Treatment of Idiopathic Persistent Hiccups with Positive Pressure Ventilation -A Case Report-

Design

Case report

Case Presentation

A 41-year-old Korean male, without significant medical history, presented with idiopathic persistent hiccups (15 to 20 per minute) lasting for 10 days which continued through his sleep. The patient had no history of repeated hiccupping episodes, but the patient's hiccup contractions were severe and caused upper abdominal discomfort. Physical examination, imaging, and lab showed no abnormalities. Nonpharmacological treatment and daily cisapride 30 mg, omeprazole 40 mg, and baclofen 30 mg administered orally for 9 days were not successful. Subsequently, gabapentin 300 mg PO daily was added but soon discontinued due to dizziness. Left phrenic nerve block with 4 mL of 1% lidocaine was then performed using the neurostimulation method, but hiccups recurred again despite the repeated phrenic nerve block. As a last resort, the positive pressure ventilation therapy was initiated after 8 hours of NPO status. 

Propofol 2.0 mg/kg was given intravenously and succinylcholine 70 mg was soon followed after the loss of eyelash reflex. Ventilation was maintained via a facial mask with an air/oxygen mixture containing 50% oxygen and no inhalational anesthetic. A tidal volume of 650 mL was delivered at a rate of 8 breaths/min, and peak inspiratory pressure (PIP) was 25 cm H₂O. The patient began spontaneous ventilation after two minutes of positive pressure ventilation therapy and regained full consciousness ten minutes after the injection of propofol. Hiccups disappeared and did not recur. At the 10 week follow-up, no further episodes of hiccups had occurred.

Study Author Conclusions

Success in treating hiccups has been reported with pharmacologic treatments including cisapride, omeprazole, baclofen, amitriptyline, valproic acid, and nifedipine. Due to the fact that the etiology of persistent hiccups is probably multifactorial, treatment of persistent hiccups frequently requires a combination of pharmacologic agents with different sites of activity. Omeprazole, an inhibitor of gastric acid secretion, and cisapride, a gastroprokinetic agent, are thought to reduce an assumed afferent input from the periphery to a hiccup center. Baclofen is thought to depress reflex hiccup activity.

In addition to pharmacologic treatment, interventional methods have been advocated for intractable cases of hiccups. A phrenic nerve block is thought to block the efferent nerve fibers and suppress the reflex arc of hiccups. It has been suggested that if the hiccups do not stop after the first attempt at phrenic nerve block, the nerve block should be repeated.

Inhalational anesthetic might increase the possibility of hiccups via the gamma-aminobutyric acid receptor. Therefore, in the present case, an inhalational anesthetic was not used. To stop involuntary powerful spasms of the diaphragm and to allow for short-term positive pressure ventilation, succinylcholine was selected. Propofol was also used as a short-acting intravenous anesthetic to permit early recovery after the abolishment of the hiccups. In the present study, the hiccups continued when the loss of the eyelash reflex induced by propofol occurred, but stopped after injection of succinylcholine followed by positive pressure ventilation. This technique may terminate spasmodic diaphragm contractions by effectively immobilizing the diaphragm. Therefore, positive pressure ventilation and muscle relaxants could be effective in the treatment of idiopathic persistent hiccups.

A 34-year-old male with no significant past medical history was scheduled for an arthroscopic anterior cruciate ligament reconstruction. A 3 mL levobupivacaine 0.5% injection was administered in the L4-L5 interspace for subarachnoid block. Approximately two minutes following a 2 mg midazolam injection for sedation, the patient developed hiccups. Due to unsuccessful reassurance, midazolam 1 mg was administered; however, there were no changes in the frequency of the hiccups. After 5 minutes, the patient complained of pain near the subscapular region, which was treated with fentanyl 30 mcg intravenously. Frequency of hiccups reduced and completely resolved after an additional 5 minutes. There was no further recurrence of hiccups.

Most hiccups are acute and end within minutes; however, sudden hiccups post sedation can present a safety hazard for patients. It is noted that drug-induced hiccups appear to be more common in men than in women.

Overall, various drugs have been utilized to manage intraoperative hiccups including ketamine 25 mg intravenous (IV), ephedrine 5 mg IV, atropine 0.5 mg IV and dexmedetomidine 50 g IV over 10 minutes. Despite benzodiazepines being associated with the cause of hiccups, patients with terminal hiccups have been successfully managed by intravenous midazolam. However, the author’s concluded that an additional dose of midazolam did not eliminate the hiccups for this patient. Although opioids are thought to cause hiccups as well, a small dose of intravenous fentanyl appeared to be beneficial in resolving hiccups.

Chlorpromazine (Thorazine) in the Treatment of Intractable Hiccups

Case Series

A 57-year-old male underwent an uncomplicated abdominoperineal resection after which he began to hiccup 3 days later. Following heavy sedation and carbon dioxide inhalations, the hiccups remained persistent for 9 days, which lead to his inability to eat and need for intravenous (IV) fluid therapy. Chlorpromazine 50 mg IV was initiated, and hiccups stopped within 3 minutes with no recurrences reported.

A 70-year-old male began to hiccup after a suprapubic prostatectomy for benign prostatic hypertrophy. His hiccups persisted for two weeks despite therapy with IV barbiturates. By day 14, the patient was unable to sit up and was given chlorpromazine 25 mg IV and 25 mg intramuscularly. The hiccups stopped within minutes after which he was able to eat without any recurrences.

Case 3

A 43-year-old male presented to the hospital with a prolonged 12-hour duration of acute posterior wall myocardial infarction. After admission, he began to hiccup persistently, which remained uncontrolled despite attempts with medication. On day 4, chlorpromazine 50 mg IV was administered after which the patient's hiccups stopped without any recurrence.

Case 4

A 36-year-old male was reported to experience daily, intermittent hiccups for 9 months despite being given every known therapy for hiccups at the time, which included psychiatric treatment and phrenic nerve crush. He then presented to the hospital after 5 days of continued hiccups and was initiated on chlorpromazine 50 mg IV; hiccups stopped immediately. Chlorpromazine 25 mg three times a day was administered the following day after which the patient did not experience recurrent hiccups.

Chlorpromazine has a wide range of pharmacological activities. The authors note that the effects vary based on patient tolerance. As a result, patients should be closely monitored for several hours after receiving the medication intravenously. Although chlorpromazine was found to be a safe and beneficial medication for treating intractable hiccups, if the cause of the hiccups remains untreated, the hiccups may return.

A 35-year-old male patient presented with a complaint of hiccups ongoing for 15 hours, which started early in the morning and continued until midnight. Hiccups did not resolve with nonpharmacological methods at home. The patient has had 12 hiccup attacks in the past 5 years which continue for 12-60 hours and resolved with medication in the hospital. Medical investigation revealed no pathological source for the hiccups.

Esomeprazole 40 mg intravenous (IV) and 10 mL of oral sodium alginate were administered with no resolution. Metoclopramide and chlorpromazine IV in 500 mL isotonic solution were administered within 30 minutes; chlorpromazine hydrochloride infusion was repeated twice with no resolution of the hiccup. Mesotherapy with intradermal injection (2 mg thiocolchicoside and 16.2 mg lidocaine) adjacent to the vagal nerve and the sternocleidomastoid muscle was administered due to no regression of symptoms. A second injection was given in three points in the epigastrium region immediately adjacent to the diaphragm.

As a result, the hiccup ended 15 minutes after the mesotherapy procedure with no recurrence. There were no complications or another hiccup attack occurrence at follow-up one week later.

There is no optimal primary medical treatment for persistent hiccups because experience with many drugs on hiccups is based on case reports. The U.S. Food and Drug Administration has approved only one drug for treatment of hiccups (chlorpromazine). Metoclopramide is often preferred in the treatment of hiccups when chlorpromazine cannot be used. When using chlorpromazine and metoclopramide together, the effectiveness is within 30 minutes; however, there may be side effects.

Intradermal injections around the sternocleidomastoid muscle stimulate the vagal nerve, which causes the hiccups to stop. Intradermal mesotherapy is a more feasible procedure than cervical epidural anesthesia and phrenic nerve block with a lower risk of developing complications. In this case, hiccups were successfully terminated after intradermal injection. For these reasons, the authors recommend intradermal injection as first-line therapy in the treatment of persistent hiccups. Since drug therapy has extrapyramidal side effects, intradermal mesotherapy may be a better choice in the treatment of hiccups.

In conclusion, the application of intradermal injections successfully ended hiccups in a patient that did not respond to medical treatment, and no complications developed during the follow-up.

A 47-year-old male with a past medical history of irritable bowel syndrome, seronegative arthritis, nephrolithiasis, and recurrent hiccups (treated non-pharmacologically) presented to the hospital with small bowel obstruction secondary to diverticulitis. He was treated for a ureteral stone and had a laparotomy for a diverticular abscess. After the procedure, the patient began to experience hiccups that occurred approximately every 10 seconds. Over 24 hours, the patient was given metoclopramide, prochlorperazine, chlorpromazine, and haloperidol in attempt to treat the hiccups; however, the patient obtained only partial relief for less than 2 hours. Additionally, following the last few injections, the patient experienced a dystonic reaction which required immediate diphenhydramine and discontinuation of the medications. The patient's medications at this time included epidural infusion of 0.1% bupivacaine, morphine, and antibiotics.

On postoperative day 1, the patient continued to experience hiccups and was initiated on a 100 mg (1.5 mg/kg) intravenous lidocaine infusion over 5 minutes. The hiccups resolved completely within a few minutes until recurrence 8 hours later but were less frequent. However, the next day, the hiccups returned for which the patient was given intravenous (IV) normal saline 2 mL and IV verapamil 2 mg, which provided no relief. Lidocaine 50 mg (0.75 mg/kg) IV was administered 20 minutes later after which the patient experienced immediate resolution of the hiccups again. He remained without hiccups until discharge. 

Hiccups can be due to different disorders such as central nervous system dysfunction, toxic-metabolic abnormalities, or neuronal dysfunction in the nerve roots or reflex arc between the inspiratory and glottic closure complexes. Thus, lidocaine can be beneficial to treat hiccups. Lidocaine is a local anesthetic that works by blocking sodium channels to prevent nerve conduction. It can decrease neuronal excitability and ectopic discharges.

In this patient, the systemic absorption of epidural bupivacaine may have contributed to the membrane-stabilizing effect of lidocaine, and thus played a role in the cessation of hiccup. An alternative explanation is that the patient exhibited a positive placebo response despite his negative response to the intravenous administration of normal saline. In conclusion, this report and previous ones indicate that the use of sodium channel blockers may be an effective treatment for chronic, intractable hiccups.

Metoclopramide in hiccup 

Design

Retrospective, observational study

N= 14

Objective

To determine if intravenous metoclopramide will provide relief for intractable hiccups in patients with major illnesses

Study Groups

Metoclopramide 10 mg orally every 6 hours 

Metoclopramide 5 to 10 mg parenterally (I.M or I.V) every 8 hours 

Inclusion Criteria

Adult patients with intractable hiccup of over 24 hours' duration; patients that failed a trial of antacids, anticholinergics, antihistaminics, phenothiazines, and sedatives 

Exclusion Criteria

None reported 

Methods

Patients were given metoclopramide 10 mg orally every 6 hours or 5-10 mg parenterally every 8 hours. If given IM or IV, metoclopramide 10 mg IM was first given then 5 mg IV was given after 6 hours of the first dose. Metoclopramide 5 mg IV was given subsequently when needed.

Duration

N/A

Outcome Measures

Primary outcome: Hiccup resolution, no hiccup resolution

Baseline Characteristics

All patients (N= 14)

Viral hepatitis with esophagitis 

Diabetic ketosis with dilatation of the stomach

Calculus cholecystitis with hiccups

Inferior wall myocardial infarction

Cor pulmonale with diabetes with renal failure and digitalis toxicity

Pancreatic abscess following pancreatitis

Chronic active liver disease (alcoholic with viral hepatitis) with renal failure

Terminal chronic renal failure with hemorrhagic gastritis

Results

With parenteral metoclopramide therapy, the first IM dose stopped hiccups within minutes but came back in about 6 hours. When the drug was repeated with 5 mg IV, relief was given within 15 minutes of the IV dose.

When the very first patient was given 10 mg IV as the first dose, they complained of chest pain minutes after injection but a resting ECG showed no abnormality. Thereafter, IV dosage was limited to 5 mg for the second dose.

Patients on parenteral therapy were placed on oral therapy after 24-48 hours of parenteral therapy. Metoclopramide did not affect the original disease and controlled the hiccups.

Adverse Events

None reported

Study Author Conclusions

Metoclopramide relief of hiccup which had proved refractory to other procedures was invariably followed by very desirable and welcome sleep in all the patients. Observations in these patients convincingly reveal the therapeutic efficacy and safety of metoclopramide in hiccup of diverse organic etiology. It is hoped it will find wider use in hiccup and more organized trials will be undertaken at more centers in various countries. 

InpharmD Researcher Critique

A weakness of this study is that the drug, metoclopramide, was not readily available at this institution. Also, due to the nature of hiccup occurrence and cessation, it was hard to plan a study since patients looking for quick relief to hiccups were not available as well.

The study's methods were not organized well and there were no baseline characteristics presented aside from their other diagnoses. The authors did not state if other patients of the trial were given metoclopramide or which dosage form was given.