The Journal of Pulmonary Technique...considered a small set of evidence-based interventions for...

The Journal of Pulmonary Technique

Blood Gas AnalysisSepsis ManagementBilirubinPleural Fluid pH

2 Respiratory Therapy Special Supplement (2007)

A single measurement is like a snapshot: one moment frozen intime. However, in medical care the patient’s condition isconstantly changing, and only the tracking of individualmeasurements can produce the right picture—or rather, theright movie. The data of most patients in an ICU exhibitidentifiable trends, and these are useful in making diagnosesand managing drugs, ventilation and other therapeutic factors.Putting together the individual data chunks can also help indifferentiating between acute and chronic patient conditions.

At the core of this process is a data management and ITconnectivity software solution which enables you to transformthe data into meaningful information and which is tailored tothe needs of an ICU. Automated acid-base trending, forexample, results in a more precise diagnosis and therapymonitoring. Accurate, graphical mapping (a feature of the cobasb 221 from Roche) efficiently assists the healthcare professionalin rapidly identifying metabolic and respiratory acid-basedisturbances without needing a calculator. It also helps inmonitoring the effectiveness of therapy.

The onboard patient-trending feature of the new cobas b 221analyzer makes possible real-time and/or historical trending ofany four test parameters simultaneously (PO2, PCO2, pH,glucose, lactate, BUN, co-oximetry, sodium, potassium, chlorideand ionized calcium). Onboard patient trending helpshealthcare providers to follow the progress of their patient’scondition during the course of treatment. Respiratory therapistscan trend any four blood gas and co-oximetry parameters.

In the ICU, a single set of data has very little predictive powerunless it is set in context with other data. Only then can

From Data to ActionableInformation

Making a Difference in the Intensive Care Unit

Thomas Klein, MD, MSc

actionable information be derived. One of the burning issues inthe ICU with regard to following a patient’s trend and reactingimmediately is tight glycemic control.

In 2001 Greet Van den Berghe published a ground-breakingstudy, the first to clearly demonstrate the benefits of tightglycemic control in the ICU. This randomized controlled trialincluded 1548 patients in a mainly surgical intensive care unitreceiving mechanical ventilation. The study compared mortalityand morbidity in relation to intensive insulin therapy (IIT),aiming at a tight glucose control (TGC) (glucose level 80 - 110mg/dl) with conventional treatment (insulin infusion if glucose >215 mg/dl; maintenance glucose 180 - 200 mg/dl). Glucose wasdetermined using a blood gas analyzer at 1- to 4-hour intervals.

The results were impressive: intensive insulin treatment resultedin a 42% reduction in mortality compared with conventionalinsulin treatment. The greatest reduction documented related todeaths due to multiple organ failure with a septic focus.Incidence of morbidity was unrelated to a history of diabetes orhyperglycemia. Intensive insulin treatment also significantlyreduced the need for prolonged ventilatory support, renalreplacement therapy, and prolonged use of antibiotics (lowerrate of bacteremia). It also reduced the length of stay in theintensive care unit.

This study highlighted the value of TGC and hence of glucosedetermination on the spot for IIT. Rapidly available glucose

results are a prerequisite for TGC, and they enablea more efficient use of intensive care resources.With a Roche blood gas analyzer, intensive careunit caregivers have convenient access to a self-contained glycemic control platform for measuringand tracking glucose results.

Note, Figure 1: The figure in this article is adaptedfrom Intensive Insulin Therapy In Critically IllPatients, by Greet Van Den Berghe, MD, PhD;Pieter Wouters, MSc; Frank Weekers, MD; CharlesVerwaest, MD; Frans Bruyninckx, MD; Miet Schetz,MD, PhD; Dirk Vlasselaers, M; Patrick Ferdinande,MD, PhD; Peter Lauwers, MD; Roger Bouillon, MD,PhD, The New England Journal of Medicine,Volume 345 November 8, 2001 Number 19,downloaded from www.nejm.org at HoffmanLaRoche on March 23, 2006, © 2001 MassachusettsMedical Society.

Respiratory Therapy Special Supplement (2007) 3

The Surviving Sepsis Campaign (SSC), an initiative of theEuropean Society of Intensive Care Medicine, the InternationalSepsis Forum, and the Society of Critical Care Medicine, hasbeen developed to improve the management, diagnosis, andtreatment of sepsis. The SSC aims to reduce mortality fromsepsis via a multi-point strategy, primarily:

• Building awareness of sepsis• Improving diagnosis • Increasing the use of appropriate treatment • Educating healthcare professionals • Improving post-ICU care • Developing guidelines of care • Facilitating data collection for the purposes of audit and

feedback

The website survivingsepsis.org provides information andresources for patients, healthcare professionals, and the generalpublic.

Severe Sepsis BundlesThe SSC site has arranged its information for caregivers in so-called “bundles,” whereby specific information can be searchedquickly and handily. The Severe Sepsis Bundles are a distillationof the concepts and recommendations found in the practiceguidelines. They are designed to allow teams to follow thetiming, sequence, and goals of the individual elements of care,in order to achieve the goal of a 25% reduction in mortality fromsevere sepsis. Individual hospitals can use the bundles to createcustomized protocols and pathways specific to theirinstitutions. However, the SSC notes that all of the elements inthe bundles should be incorporated in those protocols. Theaddition of other strategies not found in the bundles is notrecommended. The bundle forms the basis for themeasurements that improvement teams can conduct to followtheir progress.

To achieve the greatest results, hospitals are urged toincorporate two Severe Sepsis Bundles. Each bundlearticulates requirements for specific timeframes. The SepsisResuscitation Bundle is for tasks that should begin immediately,but must be done within 6 hours for patients with severe sepsisor septic shock. The Sepsis Management Bundle is for tasks thatshould begin immediately, but must be done within 24 hours forpatients with severe sepsis or septic shock.

The ConceptA “bundle” is defined as a group of interventions related to a

disease process that, when implemented together, result inbetter outcomes than when implemented individually. Thescience behind the elements of the bundle is well-established asgenerally accepted practice. Bundle components can be easilymeasured as completed or not completed. As such, the overallbundle, all of the elements taken together, can also be measuredas completed or not completed.

The SSC recommends that in general, teams should take thebundles and build protocols for use at their own institutions.The protocols should very closely mirror the bundles, but allowflexibility for logistical and other needs specific to the localhospital. It is important to accurately mirror the content of thebundles in any given approach because the measures used toassess progress are designed around the specificationscontained in the bundle elements.

The severe sepsis bundles form the core of the implementationphase of the Surviving Sepsis Campaign. Bundle science is theresult of an integration of medical science and improvementwork. Several years ago, as a part of an Institute for HealthcareImprovement (IHI) initiative on care in the ICU, participantsconsidered a small set of evidence-based interventions forpatients on mechanical ventilation. These interventions were:DVT prophylaxis, peptic ulcer disease prophylaxis, elevation ofthe head of the bed, and sedation vacation. This set of fourinterventions is known as the ventilator bundle. Each of theteams measured the degree of compliance with the bundle,giving credit for medical contraindications. For each patient, a 1or 0 was recorded, indicating whether or not all four elementsof the bundle were implemented. A marked reduction inventilator-associated pneumonia was noted when teamsconsistently implemented the bundle.

The use of the bundle prompted various disciplines in the ICUto reorganize their work. The results for ventilator-associatedpneumonia were interesting and unexpected because for onlytwo of the four elements in the bundle was there any scientificevidence that the element itself would reduce ventilator-associated pneumonia. This new method of clinicalimprovement, a bundle process that combines the best ofmedical science and improvement science, is developed in thefollowing way:

1. Identify a set of four to six evidence-based interventions thatapply to a cohort of patients with a common disease or acommon location.

2. Develop the will in the providers to deliver the interventionsevery time they are indicated.

3. Measure compliance as “all” or “nothing.”

The Surviving Sepsis CampaignLes Plesko

Les Plesko is editor of Respiratory Therapy.

4. Redesign the delivery system to ensure the interventions inthe bundle are delivered.

5. Measure related outcomes to ascertain the effects of thechanges in the delivery system.

The sepsis bundles were developed in just such a manner, basedon the experience of the ventilator bundle. The goal now is tomotivate the providers to deliver the sepsis interventions everytime they are indicated based on hospital policies. If the bundleelements are reliably performed the desired outcome ofreducing sepsis-related deaths by 25% can be achieved.

The Bundle ElementsThe sepsis bundles listed below distill the SSC practiceguidelines into a manageable format for use at most institutions.They represent specific changes the campaign has identified asessential to the care of severely septic patients. Following thebundles will eliminate the piecemeal or inappropriateapplication of standards for sepsis care that characterizes mostclinical environments today.

The bundles are not ready-made protocols for individualhospitals. Instead, hospitals should use them as a template tocreate customized protocols and pathways that will work wellwithin their institutions. All of the elements in the bundles mustbe incorporated into those protocols. If all of the elements ofthe bundles are not incorporated into a customized protocol,performance on the measures will suffer.

Sepsis Resuscitation BundleEvidence-based goals must be completed within 6 hours forpatients with severe sepsis, septic shock, and/or lactate > 4mmol/L (36 mg/dL). For patients with severe sepsis, as many asseven bundle elements must be accomplished within the first 6hours of presentation. Some items may not be completed if theclinical conditions described in the bundle do not prevail, butclinicians must assess for them. The goal is to perform allindicated tasks 100 percent of the time within the first 6 hoursof identification of severe sepsis.

• Bundle Element 1: Measure serum lactate • Bundle Element 2: Obtain blood cultures prior to antibiotic

administration • Bundle Element 3: Administer broad-spectrum antibiotic

within 3 hours of ED admission and within 1 hour of non-EDadmission

• Bundle Element 4: In the event of hypotension and/or serumlactate >4 mmol/L: a. Deliver an initial minimum of 20 mL/kg of crystalloid or

an equivalentb. Apply vasopressors for hypotension not responding to

initial fluid resuscitation to maintain mean arterialpressure (MAP) >65 mm Hg

• Bundle Element 5: In the event of persistent hypotensiondespite fluid resuscitation (septic shock) and/or lactate >4mmol/L: a. Achieve a central venous pressure (CVP) of >8 mm Hg b. Achieve a central venous oxygen saturation (ScvO2) > 70%

or mixed venous oxygen saturation (SvO2) > 65%

Sepsis Management BundleEvidence-based goals must be completed within 24 hours forpatients with severe sepsis, septic shock and/or lactate > 4mmol/L (36 mg/dl). For patients with severe sepsis, as many as

four bundle elements must be accomplished within the first 24hours of presentation. Some items may not be completed if theclinical conditions described in the bundle do not prevail, butclinicians must assess for them. The goal is to perform allindicated tasks 100 percent of the time within the first 24 hoursfrom presentation:

• Bundle Element 1: Administer low-dose steroids for septicshock in accordance with a standardized ICU policy. If notadministered, document why the patient did not qualify forlow-dose steroids based upon the standardized protocol.

• Bundle Element 2: Administer recombinant human activatedprotein C (rhAPC) in accordance with a standardized ICUpolicy. If not administered, document why the patient didnot qualify for rhAPC.

• Bundle Element 3: Maintain glucose control >70, but <150mg/dL

• Bundle Element 4: Maintain a median inspiratory plateaupressure (IPP) <30 cm H20 for mechanically ventilatedpatients

Measuring and Documenting the BundlesUsing the SSC performance improvement database will help theteam and hospital evaluate improvements necessary toconsistently achieve specific bundle elements. Engaging PDSA(Plan, Do, Study, Act) cycles for each bundle element whereperformance is lower than desired, will assist the team todevelop/alter protocols and order sets and put systems intoplace to correct deviations. The performance improvementdatabase allows users to enter data directly from individualpatient charts. In the background, the SSC database aggregatesthat information across units, institutions, or hospital systemsgauging success with the SSC quality indicators. At the end ofeach month, or any time desired, the data is transformed intobundle compliance graphs. This offers the visual stimulationnecessary to motivate the team toward positive change. Postingthe graphs presents opportunities for discussions at meetingsand in the unit or emergency department so that protocoladjustments, perhaps equipment purchases, or otherimplementation approaches can be acted upon. Entering datainto the database concurrently will reveal in real time if thebundles were achieved or if policy was followed. Retrospectivedata collection is not ideal because all too often, the carememory can be lost. The campaign recommends thatinformation is entered directly into the database not placed ontoa paper tool first and then entered. This duplicative effort yieldsno benefit.

The Severe Sepsis Quality Indicators should be used inconjunction with the bundles to help improvement teamsunderstand the measures that will be used to evaluate theirprogress in improving the care of severely septic patients.

The above information is adapted from the Surviving SepsisCampaign website, © 2001-2007 Society of Critical CareMedicine. The Site is owned and operated by the Society ofCritical Care Medicine, the International Sepsis Forum, and theEuropean Society of Critical Care Medicine for the benefit ofthe goals of the SSC. All services, content, data, information andother materials on or directly accessible from the Site areowned by the three societies. The Site is protected by UnitedStates and international copyright and trademark laws. Anothervaluable resource is the Institute for Healthcare Improvement.The Institute for Healthcare Improvement (IHI) is a not-for-



profit organization leading the improvement of health carethroughout the world. IHI was founded in 1991 and is based inCambridge, Massachusetts. IHI’s work is funded primarily

through its own fee-based program offerings and services, andalso through the support of a group of foundations, companies,and individuals.

Measuring Serum LactateThe Surviving Sepsis Campaign offers the following guide forthe measurement of serum lactate, as provided on its“bundle.”

Hyperlactatemia is typically present in patients with severesepsis or septic shock and may be secondary to anaerobicmetabolism due to hypoperfusion. The prognostic value ofraised blood lactate levels has been well established in septicshock patients,1 particularly if the high levels persist.2,3 Inaddition, blood lactate levels have been shown to havegreater prognostic value than oxygen-derived variables.4

Obtaining serum lactate is essential to identifying tissuehypoperfusion in patients who are not yet hypotensive butwho are at risk for septic shock.

However, the interpretation of blood lactate levels in septicpatients is not always straightforward. A number of studieshave suggested that elevated lactate levels may result fromcellular metabolic failure in sepsis rather than from globalhypoperfusion. Elevated lactate levels can also result fromdecreased clearance by the liver.

Given the high risk for septic shock, all patients with elevatedlactate > 4 mmol/L (36 mg/dl) will enter the early goal-directed therapy portion of the Severe Sepsis ResuscitationBundle, regardless of blood pressure.

This approach is consistent with the trial that established thevalue of early goal directed therapies.5

Serum lactate must be available in your institution with rapidturnaround time (within minutes) to effectively treat severelyseptic patients. An arterial blood gas analyzer located in theclinical laboratories usually accomplishes this. However, anymeans of rapid turnaround time will be acceptable. It isessential for hospitals to invest in adequate equipment inorder to meet present standards of care for septic patients.

The technique of obtaining serum lactate by venipuncturetypically carries a 24- to 48-hour turnaround time and will notbe suitable to care for septic patients. This technique alsorequires special collection conditions, such as without theuse of tourniquet, hindering clinical care.

Tips• If serum lactate is not rapidly available in your institution,

invest in equipment to make rapid assessment possible.This should be presented to hospital and laboratoryadministration as a present standard of care.

• Create a standardized protocol to manage severe sepsisthat includes measurement of serum lactate.

• Include a prompt on arterial blood gas requisitions orphysician order entry to prompt users to order lactate forsuspected severe sepsis.

References1 Weil MH, Afifi AA. Experimental and clinical studies on

lactate and pyruvate as indicators of the severity of acutecirculatory failure (shock). Circulation. 1970;41:989–1001.

2 Vincent JL, Dufaye P, Berre J, et al. Serial lactatedeterminations during circulatory shock. Critical CareMedicine. 1983;11:449–451.

3 Friedman G, Berlot G, Kahn RJ, et al. Combinedmeasurements of blood lactate concentrations and gastricintramucosal pH in patients with severe sepsis. CriticalCare Medicine. 1995;23:1184–1193.

4 Bakker J, Coffernils M, Leon M, et al. Blood lactate levelsare superior to oxygen derived variables in predictingoutcome in human septic shock. Chest. 1991;99:956–962.

5 Rivers E, Nguyen B, Havstad S, et al. Early goal-directedtherapy in the treatment of severe sepsis and septic shock.New England Journal of Medicine. 2001;345:1368–1377.

Content adapted extensively from: Vincent JL, Gerlach H. Fluidresuscitation in severe sepsis and septic shock: An evidence-basedreview. Critical Care Medicine. 2004;32(11):(Suppl.)S451-S454.


Is there any doubt that sepsis is a serious problem? Of coursenot. But unlike many conditions which offer problematicmedical solutions, testing for, prevention of, and treatment forsepsis are all well within the bounds of the achievable.

According to an article in Critical Care,1 published on BioMedCentral, “Despite continuous advances in technologic andpharmacologic management, the mortality rate from septicshock remains high. Care of patients with sepsis includesmeasures to support the circulatory system and treat theunderlying infection. There is a substantial body of knowledgeindicating that fluid resuscitation, vasopressors, and antibioticsaccomplish these goals.”

The sepsis story begins, more often than not, in the emergencyroom, which has become the first line of care and even primarymedical resource for so many Americans. According to thestudy, “National estimates of severe sepsis in US emergencydepartments,”1 the ER often serves “as the first site for therecognition and treatment of patients with suspected severesepsis.” Authors Wang et al noted that out of 331.5 millionemergency room visits, about 2.3 million were for sepsis. Severesepsis patients account for 500,000 emergency visits each year,and patients spent about five hours per visit. “Nationally, fewother disease groups have this collective size, morbidity, andmortality.”

According to a recent study by Ngyuen et al, “patients sufferingfrom severe sepsis or septic shock have a mortality rate of20–54%. Among the 751,000 annual cases of severe sepsis in theUnited States, approximately 458,200 cases are firstencountered in the emergency department.”3

All the more reason that early identification and treatment forsepsis should be deemed a bulwark against the condition,insofar as identification and treatment can be readilyaccomplished in the ER or emergency department setting, andcan improve long-term outcomes.

In the Wang study, over a four-year period, one of 33 patientspresenting with infection was suspect for severe sepsis, withsymptoms of fever, respiratory infection, or genitor-urinaryinfection. Patients also presented with hypotension and/orcardiovascular dysfunction. These conditions were severeenough that more than half the study group, drawn from a non-metropolitan, middle class area, arrived at the emergency roomby ambulance.

Of course it makes sense that the emergency setting is wherepatients first show up with signs of sepsis, given its community-acquired nature. Yet, according to Wang and co-authors, “sepsiscare has not received the public health attention given topatients suffering from other conditions. Efforts to improve thecare of severe sepsis nationally offer hope if implemented inways analogous to these other illnesses, with broader strategiesto maximize public access to appropriate care.” Given the crisisof emergency room overcrowding, the authors suggest thatregional sepsis centers could offer the services currently offeredby specialized trauma and stroke centers. But whatever theapproach, guidelines need to be modified to accommodate earlyidentification and treatment.

Bundle UpOne solution to the sepsis crisis is the implementation of so-called “sepsis bundles” in ER departments. The idea of bundlesas treatment modalities has been refined by the “SurvivingSepsis Campaign,” a national effort to implement quality carethrough a unique method of grouping treatment strategies.2 Arecent hallmark study by Nguyen et al examined how bundlingcould be effective employed as part of the emergency protocol.In the study, “Implementation of a bundle of quality indicatorsfor the early management of severe sepsis and septic shock isassociated with decreased mortality,”3 researchers looked athow implementing a severe sepsis bundle provided “a qualityindicator set with feedback to modify physician behavior relatedto the early management of severe sepsis and septic shock.”

Ngyuen et al studied 330 emergency department patientsadmitted for severe sepsis or septic shock. The sepsis bundleapplied the following treatment parameters: 1) initiate centralvenous pressure monitoring within two hours; 2) provideantibiotics within four hours; 3) initiate immediate therapy andcomplete therapy by six hours; 4) administer corticosteroids ifappropriate; and 5) monitor for lactate clearance.

Quick ResultsUsing the sepsis bundle achieved quick results in many patients.According to Nguyen et al, “Bundle compliance increased fromzero to 51.2% at the end of the study period. During theemergency department stay, patients with the bundle completedreceived more CVP/SCVO2 monitoring and more antibioticscompared with patients with the bundle not completed.Completion of early goal-directed therapy was significantlyassociated with decreased mortality. In-hospital mortality wasless in patients with the bundle completed compared withpatients with the bundle not completed… Patients with thebundle completed had higher percentage compliance of all

Laszlo Sandor is a contributing editor to Respiratory Therapy.

Getting Our Priorities Straight: Treatment OfSevere Sepsis In The Emergency SettingLaszlo Sandor

Continued on page 9…

How can automated acid-basemapping help you deliver amore precise diagnosis andtherapy monitoring?Accurate, graphical acid-base mapping on the cobas b 221 bloodgas system can help clinicians:• Rapidly identify metabolic and respiratory acid-base disturbances

without the need for a calculator• Efficiently assist physicians to monitor the effectiveness of therapy• Easily distinguish between compensatory responses and mixed

acid-base disturbances• Differentiate between acute and chronic patient conditions

in complex environments such as the ED or ICU

Automated acid-base mapping on thecobas b 221 system creates a graphical

representation of patient results.

Assessing sepsis, and the right treatment, is not necessarily aneasy task. In the excerpt below, published online by BioMedCentral, several physicians hashed out possible treatmentscenarios for a number of complex cases. The excerpt is only apartial summary for the complete summary, please type the titleof the article into the BioMed Central search box.

Care of patients with sepsis includes measures to support the

circulatory system and treat the underlying infection. There is

a substantial body of knowledge indicating that fluid

resuscitation, vasopressors, and antibiotics accomplish these

goals. Recent clinical trials have provided new information on

the addition of individual adjuvant therapies. Consensus on

how current therapies should be prescribed is lacking. We

present the reasoning and preferences of a group of

intensivists who met to discuss the management of an actual

case. The focus is on management, with emphasis on the

criteria by which treatment decisions are made. It is clear

from the discussion that there are areas where there is

agreement and areas where opinions diverge. This

presentation is intended to show how experienced intensivists

apply clinical science to their practice of critical care

medicine.1

One case presented a 56-year-old male with nausea, shortness ofbreath, and diaphoresis. Over the previous 2 days he had noteda productive cough, associated with midline chest pain, shakingchills, and diarrhea. He had no abdominal pain and no swellingor pain in the legs. Over the past 3 months he had lost 30 lb(approximately 13.6 kg) in weight and he sought medicalattention for left shoulder pain. A bone scan was reportedlynegative. Physical examination revealed normal temperature,tachycardia. His respirations were labored, at 26 breaths/min,and oxygen saturation was 89%. He was put on a nonrebreathermask, and his oxygen saturation increased to 98%. Breathsounds were diminished in the right upper lung zones.

The first physician taking part in the roundtable noted that theman’s condition sounded like community-acquired pneumonia(CAP), possibly with an atypical pathogen. Perhaps the diarrheawas a red herring. Weight loss and left shoulder pain in a 53-year-old former smoker raises concern for lung cancer withpossible postobstructive pneumonia. “This patient also hasevidence of severe sepsis… He has respiratory failure… He isprobably hemoconcentrated, and clinically we would expecthim to be hypovolemic from diarrhea, high insensible losses,and poor oral intake.

The second doctor offered a different diagnosis: “I mightdisagree with you that this patient has severe sepsis. What if,

after 2 or 3 l saline, his blood pressure, heart rate, andcreatinine normalize? I think this illustrates one of the greatesttriage challenges in this area, and that is differentiating infectionwith sepsis from another very common scenario—infection withdehydration and hypovolemia. I think the most important pointis not to confuse sepsis with hypovolemia from any cause,including hemorrhage.

Other doctors in the roundtable added: The first steps in thecare of patients like this should be very systematic. Once thetachycardia was assessed and assuming the chest radiographconfirms pneumonia, I would initiate prompt antibiotic therapybased on the most likely type(s) of infection; ensure adequatehemodynamic and respiratory support; try to identify the sourceof infection; identify and ascertain the extent of his organdysfunction; and, based on that, develop an overall treatmentplan… We need to treat this suspected infection. Although achest radiograph is not initially available, there is a strongclinical suspicion for pneumonia, as a source of major infection,and empiric antibiotic coverage should be started.

The patient was given 2 l of normal saline and a chestradiograph was obtained. He was given a total of 18 mgadenosine with no response; and then 2.5 mg intravenousverapamil in three doses, with a decrease in heart rate to 110beats/min. Atrial fibrillation was diagnosed. His blood pressurefell with these interventions. The chest radiograph showed adense opacity in the right-upper lobe with patchy opacities inthe right-lower lobe, the lingula, and left-upper lobe. There wereno clear air bronchograms or lateral shift to suggest lobarcollapse.

The doctors’ diagnoses were as follows: There is no clearevidence of an endobronchial lesion or airway obstruction. This,along with the history of a recent negative bone scan, makescancer less likely. Active tuberculosis is possible, and sputumshould be sent for appropriate studies. With the complaint ofmidsternal pleuritic chest pain, there is concern of pericardialinvolvement. However, there are no suggestive changes on theECG, and the heart size looks normal, somewhat narrow, andprobably under-filled, which is consistent with hypovolemia…Do we need to consider any other diagnostic tests for CAP in apatient with severe sepsis?... The purist’s goal is to try toestablish a bacteriologic diagnosis, but the realization is thatone must initially treat broadly because no single test has thesensitivity and specificity to allow one to treat narrowly… Theinitial approach should be to volume replete him aggressivelyand see whether the hemodynamics improve, and then addressany persistent tachycardia only after he is volume replete. Inthis case, rate controlling agents may not be the first line of


Critical Care for Severe Sepsis

therapy, given a strong suspicion for sepsis. If the need arisesthen support him with invasive or noninvasive ventilation andget him through this… If you think the patient is more at riskfor death from severe sepsis than from demand ischemia, thenyour attention should be directed toward the interventions thatare most likely to give the patient benefit. Because this patienthad no prior history of coronary disease, the risk/benefit movesone step toward sepsis interventions rather than acutemyocardial infarction interventions.

The above is a much-truncated sample of a longer moreinvolved discussion, presented to highlight the particular andunique parameters that need to be assessed and addressedwhen dealing with cases of severe sepsis. However, as onedoctor noted, the data often “make a case for early treatment inall respects. Early intervention of almost anything is better thanlater intervention. Given what we know of the sepsis cascade,the further it rolls on the worse it gets. For most of us who havebeen sepsis investigators for a long time, the generalizedexpectation is that the earlier we intervene the better thechances that one can interrupt the sepsis cascade.”

The article concludes, “the analysis and commentary of the careprovided to [the] patient with severe sepsis and septic shockhighlight the challenges in assessing and managing critically illpatients. The participants provided their perspectives on therecognition of physiological instability and the definition ofsevere sepsis and septic shock; at what point a patient shouldbe admitted to the ICU; the importance of early goal-directedresuscitation therapy and the choice of resuscitation fluid; whento consider intravascular monitoring; the use of low-dosecorticosteroids and drotrecogin-alpha; and at what point animproving patient should leave the ICU. The… assessment ofthe patient begins with recognition of the signs and symptomsof a serious infection… Patients often present with tachycardiaand electrocardiographic abnormalities that may reflect sepsis,infection with vasodilation and hypovolemia or cardiacischemia. Distinguishing sepsis and an ineffective circulationfrom an acute coronary syndrome can be challenging. All of theparticipants agreed that, regardless, the most important effortshould be directed toward restoring adequate intravascularvolume. All agreed that the adequacy of volume resuscitationwas best determined from cumulative data, including serialhemodynamic measurements, measurements of arterial andcentral venous oxygenation, and the response to volumeinfusion.

Source1 Roundtable debate: Controversies in the management of the

septic patient—desperately seeking consensus. AaronWaxman, Nicholas Ward, Taylor Thompson, Craig Lilly, AlanLisbon, Nicholas Hill, Stanley Nasraway, Stephen Heard,Howard Corwin, Mitchell Levy. © 2004 BioMed Central Ltd,Critical Care 2005, © 1999-2007 BioMed Central Ltd.


quality indicators. There was no difference in ED length of stayand hospital length of stay between patients with the bundlecompleted compared with patients with the bundle notcompleted.” The study demonstrated that the use of antibiotics,therapy, administration of corticosteroids, and protein C andlung-protective strategies offered effective survival benefits.However, the authors noted, overall success in the treatment ofsevere sepsis must rely on effective sepsis managementtechniques, as well as the mapping of quality indicators to trackresults.

ImplementationIn the Nguyen study, once patients met participation criteria,hemodynamic monitoring was begun, and mechanicalventilation started if necessary. Corticosteroid was given forvasopressor-dependent patients or those with suspected adrenalinsufficiency. A repeat lactate level was obtained to assess forlactate clearance.

Nguyen’s study suggests that the severe sepsis bundle “can beimplemented as standard care through the use of compliancemeasurements and feedback. Using a stringent bundle andquality indicators, requiring CVP and SCVO2 monitoring, currentcompliance is also relatively higher than with other therapies forsevere sepsis. Lung-protective strategies have been achievedonly in 39% of patients on day 2 of acute lung injury. Tightglucose control was achieved in 19% of the time with routineinsulin protocols. The administration of rhAPC was 14.3% inpatients with bundle completed in this study. The bundle isunique in that it is applicable during the earliest hours of severesepsis presentation. The items themselves are inherent qualityindicators with supporting evidence associated with improvedoutcome. Most important, the bundle quality indicators wereaccepted by the implementing physicians as valid and feasible apriori bundle implementation.”

The study concluded that the severe sepsis bundle could besuccessfully applied in the emergency department, using thebasic model, with no need for additional staff, and thatcompletion of the severe sepsis bundle program gave strongindicators associated with improved outcome.

Sources1 National estimates of severe sepsis in United States

emergency departments. Henry E. Wang, MD, MS; Nathan I.Shapiro, MD, MPH; Derek C. Angus, MD, MPH; Donald M.Yealy, MD. Copyright © 2007 by the Society of Critical CareMedicine and Lippincott Williams & Wilkins.

2 For more, see the article on the Surviving Sepsis Campaign inthis issue.

3 Implementation of a bundle of quality indicators for the earlymanagement of severe sepsis and septic shock is associatedwith decreased mortality. H. Bryant Nguyen, MD, MS; StephenW. Corbett, MD, PhD; Robert Steele, MD; Jim Banta, PhD,MPH; Robin T. Clark, BS; Sean R. Hayes; Jeremy Edwards;Thomas W. Cho, MD; William A. Wittlake, MD. Copyright ©2007 by the Society of Critical Care Medicine and LippincottWilliams & Wilkins.

Priorities, continued from page 6

Why is a 1-minute bilirubin testespecially important in the NICU?Timely monitoring of critical newborns can reduce the risk of

potentially life-threatening diseases and enhance neonatal care for

hyperbilirubinemia.

Kernicterus is a serious condition that can occur in infants with elevated

bilirubin levels ( >20 mg/dL).1 The cobas b 221 blood gas system

can help reduce the risk of kernicterus by delivering fast, actionable

bilirubin results in the NICU.

The cobas b 221 system delivers bilirubin results

in 1 minute or less.


Sepsis-InducedHypoperfusionThe following is an edited version of the article, HemodynamicOptimization of Sepsis-Induced Tissue Hypoperfusion by Sergio L. ZanottiCavazzoni and R. Phillip Dellinger, with the Robert Wood Johnson MedicalSchool, University of Medicine and Dentistry of New Jersey, Camden, NJ,reprinted from BioMed Central, Critical Care 2006, 10 (Suppl 3):S2, © 2006BioMed Central Ltd.

Severe sepsis and septic shock are among the most importantcauses of morbidity and mortality in patients admitted to theintensive care unit. Sepsis is associated with a spectrum ofcardiovascular derangements that may lead to development oftissue hypoperfusion.

The hemodynamic profile of severe sepsis and septic shock ischaracterized by components of hypovolemic, cardiogenic, anddistributive shock. In the early phases, increased capillary leakand increased venous capacitance will result in a decrease invenous return to the heart. Cytokines released as a result of thehost response to sepsis may also cause direct myocardialdepression. The end result of these changes is a decrease instroke volume and ejection fraction, leading to a compensatorytachycardia, increased ventricular compliance, and a decreasein arteriolar resistance. Fluid therapy and administration willmodify this hemodynamic profile. In the early stages of sepsis,prior to fluid therapy, patients may present with a decreasedcardiac output. Fluid therapy will usually result in ahyperdynamic state with a high normal or elevated cardiacoutput. After adequate restoration of left ventricular preload,hypotension – if present – is dependent on the degree ofdecreased systemic vascular resistance and on impairment ofcontractility.

Even with restoration of adequate blood pressure and normal orsupranormal cardiac output, signs of tissue hypoperfusion maypersist. This distributive shock may be related to maldistri-bution of blood flow at the regional or microvascular leveland/or a cellular inability to utilize oxygen despite adequateoxygen delivery. It is believed that early intervention withaggressive hemodynamic support can limit the damage ofsepsis-induced tissue hypoperfusion and limit or prevent thedevelopment of endothelial injury. Support for this hypothesis isoffered by the results of the early goal-directed therapy (EGDT).

Septic shock has traditionally been utilized to conceptualize theclinical syndrome of persistent sepsis-induced tissuehypoperfusion. Blood pressure alone is unlikely to be sufficientin identifying the presence or absence of tissue hypoperfusionin patients with sepsis; patients with sepsis-inducedhypoperfusion can present with normal blood pressures. It istherefore important to recognize other signs. Markers of tissuehypoperfusion can be classified into two groups: indices ofglobal hypoperfusion and indices of regional hypoperfusion. Arecent International Sepsis Definitions Conferencerecommended expanding the diagnostic criteria for sepsis.Many of these criteria, including altered mental status, organdysfunction parameters, acute oliguria, hyperlactatemia anddecreased capillary refill or motling, suggest the presence oftissue hypoperfusion. It is clinically important that tissuehypoperfusion be recognized, despite what may appear to be

normal blood pressures, and should trigger timely andaggressive hemodynamic support interventions.

Patients with evidence of sepsis-induced tissue hypoperfusionshould be treated in a monitored area, preferably an intensivecare unit. Noninvasive monitoring with continuous electrocar-diography and pulse oximetry should be initiated. Arterialpressure monitoring with an indwelling arterial catheter canprovide accurate and continuous blood pressure measurements.This is especially useful in patients with very low blood pres-sures, in whom noninvasive blood pressure measurements maybe inaccurate, or in patients on vasopressors, in whom suddenchanges in blood pressure may occur. The radial artery ispreferred, although the femoral artery is also commonly utilized.

Central venous pressure has been used for many years as amonitor of central venous blood volume. Normal CVP isapproximately 2–8 mmHg. It is commonly accepted that a verylow CVP is indicative of low intravascular volumes and supportsthe administration of crystalloids or colloids for volumeexpansion and improvement in tissue hypoperfusion. However,an elevated CVP does not always correlate with adequateintravascular volume.

Despite the ongoing debate surrounding use of the pulmonaryartery catheter, it is still utilized and when used appropriately itcan provide important information to assist in choosinghemodynamic interventions in patients with sepsis. The PACallows measurements of intracardiac pressures, determinationof cardiac output and mixed venous oxygen saturation.Information obtained from the PAC can be useful in diagnosingdifferent causes of shock as well as monitoring diseaseprogression and response to therapeutic interventions. Thepulmonary artery occlusion pressure, as a reflection of leftventricular end-diastolic pressure, is presumed to correlate withleft ventricular end-diastolic volume. Although cliniciansassume that a high PAOP represents a high intravascularvolume, many patients with elevated PAOP may still requirehigher intravascular volumes to ensure that there is adequateCO in patients with decreased ventricular compliance. Changesin PAOP in relation to intravascular volume are stronglyinfluenced by myocardial compliance. It is important torecognize this relationship and appreciate that myocardialcompliance may be different from patient to patient and mayalso change in an individual patient through the course ofcritical illness. It is useful to utilize the information provided bythe PAC in a dynamic way, assessing changes in PAOP and theirimpact on CO as hemodynamic interventions are instituted.

SvO2 can be measured in patients using a PAC. Thedeterminants of SvO2 include CO, oxygen demand, hemoglobin,and arterial oxygen saturation. Normal SvO2 is 70–75%. In sepsisSvO2 may be elevated secondary to maldistribution of flow.However, patients with sepsis may also present with a low ornormal SvO2. Values of SvO2 must be interpreted within theoverall context of the hemodynamic profile. Although a normalor high SvO2 does not always indicate adequate resuscitation, alow SvO2 should trigger aggressive interventions to increaseoxygen delivery to the tissues and minimize sepsis-inducedtissue hypoperfusion.

Recently, continuous measurement of central venous oxygensaturation using a central venous catheter has garneredincreasing attention. But monitoring techniques do not directly

affect outcome. It is the proper use of this information to guideclinical interventions that potentially has an impact on patientoutcomes. Current recommendations for hemodynamicmanagement of septic shock include arterial canulation formonitoring of blood pressure and assessment of cardiac fillingpressures.

The principal goals of hemodynamic support in patients withsepsis are restoration of effective tissue perfusion andnormalization of cellular metabolism. In order to facilitatehemodynamic optimization targets for treatment includeintravascular volume, blood pressure, and CO.

Restoration of adequate intravascular volume should be the firstgoal in resuscitation. Adequate intravascular volume should bedetermined by achieving filling pressures associated withmaximal increases in CO. In patients who are not undergoinginvasive monitoring, establishing goals for clinical markers ofperfusion such as heart rate, mean arterial pressure, and urineoutput is appropriate. However, in many patients these markersmay be unreliable as sepsis-induced tissue hypoperfusion mayoccur even with normal values. Changes caused by positivepressure ventilation in systolic arterial pressure or pulse arterialpressure can predict which patients will respond to fluid loadingwith an increase in their CO. The degree of change observed insystolic arterial pressure or pulse arterial pressure during therespiratory cycle correlates directly with the response in termsof CO augmentation that a patient will have to a predeterminedfluid challenge.

Blood flow to vital organs is usually preserved at a relativelyconstant rate by autoregulatory mechanisms when mean arterialpressure is maintained between 60 and 120 mmHg. When MAPdrops below 60 mmHg hypoperfusion can occur. It is importantto appreciate that in patients with chronic hypertension therelationship between MAP and organ perfusion might be shiftedto the right. This means that patients with chronic hypertensionmight need a higher MAP to ensure that there is adequate organflow to vital organs. Current guidelines recommend themaintenance of a MAP of 65 mmHg or greater as an endpointfor resuscitation. It is important to supplement this end-pointwith other markers of perfusion as well as clinicalconsiderations.

Most patients with sepsis will have adequate CO after aggressivefluid resuscitation. However, in early unresuscitated sepsis andin a subgroup of patients later in the disease process and afteradequate resuscitation, there is evidence of low or inadequateCO. The CO can be measured using thermodilutionmeasurements with PACs and echocardiographically derivedmeasurements. In addition, the measurement of SvO2 or ScvO2

can be utilized as a surrogate for adequate CO. As a general ruleone should aim for a cardiac index (CO [l/min]/body surfacearea [m2]) of 3.0 l/min per m2 or greater. A SvO2 of at least 65%or a ScvO2 of at least 70% can be used as targets of adequateoxygen delivery.

The Surviving Sepsis Campaign recommends that the followingend-points of resuscitation be targeted: CVP 8-12 mmHg (higherin mechanically ventilated patients); MAP at least 65 mmHg;urine output at least 0.5 ml/kg per hour; and ScvO2 or SvO2 of atleast 70%.

TherapyThe initial step is aggressive fluid resuscitation. There is,however, controversy over the optimal type of fluid, crystalloidsversus colloids. Meta-analyses of clinical studies performed ingeneral critical care patient populations have demonstrated nodifference in clinical outcomes between patients fluidresuscitated with crystalloids and those receiving colloids, soextrapolation of these results to patients with sepsis-inducedtissue hypoperfusion is difficult. In patients with septic shocktargets of resuscitation can be achieved with both types.

Patients with sepsis-induced tissue hypoperfusion often presentwith significant intravascular volume deficits. It is important toinitiate aggressive resuscitation as soon as possible. The firststep should be an adequate volume challenge with at least 20cc/kg of crystalloids or an equivalent amount of colloids.Resuscitation should continue until end-points of CVP, MAP, andCO are met with the administration of fluid challenges. Onceend-points are met it is important to re-evaluate tissue perfusioncontinuously to determine the need for further volumeexpansion.

Blood transfusions have been associated withimmunosuppression, and there are concerns regarding theultimate ability of stored red blood cells to carry and deliveroxygen. It is probably appropriate to target hemoglobin of 8–10g/dl in patients with sepsis, recognizing that some patients withaltered oxygen transport will likely benefit from bloodtransfusions targeted at achieving a ScvO2 or 70% or more.

Some patients may remain hypotensive despite adequate fluidreplacement. In these patients vasopressor agents to increaseMAP should be utilized. Catecholamines have traditionally beenused to raise blood pressure in patients with septic shock. Theideal vasopressor has been a subject of unresolved discussion.Important factors to consider in choosing a vasopressor includeother hemodynamic effects, individual patient characteristics,and potential effects of vasopressors on regional vascular beds.

Vasopressors should be utilized in patients who remainhypotensive after volume expansion or during volumeresuscitation in the presence of life-threatening hypotension.Vasopressor therapy should be targeted to maintain a MAP of 65mmHg or greater. Norepinephrine or dopamine should be usedas first-line agents to correct hypotension in patients withsepsis. Epinephrine and phenylephrine are recommended inpatients who do not respond to initial vasopressors. Finally,vasopressin is not recommended as a first-line agent. It can beused as hormone replacement, given at low doses 24 hours afterthe onset of shock, in cases refractory to other vasopressors.

Cardiac function is impaired in most patients withsepsisinduced hypotension after fluid resuscitation. Myocardialdysfunction in sepsis is complex and usually characterized byventricular dilation, decreased ejection fraction, and impairedcontractile response to fluid resuscitation. In patients with lowCO despite fluid administration, it is recommended thatinotropic agents be utilized to increase CO. The agent of choiceis dobutamine, which at doses ranging from 2 to 28 µg/kg permin results in increased cardiac index, stroke volume, and heartrate in patients with sepsis. In patients with hypotension,dobutamine should be used in conjunction with a vasopressoragent. Dopexamine has also been proposed, but it is notcurrently approved for use in the US. The use of inotropes to


achieve supranormal or supraphysiologic CO in sepsis is notrecommended. Current recommendations strongly emphasizethat strategies to increase oxygen delivery beyond normalvalues should not be implemented in patients with sepsis.

Although we have much to learn regarding this very importantaspect of sepsis, it is important to recognize tissuehypoperfusion as a medical emergency. As such it is essential toimplement therapeutic interventions. The initial interventionshould be administration of crystalloids or colloids. For patientswho require vasopressors, norepinephrine or dopamine shouldbe utilized as first-line agents. Some patients may requiredobutamine to increase low CO. Implementation ofhemodynamic interventions targeting predefined end-points is atime-sensitive therapy that has a significant impact ondecreasing morbidity and mortality from sepsis.

BLOOD GAS ROUNDTABLE

Roche DiagnosticsLarry HealyLarry Healy is Marketing Manager, Point of Care Diagnostics, RocheDiagnostics

Has your equipment facilitated results reporting throughthe hospital information systems, and if so, which systemsinterface effectively with your equipment?Roche Diagnostics offers specific IT and Data Managementsolutions with the cobas b 221 system to help hospitalsmaximize workflow efficiency and result reporting forRespiratory Therapy, the Laboratory and POC. For example,DataCare software enables staff to effectively manage patientdata for all areas. OMNILink Instrument Manager softwareoffers command and control of decentralized blood gas systems,and Axeda protected remote access provides virtual onsitetechnical support to help maximize instrument uptime. In thecentralized setting of the laboratory, interfacing with the LIS/HISthrough existing Middleware connections can significantlyreduce the cost and set-up time for blood gas connectivity. Andwith RALS-Plus data management software from MAS, POCCoordinators have a single IT solution for both blood gas andglucose.

What features (ie data storage) assist you when preparingfor lab inspections from JCAHO, CAP, FDA etc?Roche offers a full suite of blood gas, IT and Web-basedsolutions that help simplify regulatory compliance forhealthcare facilities. With 20 GB of onboard data storage, thecobas b 221 system maintains an average of five years worth ofQC, calibration and patient data for review and reporting, tosupport users with limited or no LIS capabilities. OMNILinksoftware allows remote screen sharing of decentralized systemsand immediate access to QC, calibration, and maintenance logsfrom these systems. RALS-Plus and DataCare data managementsoftware reporting functions generate the necessarydocumentation to meet compliance standards. And eQAP offersreal-time peer review of QC to help ensure system proficiency.

What do you see as an emerging trend in blood gastechnology?With the trend of managing patient health outcomes throughstandards of care, healthcare professionals need blood gassystems to do more in less time. As a result, blood gas systemsare beginning to offer expanded menus with whole bloodanalysis and rapid turnaround time, which is especiallybeneficial in high-cost areas like the ICU and the ED.

Is point of care blood gas testing becoming widelyaccepted? If so, what are the benefits?Recent market research indicates that blood gas testing ismoving to the decentralized areas of the ICU, NICU, OR and ED.This trend toward point-of-care testing can offer several benefitsto the healthcare facility and its patients. For example, POCblood gas testing with the cobas b 221 system can help reduceturnaround time for results and give the clinician immediateaccess to actionable information that can help in diagnosis,treatment decisions, monitoring the patient’s condition andevaluating response to treatment.

What barriers to implementation have you seen when aPOC Coordinator, RT director, lab manager or medicaldirector decides to purchase point of care systems?The specific barrier depends on the person’s role, of course, butthe most common concerns include ease of use, maintainingcommand and control, and making the “paradigm shift” to dotesting at the point of care. Current blood gas technology offersseveral capabilities that help overcome those barriers, though.For example, Roche’s cobas b 221 system has a multi-userinterface that makes it easier for all operators to use. Staff withcommand and control concerns—like the POC Coordinator, RTDirector and Lab Manager—have the ability to direct, monitorand report the activities of all their decentralized blood gassystems with OMNILink Instrument Manager software. Andhaving immediate access to actionable information can make iteasier to gain the medical staff’s acceptance of point-of-careblood gas testing.

Compare the blood gas technology of the past with today’sstandard as it relates to your hospital.Blood gas technology has evolved to match changing standardsof patient care. Today, blood gas systems need to maintain ahigh state of readiness, deliver results faster, providecomprehensive test menus that are driven by disease states, andoffer information technology solutions.

To maintain immediate readiness and ensure operator safety,most systems today are self-calibrating, without gas tanks, andhave programmable onboard AutoQC. Smaller sample sizes andindependent sample paths also help some systems deliver rapidturnaround on results. And analyzers like the cobas b 221system offer additional features like continuous self-monitoring,which provides updates on pending maintenance, to increaseinstrument uptime.

Because test menu parameters today are driven primarily bydisease states, on some systems they now go beyond basicblood gas profiles to include electrolytes, metabolites, COOXand bilirubin. The systems must have flexible sample inputs forsyringes and capillaries and the ability to run whole blood,serum plasma, body fluids and dialysate. Measurement rangeshave been expanded too, as a result of new cardiovascularprocedures and IV therapies.


The biggest change in blood gas technology, though, is in the ITarea. Information solutions like data and instrumentmanagement software, protected remote access and HIS/LISconnectivity have resulted in a true information paradigm shiftin blood gas technology and in its relationship to other point-of-care testing areas.

Pleural Fluid pH Analysisin the Blood GasLaboratoryThis article is specifically addressing the role of the Respiratory CarePractitioner (RCP) in the role of body fluid analysis and specifically pleuralfluid pH. Before we take an in depth look at this analyte we must firstlook at the pathophysiology of this pneumonic process.

Pleural effusion is the accumulation of fluid in the chestbetween the lung and the chest cavity. Normally there is nospace between the parietal pleura, which covers the chest wall,and the visceral pleura, which covers the lung. The normal fluidthat is present facilitates the mechanics of ventilation thatmaintains a negative intrapleural pressure therefore allowingthe lungs to remain expanded. For a diagnosis of pleuraleffusion, 75% of those patients will have a diagnosis made at theonset of the clinical findings presented. 25% of those patientswill have a positive cytology or positive culture of the aspirateanalyzed. Fifty percent of those patients have a presumptivediagnosis prior to the laboratory findings. Fifteen to 20% of thepatients will not have a diagnosis made prior to diagnosticstudies. The history and physical (H & P) exam are critical inguiding the evaluation of the pleural effusion and it isimperative that an extensive H & P be obtained from the patient.Chest examination demonstrates dullness to percussion anddiminished breath sounds, which may be, but are notnecessarily gravity dependent. Confirmation of a pleuraleffusion may include an Anterior-Posterior radiograph, lateraldecubitus whereby the patient lays on their side, and/or CT ofthe chest and abdomen. The interpretive physician is looking forclear radiographic findings that suggest a pleural spaceinfiltrate. The definitive diagnosis is a thoracentesis wherebythe physician performs a needle aspirate to a local anesthetizedarea of the chest wall and inserts the needle into the pleuralspace now occupied by an infiltrate. The sample must beobtained under anaerobic conditions, iced, and analyzed withintwo hours preferentially through the “gold standard” Blood GasAnalyzer (BGA). If the sample is not iced, in vitro glycolysis willoccur resulting in a false low pH. If the sample is exposed toroom air, then a false high pH will occur due to gasequilibration. The sample, by most clinical standards of medicalpractice, should include a diagnostic order for LDH, Protein,Glucose, Amylase, Cell Count, Cytology, and cultures in additionto pH analysis. There are about 1 million cases per year ofpleural effusions and primarily are subcategorized as transudate(movement of fluid into the pleural space due to imbalance ofhydrostatic and oncotic pressures) or exudative (caused byinflammation of the lung or pleura) effusions. Trasudativeeffusions normally have a pH 7.40-7.55 and exudative effusionsnormally have a pH less than 7.45. Categorically, most of theeffusions are by congestive heart failure, malignancy, infections,and pulmonary emboli, requiring urgent evaluation and

treatment. It is interesting to note that 25% of the pleuraleffusions are resolved within 48 hours with aggressive diuretictherapy. Cirrhosis, pulmonary embolus, infection, malignancy,immunologic disorders, lymphatic abnormalities, non-infectiousinflammation and nephritic syndrome are other commonetiologies of transudative pleural effusions. Decreased glucosein the pleural fluid may indicate a malignancy, empyema, and acomplicated parapneumonic effusion, or tuberculosis to namejust a few disease entities. Normal pH of pleural fluid is 7.60.American College Chest Physicians (ACCP) and the BritishThoracic Society agree that pH values less than 7.20 are acritical value with a parapneumonic infection and will requireimmediate drainage via chest tube insertion. 20-25% ofpneumonia patients have a parapneumonic infection and willresolve with aggressive antibiotic therapy. Decreased glucosewith a decreased pH signals the possible diagnosis of amalignant pneumonic process. A pH less than 7.28, with amalignant pneumonic process, has a 39% mortality after 3months. Two negative cytologys with a low pH indicate possibletuberculosis or rheumatoid pleurisy.

Several analytical methods have historically been performedover the years. The methods that have been and currently arebeing utilized are the pH meter, pH indicator strips, and theBlood Gas Analyzer (BGA). In studies reported in Chest (1998),pH meters and pH indicator paper reported significantly highermean pH than the BGA; therefore the clinical and researchfindings as stated earlier in this article were that the BGA is thegold standard for pleural fluid pH analysis. Blood GasLaboratories must meet regulatory standards as set forth byCLIA and other regulatory agencies such as College of AmericanPathologists (CAP). The method of testing falls into three CLIAclassifications of waived, moderately complex, and highlycomplex categories. The BGA fall into either the moderatelycomplex or high CLIA complexity category depending uponwhether the BGA has undergone 510K FDA clearance foranalyzing pleural fluid pH. It is each laboratory’s responsibilityto determine if their BGA has met the FDA clearance foranalyzing pleural fluid pH. If your instrument is 510 K FDAcleared, then CLIA recognizes this instrument’s analyte as amoderately complex instrumentation. If the BGA is not FDAcleared which is referred to as “off-label,” then the analyte isconsidered to be reported from high complexity instrumentationand must meet the 6 point high complexity CLIA category.Pleural fluid pH analyte reported from a moderate complexBGA has less regulatory requirements from CLIA as opposed toan “off-label” BGA that must meet more CLIA regulations. CLIAdoes not recognize the waived category for pleural fluid pH soto use litmus paper you must meet CAP guidelines ofproficiency testing, daily QC, method validation, and personneltraining and competency validations. The use of litmus paper iscompromised by the fact that the test results cannot be reportedin hundredths (X.XX) and the accuracy needs to be reported tothis mathematical expression, as accuracy is the critical factorin reporting pleural pH. Litmus paper relies on colorimetricdeterminations and has a falsely reportable high value aspreviously mentioned in Chest. PH meters expose the anaerobicsample to room air and have falsely high reportable pH as well.Pleural fluid samples when analyzed through the BGA should becautiously analyzed with the addition of a clot catcher betweenthe syringe and the BGA sample inlet port or an internal clotcatcher as the pleural sample presents a small risk of BGAclotting contaminates much like other blood samples introducedinto a BGA such as neonatal or patients with polycythemia.


Why use a blood gas systemwith FDA 510(k) clearancefor pleural fluid pH testing?

Only the cobas b 221 blood gassystem is FDA 510(k)-cleared

for pleural fluid pH testing.

The College of American Pathologists and articles in Chest cite blood

gas analyzers as the “method of choice” for measuring pleural fluid

pH,1,2 and only one analyzer is FDA-cleared to help you achieve regulatory

compliance: The cobas b 221 blood gas system.

Pleural fluid pH can be a clinically useful tool for managing

patients with pleural effusions—and can be especially

important in critical care environments such as the ED.

Critical values must be determined to meet CAP standards anddocumented like any other critical value in your laboratory. Wehave established any value less than 7.20 as a critical result andmust be called and read back to the ordering physician to meetCLIA, CAP, JCAHO, and other accreditation standards.

Body fluids must meet proficiency testing just like any otheranalyte and can be ordered from the CAP web site. These areperformed twice a year and reported using similar proficiencytesting methodologies.

In summary, pH pleural fluid testing provides the physician witha valuable diagnostic test that complements the clinicaldecisions necessary to provide excellence in patient outcomes.Not only does the diagnostic testing provide a diagnostic tool,but also from the financial aspect it is a revenue stream withinyour departmental operations.

Bilirubin DeterminationUsing the cobas b 221(OMNI S) Point-of-CareAnalyzerInformation for this article appeared in another format in Point of CareVolume 4, Number 1, March 2005, © 2005 Lippincott Willliams & Wilkins.The authors are Boris Rolinski, MD; Anthony Okorodudu, PhD; GeraldKost, MD; Markus Roser, MD; Jiaxi Wu, MD, PhD; Ada Goerlach-Graw,PhDk; and Helmut Kuester, MD. The article was provided for publication inRespiratory Therapy by Roche Diagnostics.

According to the Symposium Article, “Evaluation of TotalBilirubin Determination in Neonatal Whole Blood Samples byMultiwavelength Photometry on the cobas b 221 (OMNI S)Point-of-Care Analyzer,” jaundice is a common finding in healthyand diseased neonates. Because of early discharge, the risk ofkernicterus is a reemerging problem in the US. Precise andaccurate determination of plasma total concentrations isindispensable for proper management of jaundiced infants. Intheir multicenter study, Rolinski, et al investigated the analyticalperformance of the cobas b 221 (OMNI S) blood gas analyzer formeasurement of total bilirubin from neonatal whole blood usinga multiple-wavelength photometric method. Results werecompared to other results from routine clinical chemistrymethods and another device. Four hundred and ninety-sixheparinized blood samples were drawn from newborns of 39days or less. An aliquot of the whole-blood sample wasmeasured on the cobas b 221 (OMNI S) and on the RadiometerABL 735. Plasma bilirubin concentrations covered thediagnostic relevant range up to 23.7 mg/dL. There was goodagreement between the bilirubin concentrations measured inwhole blood on the cobas b 221 (OMNI S) and Radiometer ABL735 and between the comparison routine analyzers. Correlationcoefficients were above 0.94, and the slope of the regressionlines ranged from 0.971 to 1.172. The mean biases ranged from–0.3 to 1.4 mg/dL, and the differences between comparisonmethods were less than those reported in proficiency testing.Direct spectrophotometric measurement of bilirubin in neonatalwhole-blood samples gave results that compared well withthose obtained using routine chemistry methods. Noted

advantages were the very small volume of blood and the shortturnaround time. The authors of the study concluded that thecobas b 221 (OMNI S) analyzer represents a suitable method formonitoring neonatal jaundice at the point of care.

BACKGROUNDIn the newborn, hyperbilirubinemia is due to an increasedhemoglobin turnover along with immature hepaticglucuronidation. Neonatal jaundice is a common finding insofaras about 60% of infants become clinically jaundiced in the firstweek of life, and about 33% of breastfed infants have totalbilirubin levels above 12 mg/dL. Plasma bilirubin concentrationsin neonates can range as high as 40 mg/dL. Newborn jaundice isusually considered benign, with hyperbilirubinemia resolvingwithin the first week, but in rare cases, higher concentrations ofbilirubin may cause kernicterus. While the condition isconsidered rare due to prompt postnatal medical care, reportshave shown an increasing frequency. Because phototherapy orexchange transfusions may be required to lower bilirubinconcentration, therapeutic decisions must rely on determiningplasma bilirubin concentration. As such, babies with jaundiceare typically monitored for bilirubin levels from four hours aday to every other day. Thus, it’s desirable to employ methodsthat come up with quick and reliable results, using smallvolumes of whole blood. Recently, the cobas b 221 (OMNI S)blood gas analyzer was equipped with the same feature as thefirst instrument to provide total bilirubin determination in wholeblood, manufactured by Radiometer.

MULTICENTER STUDYThe study was conducted in four hospitals with NICUs, inCalifornia, Texas and Germany. Four hundred ninety-sixheparinized blood samples were analyzed, using samples from353 newborns ranging in age up to 39 days, with a median age of4 days. An aliquot of whole blood was measured on the cobas b221 (OMNI S) or the Radiometer ALB 735, and plasma wasprepared from the remaining sample. Total bilirubin in plasmawas measured by wet chemistry, and a total of ten sets ofcomparison data were obtained. One set of samples was alsomeasured for direct bilirubin and for serum indices by directphotometry. Various methods were used to assess imprecision,inaccuracy and recovery, and heparinized whole-blood sampleswere obtained from healthy volunteers. The hematocrit wasmeasured on the cobas b 221 (OMNI S) and the plasma volumecalculated. The samples were centrifuged, and a portion ofplasma supernatant was replaced by an equal volume ofbilirubin stock solution to provide desired plasmaconcentrations of 6, 24 and 48 mg/dL, after which samples werere-dispersed and used for immediate bilirubin measurement onthe cobas b 221 (OMNI S). Fresh samples were prepared daily.Control samples were prepared by dilution in albumin solutionor bovine serum albumin fraction V, or in human pool plasmawith low bilirubin concentrations to give final bilirubinconcentrations of 0,2,10 and 20 mg/dL and 0.8, 2.8, 10.8 and 20.8mg/dL for albumin-based and plasma-based samples,respectively. The samples were aliquoted and stored untilanalysis. Recovery on the cobas b 221 (OMNI S) wasinvestigated at two sites with a set of 10 accuracy controlsranging from 1 to 13 mg/dL bilirubin.

RESULTSPlasma bilirubin concentrations ranged from 0.2 to 23.7 mg/DL,which covered the range for proper diagnostic decisions.Hemoglobin concentrations varied from 10 to 23.6 g/dL.


Agreement was good between bilirubin concentrationsmeasured in whole blood on the cobas b 221 (OMNI S) andmeasured from comparison methods. The mean correlationcoefficient was 0.966 +/- 0.015 and the mean slope of theregression lines was 1.047 +/- 0.052, with mean intercept of–0.065 +/- 0.523. Mean bias was 0.41 +/- 0.51 mg/dL.

The authors observed a slight offset between the same Roche2,5-DPD method in two of the German settings, with recordedvalues slightly higher and lower, respectively than those of theOMNI S. The difference remained unexplained, but evaluationshowed that the Roche DPD method fit correctly with the cobasb 221 (OMNI S). The rest of the wet chemistry methods alsocorrelated well with the cobas b 221 (OMNI S), except for theneonatal bilirubin run in Munich. The method is a directphotometric reading from the sample diluted in buffer at twowavelengths, with recorded values about 10% lower than thoseobtained with DPD. According to the authors, the methodsuffers from interference by hemolysis and turbidity more thanmethods based on reaction with diazo dyes. As such, accordingto Rolinski, et al, direct photometry at two wavelengths isinferior to all other methods tested in the study, anddiscrepancies can be attributed to this problem rather than tomethods employed. Dry chemistry bilirubin correlated closelywith the cobas b 221 (OMNI S) whether compared with valuesobtained with TBIL or BIL slides. Comparison of the cobas b221 (OMNI S) with the Radiometer ABL 735 showed an offset of1 mg/dL between the instruments, which the authors found oddinsofar as both instruments rely on direct multiwavelengthphotometry. It was surmised that the discrepancies may haveoccurred in the calibration process, from the calculationalgorithm, or from differences in compensating the hemoglobininterference.

Outliers defined as a relative bias of >21% were observed, withthe highest number at one of the German sites. It wasspeculated that perhaps the Roche analyzer employed at thatsite was less reliable than the others, but it wasn’t possible torepeat the measurement due to sample limitations. However,differences between methods were found to be minor and muchless than differences typically reported in daily routine orproficiency testing surveys.

Results of quality control studies revealed that precision andaccuracy were well within the specified ranges of theinstruments. Precision and bias for whole-blood controls wereless accurate, but sample preparation would have contributedsignificantly to the imprecisions noted. Recovery of the 10commercial accuracy controls based on plasma matrix wasgood, with a bias from –0.13 to 1.23 mg/dL. No difference wasobserved between the control materials.

The authors note that quality control is a difficult issue formethods using whole-blood samples, and, until now, theproblem of matrix conformity of quality-control material hadbeen unresolved. This is why different matrices were used in thestudy. The Auto Trol material used for the cobas b 221 (OMNI S)is a photometer control based on dyes in aqueous solution anddoesn’t contain bilirubin. The researchers used commercial andin-house quality-control material based on serum matrix, withthe advantage that this material contains the real analyte and isstable for within-day experiments. Whole-blood controls werealso used but had to be prepped daily, which increasesimprecision and isn’t feasible for clinical routine.

CONCLUSIONSAccording to the authors, “Measurement of bilirubin is know asone of the most unreliable tests in clinical chemistry.” Untilrecently, no accepted reference method existed and nostandardization between assays of different reagent suppliershad been achieved. As such, there have been no true values torely on for comparison studies or for the care of patients, andtarget values for control materials may vary widely, dependingon the assay. Rolinski et al conclude, “Taking this intoconsideration, our study clearly demonstrates that the accuracyand precision of the cobas b 221 (OMNI S) analyzer meets theexpectations for routine laboratory method and allows for thereliable determination of bilirubin concentrations in neonatalwhole-blood samples. Advances in laboratory medicine areoften driven by the need to obtain more information from asmaller sample at a faster time than previously possible.Especially for monitoring hyperbilirubinemia in the newborn,direct photometry of neonatal whole-blood samples in a bloodgas analyzer provides fast yet reliable results from very smallsample volumes, enabling bilirubin measurement at the point ofcare.”

Pleural Fluid pHThe following information is based on the article “Prognostic Value ofPleural Fluid pH in Malignant Epithelial Mesothelioma after TalcPoudrage” by Yossef Aelony, Janis Yao and Randel King. Aelony and Kingare with the Department of Internal Medicine, Kaiser Permanente, HarborCity, CA. Yao is with the Southern California Permanente Medical Group,Pasadena, CA. Information for the article is redacted from “PrognosticValue of Pleural Fluid pH in Malignant Epithelia Mesothelioma after TalcPoudrage,” Respiration 2006;73:334–339, Copyright © 2006 S. Karger AG,Basel, Switzerland, E-Mail [email protected] Accessible online at: RanchoPalos Verdes, CA 90275 (USA) www.karger.com, www.karger.com/res.Information provided to Respiratory Therapy by Roche Diagnostics.

According to a recent article in Respiration (see above), currentstaging schemes for malignant mesothelioma are inadequate.The most accurate staging may require pneumonectomy. Theauthors note, “Low pleural pH (ppH) has long been correlatedwith poor outcome in patients with malignant pleural effusion.The mechanism of low ppH in advanced malignant disease isbelieved to be related to increased metabolism by pleural cells,decreased glucose transport into the pleural fluid, and adiffusion block of CO2 efflux out of the pleural space. Underthese conditions, lactic acid and hydrogen ions accumulate inthe pleural fluid. This lower ppH has been directly correlatedwith the extent of tumor visualized thoracoscopically and withshorter survival.”

The study by Aelony et al determines that ppH predicts survivalin neomesotheliomatous malignant pleural effusions, suggestingthat this noninvasive test might be useful for prognostication inmalignant mesothelioma. Aeolony’s study was to determinewhether baseline ppH correlates with survival in malignantepithelial pleural mesothelioma. The authors reviewed survivaldata in patients treated with thoracoscopic talc pleurodesiswhere the final diagnosis was epithelial malignant pleuralmesothelioma and charting recorded a ppH determinationperformed just before thoracoscopy. The authors monitored 26patients, of whom 25 ultimately died, identifying cutoff ppHvalues that discriminate best for survival. The mean follow-up


time was 19 ± 14 months, mean ppH was 7.30 ± 0.09, andmedian ppH was 7.32. ppH 7.32 was associated with the greatestsurvival value. Patients with ppH less than 7.32 lived a medianof 21.2 months after diagnosis compared with patients who hadppH ≤ 7.32 and lived a median of 13.4 months. The baseline ppHcorrelated with survival in epithelial mesothelioma patientstreated palliatively with pleurodesis by thoracoscopic talcpoudrage. The authors recommended that this noninvasive ppHtest should be included when staging patients with malignantmesothelioma.

BACKGROUNDLittle data exists on ppH and malignant mesothelioma. Patientswere typically diagnosed by closed needle biopsy, andpathologists considered the amount of specimen obtained to beinadequate for reaching a definite diagnosis. Limitations oninformation garnered (low rate of confirmed diagnoses,inadequate tissue typing) resulted in a lack of adequateassociation between ppH and survival. Aelony and Yao hadpreviously reported treatment results of palliative thoracoscopictalc poundage, though the results weren’t statisticallysignificant. The current study was designed to determine if thepathoracoscopic ppH in a combined group of 26 patients fromAelony and Yao’s study correlated with duration of survival afterthe procedure.

For more than 20 years, Kaiser patients with recurrentsymptomatic pleural effusion had received thoracoscopy fordiagnostic biopsy, talc pleurodesis, or both. These patients’medical data were incorporated into a prospective database. Areview of these data formed the basis for this study.Measurement of ppH was considered noninvasive because it isderived from fluid that would be sampled in any event. BaselineppH was measured in fresh pleural fluid under anaerobicconditions, obtained before the induction of the pneumothora,prior to thoracoscopy. The ppH was measured using an AVLScientific blood gas analyzer. Pleuroscopy with a parietalpleural biopsy and talc insufflation was performed using a rigidtelescope with a single-puncture technique. Microscopicanalysis was performed by our own pathologists and confirmedby the US-Canadian mesothelioma panel.

To identify a cutoff ppH value that defined a warning level forsurvival in the data, the researchers used the 18-month follow-up data, which provided sufficient information. Adjusted ROCcurves were recursively run using the same ppH cutoff valuesand were adjusted by age and side of lung affected.

ppH VALUES AND SURVIVAL Results indicated that ppH values were significantly associatedwith survival. Associations of either side of the lung affectedand age with survival were borderline significant. The mediansurvival for patients with ppH >7.32 was 21.2 months versus13.4 months for ppH ≤ 7.32. The study revealed that ppH wasthe only significant factor.

Patients were treated by the same approach, usingthoracoscopic talc pleurodesis as the primary palliativemodality of care. Three patients were subsequently treated withchemotherapy and radiation therapy and survived a mean of10.5 ± 3.1 months. After receiving talc poudrage, the patientwith ppH 7.26 survived 12.5 months, the patient with ppH 7.27,14.6 months, and the patient with ppH 7.19, 4.5 months. Theother 23 patients received no antineoplastic treatment before or

after receiving pleurodesis.

As this series demonstrates, the relation of ppH to survival inpatients with malignant effusion also applies to patients withepithelial malignant mesothelioma when the main treatment ispalliative thoracoscopic talc pleurodesis. Management wasbasically the same for all patients. Overall survival in this groupof patients was relatively good compared to other approaches.

Aelony et al noted that the ppH prognostic factor is likely to beimportant regardless of the type of subsequent treatmentreceived, but because the sample size in this study was small,the optimal ppH cutoff point might not be representative, andsuggested that a multicenter study would be necessary tocollect a large enough series to achieve statistical significancefor less frequent subtypes of mesothelioma.

All patients in this study had large effusions (>1,000 ml). Stagingproposals could not be applied using a retrospective recordreview and current surgical staging seems inapplicable forthoracoscopy patients. Recent editorials have decried theunavailability of uniform, effective staging schemes inmesothelioma.

The authors noted that prospective studies with multivariateanalysis are needed to determine whether ppH functionsindependently of these other factors, and awaited informationfrom the European Organization of Research and Treatment ofCancer and the Cancer and Leukemia Group B staging programswhich could then be combined with ppH, PET scan intensityand tumor necrosis grading, leading to prospective studiesshowing correlation with survival.

The authors concluded, “Research efforts should now focus onincorporating ppH into disease staging for all mesotheliomapatients. Ideally, controlled studies would always be conductedcomparing various modalities of treatment… and including acontrol group of patients receiving best supportive care.Notwithstanding those studies, improved staging is essential toallow prognostication for the patient, to permit bettercomparisons between phase II studies, and to facilitateselection of patients for future prospective trials.”


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