,000 topics, guidelines, abstracts, tools,
images, and summaries covering the most common conditions, diseases, and
procedures clinicians come in contact with every day.
• Cochrane Systematic Reviews - Considered the gold standard for evidence-based
medicine.
• EBM Guidelines - A unique, concise, and easy-to-use collection of clinical guidelines
for primary care combined with the best available evidence.
• POEMs Research Summaries - POEMs (“Patient-Oriented Evidence that Matters”)
Research Summaries are synopses of new evidence carefully filtered for relevance to
patient care and evaluated for validity.
• NGC Practice Guidelines - More than 1,500 high quality evidence-based guidelines
from a variety of sources.
• Pub Med
• Douglas Hambly Medical Librarian and Whitney Buckley RPH : SHS
Symptom
• Review of
Literature
• Classification
• Pathophysiology
• Assessment
• Treatment
• Discussion
Opioid Induced
Neurotoxicity
-Myoclonus-
• Review of
Literature
• Classification
• Pathophysiology
• Assessment
• Treatment
• Discussion
Dijk, J. M., & Tijssen, M. A. (2010). Management of patients with
myoclonus:available therapies and the need for an evidence-based
approach. Lancet Neurology, 1028-36.
Juba, K., Wahler, R., & Daron, S. (2013). Morphine and hydromorphoneinduced hyperalgesia in a hospice patient. J Palliat Med, 809-12.
McCann, S., Yaksh, T., & vonGunten, C. (2010). Correlation between
myoclonus and the 3-glucuronide metabolites in patients treated with
morphine or hydromorphone: a pilot study. J Opioid Manag, 87-94.
National Institute of Health. (2015, February). National Institute of
Neurological Disorders and Stroke. Retrieved August 15, 2015, from
http://www.ninds.nih.gov/disorders/myoclonus/detail_myoclonus.htm
Paramanandam, G., Prommer, E., & Schwenke, D. (2011). Adverse effects in
hospice patients with chronic kidney disease receiving hydromorphone. J
Palliat Med, 1029-33.
Patel, S., Roshan, V., Lee, K., & Cheung, R. (2011). A myoclonic reaction
with low dose hydromorphone. J Palliat Med, 1029-33.
Potter, J. M., Reid, D. B., Shaw, R. J., & Hickman, P. E. (1989). Myoclonus
associated with treatment with high doses of morphine. British Medical
Journal, 150-3.
Smith, M. (2000). Neuroexcitatory effects of morphine and hydromorphone;
evidence implicating the 3-glucuronide metabolites. Clin Exp Pharmacol
Physiol, 524-8.
Winegarden, J., Carr, D., & Bradshaw, Y. (2015). Intravenous Ketamine for
Rapid Opioid Dose Reduction, Reversal of Opioid Induced Neurotoxicity, and
Pain control in Terminal Care; Case Report and Literature Review. Pain
Medicine.
OIN/Myoclonus
OIN
Review of
Literature
Recognizing OIN
• Delirium, agitation, restlessness
Classification
Pathophysiology
Assessment
• Myoclonus, potential seizures
• Allodynia, Hyperalgesia
Treatment
Discussion
• Rapidly increasing opioid doseseems to make it worse!
Review of
Literature
• Myoclonus – the uncontrollable
twitching and jerking of muscles
or muscle groups .
Classification
Pathophysiology
Assessment
• A patient's spouse may be the
first to recognize this symptom.
Sleeping.
Treatment
Discussion
• Wide variance of frequency
reported: 2.7% to 11% or up to
87% in Hospice & PC settings.
Myoclonus
Review of
Literature
Classification
Pathophysiology
Assessment
Treatment
Discussion
Myoclonus
The clinical and etiologic
classification scheme uses
four major categories to
organize myoclonus:
1. Physiologic
2. Essential
3. Epileptic
4. Symptomatic or
Secondary
Review of
Literature
Classification
Pathophysiology
Assessment
Treatment
• Muscular contractions produce
positive myoclonus, whereas
muscular inhibitions produce
negative myoclonus (asterixis).
• Classified by distribution
•
•
•
•
Focal (one body part)
Multifocal
Segmental (spread to adjacent)
Axial (innervated by one or
several spinal levels)
Discussion
• Can be stimulus induced or occur
at rest
Myoclonus
• Can profoundly affect QOL
• As myoclonus worsens will
develop other neuroexcitatory signs:
• Hyperalgesia (increased
sensitivity to noxious stimuli)
• Delirium with hallucinations
• Eventually grand mal seizures.
IMPACT
Spectrum of Opioid-Induced Neurotoxicity
Opioid
tolerance
Mild myoclonus
(eg. with sleeping)
Delirium
Opioids
Increased
Severe myoclonus
Seizures,
Death
Hyperalgesia
Agitation
Misinterpreted
as Pain
Opioids
Increased
Misinterpreted
as Disease-Related Pain
Review of
Literature
Classification
Pathophysiology
Assessment
Treatment
Discussion
Myoclonus
• Current research implicates
the 3-glucuronide opioid
metabolites as one likely
cause of neuro-excitatory
side effects.
Metabolites
LIVER
Review of
Literature
Classification
Pathophysiology
• Exact mechanism causing myoclonus
is unknown:
• Activation of N-methyl-D aspartate
receptors leading to rice in
intracellular calcium and subsequent
neurotransmitter release has been
postulated.
Assessment
Treatment
Discussion
• Co-morbid factors can predispose
include:
• renal failure, electrolyte
disturbances, and dehydration.
• Myoclonus can occur with all routes
of administration.
Myoclonus
Review of
Literature
Classification
Pathophysiology
Assessment
Chart review
• Review the recent opioid analgesic
history.
• What is the current drug and
dose?
• How has the dose changed over
the past few days and weeks?
• Review the medication list for
potentially exacerbating drugs.
(e.g. haloperidol, phenothiazines)
Treatment
Discussion
• Recent laboratory studies if
available.
• What is the baseline diagnosis and
co-morbidities that lend toward
myoclonus….
Myoclonus
Review of Literature
Classification
Pathophysiology
Assessment
Physical Examination
• Assess frequency of myoclonic
jerks.
• Stand at the bedside and observe a
patient for 30-60 seconds. Watch for
and count the number of uncontrolled
jerking movements.
Treatment
• Determine if there is evidence of a
new or worsening delirium.
Discussion
• Complete a bedside mini-mental
assessment.
• Assess hydration status.
• Estimate prognosis: hours, days,
weeks, months or years?
Myoclonus
Review of
Literature
Classification
Pathophysiology
Assessment
Treatment
Discussion
Myoclonus
• When both specific etiology and
myoclonus physiology are uncertain;
• Treatments that have evidence of
effectiveness for CORTICAL
myoclonus should be tried first.
• Cortical physiology is the most
common mechanism for myoclonus
• CORTICAL=SECONDARY
Review of
Literature
Classification
Pathophysiology
Assessment
Treatment
Discussion
Myoclonus
• Unfortunately there is sparse evidence
from controlled clinical trials to direct
myoclonus therapy.
• Because no drug has been designed or
marketed specifically for the purpose
of treating myoclonus.
• Nearly all the evidence comes from
observational case reports and case
studies.
Review of
Literature
Classification
Pathophysiology
With most types of
myoclonus in Hospice
treatment of underlying
disorder is impossible or
ineffective.
Assessment
Treatment
Discussion
Myoclonus
In these cases-symptomatic
treatment only is justified if
the myoclonus is disabling.
TREATMENT STEPS
1. Recognize the syndrome
2. Discontinue the offending opioid
Note: naloxone does not reverse neuroexcitatory
effects, and may in fact exacerbate them
3. Consider Hydration to help clear opioid and
metabolites**
4. Consider benzodiazepines to decrease
neuromuscular irritability & adjunct anti-seizure
meds
5. Explore options to address the suffering
Approach to Changing Opioids in Settings of
O.I.N.
? Life-Threatening (severe myoclonus,seizures)
No
•
•
1.
2.
3.
Can titrate off of offending opioid
over days
As you titrate down, add
appropriate doses of an alternative
opioid:
Pain Poorly Controlled: ↑ dose of
new opioid
Pain well controlled, patient alert:
↑ new opioid, ↓offending opioid
Pain well controlled, patient
lethargic: ↓offending opioid
Yes
• Abrupt withdrawal of offending
opioid
• Aggressive hydration
• PRN dosing of either fentanyl,
sufentanil, or methadone
• Don’t try to calculate an appropriate
starting dose based on current opioid
use…. Start low and titrate up *
• After a few hours, consider starting a
regular administration (infusion,
perhaps oral methadone)
CHALLENGES IN MANAGING PAIN /
DISTRESS IN SETTINGS OF
NEUROTOXICITY
Quite possible that a substantial proportion of the current
offending opioid dose is being targeted at treating opioidinduced hyperalgesia or restlessness
The opioid has been increased to treat its own side effects
PEARL: + tolerance to the offending opioid, not “crossedover” to alternatives (incomplete cross-tolerance)
Impossible to calculate dose equivalences of alternative
opioids. Conversion charts should not be used here!
Discontinue the Offending Opioid
PEARLS
•
Simply decreasing the dose only postpones the need
to switch opioids
•
Adding a benzodiazepine without addressing the
opioid ignores potential reversibility
•
Do a stepwise conversion (days) in mild
neurotoxicity
•
Use abrupt discontinuation if life-threatening
neurotoxicity (seizures imminent)!!
Review of
Literature
Classification
Hydration/ FLUID Bolus to Clear
Metabolites
Premise: Morphine and
Hydromorphone are renally excreted.
Pathophysiology
Assessment
Treatment
Discussion
Myoclonus
Oral- SQ or IV is acceptable
Example of Aggressive Hydration
NS 500 ml bolus followed by
250 ml/hr plus furosemide 40
mg IV q6h
Literature Review
•
•
•
•
Medically assisted hydration for palliative care patients
EBM Guidelines :Last updated: 2008-05-13 © Duodecim Medical Publications Ltd
Level of evidence = D
There is insufficient evidence on the use of medically assisted hydration in palliative care
patients.
• A Cochrane review included 5 studies with a total of 453 subjects. Two were RCTs and
three prospective controlled trials. All of the studies included only participants with
advanced cancer.
• One study found that sedation and myoclonus (involuntary contractions of muscles) were
improved more in the intervention group (28 - hydration, 23 - placebo). Another study
found that dehydration was significantly higher in the non-hydration group, but that some
fluid retention symptoms (pleural effusion, peripheral edema and ascites) were
significantly higher in the hydration group (59 - hydration group, 167 - non -hydration
group). The other three studies did not show significant differences in outcomes between
the two groups.
• Comment: The quality of evidence is downgraded by imprecise results (limited study
size for each comparison) and study quality (several issues).
References
Good P, Cavenagh J, Mather M, Ravenscroft P. Medically assisted hydration for palliative care
patients. Cochrane Database Syst Rev 2008 Apr 16;(2):CD006273.
Review of
Literature
Classification
Pathophysiology
Assessment
Treatment
Discussion
Myoclonus
Pharmacologic Therapy
A large number of medications, mainly
anticonvulsants have been used to
treat myoclonus, but few have been
evaluated in rigorous clinical trials.
Review of
Literature
Cortical (Secondary) myoclonus:
Drug treatment is primarily aimed at
augmenting deficient inhibitory processes
within the sensorimotor cortex.
Classification
Pathophysiology
Assessment
Treatment
4 most effective agents:
1. Clonazepam (Klonopin)
2. Levetiracetam (Keppra)
3. Valproic acid (Depakote)
4. Piracetam (UK only)
Discussion
Clinical trials- NONE have compared them
head to head for treatment of myoclonus.
Myoclonus
Review of
Literature
Clonazepam — The benefit for
cortical myoclonus is supported by
data from uncontrolled
observational studies.
Classification
Pathophysiology
Assessment
Treatment
Discussion
Myoclonus
Clonazepam is typically started at
0.5 mg daily or BID and gradually
increased to a total daily dose of
1.5 to 3 mg given in two-three
divided doses.
Doses as high as 15 mg daily are
often necessary but should be
introduced slowly.
Review of
Literature
Classification
Pathophysiology
Assessment
Treatment
Discussion
Myoclonus
Clonazepam SIDE EFFECTS
• Drowsy, Dizzy, Fatigue or Sedation
• Tolerance can develop- Usually over
several months.
• Abrupt reductions or withdrawals of
clonazepam can cause both an
exacerbation of myoclonus and
withdrawal seizures
OTHER Benzodiazepines to
Decrease Neuromuscular Irritability
Review of
Literature
Classification
Pathophysiology
Assessment
• Lorazepam: intermediate duration of
action; PO, SL, IV, (IM – for seizures).
2-3 mg SLOW IV
• Midazolam: short-acting; SQ, IV, SL,
IM. Usually effective immediately.
Usually 0.5-2mg/Hour SQ
Treatment
• Valium: 5-10mg PR, PO, IV
Discussion
• Be cautious with additive respiratory
depressant effects if also giving opioids
by bolus
Myoclonus
Review of
Literature
Classification
Pathophysiology
Assessment
Treatment
Discussion
Myoclonus
Data suggests the high likelihood
of combination of drugs to be
effective
• Use a benzodiazepine and an
antiseizure.
• High prevalence for
clonazepam and Keppra
Keppra Advantages
Review of
Literature
100% dose equivalency in all routesPR/IV/PO
Classification
Favorable side/effect profile:
• Most common: Fatigue, somnolence,
dizziness.
Pathophysiology
Assessment
Treatment
Discussion
Myoclonus
• Most adverse events are mild to
moderate in intensity and typically occur
during the initial titration phase.
Abrupt withdrawal of levetiracetam may
precipitate seizures or worsening of
myoclonus.
Review of Literature
Classification
KEPPRA DOSING
Initiate at 500-1000 daily BID
• Titrate upwards by 1000 mg
every 2 weeks as needed
Pathophysiology
Assessment
Treatment
Discussion
Myoclonus
• Up to 3000 mg daily dose- if
tolerated max can creep to
4000mg.
• Therapeutic Keppra doses for
myoclonus usually range between
100-3000 daily.
• Recognize OIN Early
• Escalation of pain and meds, renal failure, delirium,
twitching: starting with sleep first.
• Treat symptoms with meds and/or opioid rotation
• Consider fluids--?
• Use combo approach: Benzodiazepines and Keppra (or
other anti-seizure med)
Review
HICCUPS
The cause or bodily purpose of hiccups is not known
•
Review of
Literature
•
Classification
•
Pathophysiology
•
Assessment
•
Treatment
•
Discussion
•
•
•
Hiccups
Duodecim Medical Publications Ltd. (2014, Jan 22).
Palliative treatment of cancer. Retrieved from Evidence
Based Medicine Guidelines.
Lee, J. H., Kim, T., Lee, H., Choi, Y., Moon, S., & Cheong, Y.
(2014, Jan). Treatment of Intractable Hiccups With an Oral
Agent Monotherapy of Baclofen -A Case Report.
Pharmacotherapy, 34(1), 4-8 .
Moretto, E., Wiffen, W., & Murchison, A. (2013, Jan).
Interventions for treating persistent and intractable hiccups in
adults. Cochrane Database Syst Rev.
Porzio, G., Aielli, F., Aloisi, P., Galletti, B., & Ficorella, C.
(2010, Jul). Gabapentin in the treatment of hiccups in patients
with advanced cancer: a 5 year experience. Clin
Neuropharmacol, 33(4), 179-80.
Smith, H., & Busracamwongs, A. (2008, Feb-Mar).
Management of hiccups in the palliative care population. Am
J Hosp Palliat Care, 25, 52-4.
Steger, M., Schneemann, M., & Fox, M. (2015, Aug 25).
Systemic review: the pathogenesis and pharmacological
treatment of hiccups. Aliment Pharmacol Ther.
Tegeler, M., & Baumrucker, S. (2008). Gabapentin for
intractable hiccups in palliative care. Am J Hosp Palliat Care,
52-54.
Thompson, A., Ehret, L. J., & Brzezinski, W. (2003, MarApr). Olanzapine and baclofen for the treatment of intractable
hiccups. Am J Hosp Palliat Care, 20(2), 149-54.
Thompson, D., & Brooks, K. (2013, June). Gabapentin
therapy of hiccups. Ann Pharmacother, 47(6), 897-903.
Persistent and intractable hiccups (typically defined as lasting for more than 48 hours and one month respectively) can be of serious detriment to a patient's quality
of life, although they are relatively uncommon. A wide range of pharmacological and non-pharmacological interventions have been used for the treatment of
persistent and intractable hiccups. However, there is little evidence as to which interventions are effective or harmful.
OBJECTIVES:
The objective of this review was to evaluate the effectiveness of pharmacological and non-pharmacological interventions used in the treatment of persistent and
intractable hiccups of any aetiology in adults.
SEARCH METHODS:
Studies were identified from the following databases: CENTRAL, CDSR, DARE, MEDLINE, EMBASE, CINAHL, PsychINFO and SIGLE (last search March
2012). The search strategy for all the databases searched was based on the MEDLINE search strategy presented in Appendix 1. No additional handsearching of
journals was undertaken. Investigators who are known to be carrying out research in this area were contacted for unpublished data or knowledge of the grey
literature.
SELECTION CRITERIA:
Studies eligible for inclusion in this review were randomized controlled trials (RCTs) or controlled clinical trials (CCTs).
INCLUSION CRITERIA:
adults (over 18 years old) diagnosed with persistent or intractable hiccups (hiccups lasting more than 48 hours), treated with any pharmacological or nonpharmacological intervention.
EXCLUSION CRITERIA:
less than ten participants; no assessment of change in hiccup frequency or intensity in outcome measures.
DATA COLLECTION AND ANALYSIS:
Two independent review authors assessed each abstract and title for relevance. Disagreement on eligibility was resolved by discussion. Where no abstract was
available the full paper was obtained and assessed. We obtained full copies of the studies which met the inclusion criteria for further assessment. Two review authors
independently collected data from each appropriate study and entered them into the software Review Manager 5. Two independent review authors assessed the risk
of bias using the RevMan 5 'Risk of bias' table following guidance from the Cochrane Handbook of Systematic Reviews of Interventions (Higgins 2009).
MAIN RESULTS:
A total of four studies (305 participants) met the inclusion criteria. All of these studies sought to determine the effectiveness of different acupuncture techniques in
the treatment of persistent and intractable hiccups. All four studies had a high risk of bias, did not compare the intervention with placebo, and failed to report side
effects or adverse events for either the treatment or control groups. Due to methodological differences we were unable to perform a meta-analysis of the results. No
studies investigating pharmacological interventions for persistent and intractable hiccups met the inclusion criteria.
AUTHORS' CONCLUSIONS:
There is insufficient evidence to guide the treatment of persistent or intractable hiccups with either pharmacological or non-pharmacological
interventions.The paucity of high quality studies indicate a need for randomized placebo-controlled trials of both pharmacological and nonpharmacological treatments. As the symptom is relatively rare, trials would need to be multi-centered and possibly multi-national.
PMID: 23440833 [PubMed - indexed for MEDLINE]
Cochrane Database Syst Rev. 2013
Interventions for treating persistent and intractable hiccups in adults.
Abstract
Review of
Literature
Classification
Pathophysiology
Assessment
Treatment
Discussion
AHEAD OF PRINT
BACKGROUND:
Hiccups are familiar to everyone, but remain poorly understood. Acute hiccups
can often be terminated by physical maneuvers. In contrast, persistent and
intractable hiccups that continue for days or months are rare, but can be distressing
and difficult to treat.
AIM:
To review the management of hiccups, including a systematic review of reported
efficacy and safety of pharmacological treatments.
METHODS:
Available articles were identified using three electronic databases in addition to
hand searching of published articles. Inclusion criteria were any reports of
pharmaceutical therapy of 'hiccup(s)', 'hiccough(s)' or 'singultus' in English or
German.
RESULTS:
Treatment of 341 patients with persistent or intractable hiccups was reported in 15
published studies. Management was most effective when directed at the
underlying condition. An empirical trial of anti-reflux therapy may be appropriate.
If the underlying cause is not known or not treatable, then a range of
pharmacological agents may provide benefit; however, systematic review revealed
no adequately powered, well-designed trials of treatment. The use of baclofen and
metoclopramide are supported by small randomized, placebo-controlled trials.
Observational data suggest that gabapentin and chlorpromazine are also effective.
Baclofen and gabapentin are less likely than standard neuroleptic agents to cause
side effects during long-term therapy.
CONCLUSIONS:
This systematic review revealed no high quality data on which to base treatment
recommendations. Based on limited efficacy and safety data, baclofen and
gabapentin may be considered as first line therapy for persistent and intractable
hiccups, with metoclopramide and chlorpromazine in reserve.
Systemic review: the pathogenesis and pharmacological
treatment of hiccups: Aliment Pharmacol Ther 2015
Review of
Literature
Classification
Hiccups are usually classified as:
• Benign or Physiological: 24-48 hrs
• Persistent: 48 Hrs- 1 month)
• Intractable (>1 month).
Pathophysiology
Assessment
Treatment
Discussion
A Physiological hiccup is usually
of short duration (less than 48
hours). It may be caused by, e.g.,
overeating, ETOH, carbonated
drinks or changes in temperature.
Classification
Review of
Literature
Classification
Pathophysiology
Assessment
• Hiccup is “likely” generated by a
reflex arc involving the
peripheral branch of the phrenic
nerve, the vagus nerve and the
sympathetic nervous system.
Treatment
Discussion
Hiccups
• Any factor stimulating these
nerves and thus the reflex arc
may cause hiccup.
• Hiccups are caused by a sudden,
involuntary, myoclonic
contraction of the diaphragm and
inspiratory intercostal muscles
terminated by abrupt closure of
the glottis stopping the inflow of
air and producing the
characteristic sound.
• Hiccups usually occur with a
frequency of 4 to 60 a minute.
The medical term for hiccup is
singultus, from the Latin singult,
meaning the act of catching one's
breath while sobbing.
Hiccups -Singultus
• Central origin
Review of
Literature
•
Brain stem diseases
• Bleeding, infarction, tumor, infection, multiple sclerosis
• Peripheral causes
Classification
•
Mediastinal processes
• Lymphoma
Pathophysiology
Assessment
Treatment
Discussion
•
Diseases of the upper abdomen
• Hiatal hernia, gastric carcinoma, subphrenic abscess,
ileus, postoperative condition, ascites
• Toxic and metabolic causes
•
•
Alcohol, uremia
Drugs: steroids, antiparkinsonian drugs, anesthetic
agents, cytotoxic drugs
• Other causes
•
Psychiatric causes, "essential hiccup" with no
discernible cause
Hiccups-CAUSES
• Treatment of the cause when
possible
Review of Literature
• Brain tumors may respond to
anti-epileptics
Classification
Pathophysiology
Assessment
Treatment
Discussion
• Non-pharmacological treatments,
e.g.: the patient should try sitting
up, breathing into a paper bag,
drinking two glasses of water or
swallowing two tsps of sugar.
• Palliative- Paracentesis,
phrenectomy rarely necessary.
Treatment of Hiccups
Review of Literature
Classification
Pathophysiology
Assessment
Treatment
Discussion
• No single agent is considered the
treatment of choice for hiccups!!
• Chlorpromazine is the only FDA
approved medication, but baclofen is
commonly used.
• Unfortunately the same agents used to
treat hiccups can cause them!
• Chlorpromazine 12.5–50 mg 4 daily p.o
(may cause excessive sedation).
• Slow IV push seems to be most
effective.
MEDICATION
Review of Literature
Classification
Pathophysiology
Assessment
Treatment
Discussion
•
Metoclopramide 10–20 mg × 3–4 daily p.o./p.r. or parenterally.
•
Haloperidol 2.5-10mg PO, IM, IV SQ
•
Valproate 1Gm/day in 2 doses
•
Metoclopramide 40mg/day per rectum
•
Baclofen 10-20mg TID.
•
Gabapentin 1200-1500 mg in 3 dividied doses.
•
Prednisone (if hepatomegaly or obstructive cause)
•
Tessalon Perles 100-200 mg every 8hrs
•
Lidocaine 1mg/kg IV followed by 2mg/hr
•
Ketamine 0.4mg/kg IV
•
Carbamazapine 100-200 mg every 8hrs
•
Orphenadrine 100mg every 12 hrs
Other Meds…..
Abstract
OBJECTIVE:
To determine whether gabapentin is effective in the treatment of persistent or intractable hiccups.
DATA SOURCES:
A search of MEDLINE (1966-March 2013) using the MeSH search terms gabapentin, hiccups, and hiccups/drug therapy was
performed. Additional databases searched included Web of Science (1945-March 2013) and International Pharmaceutical Abstracts
(1970-March 2013) using the text words gabapentin and hiccups. Bibliographies of relevant articles were reviewed for additional
citations.
STUDY SELECTION AND DATA EXTRACTION:
All data sources were considered for inclusion. Preference was given for articles written in English, although one abstract in German
was used.
DATA SYNTHESIS:
Because of the low incidence of persistent or intractable hiccups, few if any controlled clinical trials are conducted on the efficacy of
drug treatment. Therefore, most of the data involve case reports or case series. We evaluated 17 case reports and 2 case series
involving gabapentin therapy for persistent or intractable hiccups.
Therapeutic outcomes with gabapentin were positive in all cases, with temporal evidence suggesting an effect, but outcomes often
were obscured by combination therapy and comorbidities in some cases. Case reports suggest that gabapentin might be useful as a
second-line agent in patients undergoing stroke rehabilitation or in the palliative care setting where chlorpromazine adverse effects
are undesirable. Gabapentin was very well tolerated, with only a few minor adverse effects.
CONCLUSIONS:
Gabapentin has a similar body of evidence as other pharmacotherapeutic agents used to treat hiccups. Gabapentin is well tolerated
and should be considered as a second-line agent in selected patients
Ann Pharmacother. 2013 Gabapentin therapy
of hiccups.
Abstract
AIM:
To evaluate safety and efficacy of gabapentin in the treatment of severe chronic hiccups in patients
with advanced cancer.
METHODS:
Charts of all patients observed in the palliative care unit of a 4-bed hospital and at home by our
Home Care Service were reviewed retrospectively.The presence of hiccups was routinely assessed.
Patients with severe chronic hiccups were treated with gabapentin (300 mg t.i.d.). Doses of
gabapentin were titrated based on the response to treatment.Gabapentin-related adverse effects were
recorded.
RESULTS:
Thirty-seven (3.9%) of 944 in-hospital patients and 6 (4.5%) of 134 patients observed at home
presented severe chronic hiccups.We registered an improvement of hiccups, defined as complete
resolution of hiccups, in 31 (83.8%) of 37 in-hospital patients and 4 (66.7%) of 6 patients observed
at home.Four (10.8%) of the 37 in-hospital patients and 2 (33.3%) of the 6 patients observed at
home experienced a reduction of hiccups.In 2 patients (5.4%), we registered a worsening of
hiccups.Responses were observed in 32 patients (74.4%) with gabapentin at a dosage of 900 mg/d
and in 9 patients (20.93%) at 1200 mg/d.In 2 patients (4.65%), grade 2 sleepiness was observed and
in 10 patients (23.25%), grade 1 sleepiness was observed based on the Epworth Sleepiness Scale.
CONCLUSION:
The results of the study allow suggesting gabapentin at least as a promising drug in the treatment of
severe chronic hiccups in advanced cancer patients.
Clin Neuropharmacol. 2010 Gabapentin in the treatment of hiccups in
patients with advanced cancer: a 5-year experience.
“Strong evidence for a specific treatment regimen for
intractable hiccups is lacking in the primary literature.”
“Our case report adds to the available literature, as there are
currently no published data on the use of combination
therapy for the treatment of intractable hiccups, and the
combination of baclofen and olanzapine significantly
improved our patient's quality of life.”
.
Thompson, A., Ehret, L. J., & Brzezinski, W. (2003, Mar-Apr).
Olanzapine and baclofen for the treatment of intractable
hiccups. Am J Hosp Palliat Care, 20(2), 149-54
• Many etiologies for hiccups.
• Try to treat underlying cause
• Assess comfort of patient and utilize non
pharmacological methods when able.
• Usually multi-drug approach is most beneficial in hospice
patients.
• Thorazine is only FDA approved for hiccups.
Review
“Hiccup”
TERMINAL SECRETIONS
• Death Rattle
Review of
Literature
• Terminal Rattle
Classification
Pathophysiology
• Terminal Respiratory secretions
(TRS)
Assessment
Treatment
Discussion
• Oropharyngeal secretions
• Upper airway secretions
Terminal Secretions
• Increased airway secretions may
Review of Literature
Classification
interfere with a patient’s ability to
sleep, worsen dyspnea, precipitate
uncomfortable coughing spells, and
predispose to infections.
Pathophysiology
Assessment
• Reported frequency: 31-92%
Treatment
• Terminal secretions usually portend
Discussion
death in 24-72 hours.
Terminal Secretions
Review of
Literature
Classification
Pathophysiology
Assessment
Treatment
Discussion
• Studies bear out that the patient is
not distressed and that 80% of
family members are.
• Results were varied on nurses
perceptions of patient distress.
• Once consciousness is reduced to
the point that they no longer have
cough reflexes it is unlikely that
patients are distressed by the
secretions.
Patient Distress
• Accumulation of upper airway
secretions
Review of Literature
Classification
Pathophysiology
Assessment
Treatment
Discussion
• Loss of the ability to swallow may
result from weakness, cachexia, and
decreased neurologic function.
• The gag reflex and reflexive clearing
of the oropharynx decline, and
secretions from the tracheobronchial
tree accumulate.
• Oscillation of secretions in the
hypopharynx and bronchial tree
generates gurgling, crackling, or
rattling sounds with each breath.
Terminal Secretions
Type 1
• The “Common Death
Rattle”
• Secretions are heard when
swallow reflex is
inhibited, pooling of
saliva.
Type 2
• Primarily bronchial
• Develops over days
• Lack of ineffective
cough effort
• Pulmonary
pathology
• “Psuedo” Death
Rattle
Terminal Secretions
Review of Literature
Classification
Pathophysiology
Assessment
Treatment
Discussion
• Important distinction between a rattle
caused by non expectorated saliva and
bronchial secretions and a rattle
produced by respiratory pathology.
• The “real death rattle” responds
favorably to repositioning, anticholinergic therapy by antimuscarinic
drugs.
• Pseudo rattle does not. Suction often is
the only tx.
• A lot of patients have a “mixed case”
especially brain involvement, or
pulmonary pathology.
“Pseudo Death Rattle”
?
REVIEWS
Abstract
BACKGROUND:
Noisy breathing (death rattle) occurs in 23 to 92% of people who are dying. The cause of death rattle remains unproven but is presumed to be due to an
accumulation of secretions in the airways. It is therefore managed physically (repositioning and clearing the upper airways of fluid with a mechanical
sucker) or pharmacologically (with anticholinergic drugs).
OBJECTIVES:
To describe and assess the evidence for the effectiveness of interventions used to treat death rattle in patients close to death.
SEARCH STRATEGY:
Randomised controlled trials (RCTs), before and after studies and interrupted time series (ITS) studies in adults and children with death rattle were sought
by MEDLINE (1966 to 2007), EMBASE (1980 to 2007), CINAHL (1980 to 2007), the Cochrane Pain, Palliative and Supportive Care Trials Register and
the Cochrane Central Register of Controlled Trials. In addition, the reference lists of all relevant trials and reports were checked and investigators who are
known to be researching this area were contacted for unpublished data or knowledge of the grey literature.
SELECTION CRITERIA:
RCTs, controlled before and after studies and ITS reporting the outcome of pharmacological and non-pharmacological interventions for treating death
rattle.
DATA COLLECTION AND ANALYSIS:
Data was extracted by two independent review authors and trials were quality scored. There was insufficient data to carry out an analysis.
MAIN RESULTS:
Thirty studies were identified, of which only one study met the inclusion criteria. This small study was a randomised placebo-controlled trial of the use of
hyoscine hydrobromide in patients with death rattle. Hyoscine hydrobromide tended to reduce death rattle compared to placebo but this was not
significant. A larger randomised study, comparing atropine, hyoscine butylbromide and scopolamine, is in progress.
AUTHORS' CONCLUSIONS:
There is currently no evidence to show that any intervention, be it pharmacological or non-pharmacological, is superior to placebo in the treatment of death
rattle. We acknowledge that in the face of heightened emotions when death is imminent, it is difficult for staff not to intervene. It is therefore likely that the
current therapeutic options will continue to be used. However, patients need to be closely monitored for lack of therapeutic benefit and adverse effects
while relatives need time, explanation and reassurance to relieve their fears and concerns. There is a need for more well-designed multi-centre studies with
objective outcome measures and the ability to recruit sufficient numbers.
Cochrane Database Syst Rev. 2008
Interventions for noisy breathing in patients near to death.
Death rattle is a frequent symptom (25%-50%) in the terminal stage of life, but there is neither
standardized treatment nor prospective investigation performed on the effectiveness of
anticholinergic drugs.
The aim of the present study was to investigate the effectiveness of three different anticholinergic
drugs in the treatment of death rattle in the terminal stage of life. Terminal patients who
developed death rattle were randomly assigned 0.5mg atropine, 20mg hyoscine butylbromide, or
0.25mg scopolamine.
Each treatment was initiated with a subcutaneous bolus, which was followed by continuous
administration of the same drug. The intensity of death rattle and side effects were prospectively
scored at different time points. Three hundred and thirty-three eligible patients were randomized
to atropine, hyoscine butylbromide, or scopolamine after informed consent from the patient or the
appointed representative.
For the three drugs, death rattle decreased to a nondisturbing intensity or disappeared after one
hour in 42%, 42%, and 37% of cases, respectively (P =0.72). Further, effectiveness improved
over time without significant differences among the treatment groups (effectiveness at 24 hours
was 76%, 60%, and 68%, respectively).
In an analysis on the three groups together, treatment was more effective when started at a
lower initial rattle intensity; median survival after start of therapy was 23.9 hours. These data
suggest that there are no significant differences in effectiveness or survival time among atropine,
hyoscine butylbromide, and scopolamine in the treatment of death rattle.
Atropine, Hyoscine Butylbromide, or Scopolamine Are Equally Effective for the Treatment
of Death Rattle in Terminal Care , Abstract: J of Pain and Symp Mgt 2009
Abstract
BACKGROUND:
Studies examining the effectiveness of treatment in reducing the noises of death rattle have been conducted; however, the physical impact of
death rattle on the patient experiencing the phenomenon has not been investigated. Treatments may be undertaken to appease family and
staff but these treatments may be more burdensome than beneficial to the patient. Further, nonbeneficial treatments increase the cost of care.
OBJECTIVE:
To determine if patients with naturally occurring death rattle experience respiratory distress.
DESIGN:
A prospective, two-group observation study was conducted. Patients who were near death were stratified into those with and without death
rattle.
SETTING/SUBJECTS:
Seventy-one dying patients were recruited from three palliative care and hospice settings. Patients were excluded if they had an artificial
airway or if their clinical condition caused a secondary source of death rattle, identified as pseudo-death rattle.
MEASUREMENTS:
Daily observations were made for death rattle intensity and respiratory distress along with use of antisecretory medications.
RESULTS:
About half of the sample had no death rattle (55%).There were no differences in respiratory distress when patients with and without death
rattle were compared (t=1.48, p=0.143). Death rattle intensity and respiratory distress were not correlated (r=-0.13, p=0.477). Few patients
(17%) were medicated with antisecretory agents. Many (58%) patients receiving an antisecretory agent did not experience a reduction in
death rattle.
CONCLUSIONS:
Respiratory distress was not associated with death rattle among patients who were near death. In many cases, antisecretory agents did not
produce quiet breathing.
J Palliat Med. 2013
Death rattle is not associated with patient respiratory distress: is
pharmacologic treatment indicated?
Abstract
CONTEXT:
Noisy breathing because of respiratory tract secretions (RTS), often referred to as "death rattle," occurs in up to half of all
dying patients. Despite a lack of evidence showing benefit compared with placebo, antimuscarinic medications have been
used in an attempt to decrease noise associated with RTS and to decrease family distress.
OBJECTIVES:
The goal of this study was to compare the efficacy of the antimuscarinic medication atropine with that of placebo in
reducing noise associated with death rattle.
METHODS:
Terminally ill adult hospice inpatients who developed noisy breathing as a result of RTS were randomized to double-blind
treatment with atropine or placebo. Study drug was given as a single sublingual dose. Noise from breathing was monitored
at baseline and at two and four hours.
RESULTS:
One hundred thirty-seven participants were randomized to atropine or placebo. Reduction in noise score from baseline to
two hours after dose occurred in 37.8% and 41.3% of subjects treated with atropine and placebo, respectively (P=0.73).
Noise score reduction at four hours occurred in 39.7% and 51.7% of subjects treated with atropine and placebo, respectively
(P=0.21). Differences between groups were not significant at either time point. Atropine was well tolerated. Heart rate
increased slightly in both groups (+1.1/minute for atropine and +3.1/minute for placebo) but not significantly.
CONCLUSION:
Sublingual atropine given as a single dose was not more effective than placebo in reducing the noise associated with death
rattle.
J Pain Symptom Manage. 2013
Randomized double-blind trial of sublingual atropine vs. placebo for the
management of death rattle.
Abstract
PURPOSE:
Anticholinergic medications for reducing noisy respirations in adult hospice patients are evaluated.
SUMMARY:
Anticholinergic medications used to reduce noisy respirations from retained secretions in terminal
patients include atropine, glycopyrrolate, scopolamine, and scopolamine derivatives.
Pharmaceutical anticholinergic treatment of retained secretions in hospice patients was evaluated in
six studies, three of which compared the efficacy of glycopyrrolate to scopolamine in actively dying
patients. Subcutaneous glycopyrrolate, scopolamine hydrobromide, and scopolamine butylbromide
were similar in their ability to reduce noisy respirations overall and lower and the level of distress
exhibited by family members and visitors. Two of the six studies compared the efficacy of
medication therapy after institutional formulary changes from scopolamine to glycopyrrolate. The
same dosages of subcutaneous glycopyrrolate and scopolamine, which delivered an initial bolus
followed by continuous infusion, were reported in each study. Both studies concluded that there was
equivalent efficacy between the two products. One study reported a more rapid response in patients
treated with glycopyrrolate. In comparison, the last study reported more rapid responses in patients
who received scopolamine compared with patients who received glycopyrrolate. Retrospective
reports described symptom improvement with parenteral scopolamine in most patients.
CONCLUSION:
Parenteral and transdermal anticholinergic medications are useful for the reduction of noisy
respirations in hospitalized hospice patients. Difficult administration makes oral and sublingual
products less desirable for use in this population.
Am J Health Syst Pharm. 2009 Anticholinergic medications for
managing noisy respirations in adult hospice patients.
• Semi prone or HOB 30 with side to side
positioning, frequent oral care.
Review of Literature
Classification
Pathophysiology
Assessment
Treatment
• A minute or two of Trendelenburg
positioning can be used to move fluids
up into the oropharynx for easier
removal; aspiration risk is increased,
however.
• Avoidance of IV hydration
• LOTS of family teaching
Discussion
• Some patients may benefit from
suctioning to clear excessive secretions
if they have a lot of drooling.
Secretions
• Antimuscarinic drugs are the
mainstay of treatment.
Review of
Literature
Classification
Pathophysiology
Assessment
Treatment
• These include: atropine,
scopolamine (hyoscine
hydrobromide), hyoscine
butylbromide, and glycopyrronium
• They are used to diminish the noisy
sound by reducing airway
secretions.
Discussion
Pharmacology TREATMENT
Review of Literature
Classification
Pathophysiology
Assessment
Treatment
• The primary difference in these
drugs is whether they are tertiary
amines which cross the blood-brain
barrier (scopolamine, atropine,
hyoscyamine)
• Quaternary amines, which do not
(glycopyrrolate).
• Drugs which cross the blood-brain
barrier are apt to cause CNS toxicity
(sedation, delirium).
Discussion
PEARLS
• ALL can cause: Dry mouth,
Flushing, Tachycardia, Blurred
Vision, Urinary retention,
Constipation
Drug
Trade
Name
Route
Starting
Dose
Onset
scopolamine (hyoscine)
hydrobromide
Transderm
Scop
Patch
One 1.5 mg ~12 h (24 h to steady state)
patch
Up to 3
patches
hyoscyamine
Levsin
PO, SL
0.125 mg
30 min
glycopyrrolate
Robinul
PO
1 mg
30 min
glycopyrrolate
Robinul
SubQ,
IV
0.2 mg
1 min
atropine
Atropine
SubQ, IV
0.1 mg
1 min
Multiple
sources
Sublingual
1gtt (1%
30 min
ophth. soln)
sulfate
atropine sulfate
From Fast Facts: CAPC
In palliative medicine
there are still no accepted
guidelines for the
treatment of death rattle in
the final phase of life.
Final Word?
Retention of
urine or stool
Pain
Multisystem
organ failure
Mets to brain
Paraneoplastic
syndrome
PTSD
Delirium
Review of Literature
Classification
Pathophysiology
Assessment
Treatment
Discussion
Review of Literature
Classification
Pathophysiology
Assessment
Treatment
Discussion
• Many models for delirium or acute
confusional state: RASS, CAM ICU,
MMSE
• Difference between dementia and
delirium.
• Are they safe?
• Are they harming others?
• Do they seem scared?
• Can you safely administer meds?
Delirium
Nearing Death Awareness
Review of
Literature
Classification
Pathophysiology
Assessment
Treatment
Discussion
Treat reversible causes!
•
•
•
•
•
Gentle reassurance;
Reorientation
Sleep-wake cycles
Safety precautions; aide presence
Reduce and review current
medications
• Hydration?
Non Drug TREATMENT
Review of Literature
Classification
Pathophysiology
• Management depends on where
one is in the disease trajectory.
Assessment
Treatment
Discussion
• Focus can be mainly on intensive
symptom management
• May need to progress to
Palliative Sedation- if severe treat
as a medical emergency
Delirium
Drug Therapy for delirium in terminally ill adultsCochrane Review 2004
One trial met the criteria for inclusion. In the 2012 update search
we retrieved 3066 citations but identified no new trials. The
included trial evaluated 30 hospitalized AIDS patients receiving
one of three agents: chlorpromazine, haloperidol and lorazepam.
The trial under-reported key methodological features.
Authors' conclusions
There remains insufficient evidence to draw conclusions about
the role of drug therapy in the treatment of delirium in
terminally ill patients. Thus, practitioners should continue to
follow current clinical guidelines. Further research is essential.
Cochrane Reference
Gagnon, P. (2008). Treatment of delirium in supportive and palliative care. Curr Opin
Support Palliat Care.
Jackson, K., & Lipman, A. (2009). Drug Therapy for delirium in terminally ill adult
patients. The Cochrane Library.
Kehl, K. (2004). Treatment of terminal restlessness: a review of the evidence. J Pain
Palliat Care Pharmacother.
Twycross, R. (2005). Neuroleptics in terminal restlessness. J Pain Palliat Car
Pharmacother.
White, C., McCann, M., & Jackson, N. (2007). First do no harm...Terminal restlessness
or drug induced delirium. J Palliat Med, 345-51.
CAPC: Fast Facts: Delirium- Update on Newer Agents, Pharmacologic management of
delirium- update.
Other References
Currently there are no FDA approved indications for the
management of delirium.
No published double blind, randomized, placebo-controlled
trials to guide the pharmacological management.
No consensus between medical providers that are leading
specialists in the field about how to treat delirium.
Irwin, S., Pirrello, R., Hirst, J., Buckholz, G., & Ferris, F.
(2013, Jan). Clarifying Delirium Management: Practical,
Evidenced-Based, Expert Recommendations for Clinical
Practice. Journal of Palliative Medicine, 16(4).
The Golden One!!
Once a diagnosis of delirium is made:
•
•
•
•
Assess associated symptoms that need to be addressed
Look for any likely underlying cause
Assess the patients functional status and prognosis
What are the Patient and families goals of care??
The above will help determine whether the
delirium is potentially reversible or irreversible.
Delirium
Potential reversibility- One has to know underlying diagnosis,
comorbidities, prognosis, functional status, etc.
Irreversible delirium: Time limited diagnostic and adequate
therapeutic trial to reverse the delirium is:
1. Inconsistent with goals of care
2. Fails to discover etiologies or fails to reverse
3. The underlying physiological processes are irreversible; end
stage organ failure, imminent death (hours to days)
As dying is an irreversible process, the
associated delirium is also irreversible and
should be managed accordingly.
Medication Management
Guidelines
Neuroleptics
** First Line**
Vella-Brincat, J., & Macleod, A. (2004). Haloperidol in
Palliative Care. Palliative Medicine.
Haloperidol
Dr. Paul Janssen
1926-2003
• Follow first order kinetics. Biological effects are related
to plasma concentrations.
• Utilize titration techniques- don’t dose sooner, don’t dose
longer.
• Rapid and safe titration can be used until symptoms are
relieved.
• Continue to assess benefits and side effects
• Once symptom controlled the total dose in last 24hrs
should be administered routine once every half life.
Pharmacological Principles
• Antipsychotics can be safely dosed:
• IV once every 15minutes
• SQ every 30 min
• Oral every 60 minutes
• Used until agitation controlled or max recommended dose
in 24hrs is reached.
• Similar to ER
Example
Reversible
• 1-First Generation
Antipsychotics
•
Haldol 1-2mg use titration
technique: Max 100mg/D
• Chlorpromazine 25-50 mg
use titration technique Max
2000 mg/D
Second generation- No evidence
for use at this time
Benzodiazepines- Not used
generally as first or second line
except ETOH w/d.
Opioids- No role in delirium
except possible sedation and
pain relief. No anti-agitation
properties.
Irreversible
1-First Generation AntipsychoticsHaldol and Chlorpromazine
1- Benzodiazepines may be also
appropriate to control symptoms
associated with signs of dying
(muscle tension, myoclonus,
distress, anxiety, etc.)
• Concurrent use is warranted.
• Lorazepam- 1-2 mg use titration
technique (15-30-60)MAX
40mg/day
• Midazolam 0.1-0.2 mg/kg load
repeat every 30min until
controlled the continuous at 25%
of total needed to control. MAX
240mg/day
• *Phenobarbital and Propanol
Hyperactive
Treat acute delirium with active psychosis and safety issues
as a medical emergency.
Families will remember this death for as long as they live
Review-Discuss-?