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Horrible Hiccups
Sarah Wilcox
SpR Palliative Medicine
York Hospital. May 2005.
Case History
72 yr old man
July 2004 admitted with painless
jaundice/itch/malaise.
USS Mass head of pancreas
Whipple’s procedure
Post-op: non-functioning
gastrojejunostomy and onset of hiccups
Underwent further laparotomy/gastrectomy
Persistent non-functioning and ongoing
hiccups, therefore 3rd laparotomy in 8
weeks and revision gastojejunostomy.
Unfortunately had adhesions ++ and
accidental perforation of bowel resulted in
R hemi-colectomy
Declined oncology input and discharged
after 3 months in surgical ward
Progress
Reviewed in clinic with ongoing hiccups
Tried:-
metoclopramide – no help
haloperidol – felt awful on it. Hand shaking
uncontrollably, drooling, confused.
Discontinued by patient.
chlorpromazine (prn only) – no help
Further Progress
By Jan 2005 hiccups had become
intolerable. Unable to sleep, eat. Low in
mood.
Admitted by the surgical team and
commenced baclofen
First contact with PCT “help!”
Initial Assessment
 PMH:
micturition syncope 2001
Rh fever as a child
BUT!
Retired 6 years early due to shaking r hand
Handwriting shaky and becoming illegible
Mental slowing – poor concentration
Falls at home and unsteady on feet
Low mood due to above and hiccups
Drugs: lansoprazole 30mg od
metoclopramide 10mg tds
baclofen 5mg bd
Social:
married, no children
retired carpet fitter
Examination
Paucity of voluntary speech (bradyphrenic)
Lack of facial expression
Psychomotor retardation
No tremor at rest but tremulous on exertion
No cogwheeling or pill-rolling
Handwriting small and spidery
Festinant gait
Conclusion
New diagnosis of Parkinsonism
Plan:
collateral history from wife/GP
neurology opinion ? Idiopathic vs
drug-induced
stop metoclopramide
avoid haloperidol/neuroleptics
But what to do for hiccups???
In view of low mood and case report in
Psychosomatics, decided to try sertraline
50mg od
Seen by Consultant Neurologist the
following day
– Confirmed likely Parkinson’s
– Commenced madopar
Next Day
Crash call. Found unresponsive on the
floor after trying to mobilise to bathroom
BP 80/40mmHg with postural drop
Medical Reg. stopped baclofen and
madopar (both thought to lower BP)
Hiccups worsened over weekend
By Monday
Very low – physically exhausted and lack
of sleep due to continuous hiccuping
Team planned to CT thorax and abdomen
to check for a subdiaphragmatic collection
and arrange OGD
What to do for hiccups?
Neurology advice
Not to rechallenge with madopar, even half
dose
Possible options for Parkinson’s
amantadine or selegiline (but would have
to stop sertraline with the later)
Palliative Care Advice
Hiccups likely largely due to a mechanical
cause following extensive surgery
May have nothing else to offer but we
can’t say nothing to offer
? Benzodiazepines
?nifedipine (but hypotensive)
Dr Wilcox to do a lit search
Literature Review
Single case report of using amantadine in
longstanding hiccups in a patient with
newly diagnosed Parkinson’s
DW Neurology – worth a try as relatively
few side effects and unlikely to worsen BP
Prescribed amantadine 100mg od
Response
 4 days later hiccups much improved – less
frequent episodes and shorter duration
“manageable”
 Nursing staff also commenting on increased
facial expression – now able to smile and make a
joke
 Plan to increase amantadine to 100mg bd after 1
week
 CT shows progressive intra-abdominal disease –
to discuss options with Oncology
Next Problem
 Serum Na has gradually dropped over two weeks
 coincides with starting sertraline ?SIADH
 Serum osm 267 (275-95) and urine osm 210
(300-900)
 However, reluctant to disrupt the status quo as
asymptomatic
 Discharged home with plan for Oncol review as
OP
Progress at home
Quiet for several weeks
Phone contact with wife – opted against
chemotherapy in case it sets off his hiccups
Distress calls from wife – hiccups returned.
Seen in clinic – to stop sertraline as ?low
Na now contributing to hiccups
Things settle again over several days
Terminal Stages
Admitted with likely CVA. Reduced
conscious level and unable to swallow
safely
All oral medication discontinued
No return of hiccups
Died three weeks later on S/D diamorphine
and midazolam.
Hiccups never recurred
Learning Points
Safe use of drugs in Parkinson’s patient
? Successful use of amantadine for hiccups
SIADH associated with TCAs
Never give up!
Hiccups Literature
Lots of case reports/review articles
Little hard evidence-base
Only one RCT for baclofen (see later)
Case series for chlorpromazine,
metoclopramide, valproate and nifedipine
all showed some benefit
Case reports for lots of varied drugs
Hiccups Overview
 Caused by an abrupt reflex closure of the glottis
after contraction of the inspiratory muscles
 Also called hiccough or singultus
 Persistent >48hrs or recur at frequent intervals
 Intractable – continuous for weeks/months/years.
Significant morbidity
 Primitive reflex ?functional or behavioural role
 Record: every 1.5 secs for 69 years and 5 months
Hiccup Reflex Arc
Afferent: vagus and phrenic nerves and
sympathetic chain T6-T12
Hiccup centre in cervical cord (C3-C5)
Efferent: phrenic nerve, glottic nerves,
nerves to accessory muscles of respiration
Usually stop during sleep
Causes of Hiccups
 Anything that interrupts the reflex pathway
(structural, metabolic, inflammatory, neoplastic
or infectious)
 Underlying organic cause in 90% of men (but
fewer women)
 More than 100 listed causes
 Commonest is gastric distension
 Prevalence of 19 cases in 942 palliative care
patients in 1 setting
Hiccup treatments - physical
Plato recommended a slap on the back
Sneezing/Valsalva’s manoeuvre/breath
holding/hyperventilating/paper bag may
help benign hiccups
Granulated sugar/ice water/peanut butter
Forced gastric emptying
Forcible tongue traction!
Drinking from the far side of a glass?
Hiccup treatments – drugs 1
 GI tract agents
1. Metoclopramide 10-20mg tds reduces
gastric distension + ? DA action
2. Asilone 10ml qds – defoaming antiflatulent
3. Lansoprazole 30mg od – gastric irritation
is a common cause of hiccups
Hiccup treatments – drugs 2
 Antipsychotics:
1. Chlorpromazine 25-50mg iv rptd after 2-
4hrs relieved hiccups in 41/50 patients
w/o recurrence. Can then continue oral
dose for 7-10 days. Thought to act via
DA blockade in hypothalamus
2. Haloperidol 1.5mg tds starting dose
3. ?levomepromazine
Hiccup treatments – drugs 3
 Anticonvulsants
1. Sodium valproate – case series of 5
showed some benefit but side effects
troublesome
2. Phenytoin – iv bolus followed by oral
therapy not consistently effective
3. Carbamazepine – case reports only
4. Benzos – not helpful. May cause hiccups.
Hiccup treatments – drugs 4
 Antispasticity agents
Baclofen – thought to decrease hiccup reflex
excitability. One double-blind, placebo
controlled crossover RCT in only 4 men with
resistant hiccups. Symptomatic improvement
seen using 5mg tds increased to 10mg tds but
no elimination of hiccups. Caution in elderly,
renal impairment and withdraw gradually
 Nifedipine – relaxes smooth muscle. Ltd
efficacy
Hiccup treatments – drugs 5
Amantadine – dopamine agonist
Case report in NEJM: women with
persistent hiccup for 35 years thought to be
due to fibrotic lung changes and chronic
gastritis developed clinical features of
Parkinson’s. Rx amantadine 100mg od
which dramatically interrupted her hiccups
and remained hiccup free after 1 year of Rx
Hiccup treatment – drugs 6
 Anti-depressants
1.
2.
Amitriptyline. 1 case report in NEJM of 17yr
old with hiccups for 1 year. Known type 1 DM
and epilepsy. Rx 10mg tds and hiccups
resolved
Sertraline. 1 case report using 150mg od in a
depressed patient who coincidentally had 3
years of intractable hiccups. Hiccups ceased
and did not recur until attempted dose reduction
Other Treatments
Electrical stimulation or chemical/surgical
disruption of the phrenic nerve
Temporary measures e.g bilateral phrenic
nerve block/crush procedures not always
successful and can result in resp. failure
? Glossopharyngeal nerve blocks – less
invasive
Pray to St Jude (patron saint of lost causes)
Hyponatraemia/SIADH and
anti-depressants
EPIDEMIOLOGY
Can be caused by any class of antidepressant (SSRIs > TCAs, MAOIs and
others)
Incidence approx 5 per 1000 per year in all
patients prescribed SSRIs
5-7% of all acute admissions to hospital
have hyponatraemia (often SIADH)
Risk factors
 Increased risk in >65 years, women, summertime
(?increased sweating), first few weeks of Rx
 Mean time to onset 4-28 days with SSRIs (most
hospitalised within 12 days of starting)
 Recent dose increase is also associated
 Diuretics increase risk of developing
hyponatremia in elderly patients on SSRI
Mechanism
Unknown!
? Increased ADH secretion from posterior
pituitary or potentiating the effect of ADH
on the kidney
DA/5-HT/cholinergic and noradrenergic
activity can all affect ADH secretion
Management
 In general stop offending drug (and/or fluid
restrict)
 However, hyponatraemia may settle while
continuing medication, especially if mild.
Average time was 7 days in 1 study of SSRIs
(?correction of ADH level)
 Average time for correction of hyponatraemia
from stopping drug was 15 days in one study
 Rechallenge with a drug from the same or a
different class of anti-depressants usually results
in recurrence of hyponatraemia
References
1. Hiccups and their cures, Lewis JH, Clinical Perspectives
in Gastroenterology, 2000; 3(5): 277-83.
2. Hiccups a treatment review, Friedman NL,
Pharmacotherapy, 1996; 16(6): 986-95.
3. Smith HS and Busracamwongs A. Management of
hiccups in the palliative care population. American
Journal of Hospice and Palliative Care, 2003; 20(2): 14953
4. Askenasy JJM. Persistent hiccup cured by amantadine.
NEJM, 1988; 318(11): 711.
References
5. Stalnikowicz et al. Amitriptyline for intractable hiccups.
NEJM, 1986; 315(1): 64-5.
6. Vaidya V. Sertraline in the treatment of hiccups.
Psychosomatics, 2000; 41(4): 353-5.
7. Bogunovic OJ. Hyponatraemia secondary to antidepressants. Psychiatric Annals, 2003; 35(5): 333-9.