David Balfe

Improvement in serial cardiopulmonary exercise testing following enzyme replacement therapy in Fabry disease

SummaryBackground. Fabry disease is an X-linked genetic disorder resulting in the accumulation of glycosphingolipids in various organs, leading to exercise intolerance and early mortality. Enzyme replacement therapy (ERT) has recently been approved for use in Fabry patients. Goals of study. To assess baseline cardiopulmonary exercise characteristics in both invasive and noninvasive tests and to study the impact of ERT on exercise. Methods. A total of 15 patients with Fabry disease underwent baseline cardiopulmonary exercise tests. Six patients were randomized 2:1 to receive either ERT or placebo. We performed serial cardiopulmonary exercise tests at baseline and every 3 months over a period of at least 18 months. The baseline test was compared to the last two exercise tests for each patient. Results. Mean age was 32 years. Mean VO2 max was 1.680 ± 0.67 L/min and increased by 0.459 ± 0.64 L/min in the patients receiving ERT. Mean VO2 max was 1.462 ± 0.25 L/min and decreased by 0.116 ± 0.44 L/min in patients on placebo. Mean oxygen pulse (VO2/HR) increased by 1.71 with enzyme, but increased only 0.025 in patients taking placebo. Estimated stroke volume (SV) increased by 10 ml in patients on ERT. Conclusions. In this small cohort, exercise tolerance increased in patients receiving enzyme replacement therapy. Cardiopulmonary exercise testing is a useful test in measuring the response to therapy in Fabry disease patients.

Cardiopulmonary Exercise Testing in Fabry Disease

Background: Fabry disease is a rare X-linked disorder that results from a deficiency in a lysosomal enzyme known as α-galactosidase A, with accumulation of globotriaosylceramide (Gl3). Early manifestations include angiokeratomas, acroparesthesias, and hypohidrosis and may progress to renal failure, cardiac dysfunction, and stroke. Patients exhibit decreased exercise tolerance and often complain of fatigue. Objective: Our study evaluates the cardiopulmonary characteristics in a cohort of Fabry disease patients at rest and during exercise. Methods: Thirty-nine patients with a diagnosis of Fabry disease underwent a health screening history and physical examination, an electrocardiogram, an echocardiogram, pulmonary function testing (spirometry), and a non-invasive cardiopulmonary exercise test. A control group was selected for comparison. Results: Eighteen of the 39 Fabry patients (46%) exhibited a significant decrease in diastolic blood pressure (DBP) during exercise. The average decrease in DBP was 10 mm Hg. The maximum drop in DBP was 44 mm Hg. The drop in DBP was evident in 9 of the 24 female patients (38%). None of the control patients had a significant drop in DBP during exercise. Conclusions: Our finding of a significant decrease in DBP in patients with Fabry disease may explain deficits in exercise tolerance. It is notable that this abnormality is manifested in female patients, even though they are typically not as severely affected as males.

Carboxyhemoglobin and its correlation to disease severity in cirrhotics.

Goal To assess the correlation of serum carboxyhemoglobin (CO-Hb) to severity of liver disease as compared with Model for End Stage Liver Disease (MELD) score, Child Pugh score, and clinical parameters. Background There are 2 sources of carbon monoxide (CO) in humans, exogenous sources include those such as tobacco smoke and inhaled motor vehicle exhaust. The endogenous source is via the heme-oxygenase pathway, in which a heme molecule is broken down into biliverdin with release of an iron (Fe) and CO molecule. Normal serum CO-Hb levels in nonsmokers is 0% to 1.5% and 4% to 9% in smokers. Activity of the heme-oxygenase pathway may be increased in the cirrhotic patient, as measured indirectly by exhaled CO and serum CO-Hb. This may be due to alterations in vascular tone in the splanchnic circulation in cirrhotics that may lead to elevated CO production. One published study also showed that those with spontaneous bacterial peritonitis had higher levels of both CO and CO-Hb. The MELD score uses prothrombin time (INR), creatinine, and bilirubin in the prediction of short-term mortality in decompensated cirrhotics while awaiting liver transplant. Measurement of endogenous CO-Hb may correlate to severity of liver disease. Study Retrospective analysis was done of 113 adult patients who were evaluated for liver transplantation between September 1996 and July 2003 and had pulmonary function testing with CO-Hb as part of their evaluation. We excluded any patients with a history of smoking. Clinical parameters used for comparison included grade of esophageal varices (n=75), spleen size (n=51) measured on abdominal ultrasound or computed tomography scan, aminotransferases, and disease duration. Serum CO-Hb levels were measured from whole blood, sent refrigerated to ARUP laboratories (Salt Lake City, UT) and analyzed via spectrophotometry. Bivariate analysis was performed by means of the Pearson product moment correlation. Results The mean CO-Hb level was 2.1%, which is higher than the expected normal population controls. No correlation was found, however, with MELD score, Child Turcotte Pugh score, or other biochemical or clinical measurements of disease severity. Conclusions Although CO and CO-Hb production may be increased in the cirrhotic patient, in this study no correlation was found to disease severity as measured by the MELD score. Further studies are needed to assess the role of CO in other complications of cirrhosis including infection and circulatory dysfunction.

Airflow limitation and breathing strategy in congestive heart failure patients during exercise.

Background: Congestive heart failure (CHF) patients experience dyspnea on exertion and therefore have decreased exercise tolerance. Objective: This study explores the hypothesis that stable New York Heart Association (NYHA) class III CHF patients without a history of pulmonary disease exhibit airflow limitation with increasing exercise. Methods: We characterized flow limitations and breathing reserves at baseline, during exercise before anaerobic threshold (pre-AT), and after anaerobic threshold (post-AT) in CHF patients and normal subjects. Data were collected in the form of maximal flow volume loops and subsequent tidal flow volume loops at baseline and during exercise. Expiratory flow limitation was expressed as percent of tidal volume that corresponded with overlap of the tidal flow volume loops and maximal flow volume loops during expiration. The area directly between the maximum flow volume loops and the tidal flow volume loops during the expiratory phase is expressed as expiratory flow volume reserve (EFVR). Results: CHF patients experienced expiratory flow limitation during exercise (pre-AT and post-AT) that was significantly increased compared to baseline and to normal subjects at similar exercise levels (CHF, baseline 8.5 ± 7, pre-AT 37 ± 10, post-AT 38 ± 8%, n = 9, p < 0.05). Both CHF patients and normal subjects increased EFVR during exercise, but only the normal subjects increased EFVR to a significantly different value at post-AT exercise levels (normal subjects, 9.5 ± 2, 11 ± 2, 32 ± 4%, n = 7, p < 0.05). Both CHF patients and normal subjects increased end inspiratory lung volume (EILV) during exercise, but only the normal subjects significantly increased EILV at post-AT exercise levels (normal subjects, 49 ± 4, 55 ± 5, 76 ± 4%, p < 0.05). Inspiratory capacity (IC)/forced vital capacity (FVC) ratios were increased in CHF patients compared to normal subjects. However, IC/FVC values did not change during exercise in either group. Conclusions: CHF patients cannot utilize their full respiratory capacity during exercise secondary to expiratory flow limitation and an inability to increase EILV and EFVR.

The inspiratory capacity/total lung capacity ratio as a predictor of survival in an emphysematous phenotype of chronic obstructive pulmonary disease

Background Forced expiratory volume in 1 second (FEV1) grades severity of COPD and predicts survival. We hypothesize that the inspiratory capacity/total lung capacity (IC/TLC) ratio, a sensitive measure of static lung hyperinflation, may have a significant association with survival in an emphysematous phenotype of COPD. Objectives To access the association between IC/TLC and survival in an emphysematous phenotype of COPD. Methods We performed a retrospective analysis of a large pulmonary function (PF) database with 39,050 entries, from April 1978 to October 2009. Emphysematous COPD was defined as reduced FEV1/forced vital capacity (FVC), increased TLC, and reduced diffusing capacity of the lungs for carbon monoxide (DLCO; beyond 95% confidence intervals [CIs]). We evaluated the association between survival in emphysematous COPD patients and the IC/TLC ratio evaluated both as dichotomous (≤25% vs >25%) and continuous predictors. Five hundred and ninety-six patients had reported death dates. Results Univariate analysis revealed that IC/TLC ≤25% was a significant predictor of death (hazard ratio [HR]: 2.39, P<0.0001). Median survivals were respectively 4.3 (95% CI: 3.8–4.9) and 11.9 years (95% CI: 10.3–13.2). Multivariable analysis revealed age (HR: 1.19, 95% CI: 1.14–1.24), female sex (HR: 0.69, 95% CI: 0.60–0.83), and IC/TLC ≤25% (HR: 1.69, 95% CI: 1.34–2.13) were related to the risk of death. Univariate analysis showed that continuous IC/TLC was associated with death, with an HR of 1.66 (95% CI: 1.52–1.81) for a 10% decrease in IC/TLC. Conclusion Adjusting for age and sex, IC/TLC ≤25% is related to increased risk of death, and IC/TLC as a continuum, is a significant predictor of mortality in emphysematous COPD patients.

Reality bites: a case of severe rattlesnake envenomation.

Rattlesnake venoms can cause a wide range of adverse human health effects. However, with the availability of modern antivenin, toxicity can generally be minimized and controlled. We present a rare case of rattlesnake envenomation resulting in severe systemic effects and syndrome relapse. Management considerations and patient course are described in the context of the current literature.

To Treat or to Palliate? A Case of Endocarditis, Severe Sepsis, and Advanced Cancer.

Introduction: One of the biggest challenges in critical care medicine is balancing a patient’s or family’s desires for aggressive therapy with the avoidance of futile care. Patients with noncurable cancer present a specific challenge, as their life expectancy is already limited, and their prognosis is determined by multiple factors, including the type of malignancy, their functional status, and their acute medical issues. Palliative care consultation has been shown to help with this problem by providing clarification of prognosis and goals, symptom management, and discharge planning. The exact role and timing of a palliative care consultation, however, remains unclear. Many physicians only consult palliative care when the decision to withdraw care has already been made. We present a case where early palliative care referral for a patient with metastatic colon cancer and septic shock allowed for collaboration between the intensivists and palliative care physicians during both invasive life-sustaining procedures and eventual comfort care. Initial Presentation: A 56-year-old Caucasian male presented to Cedars-Sinai medical center with a 1-week history of abdominal pain. He had recently been diagnosed with stage IV colon cancer in another hospital and treated with a cycle of unspecified chemotherapy via a peripherally inserted central venous catheter (PICC). No surgery was performed. One week after returning home, the patient developed progressive abdominal pain, nausea, vomiting, fatigue, fever, and a cough. He denied any diarrhea, constipation, or melena. Whereas he had been fully functional at baseline, his fatigue was so profound that he became bedbound. In the Emergency Department, the patient’s vital signs included a temperature of 104 degrees of Fahrenheit, a heart rate of 145/min, a blood pressure of 84/45 mm Hg, and a respiratory rate of 20/min. A physical exam revealed an ill-appearing diaphoretic male with a distended, tender abdomen. His lung examination showed left basilar crackles but no wheezes. His extremities were notable for significant pitting edema and several hemorrhagic bullae bilaterally. A Foley catheter was placed with the return of a small amount of dark-colored urine. There was no PICC line in either right or left upper extremities. His mental status was fully intact. Question #1: What are the differential diagnoses based on the initial history and physical exam? Response: The patient meets criteria for severe sepsis, with the presence of systemic inflammatory response syndrome (SIRS), hypotension, and signs of end organ hypoperfusion. Given his history and physical examination, abdominal etiologies such as cholecystitis, intestinal perforation, acute hepatitis, pancreatitis, mesenteric ischemia, and spontaneous bacterial peritonitis are diagnoses to consider. Thrombotic thrombocytopenic purpura and purpura fulminans may also present similarly. His recent hospitalization puts him at risk of nosocomial infections, including pneumonia and urinary tract infection. Given his recent PICC line placement, he is at risk of developing endocarditis. If he is neutropenic secondary to his recent chemotherapy, he is also susceptible to fungal and viral infections, such as candidiasis, aspergillosis, and cytomegaloviral infection. Noninfectious diagnoses to consider are deep venous thrombosis and pulmonary embolism. Initial Work-up: Laboratory data was significant for a platelet count of 16 000/UL and international normalized ratio (INR) of 2.3. White blood cell (WBC) was 6600/UL with 81% neutrophils and 3% bands. Total bilirubin was 1.8 mg/dL, albumin 2.4 g/dL, alkaline phosphatase 274 U/L, and AST 184 U/L. Lactic acid was 5.6 mmol/L. Complete details of the laboratory results can be found in Table 1. An EKG was notable only for sinus tachycardia and was without ST segment changes or T-wave inversions. A chest x-ray showed a left lower lobe infiltrate with bilateral pleural effusions (Figure 1). A lower extremity Doppler study was negative for deep-vein thrombosis

Cardiopulmonary Exercise Testing in the Evaluation of the Patient with Emphysema

Comprehensive exercise testing offers an opportunity to study the cellular, cardiovascular, and ventilatory systems’ responses simultaneously under controlled conditions (1).