Horrible Hiccups

Sarah Wilcox

SpR Palliative Medicine

York Hospital. May 2005.

Case History

72 yr old manJuly 2004 admitted with painless

jaundice/itch/malaise.USS Mass head of pancreasWhipple’s procedurePost-op: non-functioning

gastrojejunostomy and onset of hiccupsUnderwent 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 hiccupsTried:-

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 expressionPsychomotor retardationNo tremor at rest but tremulous on exertionNo cogwheeling or pill-rollingHandwriting small and spideryFestinant gait

Conclusion

New diagnosis of ParkinsonismPlan: 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 dropMedical 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 ?SIADHSerum osm 267 (275-95) and urine osm 210

(300-900)However, reluctant to disrupt the status quo as

asymptomaticDischarged home with plan for Oncol review as

OP

Progress at home

Quiet for several weeksPhone contact with wife – opted against

chemotherapy in case it sets off his hiccupsDistress 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 discontinuedNo return of hiccupsDied 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 hiccupsSIADH associated with TCAsNever give up!

Hiccups Literature

Lots of case reports/review articlesLittle hard evidence-baseOnly 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 singultusPersistent >48hrs or recur at frequent intervals Intractable – continuous for weeks/months/years.

Significant morbidityPrimitive reflex ?functional or behavioural roleRecord: 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 respirationUsually 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 distensionPrevalence of 19 cases in 942 palliative care

patients in 1 setting

Hiccup treatments - physical

Plato recommended a slap on the backSneezing/Valsalva’s manoeuvre/breath

holding/hyperventilating/paper bag may help benign hiccups

Granulated sugar/ice water/peanut butterForced gastric emptyingForcible 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 anti-flatulent

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 dose3. ?levomepromazine

Hiccup treatments – drugs 3

Anticonvulsants1. 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 only4. Benzos – not helpful. May cause hiccups.

Hiccup treatments – drugs 4

Antispasticity agentsBaclofen – 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 agonistCase 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. 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

2. 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

EPIDEMIOLOGYCan be caused by any class of anti-

depressant (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 associatedDiuretics 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): 149-53

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 anti-depressants. Psychiatric Annals, 2003; 35(5): 333-9.