vol VIII no2, 15 april 2002

                                         STEROID RESISTANT ASTHMA 

     Chronic asthma is an eminently steroid responsive disease. When patients show no response to steroids or require high doses of steroids for asthma control, they require a detailed evaluation of many conditions which includes steroid resistant asthma.

     Steroid resistant asthma is a diagnosis of exclusion. If true steroid resistance is proven, steroids have to be stopped and alternative anti inflammatory therapy be instituted.

 Causes of poor response to steroids are:

1.        Wrong diagnosis of asthma or associated/ complicating conditions with asthma such as Allergic bronchopulmonary aspergillosis (ABPA), gastroesophageal reflux disease (GERD), postnasal drip and obstructive sleep apnoea (OSA).

2.        Insufficient dose of steroids reaching airways.

3.        Continuing exposure to sensitizing agents.

4.        Asthma inducing drugs like beta blockers or asprin.

5.        Excessive use of beta- 2 agonists.

 Definition of steroid resistant asthma

Those patients with baseline, morning pre- bronchodilator FEV1 < 70-80% of predicted who improve significantly with beta agonists but by < 15% after 40 mg prednisolone for 14 days are defined as having steroid resistant asthma.

 

Types of steroid resistant asthma

 TYPE I RESISTANCE: is a relative steroid resistance characterized by an increased Kd (dissociation constant) of the steroid receptors, leading to a decreased affinity of the receptors to steroid. This reduced affinity is limited to T- cells and as non T- cells have a normal affinity, these patients are prone to side effects of the steroids. Patients with Type I resistance become sensitive to steroids after a brief period of withdrawl of steroids or if higher doses of steroids are used.

 TYPE II RESISTANCE: this is a complete steroid resistance which is analogous to primary cortisol resistance. These patients have a reduced number of steroid receptors. These patients donot respond to even large doses of steroid and do not experience steroid side effects. 

Approach to steroid resistant asthma

 1.       Rule out alternative diagnoses or associated illnesses

Adults

                Vocal cord dysfunction                                                      Hyperventilation  syndrome

                Allergic bronchopulmonary                                               Endobronchial obstruction

                aspergillosis (ABPA)                                                          Factitious asthma

                COPD                                                                                     Gastroesophageal reflux

                Postnasal drip                                                                       disease (GERD)

                Obstructive sleep apnea

 

Children

                Foreign body aspiration                                                     Tracheobronchomegaly

                Cystic fibrosis                                                                      Alpha 1 antitrypsin  deficiency

                Bronchiolitis obliterans                                                       Vocal cord dysfunction

 

2.       Assure that adequate doses of steroids reach the airway

v      Optimize the dose of steroids

v      Proper technique of inhaler use should be reinforced

v      Ensure good compliance to treatment

in case of oral steroids, rule out poor gastrointestinal absorption (concomitant antacid, cholestyramine, charcoal therapy) and rapid eleminination (concomitant anticonvulsant therapy)

Treat local side effects of steroids 

v       Terminate the exposure to allergens at home in the work place. Rule out the aggravating factors such as GERD, OSA, rhinitis, drug intake (aspirin, beta blockers, excessive beta agonist use)

v       Ensure a strict management plan for six months with objective methods of control such as spirometry on office visits and routine peak flow monitoring.

v      Maximise anti - inflammatory and reserve bronchodilator therapy for rescue treatment and nocturnal exacerbations, consider use of long acting beta agonists and theophylline in accordance with chrono pharmacological principles.

v      If patient is on oral glucocorticosteroids, consider a split-dosing regime with the second dose administered in the afternoon.

 With above all measures, if the patients fail to improve or maintain improvement, a diagnosis of steroid resistant asthma should be seriously considered and glucocortico pharmokinetics and glucocortico receptors should be evaluated.

 

 

Alternative therapies in steroid resistant asthma

v      Methotrexate @ 10-15 mg/week                                                * Gold salts

v      Intravenous immunoglobulin given                                          * Troleandomycin

      once a month for 6 months                                                           * Cyclosporine @ 3-5

                                                                                         m g/kg/day

 

 

Future theraputic strategies for SRA

v                    Anti adhesion molecules                  * Potassium channel  openers

v                    Anti cytokine agents                         * Newer steroids with better binding properties

v                    VIP analogs

v                    Nitrodilators

v                    Selective PDE4 inhibitors

  Dr. Uma MaheshwariMD (Med.). DM (Pulm & Critical Care Med)

Senior Resident, PGIMER, Chandigarh

 

RESPIRATORY DISEASE IN PREGNANCY  (III) 

Acute Respiratory Distress in Pregnancy

The reduced functional residual capacity and increased oxygen consumption found in normal pregnancy increases the risk of hypoxemia during intubation and in the event of apnea.

v      Fetal viability depends on adequate oxygen delivery. As a result of dilutional anemia of pregnancy, cardiac output becomes the critical determinant of fetal oxygen delivery and must be maintained.

v      Vasoactive drugs should be used with caution in pregnancy patient, since they may reduce uterine blood flow.

v      In ARDS, permissive hypercapnia is not an attractive option since fetal acidosis limits the ability to bind oxygen to fetal hemoglobin.

v      Cardiopulmonary resuscitation must be modified in pregnancy : it includes emergency cesarean section in selected patients. Delivery with in 4 to 5 minutes of the arrest will improve the chance of a good outcome for both the mother and the fetus.  

 

Differential diagnosis of Acute Respiratory Distress in Pregnancy.

Disorder

Distinguishing Features

         Chest Radiograph

 

                                                                                 

Venous thromboembolism       Evidence of deep venous                             Normal / atelectasis /

                                                 Thrombosis, pleuritic chest pain,                          effusion

                                                  positive V/Q scan, leg dopplers                   

                                                  angiogram

Amniotic fluid embolism          Hemodynamic collapse,                              Normal / pulmonary    

                                                  seizures, disseminated                                          edema

                                                  intravascular coagulation (DIC)   

Pulmonary edema secondary       Hypertension, proteinuria                          Pulmonary edema

To preeclampsia

Tocolytic Pulmonary edema         Tocolytic administration,                          Pulmonary edema

                                                        rapid improvement

Aspiration pneumonitis                  Vomitting, reflux, fever                          Focal infiltrate/

                                                                                                                        Pulmonary edema

Peripartum cardiomyopathy           Gradual onset, cardiac gallop                 Cardiomegaly,

                                                                                                                         Pulmonary edema

Pneumomediastinum                     Occurs during delivery,                            Pneumomediastinum,

                                                      subcutaneous emphysema                           subcutaneous air

Air embolism                                  Profound hypotension, cardic                  Normal / pulmonary

                                                                    murmur                                           edema

Others : asthma, pneumonia             As for nonpregnant patint                       As for nonpragnant

Cardiac disease,ARDS                                                                                        patient

 

Amniotic   Fluid   Embolism

v       Causes 11-13% of all maternal deaths with mortality of 86%

v       Most important risk factor for amniotic fluid embolism are maternal age and multiparity. Other less important risk factors include lower segment cesarean section, intrauterine manipulation, pregnancy with intrauterine growth retardation. The classic presentation is the abrupt onset of severe dyspnea, tachypnea, and cyanosis during labour or soon after delivery associated with cardiovascular collapse, hypoxemia and seizures. Shock and bledding can be the intial presentation.

v      Pathophysiology : The cellular and other debris present in the fluid embolism may cause mechanical obstruction of pulmonary vasculature. It can also cause maternal systemic reaction, cytokine release and ARDS. Elevation of PCWP, and depressed left ventricular performance have also been observed in some patients.

v      Pulmonary microvascular cytology analysis can be useful in making a diagnosis of amniotic fluid embolism. It is obtained by withdrawing blood from the distal lumen of pulmonary artery catheter after wedging. In patients with amniotic fluid embolism, there will be large numbers of fetal squames, mucin, hair which are coated with neutrophilis.

v      Treatment is supportive and is aimed at ensuring adequate oxygenation and stablizing the circulation. Factor replacement therapy may become necessary for bleeding due to DIC. Intravenous corticosteroids has been reported to be of benefit in limited case reports.

 Tocolytic- induced pulmonary edema

v      Most common cause of pulmonary edema in pregnancy.

v      Associated with beta - adrenergic agonist use (ritodine, terbutaline, isoxuprine, salbutamol) which are used to inhibit preterm labour.It is never seen when these agents are used for treatment of asthma.

v      Pathogenesis : pulmonary capillary leak is suggested as the cause since PCWP is normal in most patients. Fluid overload has also been speculated as the cause of pulmonary oedema.

v      Dyspnea, tachypnea, and crackles are typical and they occur during or less than 24 hrs. afters tocolytic agents are stopped.

v      Responds promptly to oxygen and diuretics.

 

Dr. Balamugesh T., M.D.

Senior Resident

Department of Pulmonary Medicine

PGIMER, Chandigarh.                                        

 

 

 

LUNG FUNCTION TESTING: SELECTION OF REFERENCE VALUES (I)

During the last 4 decades lung function tests have evolved from tools for physiologic studies to clinical tools for case management, routine health examination and public health screening. These tests are interpreted in relation to reference values and in terms of whether or not they are within the normal range. 

Sources and variation in lung function

Like all clinical measurements, lung function tests are subjected to variations due to technical and biologic factors, disease or dysfunction.

In clinical pulmonary function testing. It is important to minimize  the variation caused by disease can be properly interpreted. 

The American Thoracic Society recommends that :

1.        Laboratory directors should be constantly on guard to maintain the precision and accuracy of the measurements made in the laboratories and should be aware of the potential sources of technical variation.

2.        The spirometer should be kept between 17- 40 degree celsius to minimize temperature related errors.

3.        Computer calculations should be validated. 

Statistical considerations

Reference equations provide a context for evaluating the pulmonary function values of an individual patient or subject in comparison to the distribution of measurements in a reference population. Regression equations are economical and efficient method to describe expected values as a function of sex, height and age. Linear regression is the most common model used to describe pulmonary function data in adults. Complex equations provide more plausible models and reduce the average differences between observed and predicted values in comparison with simple linear equations at the cost of increased complexity of computations.

Distributions of FEV1 and FVC in population studies are close to gaussian curve in the middle age range, but not at extremes. Distributions of the flow measurements and the ratios measures are not symmetric. A lower limit can be estimated from a regression model. For spirometry values less than 5th percentile are taken as below in the expected range. 

Selecting reference values

The choice of reference values should be matter of careful consideration of laboratory directors and should not be left to the judgement of manufactures of automated equipment. The source of the reference values shuld be indicated on the reports. The following must be kept in mind :

i.                     Epidemiological considerations

            The reference values should not come from studies based on hospital patients. It should be based on cross- sectional studies and the subjects should be free of respiratory symptoms and disease. The reference values for both males and females must be chosen from the same population- source and there should be based on nonsmokers. Altitude is also important in selection of reference values for flow rates and DLCO. 

ii            Statistical considerations

             The prediction equation for adults should include age and height as independent variables. Separate equations are mandatory for men and women. Linear equations perform adequately for adults though they may overpredict in young adults and underpredict in the elderely. Reference equations should not be extrapolated for ages and heights beyond those covered by the data that generated them.

  

Lower limits of normal (LLN)

The normal ranges should be based on calculated fifth percentiles. The LLN are variable and patient values that lie close to the lower ;limits should be interpreted with caution. The use of 80% of the predicted for LLN for adult pulmonary function test parameters is not recommended. It may be acceptable in children. In adults, it is not acceptable to use a fixed FEV1/ FVC ratio as LLN.

 

                                                                                               Dr. Vinod Chandran, MD (Medicine)

                                                                                               Senior Resident, Internal Medicine                                                                                                                                   PGIMER, Chandigarh.