Doxapram chemical structure
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Doxapram

Doxapram hydrochloride (marketed as DopramĀ®) is an analeptic agent (a stimulant of the central nervous system). Administered intravenously, doxapram stimulates the respiratory rate, leading to an increase in tidal volume. more...

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Mode of action

Doxapram stimulates chemoreceptors in the carotid arteries. This stimulates, indirectly, the respiratory centre in the brain stem.

Presentation

Doxapram is a white to off-white, odorless, crystalline powder that is stable in light and air. It is soluble in water, sparingly soluble in alcohol and practically insolible in ether. Injectable products have a pH from 3.5-5. Benzyl alcohol or chlorobutanol is added as a preservative agent in the commercially available injections.

Uses

Doxapram is used in intensive care settings to stimulate the respiratory rate in patients with respiratory failure.

It is equally effective as pethidine in suppressing shivering after surgery (Singh et al 1993).

Side effects

High blood pressure, tachycardia (rapid heart rate), tremor, sweating and vomiting may occur. Convulsions have been reported. It cannot be used in patients with coronary heart disease, epilepsy and high blood pressure. It is also contraindicated in newborns and small children, mainly due to the presence of benzyl alcohol.

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Central alveolar hypoventilation syndrome with gastroesophageal reflux - Ondine's curse
From CHEST, 9/1/96 by Shin-ichi Takeda

Congenital central hypoventilation syndrome (Ondine's curse) is a rare disorder with lack of automatic control of ventilation during sleep. We have reported a case of Ondine's curse in a patient who underwent Nissen's fundoplication for gastroesophageal reflux (GER) at age 5 months. Ventilatory challenge test during sleep was done to confirm central alveolar hypoventilation. This female patient, without cor pulmonale, was a good candidate for diaphragm pacing. Thus, the patient underwent implantation of a diaphragm pacer at age 3 years; she had required mechanical ventilation since birth. Diagnosis, pathogenesis, and problems in the setting of diaphragm pacing for an infant are discussed. (CHEST 1996; 110:850-52)

Key words: congenital central alveolar hypoventilation; diaphragm pacing; gastroesophageal reflux

Abbreviations: ET=endothelin; GER=gastroesophageal reflux; LES=lower esophageal sphincter; NREM=nonrapid eye movement

Congenital central hypoventilation syndrome, so-called Ondine's curse, is an extremely rare disorder of ventilation control,[1-5] characterized by hypoventilation during sleep. To our knowledge, only 50 cases have been reported to date in the English-language literatures. This peculiar syndrome has been believed to be caused presumably by congenital failure of the central automatic system.[3-7] This report describes 1 case of a 3-year-old infant with Ondine's curse, who underwent Nissen's fundoplication for gastroesophageal reflux (GER), and finally underwent implantation of a diaphragm pacemaker:

CASE REPORT

A full-term female infant weighing 2,860 g was the product of a normal pregnancy and vaginal delivery. After delivery, the baby cried immediately and had an Apgar score of 9/10. During the first 8 h of her life, the infant experienced apneic episodes associated with cyanosis while sleeping. Results of laboratory examination were normal. Chest radiographs showed neither cardiomegaly nor pulmonary disease, and skull radiographs, cranial CT, and EEG were normal. Because cyanosis persisted without any improvement by medical treatment, the infant was intubated and placed on a regimen of mechanical ventilation on the first day of her life. The infant did well when awake; however, mechanical ventilatory support was needed when she was sleeping. During the next 2 months, she received therapeutic trials with caffeine, progesterone, thyroxine, and oral doxapram for the sake of respiratory shmuli. None of these drugs were successful in improving sleep apnea. When she was 4 months of age, a tracheostomy was created, but ventilation was entirely normal while awake. Furthermore the parents gradually became aware of vomiting usually during sleep. Under a diagnosis of GER, Nissen's fundoplication was performed when she was 5 months old; thereafter this symptom improved.

At 3 years of age, the patient was referred to our hospital for diaphragm pacer implantation. The patient was evaluated by measuring end-tidal [O.sub.2] and C[O.sub.2] (RM300 Minato Medical Science Ltd; Osaka, Japan) and ventilatory movement by respiratory inductive plethysmograph (Respigraph; NIMS; Miami Beach, Fla). Soon after she fell sleep, electrodes for monitoring extraocular movements were attached and polygraphic recording was begun.[5,7] Long apnea persisted associated with oxygen desaturation with hypercapnea during quiet sleep (non[NREM]). During active sleep (REM), small irregular respiration was noted 10 to 15 s after interruption of the mechanical ventilation, followed by spontaneous arousal. Based on these findings, we have confirmed the diagnosis of congenital central hypoventilation syndrome. The patient was doing well when awake in room air, and an echocardiogram showed no evidence of pulmonary hypertension. Phrenic nerve stimulation test revealed normal conduction time and satisfactory diaphragm excursion. Implantation of diaphragm pacer was thus indicated and surgery was done at when the patient was 3 years, 1 month old.

When the patient was under general anesthesia, pacing electrodes were attached to the intrathoracic part of the bilateral phrenic nerves through third intercostal thoracotomy. Receivers were implanted in the subcutaneous pocket made on the wall of the abdomen. We applied four pole nerve electrodes with sequential stimulation system (Astrostim: Atrotech Co., Tampere, Finland) introduced by Talonen et al,[8] which have been widely used recently.[8-10] Bilateral diaphragm pacing was initiated on the 14th postoperative day without any problem while sleeping. In the postoperative periods, manometric study and upper GI series revealed slight residual GER as shown in Figure 1.

Trials for removal of the tracheostomy tube were unsuccessful due to upper airway obstruction during pacing. Except for a minor complication of wire breakage, the diaphragm pacing was uneventful, and the patient was discharged from the hospital and continued electrophrenic respiration at home.

DISCUSSION

Congenital central hypoventilation (Ondine's curse) is a rare and poorly understood condition; this disorder is believed to be due to a lack of ventilatory response during sleep. No specific etiologic anatomic abnormalities have been identified thus far in these patients.[2-5,7] Usually ventilation is normal in these patients when they are awake, but it becomes markedly depressed or lost during sleep, particularly in REM periods.[5,7] According to the studies described by Paton et al,[6] hypoxic and hypercapnic ventilatory responses were also impaired even in the awake state, and actual normal ventilation can be maintained by behavioral control.

The most common associated anomaly is Hirshsprung's disease, which appeared in 17 cases,[9,11,12] and GER was also reported in 1 case.[12] In this patient, combination with GER was apparent during sleep and this combination seemed to be rare. In terms of motor control, lower esophageal sphincter (LES) muscle shares a similar neural pathway with the crural part of the diaphragm. Therefore, contraction of the diaphragm exerts an important sphincteric action at the LES, serving as an antireflux barrier.[13] One possible explanation for GER with Ondine's curse is that relaxation of the LES as well as the diaphragm might coexist during sleep whether apparent or subclinical.

A high incidence with an associated anomaly named as Ondine-Hirshsprung syndrome[12] has not been fully explained. Hirshsprung's disease is generally considered to be a result of impaired migration of neural crest cells during development. Recent dramatic progress in molecular biology has provided an insight for explanation of such congenital disorders. Endothelin-1 (ET-1), discovered as a vasoconstrictive peptide having various actions on circulation, has been found to play an important role in development.[14,15] ET-1 knockout mice showed craniofacial anomaly and died of respiratory failure due to the defect of central respiratory control.[14] However, all the mice that were ETB receptor (ETB) knockout exhibited a similar anatomic feature with Hirschsprung's disease;[15] and this disorder has been explained as a defect of neural crest migration during development due to the genetic defect of ETB receptor. We speculate that Ondine-Hirshsprung syndrome maybe caused by the genetic disruption of an ET system, and further molecular biological studies are needed to elucidate the mechanism of Ondine's curse.

In patients with sleep apnea, prolonged mechanical ventilation is hazardous and difficult to accomplish at home. Diaphragm pacing during sleep is a more favorable treatment in terms of maintaining physiologic respiration.[1-3,7,9,10] In infants, unilateral pacing is not recommended because of inadequate ventilation.[1,2,9,10] To minimize phrenic nerve damage, four-pole sequential pacing[8] has been reported to be an improved pacing system, so we applied it for this patient. During diaphragm pacing, the tracheostomy had to be left because of upper airway obstruction, which was probably due to the absence of laryngeal muscle activation without central stimulus.[16,17]

One other case of Ondine's curse with GER is reported with discussion of possible pathogenesis and therapeutic yield.[12]

REFERENCES

[1] Hunt CE, Matalon 8v, Thompson TR, et al. Central hypoventilation syndrome experience with bilateral phrenic nerve pacing in three neonates. Am Rev Respir Dis 1978; 118:23-8

[2] Ruth v, Pesonen E, Raivio KO. Congenital central hypoventilation syndrome treated with diaphragm pacing. Acta Pediatr Scand 1983; 72:295-97

[3] Wells HH, Kattwinkel J, Morrow JD. Control of ventilation in Ondine's curse. J Pediatr 1980; 96:865-67

[4] Oren J, Kelly DD, Shannon DC. Long-term follow-up of children with congenital central hypoventilation syndrome. Pediatrics 1987; 80:375-80

[5] Guilleminault C, McQuitty J, Ariagno RL, et al. Congenital central hypoventilation syndrome in six infants. Pediatrics 1982; 70:684-94

[6] Paton JY, Swaminathan S, Sargent CW, et al. Hypoxic and hypercapnic ventilatory responses in awake children with congenital central hypoventilation syndrome. Am Rev Bespir Dis 1989; 140:368-72

[7] Yasuma F, Nomura H, Sotobata I, et al. Congenital central hypoventilation (Ondine's curse): a case report and review of the literature. Eur J Pediatr 1987; 146:81-3

[8] Talonen PP, Baer GA, Hakkinen V, et al. Neurophysiological and technical considerations for the design of an implantable phrenic nerve stimulator. Med Biol Eng Comput 1990; 28:31-7

[9] Elageole H, Adorph VR, Davis GM, et al. Diaphragmatic pacing in children with congenital central hypoventilation syndrome. Surgery 1995; 118:25-8

[10] Weese-Mayer DE, Morrow AS, Brouillette RT, et al. Diaphragm pacing in infants and children: a life-table analysis of implanted components. Am Bev Respir Dis 1989; 139:974-79

[11] El-Halaby E, Coran AG. Hirchsprungs disease associated with Ondine's curse: report of three cases and review of the literature. J Pediatr Surg 1994; 29:530-35

[12] Verloes A, Elmer C, Lacombe D, et al. Ondine-Hirshsprung syndrome (Haddad syndrome) further delineation m two cases amd review of the literature. Eur J Pediatr 1993; 152:75-7

[13] Mittal RK, Rochester DF, McCallum BW. Electrical and mechanical activity in the human lower esophageal sphincter during diaphragmatic contraction. J Clin Invest 1988; 81:1182-89

[14] Kurihara Y, Kurihara H, Suzaki H, et al. Elevated blood pressure and craniofacial abnormalities in mice deficient in endothelin-1. Nature 1994; 368:703-10

[15] Hosoda K, Hammer RE, Richardson JA, et al. Targeted and neural (Piebald-Lethal) mutations of endothelin-B receptor gene produce megacolon associated with spotted coat color in mice. Cell 1994; 79:1267-76

[16] Glenn WOOL, Gee JBL Cole DDR, et al. Combined central alveolar hypoventilation and upper airway obstruction: treatment by tracheostomy and diaphragm pacing. Am J Med 1978; 64: 50-60

[17] Olson TS, Woodson GE, Heldt GP. Upper airway function in Ondine's curse. Arch Otolaryngol Head Neck Surg 1992; 118:310-12

(*) From the First Department of Surgery, Osaka University Medical School (Drs. Takeda, Fujii, and Matsuda), Department of Pediatric Surgery, Kure National Hospital (Dr. Kawahara), and Department of Surgery, Ootemae Hospital (Dr. Nakahara), Osaka, Japan. Manuscript received January 23, 1996, revision accented March 13. Reprint requests: Dr. Takeda, First Department of Surgery, Osaka University Medical School, 2-2 Yamadaoka, Suita City, Osaka 565, Japan

COPYRIGHT 1996 American College of Chest Physicians
COPYRIGHT 2004 Gale Group

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