Treating a Hiccup

Motivation: Last Sunday evening, I was crouching before a window in a dim room watching the dying sun and tracing uneasy thoughts about end of summer break and impending residency.  My solemn reverie was suddenly interrupted by high pitched sounds.  My brother had been struck by a bout of hiccups - incessant hiccups.  I called out for him to stop or restrain himself.  He shot back that since I was now a doctor, I could at least tell him how to stop hiccups.  I did not know.  I lost the argument.  Well, how do you treat hiccups?

As background, a hiccup - or the medical term singultus - is a sudden inspiration ending with sudden glottic closure.  There is no known physiological reason for hiccup!  The most common cause of hiccups is gastric distension.  The hiccup reflex arc has afferent nerve pathways of phrenic and vagus nerves, central mediator in the brainstem, and efferent pathways involving the phrenic nerve.  Thus, irritation at any point in the pathway from thoraco-abdominal pathology to CNS neoplasms can give rise to hiccups.  Hiccups lasting more than 48 hours are termed persistent while hiccups lasting longer than a month are called intractable.  Traditional pharmacotherapy of hiccups involves the antipsychotic chlorpromazine though the literature is thin on evidence.  But, given the side effects of chlorpromazine, alternative therapy is needed.  Recently, gabapentin was tried.

Paper: Porzio, G. et. al. Gabapentin in the Treatment of Hiccups in Patients With Advanced Cancer: A 5-Year Experience.  Clinical Neuropharmacology (2010) 33: 179-180.  http://www.ncbi.nlm.nih.gov/pubmed/20414106

Methods: This study was conducted in Italy on patients with advanced cancer in two settings: (1) a palliative in-patient care unit and (2) home comfort care service.  Patients were assessed for presence of persistent (>48 hours) hiccups that were rated at least 7 out of 10 in the patient's subjective assessment of severity of hiccups (10 means worst hiccups of life).  These patients were treated with gabapentin (300 mg thrice daily) with titration according to response.

Results:
Patients:  In the palliative in-hospital service, 37 of 944 patients (3.9%) had severe hiccups.  In the home care setting, 6 of 134 patients (4.5%) had severe hiccups.  Most patients (31/43) had advanced abdominal cancers.  The rest had advanced cancers from other locations.

Gabapentin result: After gabapentin administration, of the 37 inpatients, 31 experienced complete resolution while 4 had improvements.  Two end-stage patients on midazolam therapy experienced worsening of hiccups.  Among the 6 home care patients, 4 had complete resolution while the other 2 had improvement.  The maximum used dose of gabapentin was 1200 mg/day.  The most common side-effect was transient drowsiness.

Discussion: The paper in its design and power has many limitations, but it does demonstrate some remarkable results.  Among the 37 in-patients with severe hiccups, 35 (>90%) had improvements in hiccups, and the majority experienced complete resolution!  Another benefit of gabapentin over current therapy with chlorpromazine is that the only major side effect of gabapentin (in this trial) is transient drowsiness.  The paper, of course, has many limitations.  There was no placebo arm to the intervention, and the trial was unblinded.  So, the observed effect could be entirely a placebo response or an observer bias.

Despite the fact that about 4% of patients with advanced cancers are afflicted with severe hiccups decreasing quality of life, there have not been large randomized trials conducted for treatment of hiccups.  The future for hiccups trials does not appear too bright either.  This prospective design may be the level of the quality of data that is going to be available for some time.  So, if I had to treat hiccups, I would probably try gabapentin first given the tolerable side-effect profile of the drug.

To Salt and Death

Motivation: Last week, I eavesdropped on the subway.  Two old men were joking about their health when one man remembered recently hearing on the news that eating less salt kills you.  The other guy did not believe him. I did not believe him.  But, after flipping out my phone, a quick search of Google News revealed many recent articles stating exactly that.  Also, the articles cited a May issue of the authoritative journal JAMA.  We know that eating more salt results in increased blood pressure in the short term but does eating less salt really kill you in the long run?

Paper: Fatal and Nonfatal Outcomes, Incidence of Hypertension, and Blood Pressure Changes in Relation to Urinary Sodium Excretion.  Stolarz-Skrzypek et. al. JAMA (2011) 305: 1777-1785.  http://jama.ama-assn.org/content/305/17/1777.abstract

Methods: In this prospective study, European patients older than age 20 were recruited who did not have diagnosed cardiovascular disease at baseline.  On initial exam, a 24-hour urinary sample was collected for sodium excretion measurement (to reflect total sodium consumption).  Baseline measurements were obtained in 3681 patients, who were followed for mortality and morbidity.  A smaller subset of 2856 patients agreed to undergo follow-up exams.  Of these patients, a cohort of 2096 patients were followed for development of hypertension (760 already had hypertension at baseline).  A third cohort of 1499 patients were followed with serial urinary sodium measurements to establish a relationship between blood pressure and urinary sodium excretion - these patients were untreated with any antihypertensive medications.

Results:
Patient selection: Overall, the cohort had 52.7% women, and all participants were white.  The mean age was 40.9 years with smoking rate of 28.4% and alcohol intake (>5g/day) rate of 24.1% .  At baseline, average BP was 124.7/76.3 and total cholesterol was 209 mg/dL.

Salt and Death: The authors divided the patients into three groups based on urinary sodium excretion: low sodium excretion (1220 patients), medium (1250), and high (1211).  In the cohort, 219 patients died.  After adjusting for other variables like age, sex, smoking, drinking, diabetes, cholesterol, and educational attainment, the hazard ratios for all mortality in the three groups (from low to high) were: 1.14, 0.94, and 1.06 (p = 0.10).  For cardiovascular deaths, there were 84 events.  The adjusted hazard ratio in the three groups from low sodium to high sodium were: 1.56 (CI: 1.02-2.36), 1.05 (0.72-1.53), and 0.95 (0.66-1.38), p = 0.02.  The trend for non-cardiovascular deaths were not significant.

Cardiovascular Events:  The rates of coronary events, strokes, and all cardiovascular events across the three sodium groups were not significantly different.

Incidence of Hypertension: The baseline levels of urinary sodium levels were not predictive of incidence of hypertension.  Incidence of hypertension was about 25% in all groups.

Sodium to Blood Pressure Levels: Systolic blood pressure was positively correlated with 24 hour urinary sodium excretion.  A 100 mEq/L increase in sodium excretion resulted in only 1.14 mm Hg increase in systolic blood pressure (!).  Diastolic pressure was unaffected by sodium excretion levels.

Discussion: In summary, I think that this paper is an excellent example of data that ought to be consumed with caution and probably not fit for broad sweeping popular media coverage.  This study has several important limitations.  First, the study design is prospective meaning that while we may see associations between urinary sodium levels (and presumably sodium consumption) and medical endpoints, it would be hard to infer causality.  For example, why do some people consume less sodium?  Other than trying to be healthy, the people eating less sodium may have been poorer or may have other habits like strenuous jobs that prevented them from eating.  The study did not really adjust for socioeconomic status.  Also, the study population was relatively young (average age 40.9 years).  In a younger cohort, other factors like genetics may be more important than dietary habits.  Finally, many patients (259) were lost to follow-up.

The most provocative point in the paper is the weak association shown between decreased sodium consumption and increased cardiovascular mortality.  The association is weak with a few events (10 events in the high sodium excretion group).  While the point is interesting, I think that it would be a stretch to say that decreased sodium consumption increases mortality.  There are many confounding variables that could affect the result, and this study probably calls for a randomized intervention trial.  Finally, the other point that I found interesting is that the incidence of hypertension did not differ among groups with varying sodium consumption.  This may suggest that while sodium consumption affects blood pressure, primary hypertension may not be caused by sodium indiscretion.

PS:  In case you are still reading, there have been some items in the news that were reviewed in this blog.  1) Fidaxomicin was recently approved by FDA as a new drug for treating C. difficile.  The drug was reviewed by Haoming here.  2) There has been a lot of buzz recently about cell phones and cancer.  The topic was reviewed in this blog here by me last year.