JOURNAL OF PALLIATIVE MEDICINE Volume 18, Number 5, 2015 ª Mary Ann Liebert, Inc. DOI: 10.1089/jpm.2014.0391
Case Discussions in Palliative Medicine Feature Editor: Craig D. Blinderman
Use of Vinegar To Relieve Persistent Hiccups in an Advanced Cancer Patient Silvia Gonella, MSc, RN1 and Flavia Gonella, Pharm 2
Abstract
Background: This case report describes a patient whose persistent hiccups significantly improved with the use of vinegar. Case Presentation: A patient with an adenocarcinoma of the colon and hepatic metastases developed hiccups the day following chemotherapy with FOL-FOX (folinic acid (leucovorin), 5-fluorouracil, oxaliplatin). Hiccups continued for seven days with no improvement from a number of commonly used pharmacological agents (chlorpromazine, metoclopramide, haloperidol, and baclofen). Relief was finally obtained after sipping vinegar. Case Management and Outcome: Hiccups occurred several times during the following chemotherapy cycles but the patient completed the treatment using vinegar when they recurred without stopping any drugs. Hiccups stopped or decreased in intensity or in rate per minute after sipping vinegar. Conclusions: Hypotheses have been developed for the molecular and physiological mechanisms underlying sour compounds’ effectiveness in relieving hiccups. Further studies should explore the potential role of vinegar in relieving hiccups in advanced heavily treated cancer patients.
Introduction
H
iccups, or singultus, usually occur over a brief period of time and are self-limiting but may become exhausting when prolonged. Hiccups lasting for more than 48 hours or recurring at frequent intervals are called persistent, while hiccups occurring continuously for months or years are labeled as intractable.1 Hiccups are not a very common complaint in the hospital setting.2 A retrospective study in a Baltimore hospital between 1995 and 2000 showed 54 patients out of approximately 110,000 admissions (0.00055%) with a primary or secondary diagnosis of the hiccups.3 However, the prevalence of persistent and intractable hiccups in patients with advanced cancer has been reported at between 2.25% and 9%.4–7 Moreover, hiccups are the second most referred orphan symptom.7 The pathogenesis of hiccups is complex and unclear, although they are thought to arise through a reflex arc (see Fig. 1).8 The main afferent signals come from the diaphragm, head and neck structures, thoracic and abdominal viscera. The role of the reticular activating system, brain stem respiratory center, hypothalamus, and temporal lobes in the pathogenesis of hiccups has not yet been clarified. The main afferent routes are the phrenic and the vagus nerves and the sympathetic chain (T6-T12). The hiccups center is thought to
be between the cervical segments C3-C5 and the brain stem. The main efferent pathway is the phrenic nerves.2 Persistent or intractable hiccups are often the result of underlying structural, metabolic, inflammatory, or infectious disorders.1,2 They usually occur with phrenic, vagus, or diaphragmatic irritation from thoracic, abdominal, or pelvic neoplasms, hepatomegaly, ascites, esophagitis, gastric distension, or reflux. In the cancer population their exact etiology is difficult to identify, because neoplasms are frequently associated with other conditions, such as infectious complications, metabolic disorders, and drugs (e.g., antibiotics, benzodiazepines, corticosteroids, opioids, and cytotoxic agents), which may stimulate hiccups in different ways.2,9,10 According to Lewis1 and Becker,10 a multistep approach should be developed to treat persistent and intractable hiccups. Initially, the underlying disorder needs to be corrected, because most hiccups will stop upon successful treatment of the specific cause (e.g., use of proton pump inhibitors for gastroesophageal reflux disease related hiccups). If hiccups persist despite specific treatment, the authors advise nonpharmacological approaches. Only if they remain refractory to these measures should pharmacologic agents be considered. However, several drugs used in the treatment of hiccups have important side effects, such as hypotension, urinary
1
Department of Public Health and Community Medicine, University of Verona, Verona, Italy. Department of Drug Science and Technology, University of Torino, Torino, Italy. Accepted February 18, 2015.
2
467
468
GONELLA AND GONELLA
FIG. 1.
Physiology of the reflex arc of hiccups.
retention, glaucoma, and delirium (chlorpromazine), extrapyramidal symptoms (haloperidol), ataxia, dizziness, and sedation (baclofen, an antispasmodic gamma aminobutyric acid receptor antagonist).9 Currently there is insufficient evidence to recommend either pharmacological or nonpharmacological treatments.11 However, Lewis1 and Becker10 suggest consideration of nonpharmacological interventions before considering drugs, especially in patients already taking a number of medications, as in patients being treated for cancer. In this population it would be better to avoid, if possible, drugs that may lead to interactions, adverse effects, and that can themselves induce hiccups. Benzodiazepines, corticosteroids, antibiotics, opioids, and cytotoxic agents have indeed been reported to be among the most common drug-induced causes in patients with cancer.9 Sour tastes, such as vinegar and lemon, have been used to treat hiccups since the 1930s, although no scientific explanation has yet to been given.1 We describe a case of the effective use of vinegar in relieving hiccups in a patient with adenocarcinoma of the colon and hepatic metastases. In addition we hypothesized the molecular and physiological mechanisms that may explain sour compounds’ effectiveness in relieving hiccups.
the morning for three days) was given as an antiemetic prophylaxis. During the first course of chemotherapy the patient complained of severe hiccups, starting the day after treatment. The hiccups were treated with chlorpromazine (25 mg three times daily, orally), metoclopramide (10 mg twice daily, intravenous), haloperidol (2 mg twice daily, orally), and baclofen (5 mg three times daily) without improvement. Gabapentin was not prescribed, since the patient reported to be allergic. Hiccups continued constantly for seven days with only a few hours of daily relief. The patient did not suffer from gastroesophageal reflux disease, and the only medication taken was alprazolam for insomnia, which had been taken regularly for over four years without adverse effects. Dexamethasone-induced hiccups12 had been hypothesized but it was decided to continue the drug. However, recent case reports suggested the potential benefit of changing dexamethasone for methylprednisolone when the dexamethasone is thought to induce hiccups.13,14 Due to the exhaustion of all the commonly used treatments and the persistence of this symptom, the decision was made (after an informed discussion with the patient) to try using vinegar. Case Management and Outcome
Case Presentation
A 58-year-old Caucasian man was surgically treated for a T3N1M1 adenocarcinoma of the colon. Staging computed tomography revealed two hepatic metastases and retroperitoneal lymphadenopathy. Adjuvant chemotherapy with FOLFOX (folinic acid (leucovorin), 5-fluorouracil, oxaliplatin) was started six weeks after surgery. Cycles were repeated every two weeks. Intravenous ondansetron (8 mg three times daily for two days) plus intravenous dexamethasone (8 mg in
After the failure of common treatments for hiccups, the patient was given a sip of vinegar and his hiccups abated within 15 minutes. The hiccups recurred the following day and were relieved again with vinegar. This pattern was repeated after the second course of chemotherapy. The hiccups occurred on day one after chemotherapy and continued for eight hours with no benefit from chlorpromazine or metoclopramide. After one sip of vinegar the hiccups decreased in intensity and eventually ceased. The patient completed the
SOUR COMPOUNDS IN RELIEVING HICCUP IN CANCER
469
following chemotherapy cycles without stopping any drugs and using vinegar whenever the hiccups recurred. The hiccups either ceased or decreased in intensity after sipping vinegar.
less frequently converted into action potentials, with a parallel reduction in hiccups frequency and/or intensity. The hiccups may have terminated due to high hydrogen concentrations, which have been hypothesized to prevent the attainment of the threshold value. Subsequently, the transmission of the action potential would be blocked with symptom cessation. In summary, vinegar increases intracellular H + concentrations when absorbed by the gastric cells, and high vinegar induced H + concentrations may block or at least reduce the intensity of hiccups. Although there is a scientific rationale for the mechanism by which vinegar may be useful for treating hiccups, this is a single case study. Obviously, more observations and controlled studies are necessary before recommending this as a therapeutic option. Furthermore, in cancer patients, several etiologies may lead to hiccups, and therefore the effectiveness of vinegar may change according to the etiology. However, vinegar could be considered as a nonpharmacological approach when (1) hiccups persist despite treatment of the inferred etiology and (2) the discontinuation of drugs that may be causing hiccups cannot feasibly be stopped. Instances of this would be (1) hiccups associated with antineoplastic agents in those undergoing strictly scheduled chemotherapy cycles, (2) antibiotic-induced hiccups in aplastic patients, and (3) dexamethasone-related hiccups in hematological malignancies where corticosteroids are an important treatment component, often included in the antiemetic prophylaxis for the prevention of nausea and vomiting. A recent systematic review11 has found that currently neither pharmacological nor nonpharmacological interventions have enough evidence to be recommended for the treatment of hiccups, because the bulk of studies have poor quality and because few randomized controlled trials are available. Future studies should investigate the use of vinegar in treating hiccups in patients with advanced cancer.
Conclusion
In the past, nonpharmacological remedies such as vinegar were largely used, but then they fell out of favor with the widespread use of pharmacotherapy.1 No studies have been published for 40 years until 2009 with an Australian article’s anecdotal report of the relief of hiccups from sucking the juice of a lemandarin, a citrus hybrid produced from crossing a lemon and a mandarin.15 Sour tastes were hypothesized to ‘‘irritate’’ the soft palate or pharynx, inhibiting afferent impulses and interrupting the hiccup reflex,1 but the possible molecular and physiological mechanisms underlying their efficacy have not been established. It is largely known that at the level of the peripheral terminal sensory afferents (in this case at the gastric plexus level), external stimuli generate graded potentials that electrically decay along the soma of the sensory cell.16 When the activation threshold of sodium channels at the axon hillock is achieved, this potential is converted into an ‘‘all or nothing’’ signal, giving rise to an action potential. These action potentials self-propagate regardless of the extracellular sodium concentration.16 Briefly, the peripheral sensory cells change the peripheral stimulus into a graded potential, which may in turn be converted into an action potential. The frequency of action potentials represents the intensity and the duration of the peripheral stimulus.16 Therefore, the stronger or longer the peripheral stimulus is, the greater the frequency of action potentials, and the higher the hiccupping frequency and/or intensity. In summary, the peripheral stimulus is converted into a graded potential, and after exceeding the threshold value (between - 40 mV and - 30 mV), it is in turn transformed into an action potential.16 Beyond this value, sodium quickly enters the axon hillock until reaching a value of + 63 mV. Then the afferent stimulus goes up to the hiccup center where it is processed and finally goes down the phrenic nerve to the diaphragm, the external intercostals, the scalene muscles, glottic structures, and the esophagus (efferent stimulus).16 The chemical formula of vinegar is CH3COOH. Vinegar dissociates into CH3COO - + H + when absorbed by the gastric cells.17 We hypothesized that high concentrations of intracellular H + may block or at least reduce the intensity of graded potentials and consequently prevent their transformation into ‘‘all or nothing’’ signals. High H + concentrations have been hypothesized to block sodium entry into the axon hillock by a double competitive mechanism:16,17 (1) the H + ion as well as the Na + ion each have only one positive charge and (2) H + and Na + have comparable atomic dimensions. If there is not enough sodium at the axon hillock, the threshold value will not be reached; therefore, the afferent stimulus will be blocked. Vinegar was found to completely terminate our patient’s hiccups or reduce them in frequency or intensity. It is largely recognized that duration and intensity of the peripheral stimulus influence the amplitude of the graded potential.16 Vinegar-induced high H + concentrations reduce sodium entry in the axon hillock; therefore, the graded potentials are
Author Disclosure Statement
The authors report no conflicts of interest. This report received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. The patient gave oral permission for this report to be published. References
1. Lewis JH. Hiccups: Causes and cures. J Clin Gastroenterol 1985;7:539–552. 2. Calsina-Berna A, Garcia Gomez G, Gonzalez-Barboteo J, et al.: Treatment of chronic hiccups in cancer patients: A systematic review. J Palliat Med 2012;15:1142–1150. 3. Cymet TC: Retrospective analysis of hiccups in patients at a community hospital from 1995–2000. J Natl Med Assoc 2002;94:480–483. 4. Potter J, Hami F, Bryan T, et al.: Symptoms in 400 patients referred to palliative services: Prevalence and patterns. Palliat Med 2003;17:310–314. 5. Porzio G, Aielli, F, Verna L, et al.: Gabapentin in the treatment of hiccups in patients with advanced cancer: A 5year experience. Clin Neuropharm 2010;33:179–180. 6. Walsh D, Donnelly S, Rybicki L: The symptoms of advanced cancer: Relationship to age, gender and perfor-
470
7. 8. 9. 10. 11. 12. 13.
GONELLA AND GONELLA
mance status in 1,000 patients. Support Care Cancer 2000; 8:175–179. Mercadante S, Porzio G, Valle A, et al.: Orphan symptoms in advanced cancer patients followed at home. Support Care Cancer 2013;21:3525–3528. Smith HS: Hiccups. In: Walsh D (ed): Palliative Medicine. Philadelphia, PA: Elsevier Saunders, 2009, pp. 894–898. Marinella MA: Diagnosis and management of hiccups in the patient with advanced cancer. J Support Oncol 2009; 7:122–127,130. Becker DE: Nausea, vomiting and hiccups: A review of mechanisms and treatment. Anest Prog 2010;57:150–157. Moretto EN, Wee B, Wiffen PJ, et al.: Interventions for treating persistent and intractable hiccups in adults. Cochrane Database Syst Rev 2013;1:CD008768. Ratogi RB, Singhai RL: Adrenocorticoids control 5hydroxytryptamine metabolism in the rat brain. J Neurol Trasm 1978;42:63–71. Lee GW, Oh SY, Kang MH, et al.: Treatment of dexamethasone-induced hiccup in chemotherapy patients by methylprednisolone rotation. Oncologist 2013;18:1229– 1234.
14. Kang JH, Hui D, Kim MJ, et al.: Corticosteroid rotation to alleviate dexamethasone-induced hiccup: A case series at a single institution. J Pain Symptom Manage 2012;43:625–630. 15. Gilbar P, McPeherson I: Severe hiccup during chemotherapy: Corticosteroids the likely culprit. J Oncol Pharm Pract 2009;15:233–236. 16. Carbone E: Potenziali d’azione: Genesi, conduzione e propagazione [Action potentials: Origin, propagation and run]. In: Carbone E, Cicirata F, Aicardi G (eds): Fisiologia Dalle Molecole Ai Sistemi Integrati [Physiology from Molecules to Integrated Systems]. Napoli: Edises, 2010, pp. 29–57. 17. Braun WH, Foote CS, Iverson BL: Chimica Organica [Organic Chemistry], 3rd ed. Napoli: Edises, 2006.
Address correspondence to: Silvia Gonella, MSc, RN Department of Public Health and Community Medicine University of Verona Piazzale Antonio Scuro 10 Verona, Italy 37134 E-mail: [email protected]
Case Discussions in Palliative Medicine Feature Editor: Craig D. Blinderman
Use of Vinegar To Relieve Persistent Hiccups in an Advanced Cancer Patient Silvia Gonella, MSc, RN1 and Flavia Gonella, Pharm 2
Abstract
Background: This case report describes a patient whose persistent hiccups significantly improved with the use of vinegar. Case Presentation: A patient with an adenocarcinoma of the colon and hepatic metastases developed hiccups the day following chemotherapy with FOL-FOX (folinic acid (leucovorin), 5-fluorouracil, oxaliplatin). Hiccups continued for seven days with no improvement from a number of commonly used pharmacological agents (chlorpromazine, metoclopramide, haloperidol, and baclofen). Relief was finally obtained after sipping vinegar. Case Management and Outcome: Hiccups occurred several times during the following chemotherapy cycles but the patient completed the treatment using vinegar when they recurred without stopping any drugs. Hiccups stopped or decreased in intensity or in rate per minute after sipping vinegar. Conclusions: Hypotheses have been developed for the molecular and physiological mechanisms underlying sour compounds’ effectiveness in relieving hiccups. Further studies should explore the potential role of vinegar in relieving hiccups in advanced heavily treated cancer patients.
Introduction
H
iccups, or singultus, usually occur over a brief period of time and are self-limiting but may become exhausting when prolonged. Hiccups lasting for more than 48 hours or recurring at frequent intervals are called persistent, while hiccups occurring continuously for months or years are labeled as intractable.1 Hiccups are not a very common complaint in the hospital setting.2 A retrospective study in a Baltimore hospital between 1995 and 2000 showed 54 patients out of approximately 110,000 admissions (0.00055%) with a primary or secondary diagnosis of the hiccups.3 However, the prevalence of persistent and intractable hiccups in patients with advanced cancer has been reported at between 2.25% and 9%.4–7 Moreover, hiccups are the second most referred orphan symptom.7 The pathogenesis of hiccups is complex and unclear, although they are thought to arise through a reflex arc (see Fig. 1).8 The main afferent signals come from the diaphragm, head and neck structures, thoracic and abdominal viscera. The role of the reticular activating system, brain stem respiratory center, hypothalamus, and temporal lobes in the pathogenesis of hiccups has not yet been clarified. The main afferent routes are the phrenic and the vagus nerves and the sympathetic chain (T6-T12). The hiccups center is thought to
be between the cervical segments C3-C5 and the brain stem. The main efferent pathway is the phrenic nerves.2 Persistent or intractable hiccups are often the result of underlying structural, metabolic, inflammatory, or infectious disorders.1,2 They usually occur with phrenic, vagus, or diaphragmatic irritation from thoracic, abdominal, or pelvic neoplasms, hepatomegaly, ascites, esophagitis, gastric distension, or reflux. In the cancer population their exact etiology is difficult to identify, because neoplasms are frequently associated with other conditions, such as infectious complications, metabolic disorders, and drugs (e.g., antibiotics, benzodiazepines, corticosteroids, opioids, and cytotoxic agents), which may stimulate hiccups in different ways.2,9,10 According to Lewis1 and Becker,10 a multistep approach should be developed to treat persistent and intractable hiccups. Initially, the underlying disorder needs to be corrected, because most hiccups will stop upon successful treatment of the specific cause (e.g., use of proton pump inhibitors for gastroesophageal reflux disease related hiccups). If hiccups persist despite specific treatment, the authors advise nonpharmacological approaches. Only if they remain refractory to these measures should pharmacologic agents be considered. However, several drugs used in the treatment of hiccups have important side effects, such as hypotension, urinary
1
Department of Public Health and Community Medicine, University of Verona, Verona, Italy. Department of Drug Science and Technology, University of Torino, Torino, Italy. Accepted February 18, 2015.
2
467
468
GONELLA AND GONELLA
FIG. 1.
Physiology of the reflex arc of hiccups.
retention, glaucoma, and delirium (chlorpromazine), extrapyramidal symptoms (haloperidol), ataxia, dizziness, and sedation (baclofen, an antispasmodic gamma aminobutyric acid receptor antagonist).9 Currently there is insufficient evidence to recommend either pharmacological or nonpharmacological treatments.11 However, Lewis1 and Becker10 suggest consideration of nonpharmacological interventions before considering drugs, especially in patients already taking a number of medications, as in patients being treated for cancer. In this population it would be better to avoid, if possible, drugs that may lead to interactions, adverse effects, and that can themselves induce hiccups. Benzodiazepines, corticosteroids, antibiotics, opioids, and cytotoxic agents have indeed been reported to be among the most common drug-induced causes in patients with cancer.9 Sour tastes, such as vinegar and lemon, have been used to treat hiccups since the 1930s, although no scientific explanation has yet to been given.1 We describe a case of the effective use of vinegar in relieving hiccups in a patient with adenocarcinoma of the colon and hepatic metastases. In addition we hypothesized the molecular and physiological mechanisms that may explain sour compounds’ effectiveness in relieving hiccups.
the morning for three days) was given as an antiemetic prophylaxis. During the first course of chemotherapy the patient complained of severe hiccups, starting the day after treatment. The hiccups were treated with chlorpromazine (25 mg three times daily, orally), metoclopramide (10 mg twice daily, intravenous), haloperidol (2 mg twice daily, orally), and baclofen (5 mg three times daily) without improvement. Gabapentin was not prescribed, since the patient reported to be allergic. Hiccups continued constantly for seven days with only a few hours of daily relief. The patient did not suffer from gastroesophageal reflux disease, and the only medication taken was alprazolam for insomnia, which had been taken regularly for over four years without adverse effects. Dexamethasone-induced hiccups12 had been hypothesized but it was decided to continue the drug. However, recent case reports suggested the potential benefit of changing dexamethasone for methylprednisolone when the dexamethasone is thought to induce hiccups.13,14 Due to the exhaustion of all the commonly used treatments and the persistence of this symptom, the decision was made (after an informed discussion with the patient) to try using vinegar. Case Management and Outcome
Case Presentation
A 58-year-old Caucasian man was surgically treated for a T3N1M1 adenocarcinoma of the colon. Staging computed tomography revealed two hepatic metastases and retroperitoneal lymphadenopathy. Adjuvant chemotherapy with FOLFOX (folinic acid (leucovorin), 5-fluorouracil, oxaliplatin) was started six weeks after surgery. Cycles were repeated every two weeks. Intravenous ondansetron (8 mg three times daily for two days) plus intravenous dexamethasone (8 mg in
After the failure of common treatments for hiccups, the patient was given a sip of vinegar and his hiccups abated within 15 minutes. The hiccups recurred the following day and were relieved again with vinegar. This pattern was repeated after the second course of chemotherapy. The hiccups occurred on day one after chemotherapy and continued for eight hours with no benefit from chlorpromazine or metoclopramide. After one sip of vinegar the hiccups decreased in intensity and eventually ceased. The patient completed the
SOUR COMPOUNDS IN RELIEVING HICCUP IN CANCER
469
following chemotherapy cycles without stopping any drugs and using vinegar whenever the hiccups recurred. The hiccups either ceased or decreased in intensity after sipping vinegar.
less frequently converted into action potentials, with a parallel reduction in hiccups frequency and/or intensity. The hiccups may have terminated due to high hydrogen concentrations, which have been hypothesized to prevent the attainment of the threshold value. Subsequently, the transmission of the action potential would be blocked with symptom cessation. In summary, vinegar increases intracellular H + concentrations when absorbed by the gastric cells, and high vinegar induced H + concentrations may block or at least reduce the intensity of hiccups. Although there is a scientific rationale for the mechanism by which vinegar may be useful for treating hiccups, this is a single case study. Obviously, more observations and controlled studies are necessary before recommending this as a therapeutic option. Furthermore, in cancer patients, several etiologies may lead to hiccups, and therefore the effectiveness of vinegar may change according to the etiology. However, vinegar could be considered as a nonpharmacological approach when (1) hiccups persist despite treatment of the inferred etiology and (2) the discontinuation of drugs that may be causing hiccups cannot feasibly be stopped. Instances of this would be (1) hiccups associated with antineoplastic agents in those undergoing strictly scheduled chemotherapy cycles, (2) antibiotic-induced hiccups in aplastic patients, and (3) dexamethasone-related hiccups in hematological malignancies where corticosteroids are an important treatment component, often included in the antiemetic prophylaxis for the prevention of nausea and vomiting. A recent systematic review11 has found that currently neither pharmacological nor nonpharmacological interventions have enough evidence to be recommended for the treatment of hiccups, because the bulk of studies have poor quality and because few randomized controlled trials are available. Future studies should investigate the use of vinegar in treating hiccups in patients with advanced cancer.
Conclusion
In the past, nonpharmacological remedies such as vinegar were largely used, but then they fell out of favor with the widespread use of pharmacotherapy.1 No studies have been published for 40 years until 2009 with an Australian article’s anecdotal report of the relief of hiccups from sucking the juice of a lemandarin, a citrus hybrid produced from crossing a lemon and a mandarin.15 Sour tastes were hypothesized to ‘‘irritate’’ the soft palate or pharynx, inhibiting afferent impulses and interrupting the hiccup reflex,1 but the possible molecular and physiological mechanisms underlying their efficacy have not been established. It is largely known that at the level of the peripheral terminal sensory afferents (in this case at the gastric plexus level), external stimuli generate graded potentials that electrically decay along the soma of the sensory cell.16 When the activation threshold of sodium channels at the axon hillock is achieved, this potential is converted into an ‘‘all or nothing’’ signal, giving rise to an action potential. These action potentials self-propagate regardless of the extracellular sodium concentration.16 Briefly, the peripheral sensory cells change the peripheral stimulus into a graded potential, which may in turn be converted into an action potential. The frequency of action potentials represents the intensity and the duration of the peripheral stimulus.16 Therefore, the stronger or longer the peripheral stimulus is, the greater the frequency of action potentials, and the higher the hiccupping frequency and/or intensity. In summary, the peripheral stimulus is converted into a graded potential, and after exceeding the threshold value (between - 40 mV and - 30 mV), it is in turn transformed into an action potential.16 Beyond this value, sodium quickly enters the axon hillock until reaching a value of + 63 mV. Then the afferent stimulus goes up to the hiccup center where it is processed and finally goes down the phrenic nerve to the diaphragm, the external intercostals, the scalene muscles, glottic structures, and the esophagus (efferent stimulus).16 The chemical formula of vinegar is CH3COOH. Vinegar dissociates into CH3COO - + H + when absorbed by the gastric cells.17 We hypothesized that high concentrations of intracellular H + may block or at least reduce the intensity of graded potentials and consequently prevent their transformation into ‘‘all or nothing’’ signals. High H + concentrations have been hypothesized to block sodium entry into the axon hillock by a double competitive mechanism:16,17 (1) the H + ion as well as the Na + ion each have only one positive charge and (2) H + and Na + have comparable atomic dimensions. If there is not enough sodium at the axon hillock, the threshold value will not be reached; therefore, the afferent stimulus will be blocked. Vinegar was found to completely terminate our patient’s hiccups or reduce them in frequency or intensity. It is largely recognized that duration and intensity of the peripheral stimulus influence the amplitude of the graded potential.16 Vinegar-induced high H + concentrations reduce sodium entry in the axon hillock; therefore, the graded potentials are
Author Disclosure Statement
The authors report no conflicts of interest. This report received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. The patient gave oral permission for this report to be published. References
1. Lewis JH. Hiccups: Causes and cures. J Clin Gastroenterol 1985;7:539–552. 2. Calsina-Berna A, Garcia Gomez G, Gonzalez-Barboteo J, et al.: Treatment of chronic hiccups in cancer patients: A systematic review. J Palliat Med 2012;15:1142–1150. 3. Cymet TC: Retrospective analysis of hiccups in patients at a community hospital from 1995–2000. J Natl Med Assoc 2002;94:480–483. 4. Potter J, Hami F, Bryan T, et al.: Symptoms in 400 patients referred to palliative services: Prevalence and patterns. Palliat Med 2003;17:310–314. 5. Porzio G, Aielli, F, Verna L, et al.: Gabapentin in the treatment of hiccups in patients with advanced cancer: A 5year experience. Clin Neuropharm 2010;33:179–180. 6. Walsh D, Donnelly S, Rybicki L: The symptoms of advanced cancer: Relationship to age, gender and perfor-
470
7. 8. 9. 10. 11. 12. 13.
GONELLA AND GONELLA
mance status in 1,000 patients. Support Care Cancer 2000; 8:175–179. Mercadante S, Porzio G, Valle A, et al.: Orphan symptoms in advanced cancer patients followed at home. Support Care Cancer 2013;21:3525–3528. Smith HS: Hiccups. In: Walsh D (ed): Palliative Medicine. Philadelphia, PA: Elsevier Saunders, 2009, pp. 894–898. Marinella MA: Diagnosis and management of hiccups in the patient with advanced cancer. J Support Oncol 2009; 7:122–127,130. Becker DE: Nausea, vomiting and hiccups: A review of mechanisms and treatment. Anest Prog 2010;57:150–157. Moretto EN, Wee B, Wiffen PJ, et al.: Interventions for treating persistent and intractable hiccups in adults. Cochrane Database Syst Rev 2013;1:CD008768. Ratogi RB, Singhai RL: Adrenocorticoids control 5hydroxytryptamine metabolism in the rat brain. J Neurol Trasm 1978;42:63–71. Lee GW, Oh SY, Kang MH, et al.: Treatment of dexamethasone-induced hiccup in chemotherapy patients by methylprednisolone rotation. Oncologist 2013;18:1229– 1234.
14. Kang JH, Hui D, Kim MJ, et al.: Corticosteroid rotation to alleviate dexamethasone-induced hiccup: A case series at a single institution. J Pain Symptom Manage 2012;43:625–630. 15. Gilbar P, McPeherson I: Severe hiccup during chemotherapy: Corticosteroids the likely culprit. J Oncol Pharm Pract 2009;15:233–236. 16. Carbone E: Potenziali d’azione: Genesi, conduzione e propagazione [Action potentials: Origin, propagation and run]. In: Carbone E, Cicirata F, Aicardi G (eds): Fisiologia Dalle Molecole Ai Sistemi Integrati [Physiology from Molecules to Integrated Systems]. Napoli: Edises, 2010, pp. 29–57. 17. Braun WH, Foote CS, Iverson BL: Chimica Organica [Organic Chemistry], 3rd ed. Napoli: Edises, 2006.
Address correspondence to: Silvia Gonella, MSc, RN Department of Public Health and Community Medicine University of Verona Piazzale Antonio Scuro 10 Verona, Italy 37134 E-mail: [email protected]
