Pulmonary/Critical Care

Mystery Quiz- The Answer

May 1, 2009

Posted by Vivian Hayashi MD and Robert Smith MD, Mystery Quiz Section Editors

The answer to the mystery quiz is sarcoidosis. The CXR shows diffuse, bilateral infiltration with a predominantly nodular pattern. The pulmonary hila are also prominent. The CT image shows innumerable 2-3mm nodules, many of which have a perilymphatic distribution. The lymphatics, in parallel with the pulmonary vasculature, course through the interstitium. Hence, the perilymphatic nodularity has an interstitial distribution and appears as “studding” along the interstitium which is enhanced by vascular contrast (Image 2, short arrows). Additional nodules, however, have a random distribution (Image 2, arrowhead), while others appear to be centrilobular (Image 2, long arrow). As a granulomatous disease that involves activated CD4 lymphocytes, it is not surprising to find pathological involvement of perilymphatic tissue along with lymph nodes (Image 3, arrows). That said, sarcoidosis may involve any anatomical lung site: airways, interstitium or alveoli.

Perilymphatic nodularity also appears in the fissures and along the pleura where lymphatics are found (not shown). Other lung diseases included in the differential are also characterized by small nodules on chest imaging. Depending on their origin, the nodules have different distributions. Hematogenous spread of disease, such as miliary TB, will appear as interstitial disease because it is perivascular. Interstitial nodules due to miliary TB or metastatic disease, for example, appear to have sharp borders because they are enveloped by the interstitium which gives them a smooth edge on imaging. Nodules that arise from endobronchial spread of disease, such as aspiration or aerogenous spread of infection, often appear in a centrilobular distribution. The centrilobular location is where a bronchiole, filled with material conferring the appearance of a radiographic nodule, enters the lobule. The lobule appears as a polygonal structure (distal interstitium) on CT imaging. Beyond the bronchiole, nodules will manifest with a fuzzy border because they occupy airspace. Such nodules may also appear larger depending on how much neighboring airspace is involved.

Our patient was treated with prednisone to alleviate his cough. His cough improved after a few weeks and repeat imaging showed regression of the pulmonary nodules (Image 4) and mediastinal lymphadenopathy (Image 5). Our case illustrates how patients with sarcoidosis often have imaging that is worse than would be expected from their clinical presentation.

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Mystery Quiz

April 28, 2009

Vivian Hayashi MD and Robert Smith MD, Mystery Quiz Section Editors

The patient is a 42 year old man with a history of non-productive cough for several weeks. Three weeks prior to evaluation by the pulmonary service, the patient presented to the ER with a presumed vasovagal syncopal event that occurred on a subway platform. The patient’s prior medical history included allergic sinusitis and nasal polypectomy. Other than cough, the patient denied constitutional symptoms. The patient was not taking any medications. His social history was negative for smoking, intravenous drug abuse, risk factors for HIV infection, significant occupational exposures and travel. The patient did not own any pets. PPD placed by the pulmonary service was negative. Physical exam revealed a thin man with normal vital signs including normal resting pulse oximetry, clear chest, and otherwise no focal findings.

 

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Bedside to Bench: Clubbing Revisited

April 3, 2009

Commentary by Judith Brenner MD, Associate Editor, Clinical Correlations 

Faculty Peer Reviewed 

For an internist, discovering a patient with clubbing is so rewarding since it appeals to the core of our profession, a profession which can often be very similar to that of a detective. The physical finding of clubbing was first described by the ancient Greeks, who recognized it to be a clue to much more.

When a clinician discovers clubbing of the fingers, he must consider that hypoxemia may be present, whether secondary to a cardiac or pulmonary process. In fact, more than 90% of clubbing is pathologic, with the remainder being a benign familial condition.

How do we recognize clubbing on physical exam?

Let’s begin at the bedside. One can judge finger clubbing in many ways. The simplest way is to think of the clubbed finger is as a “drumstick digit”. There is an increase in the curvature of the nail and a general rounding at the tip. However, curvature is difficult to measure at the bedside. Most physicians look for the “Shamroth Sign”. This sign, named for the doctor who first described it in 1976, is performed by looking for loss of the diamond that is usually formed in non-clubbed fingers when the dorsal surfaces of the distal phalanx of the right and left fingers are apposed. Unfortunately, though commonly considered to be a “standard” in terms of diagnosis, this sign has never been rigorously studied.

Another way to determine if clubbing is present involves use of the “phalangeal depth ratio.” This ratio compares the “distal phalangeal depth” with the “interphalangeal depth”. In normal individuals, the DPD:IPD ratio is <1. However, in clubbed fingers, the distal portion is thicker and thus, the ratio of DPD:IPD is >1.

The last finding to consider is the hyponychial angle. The normal angle is 180 degrees. With clubbing the curvature of the nail increases and the angle thus increases. An angle greater than 190 degrees is considered consistent with clubbing.

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Unfortunately determining the evidence for these findings is difficult.  No sensitivities, specificities or likelihood ratios are available.  Why? Simply because there is no gold standard.   Here’s where experience counts.  A clinician can look at a finger, observe that its appearance is not “normal” and then start to ask the appropriate questions.

Is clubbing really a marker of hypoxic disease?

The answer is: yes.  In one study of 350 patients with clubbed fingers, 80% had underlying respiratory disorders, including tumors, abscesses, cystic fibrosis, and interstitial fibrosis.  An additional 10-15% had cyanotic heart disease, endocarditis, and even thyroid disease and inflammatory bowel disease.  Only 5% were found to be either idiopathic or hereditary.

What is the unifying pathology in all of these disorders?

On a molecular level, the pathophysiology has been studied by investigating rare individuals with familial hypertrophic osteoarthropathy.  In these patients, mutations of HPGD, a prostaglandin E2 catabolizing enzyme, has been identified.  This mutation results in elevated prostaglandin levels.  Although the familial form is rare, the secondary forms of hypertrophic osteoarthropathy (HO) are more common and clubbing is often the first clue.  The clinical commonality in many patients with secondary HO is right to left shunting.  Ordinarily, prostaglandin E2 (PGE2) is metabolized in the lung.  The hypotheseis is that, with shunting, the proper metabolism is prevented.  As a result, PGE2 levels are elevated and elevated prostaglandin levels result in platelet activation. 

Activated platelets are returned to the systemic circulation and are thought to lodge in the distal phalanges, releasing their growth factors.  While trapped, the platelets release growth factors, which leads to fibrovascular proliferation, ultimately manifesting in what we clinically call clubbing.

Though compelling, these explanations are all still just hypotheses.  While many diseases associated with clubbing have shunting in common, several do not, such as Graves’ Disease and inflammatory bowel disease.  The pathophysiology in these cases remains unclear.

The Bottom line:

Clubbing is indeed a clinical clue to an underlying disorder and thus must be taken seriously when recognized.  It is diagnosed at the bedside where simple observations are made.  When present, a search for diseases of the lungs or heart that cause right to left shunting is warranted.  If cardiac and pulmonary etiologies are ruled out, one can consider other diseases that are marked by platelet excess, such as inflammatory bowel disease.  Inheritance (<5%), since it is so rare, should be accepted as the etiology only as a diagnosis of exclusion.

Coggins, KG et al. The hippocratic finger points the blame at PGE.   Nature Genetics 2008;40:691-2.

Meyers, KA et al. Does this Patient Have Clubbing? JAMA 2001;286:341-347.

Uppal, S, et al.  Mutations in 15-hydroxyprostaglandin dehydrogenase cause
Primary Hypertrophic Osteoarthropathy.  Nature Genetics 2008;40:789-93.

McGee, S.  Evidence Based Physical Diagnosis (2nd edition).

Reviewed by Nishay Chitkara MD, NYU Division of Pulmonary and Critical Care Medicine

Grand Rounds: The New Frontier of Sleep Disorders

March 18, 2009

Grand Rounds ImageCommentary by Melissa Price, MD, PGY-3

Please also see the clinical vignette presented before last week’s Grand Rounds.

At Medical Grand Rounds on March 11th, 2009, the NYU Medical Community had the immense pleasure of hosting Dr. Allan I. Pack, MD, Ch.B, and Ph.D from the University of Pennsylvania Medical Center as he indulged us in his research on the biological functions of sleep and its regulation.

Studying the importance of sleep and its disorders has never been more relevant. Not only is the Accreditation Council for Graduate medical Education (ACGME) considering to drastically alter residency programs across the nation by instilling a rule requiring all thirty-hour shifts to incorporate a five-hour period of uninterrupted sleep, studies reveal that Americans, as a group, are sleeping less than ever before. With sleep loss, or wakefulness greater than 16 hours, accumulated performance impairment and lapses commonly occur. Studies linking sleep deprivation with medical errors and increasing motor vehicle accidents are prevalent. However, if given the opportunity to have sufficient sleep, Dr. Pack showed that these lapses can resolve.

He opened his lecture by presenting sleep regulation as a two process model. The first component of this model is the direct relationship between the drive to sleep with the duration of prior wakefulness. The second component of sleep regulation is a rhythmic circadian process over a twenty-four hour day. Information from light and dark cycles is sent via the retinohypothalamic tract to the suprachiasmatic nucleus within the hypothalamus wherein molecular feedback mechanisms and oscillators help to form our sleep clocks. The relevance of the Spanish siesta was validated by research showing that early afternoon and evening are the “sleepiest periods” of the day, while early evening is the “forbidden time to sleep.” If one tries to sleep at periods of such alert clock times, sleep efficiency will be impaired.

Cleverly dubbing early-risers as larks as opposed to night owls, Dr. Pack discussed the great variation between the sleep clocks amongst individuals and posited that larks may have a biological advantage due to morning wakefulness. Additionally, there are significant variations in how people handle sleep deprivation. Furthermore, our sleep clocks and behaviors may be inherited as illustrated by twin studies and research on family advanced sleep-phase syndrome. This syndrome, with its autosomal dominant inheritance, is due to single base mutation in one clock gene (period 2).

The basis of the molecular clock is the genes that oscillate within it. By studying Drosphilia, transcription factors such as CLK: BMAL have been discovered as the core oscillator initiators. Moreover, in trying to answer the age-old question of why we sleep, Dr. Pack and his colleagues believe that “during sleep there is a rebuilding of multiple key cellular components in preparation for subsequent wakefulness.” They have found that roughly 2,000 genes involved mainly in biosynthetic pathways increases expression during the sleep cycle. Additionally, during sleep deprivation, many genes for key metabolic processes are down-regulated. There is also upregulation in brain during sleep deprivation of genes involved in the unfolded protein response. Thus, sleep deprivation leads to cellular stress in brain.

Through Dr. Pack, we can better realize that decoding the biology of sleep has remarkable implications for humankind and for the field of medicine across a multitude of disciplines. By understanding sleep, we can learn to sleep better. As sleep medicine evolves into a prominent field, the medical community eagerly awaits the decoding of one of the most unifying behaviors of all of earth’s creatures.

Naidoo N, Giang W, Galante RJ, Pack AI. Sleep deprivation induces the unfolded protein response in mouse cerebral cortex. J Neurochem 92:1150-1157, 2005.

Mackiewicz, M., Shockley, K., Romer, M., Galante, R.J., Zimmerman, J. E., Naidoo, N., Baldwin, D.A., Jensen, S. T., Churchill. G. A., and Pack, A. Macromolecule biosynthesis: a key function of sleep. Physiol Genomics 31:441-457, 2007.

Mackiewicz M, Zimmerman JE, Shockley KR, Churchill GA, Pack AI. What are microarrays teaching us about sleep? Trends Mol Med 15:79-87, 2009.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Mystery Quiz- The Answer

March 10, 2009

Posted by Vivian Hayashi MD and Robert Smith MD, Mystery Quiz Section Editors

The answer to the mystery quiz is allergic bronchopulmonary aspergillosis (ABPA). The CXR shows right upper lobe opacities, two of which appear round (Image 3, arrow) and another tubular (Image 3, arrowhead), and a left upper lobe opacity which has the characteristics of subsegmental atelectasis (Image 3, double arrows). The CT scan, performed ten days after the CXR, shows central bronchiectasis of the RUL (Image 4, arrows); tubular branching shadows (Image 6, arrow) as well as ring shadows (Image 5 and 6, arrowhead) all of which represent ectatic airways filled with mucoid material. A left upper lobe ectatic airway with thickening of the bronchial wall is also present (Image 7, arrow). The left upper lobe subsegmental atelectasis seen on the initial CXR was not visible on the CT image, indicating clearing of mucoid impaction.

ABPA is seen in a small percentage of patients with asthma and represents a complex hypersensitivity reaction to aspergillus antigens colonizing the airways. The diagnosis is established when multiple clinical findings are present. These include frequently refractory asthma, eosinophilia, serum IgE reactive to aspergillus antigen, and very elevated total serum IgE levels (>1000 IU). Characteristic imaging shows central bronchiectasis and mucoid impaction (“finger in glove” shadows, Image 6, arrow) that result in subsegmental atelectasis, often in an upper lobe distribution. The atelectasis can appear migratory as one area clears and another becomes impacted. In addition to patients with asthma, ABPA is associated with cystic fibrosis in a small percentage of cases. Treatment consists of high dose glucocorticoids followed by a slow taper. Serum IgE levels decline but typically do not normalize and recurrences of disease are associated with increasing serum IgE levels. There is some evidence that the addition of itraconazole to glucocorticoids may be helpful. The addition of the antifungal agent may decrease the burden of aspergillus colonization and lead to less hypersensitivity. Left untreated, ABPA may progress to irreversible fibrosis.

Our patient was initially treated as an asthma exacerbation due to pneumonia. However, this initial diagnosis gave way to a final diagnosis of ABPA when the serum IgE level returned at 1365 IU (reference range 0-158), serum IgE specific for Aspergillus fumigatus was elevated and the CT imaging showed characteristic findings.

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Mystery Quiz

March 6, 2009

Posted by Vivian Hayashi MD and Robert Smith MD, Mystery Quiz Section Editors

The patient is a 42 year old male non-smoker with history of poorly controlled asthma (first diagnosed in 1994, recurrent need for steroid treatments but never intubated), severe seasonal allergies with chronic sinusitis, hepatic steatosis, GERD and gout who presented with complaints of five to ten days of myalgias, productive cough, wheezing and chest tightness. His medications included albuterol, fluticasone and formoteral inhalers, montelukast, colchicine, indomethacin prn, and fexofenadine. Exam was significant for T 97.6, HR 100, BP 120/83, RR 22, O2Sat 95% on RA. The patient was moderately obese, appeared anxious and tachypneic but speaking in full sentences. Heart exam was within normal limits with no JVD. Lung exam with decreased breath sounds and scattered inspiratory and expiratory wheezing throughout. No rales nor rhonchi. Labs were significant for WBC 12.0 with 75% polys, 12.7% lymphs, 8.4% eos; mild transaminitis (ast/alt 48/89—patient’s baseline). Blood cultures pending x 2.

Admission CXR: Images 1 & 2

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Diseases 2.0: Sepsis

February 5, 2009

fluid11.jpgDiseases 2.0 – Bringing you the latest updates on disease pathophysiology and treatment

Commentary by Andrew McKinstry MD PGY-1

Faculty Peer Reviewed

For anyone who has stepped into an ICU, the septic patient is a familiar sight. Despite advances in research and management, including goal directed therapy and recombinant human activated protein C (Xigris), sepsis continues to be a major cause of mortality in the critical care setting, with an estimated 215,000 deaths annually, and costing roughly 16.7 billion dollars per year. Despite these staggering human and monetary costs, the nature of and mechanisms involved in sepsis remain either unknown or hotly contested. The continuing research into this problem is on the verge of producing a number of promising insights and interventions, from insights into the nature of the syndrome to new pharmaceutical solutions and systems-based interventions.

While sepsis is a well-documented syndrome, there is debate among sepsis researchers whether sepsis is actually a number of different processes with a common late-stage presentation. While this could seem a largely academic debate, a mechanistic understanding of sepsis would be important in determining biomarkers for use in early detection of the syndrome. Recently, procalcitonin emerged as a possible candidate for a sepsis biomarker. Studies as early as 1993 described procalcitonin as an infection variable, and a few studies early this decade showed higher levels of procalcitonin in septic states than other inflammatory states. Further investigation found that while is was another good indicator of systemic inflammation, calcitonin was not specific for sepsis to be useful as a diagnostic test. Research groups at Duke University and Henry Ford Hospital, at the University of Zurich and members of the SPEEDI trial in Copenhagen are now in the process of throwing a wide net in search of sepsis biomarkers using high-throughput protein screening.
The available armamentarium against sepsis is limited to recombinant human activated protein C (APC) which targets one of the dysregulated systems in sepsis, coagulation, and likely affects what is the major dysregulation of sepsis, inflammation. APC has been shown to improve all-cause mortality in severe sepsis, though is ineffective and potentially harmful in less severe sepsis due to a high complication risk. Looking down the pipeline, at least two other drugs that target the hypercoaguable state in sepsis are in late phase trials. Recombinant human soluble thrombomodulin and recombinant anti-thrombin are in trials for treatment of DIC in sepsis, with the hope that they might provide a similar improvement in mortality with fewer hemorrhagic complications associated with APC.

Current drug research in sepsis is primarily focused on correction of inflammatory dysfunction, and coagulation dysfunction. Earlier theories of sepsis categorized it as a purely hyperinflammatory state, and unsuccessful experimental therapies focused on broad reduction of inflammation systemically. Coritcosteroid treatment has been shown to be ineffective, and there was a mixed picture for the efficacy of monoclonal anti-TNF antibodies in sepsis. While there was a meta-analysis of trials using monoclonal anti-TNF antibodies in severe sepsis suggests some efficacy, none of the individual trials showed any significant improvement in outcome.

Current theories on mechanisms of sepsis postulate a complex, heterogenous dysfunction of inflammatory processes- a cytokine storm that can lead to a mixed hyper- and hypoinflammatory state. In animal models of bacterial sepsis, blockade of IL-22 resulted in improved bacterial clearance in the liver and kidneys with reduced kidney damage, a possible future therapy aimed at prevention of end-organ damage in sepsis. Similarly, in translational studies blocking function of IL-27, subjects showed an increase in survival- another potential target for future therapies. Hemodiafiltration using a membrane that filters cytokines shows some promise in treating the cytokine storm of sepsis- human trials have shown decreased markers of end-organ damage, though no survival benefit has yet been demonstrated. Statins, the wonder drugs that seem to have no end of new uses, also show some potential in treatment of sepsis. Prior statin use has been shown to decrease the rate of severe sepsis in hospitalized patients, and statin use in patients with multi-organ dysfunction have been shown to have improved survival.

The ability of relatively small amounts of lipopolysaccharide (LPS) from gram-negative bacteria to induce a septic-shock-like condition has long been known, but the discovery in the last decade of the receptor through which LPS induces a vasodilatory state, Toll-like Receptor 4 (TLR4), presented a promising drug-target. Eritorian is a TLR4 antagonist currently in Phase III trials for treatment of severe sepsis, and TAK-242, a small molecule cytokine inhibitor of TLR4 signaling, is also in late phase trials.

Last but not least, some of the most significant advances in treatment of sepsis have not come from new pharmaceutical interventions, but in improved delivery of care. Early goal-directed therapy was hugely successful in improving sepsis outcomes, but now researchers at the University of Pittsburgh are performing a head-to-head comparison between goal directed therapy (which requires a central venous line with all of its associated complications) to protocolized care (which does not require a central line) in the treatment of septic patients. Who knows, depending on the results of that study, maybe next year in the ICU, not every sepsis patient will need that central line that they have now.

Given the variety of research and the number of late-phase trials currently underway, the clinical approach to sepsis will likely have a number of significant changes in the next five years. Improved diagnostic tests will help ensure earlier interventions, improved protocols will improve the quality of interventions, and new pharmaceuticals will be available for treatment of both complications of sepsis and the dysfunctional inflammatory state of sepsis itself. Continued success in sepsis research may mean that at some point in the no-so-distant future, a sepsis diagnosis will be as simple as a blood test, and pharmaceutical treatment will be as straight forward as antibiotics and an inflammatory modulator. In the mean time, though, make sure those fluids are hanging.

Reviewed by Laura Evans MD, NYU Division of Pulmonary and Critical Care Medicine

Sources:

www.clinicaltrials.gov

Leaver, S. et al. Sepsis since the discovery of Toll-like receptors: Disease concepts and therapeutic opportunities. Critical Care Medicine. Vol 35, No. 5 2007. p1404-10

Leon, C et al. Discovery and Development of Toll-Like Receptor 4 (TLR4) Antagonists:
A New Paradigm for Treating Sepsis and Other Diseases. Pharmaceutical Research. Vol 25, No 8, August 2008. p1751-61.

Nakada, T et al. Continuous Hemodiafiltration with PMMA Hemofilter in theTreatment of Patients with Septic Shock. Molecular Medicine. 14(5-6) p 257-63.

Remick, D. Pathophysiology of Sepsis. The American Journal of Pathology, Vol. 170, No. 5, May 2007, p 1435-44.

Weber, G et al. Inhibition of Interleukin-22 Attenuates Bacterial Load and Organ
Failure during Acute Polymicrobial Sepsis. Infection and Immunity, Apr. 2007, p. 1690–97

Wirtz, S et al. Protection from lethal septic peritonitis by neutralizing the biological function
of interleukin 27. The Journal of Experimental Medicine. Voll 203, No 8, August 7, 2006. p 1875-81.

Breaking News: FDA Advisory Committee Calls For Ban on Long Acting Beta Agonists in Asthma

December 12, 2008

foradil.jpgCommentary by Denise Pate MD, PGY-1 

The FDA released a 460 page document regarding the safety of long acting beta agonists (LABA) for the use of asthma, in addition to a two day advisory committee meeting this week on the call to ban LABA when used alone and not in combination with an inhaled steroid. The FDA found through a meta-analysis of 110 trials studying 4 drugs—2 LABAs, Foradil and Serevent, and 2 LABA/ICS (Inhaled Corticosteroids) Advair and Symbicort. The study found that there was an increased risk of hospitalization and asthma related deaths from LABAs alone ,with 20 asthma related deaths of which 16 came from those of patients strictly taking LABA. Prior to the implementation of LABAs in asthma these drugs were used in COPD with good results. Therefore, although the FDA is calling for their ban in the use of asthma they will most likely not be pulled from the market for the use of COPD.

Despite the FDAs forceful stance against the use of LABAs, the NY Times reports that many medical associations, including the American Academy of Pediatrics, American Thoracic Society, American Academy of Allergy Asthma and Immunology, and American College of Allergy Asthma and Immunology still support the continued use of the medications.

The FDA’s role is to protect patients. However some of the officials may be detached from clinical practice where we often see the benefits of LABAs. The major contention lies between the use of LABAs alone versus LABAs with ICS, however the FDA is considering continuing studies on the safety of Advair and Symbicort, particularly in children. As the NY Times explains, LABAs may cause an increased risk in death because such agents immediately relieve symptoms, thereby potentially making patients less likely to use an inhaled steroid concurrently.Some anecdotal evidence that was published in the NEJM in the early 90s stated that two elderly patients were found dead holding their Serevent inhalers. While this is tragic, maybe the onus lies on us to properly educate our patients as to how and when to utilize their medications and simultaneously teaching them to be as vigilant as possible by taking cues from their symptoms.

Mystery Quiz- The Answer

November 8, 2008

Posted by Vivian Hayashi MD and Robert Smith MD, Mystery Quiz Section Editors

The answer to the mystery quiz is heart failure.  The CXR shows bibasilar opacities with hilar fullness on the right. The CT images are remarkable for bilateral effusions, with dependent opacities that increase in density along the anterior-posterior axis.  The lung appears clear in the anterior zone (Image 5, arrow; Coronal Image 1); ground glass opacification, characterized by parenchymal haziness which does not obscure the underlying pulmonary vessels, is evident in the mid lung (Image 5, double arrows; Coronal Image 2); and consolidation with air bronchograms is evident in the posterior areas (Image 5, arrowhead; Coronal Image 3).  The coronal images show the same increase in density along the anterior-posterior axis (Coronal Images 1-4).  Although the same density gradient of parenchymal fluid may be seen in non-cardiogenic pulmonary edema, the presence of bilateral effusions makes cardiogenic edema much more likely.

 

The mediastinal windows demonstrate adenopathy in precarinal, subcarinal and hilar areas (Image 6A, Image 7B and 7C, respectively).  The fact that enlarged mediastinal and hilar lymph nodes may accompany congestive heart failure was not appreciated until relatively recently (Slanetz PJ et al.  Mediastinal lymphadenopathy and hazy mediastinal fat: new CT findings of congestive heart failure. Am J Roentgenol 1998; 171: 1307-09).   Animal models indicate that enlarged nodes do not result simply from increased flow through interstitial lymphatics.  An additional requirement is that the efferent draining lymphatic vessels empty into a vein that has an elevated pressure (>15cm H2O), as may occur in heart failure, but less likely to occur in cases of non-cardiogenic pulmonary edema. High venous pressures slow lymphatic outflow and contribute to proximal lymph node enlargement.  The few reported biopsies of such nodes show an absence of inflammation, benign sinus histiocytosis, and slight follicular hyperplasia.

 

The CT images six days later show remarkable resolution of the airspace opacification after diuresis, along with a significant decrease in the lymphadenopathy (Images 6 and 7).  We present this case to highlight an underappreciated cause of reversible lymphadenopathy and review the image findings of pulmonary edema, herein due to hypertensive heart disease.

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Mystery Quiz

October 30, 2008

Posted by Vivian Hayashi MD and Robert Smith MD, Mystery Quiz Section Editors

The patient is a 61 year old man with a history of diabetes, chronic kidney disease, and poorly controlled hypertension on five medications who was in his usual state of health until three days prior to admission when he noted increasing exertional dyspnea associated with chest pain, abdominal distention, bilateral lower extremity edema (left greater than right).

Exam notable for BP 105/54 (lower than all other prior measurements), HR 74, O2 Saturation 90%. PaO2 57mmHg, bibasilar rales and bilateral lower extremity edema. Labs were significant for BNP 218 (ref range: 0-100), d-dimer 537 (ref range to 230), WBC 11.2 (82% polys), Hgb 9.3 (baseline 10-12), creatinine 4.2 (baseline mid 2), troponin negative x 2. EKG without ischemic changes.

Echocardiogram six months prior to admission notable for hyperdynamic LV, increased EF (70-75%) and mild concentric LV hypertrophy.

Admission CXR:

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Chest CT:

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Propofol Infusion Syndrome: An Unusual Case of Lactic Acidosis

October 1, 2008

propofol.jpgCommentary by Bani Chander MD, PGY-3 and Reviewed by Laura Evans MD, NYU Division of Pulmonary and Critical Care Medicine

Case presentation:

The patient is a 26 year-old female with long-standing refractory epilepsy, status post corpus callosotomy, and vagus nerve stimulator placement, who was admitted to the intensive care unit for management of status epilepticus. The patient was initially admitted to the inpatient epilepsy unit and placed on multiple anti-epileptic medications with little response. However, after having more than ninety seizures over the course of 1.5 days, she was transferred to the ICU for treatment with propofol for refractory status epilepticus.

Upon transfer, she was intubated and started on a high dose propofol infusion at 8mg/kg/hr with continuous EEG monitoring with a goal of achieving burst suppression. Burst suppression is an EEG pattern of brief high amplitude EEG activity interspersed with low amplitude activity. Burst suppression may be seen in many pathophysiologic states; in cases of refractory status epilepticus, however, burst suppression is the clinical endpoint to which therapy is titrated.

The patient became hypotensive with the propofol infusion and was started on phenylephrine to maintain blood pressure. Several attempts were made to decrease her propofol dose, but she continued to have prolonged bursts of seizure activity below 8mg/kg/hr. An arterial blood gas was significant for a lactate level of 3.0 mEq/L (previously normal). Over the next few days, the patient had increasing pressor requirements and required the addition of vasopressin. The lactate level peaked at 14.3, and was accompanied by decreasing urine output, a rise in serum creatinine, and a creatine phosphokinase (CPK) level above 5700: a clinical picture consistent with rhabdomyolysis. All chest radiographs, blood, and urine cultures were consistently negative with no clinical signs of infection.

Over the course of the next few days, the patient developed a wide-complex tachycardia with a new left axis deviation, as well as signs and symptoms of cardiac failure including rales on exam and pulmonary edema on chest radiograph. An echocardiogram showed new right and left ventricular hypokinesis with an ejection fraction of 35% (previously 70%). The patient received continuous venous-venous hemodialysis (CVVH) and, in an effort to titrate off the propofol, she was started on a high dose continuous lorazepam infusion. The propofol infusion was weaned within the next two days, with a complete reversal of both renal and cardiac failure and with normalization of arterial lactate and CPK. The patient was ultimately weaned off vasopressors, switched to oral antiepileptic medications with no significant seizure activity on EEG, and discharged home.

Discussion:

Propofol infusion syndrome (PRIS) is a rare and serious side effect in patients exposed to long term, high dose propofol infusions. PRIS should be suspected in any patient on a high dose propofol infusion with a rising lactate in the absence of tissue hypoxemia and other causes of lactic acidosis. The cardinal features of this syndrome include lactic acidosis, acute renal failure, rhabdomyolysis, and cardiac failure. This syndrome was initially recognized only in children, but has become increasingly recognized in adults. The mechanism of PRIS is thought to be secondary to an imbalance between energy demand and utilization which occurs by impairment of mitochondrial oxidative phosphorylation and free fatty acid utilization, ultimately leading to lactic acidosis and muscular necrosis. In animal models, propofol uncouples oxidative phosphorylation and energy production in the mitochondria [1] and inhibits electron flow through the electron transport chain. In addition, cardiac contractility is also reduced as propofol antagonizes beta-adrenergic receptor and calcium channel binding [2-4]

Because this syndrome can be fatal, special attention should be taken to all those exposed to propofol at a rate >5mg/kr/hr for more than 48 hours. If a patient requires sedation for longer than this period, alternative forms of sedation should be explored. In addition, any patient on high dose propofol for more than 24 hours should have close monitoring of both lactic acid, CPKs, and serum creatinine, as a rise in any of these may be the first markers of this potentially fatal syndrome. If the development of PRIS is suspected, the infusion should be titrated off as quickly as possible and hemodialysis should be initiated given the potentially fatal side effects of propofol and its metabolites.

Reviewed by Laura Evans MD, NYU Division of Pulmonary and Critical Care Medicine:

Definitions of status epilepticus vary slightly, but usually refer to prolonged seizure activity or frequent seizures without return to baseline neurologic status between episodes.  Refractory status epilepticus refers to ongoing seizure activity despite first and second line drug therapy.   Status epilepticus is associated with significant morbidity and mortality, most often due to the underlying cause.  Multiple drugs are available to treat status epilepticus (e.g. benzodiazepines, phenytoin (or fosphenytoin), barbiturates, and propofol are the most commonly used) and inhaled general anesthetics such as isoflurane may be used in extremely refractory cases.   Benzodiazepines and phenytoin have traditionally been first line agents for the treatment of status epilepticus, with barbiturates reserved for patients who fail to respond. 

The use of propofol to control refractory status epilepticus has been reported in four small studies which suggest that, compared to other agents, propofol may have equivalent success in terminating status epilepticus, [5-7] and may terminate refractory status epilepticus more quickly than barbiturates.1  Propofol related infusion syndrome is a rare but potentially fatal complication of propofol therapy.  Patients on high doses (>5mg/kg/hr) for greater than 48 hours appear to be at higher risk and should be followed closely[8] .


 


 References:
1- Branca et al, Influence of the anaesthetic 2,6 Di-isopropylphenol on the oxidative phosphorylation of isolated rat liver mitochondria. Biochem Pharmacol 42: 87-90
2- Schenkman et al, Propofol impairment of mitochondrial respiration in isolated perfused guinea pig hearts determined by reflectance spectroscopy. Crit Care Med 28: 172-177
3- Zhou et al, Propofol-induced alterations in myocardial beta adrenoceptor biding and responsiveness. Anesth Analg 89: 604-608.
4- Zhou et al, Modulation of cardiac calcium channels by propofol. Anesthesiology 86: 670-675
5- Rossetti AO et al. Propofol treatment of refractory status epilepticus: a study of 31 episodes. Epilepsia 2004 Jul;45(7):757-63.

6-Stecker MM et al. Treatment of refractory status epilepticus with propofol: clinical and pharmacokinetic findings. Epilepsia 1998 Jan;39(1):18-26.

7-Payne TA, Bleck TP. Status epilepticus. Crit Care Clin 1997 Jan;13(1):17-38.

8-Prasad A, Worrall BB, Bertram EH, Bleck TP. Propofol and midazolam in the treatment of refractory status epilepticus.  Epilepsia 2001 Mar;42(3):380-6.


Bibliography:

1. Intensive Care Med. 2003 Sep;29(9):1417-25.
2. Intensive Care Med. 2004. 2004 (30): 5002.
3. Anaesthesist. 2004 Oct;53(10):1009-22
4. Liolios et al, Anesth Analg 2005; (100):1804-1806
5. Branca et al, Influence of the anaesthetic 2,6 Diisopropylphenol on the oxidative phosphorylation of isolated rat liver mitochondria. Biochem Pharmacol (42): 87-90
6. Schenkman et al, Propofol impairment of mitochondrial respiration in isolated perfused guinea pig hearts determined by reflectance spectroscopy. Crit Care Med (28): 172-177
7. Zhou et al, Propofol-induced alterations in myocardial beta adrenoceptor biding and responsiveness. Anesth Analg (89): 604-608.
8. Zhou et al, Modulation of cardiac calcium channels by propofol. Anesthesiology (86): 670-675.

Mystery Quiz- The Answer

September 27, 2008

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Posted by Vivian Hayashi MD and Robert Smith MD,

Mystery Quiz Section Editors

The answer to last week’s mystery quiz is pneumatocele/pseudocyst likely due to ventilator associated lung injury (VALI) in a patient with ARDS. The patient had

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ARDS on the basis of diffuse infiltrates, hypoxemia with a PaO2/FiO2 <200mmHg, and no strong evidence of LV heart failure. His risk factor for ARDS was pneumonia, evident on his admission CXR with bibasilar infiltrates (R>L); Streptococcus pneumoniae grew on sputum culture. The overall clinical picture is best described as septic shock and multiple organ failure.

VALI may be seen when patients with acute lung injury or ARDS are ventilated with potentially injurious (high) lung volumes or high transpulmonary pressures. These latter conditions will over distend the lung and result in pathologic changes that are indistinguishable from the diffuse alveolar damage seen in cases of ARDS due to the usual causes: pneumonia, trauma, transfusion-related acute lung injury or sepsis. Pneumatoceles and pseudocysts, due to VALI, may be seen on chest imaging as well as in pathological specimens. The concept is that the underlying, initial disease causes heterogeneous lung involvement such that large tidal volumes will be distributed unevenly with regional areas of marked over distension interspersed with poorly aerated areas that are collapsed or congested. Furthermore, over distension and mechanical stress are inflammatory and cause intracellular signaling that results in cytokine synthesis in the lung, followed by spillage from the airspaces into the blood. Remote organ damage then ensues.

A strategy of low tidal volume ventilation was the basis of the ARDSnet trial which showed improved outcomes in patients managed with a tidal volume of 6cc/kg of predicted body weight, and a PEEP level that allows an acceptable PaO2. These historically low tidal volumes are designed to prevent the lung from being over-distended and subject to volutrauma and VALI. Often, the low tidal volume ventilation is associated with hypercapnea which is well tolerated in most cases. The concept includes a corollary, the “open lung,” which is the application of PEEP to prevent the lung from collapsing at end-expiration. PEEP prevents the distal airways and airspaces from undergoing shear stress injury due to cyclic opening and closing.

Our patient was managed with pressure control ventilation, with set inspiratory pressures of 32cm H2O, PEEP of 16 cmH2O, and tidal volume of about 7cc/kg of his predicted weight. The pCO2 level was allowed to remain high (permissive hypercapnia). Despite our good intentions, the patient developed a picture of VALI that was also complicated by rupture of one of the pneumatoceles and a pneumothorax that required drainage with a small bore chest tube (as seen in the soft tissues of the CT scan image). A caveat of protective low tidal volume ventilation is that over or under distension of the lung can occur with “optimal” distending pressures, 30-32cm H2O. If a patient has intraabdominal hypertension, approximately half of the abdominal pressure is transmitted to the pleural space; the transpulmonary pressure (plateau/alveolar pressure – the pleural pressure) may be significantly less than 30-32cm and be associated with under distension of the lung, and consequent atelectasis, shunting and hypoxemia. Conversely, if a patient has emphysematous lungs that are highly compliant and abnormally distensible, a pressure of 30-32cm may be associated with over distension and VALI. We speculated that this scenario was at play in our case.