The Use of Caffeine Citrate for Respiratory Stimulation in Acquired Central Hypoventilation Syndrome: A Case Series

Acquired central hypoventilation syndrome (ACHS) occurs when the respiratory centers in the brainstem, specifically the medulla oblongata and pons, are injured [1]. It is sometimes referred to as Ondine’s Curse after a Nordic myth about a man who died in his sleep because he needed to actively control his breathing after being cursed by a water nymph [2]. ACHS poses a challenge to intensivists in weaning patients off ventilatory support, as these patients are unable to maintain an adequate minute ventilation due to a reduced respiratory rate which invariably leads to hypoxia and hypercarbia.

Caffeine has been established for the treatment and prevention of apnea of prematurity in preterm neonates [3,4]. Its stimulatory action on the respiratory centres in the brainstem and diaphragm contractility could help alleviate some of the symptoms of central hypoventilation in adults and promote the success of non-invasive ventilation strategies [5]. We describe the successful use of caffeine in 2 patients with ACHS.

The primary area for producing rhythmic synaptic drive for motor neurons controlling respiratory muscles is the central pattern generator located in the brainstem, specifically in the ventrolateral area of the medulla [6]. Destruction to the ventrolateral medullary region results in decreased respiratory drive. If severe, it can be fatal and explains the inability to wean from ventilator support [7]. To date, there is no standard treatment for ACHS besides supportive ICU care. This condition often results in prolonged intubation, mechanical ventilation and ICU stay as well as increased risk of nosocomial infection, leading to increased costs and healthcare resources.

Schrader et al. reported a 52-year-old male who underwent resection of left frontal grade III astrocytoma_, received 500 mg IV caffeine after slow emergence from anesthesia, to facilitate intraoperative language mapping [8]. In a randomized, double blind, placebo-controlled study that involved 60 patients by Gouda et al., it was found that individuals who received caffeine 500 mg had significantly faster time to extubation and fewer post-extubation respiratory complications [9]. In a retrospective study of 151 patients admitted to postanesthesia care unit (PACU), Warner et al. found that intravenous caffeine enhanced the speed of recovery following general anesthesia after a median dose of 150 mg, without adverse cardiac events including tachyarrhythmia or myocardial ischemia [10]. Fong et al. randomized 8 patients to receive IV caffeine at 7.5 mg/ kg or saline and demonstrated caffeine resulted in significantly faster emergence from isoflurane anesthesia [11].

Caffeine is commonly used in neonates for the treatment of apnea of prematurity. It is a neuro-stimulant that stimulates central respiratory drive, increasing medullary respiratory centers sensitivity to carbon dioxide and improving diaphragmatic contractility [12]. It decreases but does not eliminate apnea [13]. Caffeine also provides pain relief when used together with common analgesics [14]. It can be administered via both oral and intravenous routes. It is rapidly absorbed with minimal to no first pass metabolism. The peak plasma concentration usually occurs within 1 hour and its half-life is 5 hours in adults [12]. Therapeutic drug monitoring for caffeine is available but it is not commonly practiced in view of its wide therapeutic index. The desired therapeutic range for caffeine is 3 – 15 mg/L and the expected toxic dose is ≥ 50 mg/L [7]. Symptoms of overdose include tachycardia, restlessness, nausea and vomiting.

Caffeine citrate 20mg/mL solution was prepared by our pharmacy laboratory. Our patient in case 1 was loaded with 1600 mg of caffeine (20mg/kg body weight), maintained on 800mg once daily (10 mg/ kg body weight) while the patient in case 2 was prescribed caffeine 300mg twice daily (10 mg/kg adjusted body weight in view of BMI 35). There was no loading dose administered for the patient in case 2, as she had NGT feeds intolerance prior to caffeine therapy. With a normal gastrointestinal function and ability to tolerate feeding via NGT, the absorption of oral caffeine is likely to be complete. Assuming drug clearance follows that of the general population, the steady state maximum concentration (C_max) and minimum concentration (C_min) are expected to be 17.3 mg/L and 0.6 mg/L, respectively for the patient in case 1. Caffeine serum concentration was estimated to fall within therapeutic range for approximately 12 hours after each maintenance dose. Case 2 patient’s steady state C_max and C_min were expected to be 9.3 mg/L and 1.0 mg/L respectively. Caffeine serum concentration was estimated to fall within therapeutic range for approximately 16 hours a day.

In both patients, apart from the cerebral lesions, other factors causing respiratory depression such as opioids, hypothermia and metabolic conditions were absent. Cerebral inflammation and edema occur with the primary insult [15]. These may cause initial deficits that improve with time [16] due to resolution of inflammation and blood resorption in cases of hemorrhage. It is possible that the increased respiratory drive after caffeine administration could have coincided with the resolution of cerebral inflammation and edema that occurred with the primary insult. However, the time sequence of caffeine administration and ability to be weaned from mechanical ventilation suggests a possible correlation that caffeine facilitated this. These 2 cases have demonstrated the potential role of caffeine treatment in facilitating earlier liberation from mechanical ventilation, reducing ICU length of stay and cost, as well as allowing better utilization of hospital manpower and resources. Besides, it allowed the patient in case 1 to spend quality time with family during his home leave.

We chose caffeine for these 2 cases due to its availability at our institution. Besides caffeine, there are other respiratory stimulants available. These are largely divided into two main classes based on their site of action: brainstem respiratory network and carotid bodies. Table 2 summarizes the different respiratory stimulants that have been studied in human subjects [17]. These studies involved mainly surgical patients who received general anesthesia. In view of the dearth of evidence for caffeine use in the adult ICU, future studies should focus on examining its dosage regimen and efficacy in the treatment of ACHS, as well as conditions associated with depressed GCS in adult patients.

ACHS is frequently associated with prolonged mechanical ventilation. Caffeine citrate can facilitate weaning through its neuro-stimulant effect on the respiratory centers. More randomized controlled trials are required to determine its efficacy.