CO2 retention: The key to stopping hiccups

While investigating the mechanisms behind hiccups, our team discovered what could be the sufficient physiological conditions for terminating even persistent cases.


| INTRODUCTION
Current literature offers scant information on mechanisms that cure patients suffering from hiccups, so when our team discovered a reliable method we subjected our breakthrough to rigorous investigation. The mechanism behind our method is simple: hiccups stop when the partial pressure of CO 2 in arterial blood (PaCO 2 ) reaches the same level as that in venous blood (PvCO 2 ), or approximately 50 mm Hg. Theoretically, these conditions will be consistently effective due to the connection to the body's survival instinct (more on this later). Our goal in this article is not | 2341 OBUCHI et al.
to dismiss other methods, but rather to engage in an objective discussion on the physiological conditions that stop hiccups.
In reality, our method is simply a modified version of the paper bag rebreathing method. Paper bag rebreathing, once considered an effective treatment for hyperventilation, has lost its status as a clinical treatment in recent years. 1 However, according to several previous reports, it has been revealed in experiments using felines that CO 2 inhalation suppresses the movements of the muscles associated with hiccups. [2][3][4] This suggests that our method, which simply replaces the paper bag with an airtight plastic bag, could potentially be regarded as an appropriate treatment for hiccups.
This method is likely still regarded by many clinicians as questionable at best due to its resemblance to other similar home remedies and a lack of supporting evidence until now. [4][5][6] We anticipate that the addition of objectively gathered data to the discussion will open the door for consideration of plastic bag rebreathing as a reliable clinical treatment.
We explored what transpires internally during plastic bag rebreathing by employing both volunteers and real hiccup patients to gauge the physiological conditions under which hiccups stop. Using our results, we will discuss the mechanism for stopping hiccups and the supporting theory behind our plastic bag rebreathing method.

| MATERIALS AND METHODS
Currently there are only seven clinical records of patients with persistent hiccups cured by the plastic bag rebreathing method at our institution. However, we performed these cases using techniques based on years of empirical evidence, which can be summed up in the following three points: (1) Experiment 1: the volunteer held a CO 2 sensor in his mouth, and a 20 L plastic bag filled with air was placed over his head with an airtight seal around the neck. The EtCO 2 meter measured the value of CO 2 partial pressure in the expiratory gas (EtCO 2 ) as well as that in the inspiratory gas (InspCO 2 ). A pulse oximeter was attached to his finger to measure blood oxygen level (SpO 2 ) and heart rate (HR). Rebreathing in the plastic bag was to be continued for either 10 minutes, until SpO 2 went down below 90%, or until the volunteer gave up. The EtCO 2 , InspCO 2 , SpO 2 and HR were measured every 30 seconds until the end of the experiment. The measuring instruments for EtCO 2 , InspCO 2 , SpO 2 and HR were an EtCO 2 meter (Microstream™; Medtronic, Minneapolis) and a multi-monitoring system (DS-8200; FUKUDA DENSHI, Tokyo, Japan). Incidentally, it is generally thought that EtCO 2 can be considered a virtual representation of PaCO 2 . (2) Experiment 2: All conditions were the same as Experiment 1, but we cut a 1.5 × 1.5 cm hole in the plastic bag. (3) Experiment 3: All conditions were the same as Experiment 1, but we filled the airtight plastic bag with 100% oxygen instead of air. III. After successfully completing the three experiments, we enlisted the help of two real patients with persistent hiccups to observe when hiccups stopped using the same protocol as Experiment 1. The first patient was a male in his fifties who repeatedly suffered from persistent hiccups due to chemotherapy; the second patient was a male in his sixties who had suffered from persistent hiccups for 1 month. We used video recording technology to demonstrate the successful treatment of an actual patient with hiccups. The study protocol was examined and approved by our Research Review Board (No. 16-1010, approved on Oct. 31, 2016). We obtained written permission from the patients to include anonymous information in our study, with the understanding that the patient's privacy would be completely protected. Video footage of the first patient is posted online as a video on Youtube7 (first patient in the video).

| RESULTS
I. Details from two of the seven cases at our institution in which we employed the Bucci Method are presented below. Case 1: In September 2016, a 67-year-old male who suffered from persistent hiccups for 7 days was referred to our clinic, although metoclopramide was repeatedly injected at the former clinic. He had tried various remedies listed on the Internet, such as sticking fingers in both ears, pressing on his diaphragm, alternating between deep breaths and holding his breath, rebreathing into a paper bag and so on-all in vain. The Bucci Method was performed using a 20 L air-filled plastic bag. After 2-3 minutes, the persistent hiccups were completely resolved without any discomfort. Case 2: In November 2017, an 83-year-old healthy male who suffered from persistent hiccups for eight days was referred to our clinic. After administrating oxygen using an O 2 mask with 3 L/min for about three minutes, a 20 L airfilled plastic bag was employed using the Bucci Method. It took 4 minutes 51 seconds until the hiccups stopped. SpO 2 showed 100% at the start of the manoeuvre and 98% at the time the hiccups stopped. The two cases cited above imply that the conditions 2-4 minutes in to the manoeuvre hold the key to stopping hiccups effectively. In both cases the CO 2 level in the blood most likely increased, and Case 2 suggests that the O 2 level in the blood has limited, if any, influence on the phenomenon.
II. The results of the three plastic bag rebreathing experiments were as follows: (1) Experiment 1 was stopped after 3 minutes 40 seconds when the volunteer gave up (Figure 1). InspCO 2 gradually increased from the beginning, reaching almost the same level as EtCO 2 at 1 minutes 30 seconds, whereupon both InspCO 2 and EtCO 2 continued to increase at an even pace before reaching 56 mm Hg. The duration from start to when EtCO 2 reached 50 mm Hg was 2 minutes 30 seconds. (2) Experiment 2 was finished in the prerequisite time of 10 minutes even ( Figure 2). InspCO 2 gradually increased over 2 minutes but maintained a steady value of less than 40 mm Hg thereafter. EtCO 2 also gradually increased over 2 minutes, at which point it maintained an almost constant value of 47 mm Hg. InspCO 2 levels always remained below those of EtCO 2 during this experiment, and the gaps between InspCO 2 and EtCO 2 were continuously identifiable. At the same time, SpO 2 showed an almost straight line with a constant value of 97%.

| DISCUSSION
We stumbled upon the observation that acute CO 2 retention induced by plastic bag rebreathing resolves persistent hiccups. This discovery is actually quite similar to the results achieved by other Japanese researchers during experiments using felines when they indicated that CO 2 inhalation suppresses the movements of the muscles associated with hiccups. 2,3 Although formal medical treatments such as metoclopramide injections are recommended for persistent hiccups, 4,8,9 our plastic bag rebreathing method is effective even for patients with metoclopramide-resistant hiccups. Initially we thought that mild hypercapnia would be sufficient in stopping hiccups, but after many failed experiments we gradually realized that for a stable outcome it is necessary to accumulate a substantial level of CO 2 inside the body. To clarify the necessary conditions, we conducted these experiments using a plastic bag to deliberately induce hypercapnia. As mentioned earlier, Experiment 1 revealed conditions leading to a successful case, and Experiment 2 simulated conditions that would cause a failed case. In Experiment 2, the volunteer was able to continue the plastic bag rebreathing for 10 minutes without any discomfort. On the other hand, in Experiment 3, even though SpO 2 was kept at 100%, the volunteer could not continue the experiment for the same duration because of overheating. These three results demonstrate a number of important facts in human physiology: a high level of CO 2 retention in our bodies can act as a trigger causing discomfort, such as our reaction to unbearable heat. However, before jumping to conclusions in defining what level of CO 2 should be regarded as the threshold, further investigation into human physiology was necessary.
In what way did Experiment 2 differ from Experiments 1 and 3? Airtightness. Experiment 2 demonstrated that our respiratory ventilation system is so efficient that it can easily discharge CO 2 even when given only a small slit for transference. Even the small gap between EtCO 2 and InspCO 2 indicates that PaCO 2 is still smaller than PvCO 2 ; in other words, there is a gap between PvCO 2 and PaCO 2 [Δ(PvCO 2 -PaCO 2 ) > 0 mm Hg], and as long as Δ(PvCO 2 -PaCO 2 ) is larger than zero, an individual can easily withstand hypercapnia for an extended period. But it is clear in Experiments 1 and 3 that Δ(PvCO 2 -PaCO 2 ) lowered to zero at some point, because CO 2 could not be discharged. Since PvCO 2 is normally 48 mm Hg, the point at which Δ(PvCO 2 -PaCO 2 ) became zero must be when EtCO 2 as well as InspCO 2 reached at least 48 mm Hg.
Incidentally, when hiccups stopped in two actual patients, EtCO 2 as well as InspCO 2 was 50 mm Hg in one patient and 53 mm Hg in the other. As we anticipated above, PaCO 2 reached at least 48 mm Hg in both patients at the time hiccups stopped. PaCO 2 reaching approximately 50 mm Hg must play a key role in stopping hiccups.
There are two kinds of blood gas sensors in the human body. 10,11 The central chemoreceptors, located in the medulla, detect high levels of CO 2 in the blood, while the carotid bodies detect low levels of O 2.
10,11 The central chemoreceptors are considerably more sensitive than the carotid bodies, so even small increases in CO 2 produce large increases in ventilation volume. 10 According to our rebreathing results with an air-filled 20 L plastic bag, 2 minutes in to the experiment the SpO 2 level remained around 99%; however, InspCO 2 and EtCO 2 increased to about 50 mm Hg. In such conditions, the central chemoreceptors must have worked intensely while the carotid bodies remained quiet. 10,11 It is assumed that hiccups are induced from afferent signals to the medulla through branches of the glossopharyngeal nerve distributed along the pharynx, 2,12 and the signals strike a 'hiccup centre' likely located in the medullary reticular F I G U R E 3 Results of experiment 3. The volunteer could not continue the plastic bag rebreathing for 10 minutes, even though SpO 2 levels remained at a constant 100%. EtCO 2 , End-tidal CO 2 level; InspCO 2 , Inspiration CO 2 level; SpO 2 , Peripheral capillary oxygen saturation; HR, Heart rate formation, 12,13 although the exact location has not yet been identified (Figure 4). The hiccup centre, once activated by the afferent signals, must then emit its own abnormal yet intermittent signal near the medullary inspiratory centre, in a pattern much like cardiac arrhythmia. Usually, the medullary inspiratory centre is controlled by the pneumotaxic centre located in the pons. 14 However, this rogue signal can directly enter the medullary inspiratory centre without interference from the pneumotaxic centre of the pons. It is at this point that hiccups begin. Speculation on why our manoeuvre is effective in curing hiccups is outlined in Figure 5. Our method produces conditions with high levels of both PaCO 2 and PvCO 2 (over 50 mm Hg) within a few minutes. Under these conditions, the central chemoreceptors would send strong alerts to the cerebrum that breaths have stopped and that proper measures should be taken immediately to survive. 10,11 The alerts would suppress any opposing signals from the medulla and the pons, going straight to the muscles and nerves related to respiration to normalize breaths for survival. Eventually, the hiccup centre likely located in the medulla would also be suppressed, 2,12,13 thereby resolving the hiccup problem.
What does it mean when Δ(PvCO 2 -PaCO 2 ) becomes zero ( Figure 6)? We believe it represents the moment the brain senses that suffocation will occur despite high levels of O 2 remaining in an individual's body. Under such conditions the brain will emit a stress signal to escape from the situation while the remaining O 2 is still sufficiently high. This leads us to believe that the high level of CO 2 retention, which is represented when both PvCO 2 and PaCO 2 exceed approximately 50 mm Hg, can trigger hiccups to stop. Since this reaction originates from our survival instinct, such conditions would theoretically terminate any and all hiccups without discrimination.
It is certainly understandable that clinical practitioners might be reluctant to introduce the Bucci Method because of the fear of accidental suffocation. Although our results demonstrate that a safe level of O 2 still remains in the blood at the time hiccups stop, we understand the importance of removing this fear for both clinicians and patients alike. One way this can be achieved is to administer O 2 to patients before starting treatment.
We believe our findings regarding the definitive conditions for stopping hiccups are a new discovery. Although it might be difficult at first to regard the Bucci Method as a serious option for treatment, understanding the correlation between the body's survival instincts and stopping hiccups could open new horizons in our understanding of human physiology.