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Persistent Severe Hypocapnia and Alkalemia in a 40-Year-Old Woman* FREE TO VIEW

Chia-Hsuin Chang, MD; Ping-Hung Kuo, MD; Chih-Hung Hsu, MD; Pan-Chyr Yang, MD, PhD, FCCP
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*From the Departments of Internal Medicine (Drs. Chang, Kuo, and Yang) and Oncology (Dr. Hsu), National Taiwan University Hospital, Taipei, Taiwan.

Correspondence to: Ping-Hung Kuo, MD, Department of Internal Medicine, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei 100, Taiwan.



Chest. 2000;118(1):242-245. doi:10.1378/chest.118.1.242
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A 40 -year-old woman with previously diagnosed non-Hodgkin’s lymphoma was admitted to the ICU because of a 2-day history of fever, hypotension, and shortness of breath. The patient denied headaches, vomiting, or blurred vision. Three years earlier, she had first presented for treatment with a mass in her right breast that proved to be a diffuse, large, B cell-type lymphoma. Complete remission was achieved after combination chemotherapy. Unfortunately, the patient was unable to undergo a stem-cell transplantation because intermittent fever, chills, and progressive dyspnea developed 2 weeks after chemotherapy, before peripheral stem cells could be harvested.

The patient was alert but in marked respiratory distress, with a respiratory rate of up to 35 breaths/min. BP was 80/50 mm Hg; pulse, 120 beats/min; and body temperature, 38.8°C. The neck was supple. The jugular veins were not distended. The chest was symmetrically expanded, with clear breath sounds. The other physical findings and neurologic examinations were unremarkable.

The chest radiograph was normal. Results of laboratory tests were as follows: leukocytes, 1.53 × 103/μL; hemoglobin, 10.6 g/dL; platelet count, 179 × 103/μL; potassium, 2.9 mEq/L; magnesium, 0.62 mmol/L; and serum lactate level, 6.6 mmol/L (normal, < 2 mmol/L). The arterial blood gases with the patient receiving O2, 3 L/min, by nasal cannula revealed: pH of 7.65; Pao2, 184.9 mm Hg; Paco2, 9.7 mm Hg; bicarbonate, 11.1 mEq/L; and base deficit, − 7.8 mEq/L.

In the ICU, the patient’s BP normalized after fluid therapy, and the fever subsided after the use of granulocyte-colony stimulating factor and antibiotics. The lactate level was within normal limits 2 days later. Nevertheless, the patient’s hyperventilation persisted (Table 1 ), with a respiratory rate that was maintained at 40 breaths/min. The patient’s breathing did not slow during deep sleep or after being sedated with oral flunitrazepam, 1 mg bid, or alprazolam, 1 mg tid. An MRI of the brain (Fig 1 ) was obtained.

Question:How would you confirm your suspected diagnosis, and how would you manage the patient’s hyperventilation?

Diagnosis: Central neurogenic hyperventilation due to lymphomatous involvement of the CNS

Central neurogenic hyperventilation (CNH) was defined by Plum and Swanson in 1959 as a syndrome of decreased Paco2, elevated Pao2, and respiratory alkalosis in the absence of radiographic evidence of pulmonary congestion. CNH is usually seen in deeply comatose patients who have serious CNS injuries due to head trauma, stroke, and infection. Tumors of the CNS, however, can also produce CNH. Patients with tumor-induced CNH may be awake because the reticular-activating system is not affected by the tumor in the early stages of the condition. To our knowledge, 18 cases of tumor-induced CNH have been reported in the literature. Among these patients, nine had primary CNS lymphoma, with the most frequently involved site being the pons.

There are at least three centers for the control of rhythmic breathing within the CNS: the medulla center, the pontine apneustic center, and the pontine pneumotaxic center. The medullary center is the main coordinating center of breathing, sending efferent impulses. The apneustic center in the pons acts on the medulla to promote deep and prolonged inspiration, whereas the pneumotaxic center inhibits inspiration. It has been postulated that the damaged medial pontine structures might result in disconnection of inhibitory pathways from the respiratory center in the medulla. Some investigators have attempted to explain this phenomenon by the associated changes in pH and lactate concentration of the cerebrospinal fluid, but their relationship with abnormal respiratory drive has not yet been confirmed.

Hypocapnia per se may induce enhanced net production of lactic acid when intracellular pH increases sufficiently to stimulate 6-phosphofructokinase activity of the Kreb’s cycle enzymes. Alkalosis also alters the electrical charge of serum albumin, which leads to an increase in anionic albumin. These changes contribute to the high anion gap that hyperventilating patients may demonstrate, as observed initially in this patient.

This patient’s presentation and initial arterial blood gas data on day 1 might suggest that she had a marked respiratory alkalosis (Paco2, 9.7 mm Hg) in compensation for a metabolic acidosis (bicarbonate, 11.0 mEq/L; anion gap, 20 mEq/L). The severity of the alkalemia (pH, 7.65), however, argued against this mechanism because this degree of overcompensation for metabolic acidosis should not occur under physiologic conditions. Moreover, the normal anion gap on day 3 and thereafter indicated that metabolic acidosis was an unlikely cause of the patient’s persisting tachypnea. Other causes of hyperventilation were unlikely considering that sepsis had been treated, and no evidence of severe anemia, hypoxia, salicylate intoxication, pulmonary disease, or hepatic failure existed.

The persistence of the patient’s hyperventilation during deep sleep and sedation suggested the presence of a CNS lesion causing ongoing stimulation and/or disinhibition of her respiratory center. Therefore, an MRI of the brain (Fig 1) was performed, which demonstrated a small mass lesion in the left medial temporal lobe and suspicious leptomeningeal enhancement over both parietal regions. A lumbar puncture with cytologic examination of the cerebrospinal fluid demonstrated lymphoma cells, which supported the diagnosis of CNH due to lymphomatous involvement of the CNS.

Most patients with CNH are supported by mechanical ventilation and managed with paralytic agents to control their hyperventilation until more specific therapy for the CNS lesions can take effect. Unfortunately, CNH usually ends fatally in a few weeks, although some patients may respond to brain irradiation or systemic chemotherapy.

The present patient received salvage chemotherapy with BD-HDMA (carmustine, dexamethasone, high-dose methotrexate with leucovorin rescue, and cytosine arabinoside). IV infusion of morphine, 5 mg q6h; midazolam, 3 μg/kg/min; and propofol, 15 μg/kg/min, were effective in suppressing her respiratory rate to 20 to 25 breaths/min, without the use of neuromuscular blockade or mechanical ventilation (Table 2 ). She remained arousable, and her hyperventilation gradually resolved within 1 week, enabling complete withdrawal of all respiratory suppressants.

1. Consider CNH when patients have persistent hyperventilation in the absence of other etiologic factors.

2. CNS lymphoma is the most common etiology of CNH. Patients with suspected CNH should undergo brain imaging studies and lumbar puncture.

3. Midazolam and propofol infusion may control CNH-induced tachypnea before definitive therapy becomes effective. Some patients may require mechanical ventilation and the use of neuromuscular blocking agents.

Table Graphic Jump Location
Table 1. Resets of Arterial Blood Gases After Admission to ICU
Table Graphic Jump Location
Table 2. Serial Data of Arterial Blood Gases After ICU Management
* 

With patient breathing room air.

Krendel, DA, Pilch, JF, Stahl, RL (1991) Central hyperventilation in primary CNS lymphoma: evidence implication CSF lactic acid.Neurology41,1156-1157
 
Pauzner, R, Mouallem, M, Sadeh, M, et al High incidence of primary cerebral lymphoma in tumor-induced central neurogenic hyperventilation.Arch Neurol1989;46,510-512. [CrossRef] [PubMed]
 
Plum, F, Swanson, AG Central neurogenic hyperventilation in man.Arch Neurol Psychiatry1959;81,535-549
 
Schlichtig, R, Grogono, AW, Severinghaus, JW Current status of acid-base quantitation in physiology and medicine.Anesth Clin North Am1998;16,211-234. [CrossRef]
 
Schlichtig, R, Grogono, AW, Severinghaus, JW Human Paco2and standard base excess compensation for acid-base imbalance.Crit Care Med1998;26,1173-1179. [CrossRef] [PubMed]
 
Shibata, Y, Meguro, K, Narushima, K, et al Malignant lymphoma of the central nervous system presenting with central neurogenic hyperventilation.J Neurosurg1992;76,696-700. [CrossRef] [PubMed]
 

Figures

Tables

Table Graphic Jump Location
Table 1. Resets of Arterial Blood Gases After Admission to ICU
Table Graphic Jump Location
Table 2. Serial Data of Arterial Blood Gases After ICU Management
* 

With patient breathing room air.

References

Krendel, DA, Pilch, JF, Stahl, RL (1991) Central hyperventilation in primary CNS lymphoma: evidence implication CSF lactic acid.Neurology41,1156-1157
 
Pauzner, R, Mouallem, M, Sadeh, M, et al High incidence of primary cerebral lymphoma in tumor-induced central neurogenic hyperventilation.Arch Neurol1989;46,510-512. [CrossRef] [PubMed]
 
Plum, F, Swanson, AG Central neurogenic hyperventilation in man.Arch Neurol Psychiatry1959;81,535-549
 
Schlichtig, R, Grogono, AW, Severinghaus, JW Current status of acid-base quantitation in physiology and medicine.Anesth Clin North Am1998;16,211-234. [CrossRef]
 
Schlichtig, R, Grogono, AW, Severinghaus, JW Human Paco2and standard base excess compensation for acid-base imbalance.Crit Care Med1998;26,1173-1179. [CrossRef] [PubMed]
 
Shibata, Y, Meguro, K, Narushima, K, et al Malignant lymphoma of the central nervous system presenting with central neurogenic hyperventilation.J Neurosurg1992;76,696-700. [CrossRef] [PubMed]
 
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