Critical Care 10-11 by IJCP

Volume 6, Number 3

July-September 2010

Sedation Practices for the Patient in the ICU Should C-reactive Protein Concentration at ICU Discharge be Used as a Prognostic Marker? Clostridium Difficile: Moving Beyond Antimicrobial Therapy ICU Intubation Success Hampered by Non-ideal Conditions: Based on Small Cohort Study... Pain Not Minimized after Minimally Invasive Cardiac Surgery Still Asleep at the (Ventilator) Switch? Timing of Tracheotomy Linked to Length of Stay: Study Finds to Effect on Mortality from Early Procedure more...

Asian Journal of

Critical Care Volume 6, No 3, July-September 2010

An IJCP Group Publication Dr Sanjiv Chopra Prof. of Medicine & Faculty Dean Harvard Medical School Group Consultant Editor Dr Deepak Chopra Chief Editorial Advisor

Dr KK Aggarwal CMD, Publisher and Group Editor-in-Chief Dr Veena Aggarwal Joint MD & Group Executive Editor Anand Gopal Bhatnagar Editorial Anchor

Contents Contents From the Desk of Group Editor-in-chief

Critical Care Update

KK Aggarwal

Critical Care Editorial Board Dr MM Pandit Rao Prof. Anesthesia, BJ Medical College, Pune Dr Vijay Langer Head, Dept. of Anesthesia, Moolchand Medcity, New Delhi Dr Rajesh Chauhan Sr. Anesthetist, Escorts Heart Institute, New Delhi Dr A Kale Prof. Anesthesia, AIIMS, New Delhi Dr Manju Mani Director-Critical Care, Delhi Heart and Lung Institute New Delhi Dr Tarlika Doctor Associate Professor Anesthesia, BJ Medical College, Ahmedabad Dr Sunita Jain, New Delhi

clinical practice

Sedation Practices for the Patient in the ICU

Peter J Papadakos, Jack Haitsma, Stephen Eskaros

IJCP Editorial Board Dr Alka Kriplani Asian Journal of Obs & Gynae Practice Dr VP Sood Asian Journal of Ear, Nose and Throat Dr Praveen Chandra Asian Journal of Clinical Cardiology Dr Swati Y Bhave Asian Journal of Paediatric Practice Dr Vijay Viswanathan The Asian Journal of Diabetology

research article

Should C-reactive Protein Concentration at ICU Discharge be Used as a Prognostic Marker?

Joana Silvestre, Lu铆s Coelho, Pedro P贸voa

Dr M Paul Anand, Dr SK Parashar Cardiology Dr CR Anand Moses , Dr Sidhartha Das Dr A Ramachandran, Dr Samith A Shetty Diabetology Dr Ajay Kumar Gastroenterology Dr Koushik Lahiri Dermatology Dr Georgi Abraham Nephrology Dr Sidharth Kumar Das Rheumatology Dr V Nagarajan Neurology Dr Thankam Verma, Dr Kamala Selvaraj Obs and Gyne

Advisory Body Heart Care Foundation of India Asian Journal of Critical Care Vol. 6, No. 3, July-September 2010

for the clinician

Clostridium Difficile: Moving Beyond Antimicrobial Therapy

Amesh A Adalja, John A Kellum

ICU Intubation Success Hampered by Non-ideal Conditions: Based on Small Cohort Study...

Lynne Peeples

Asian Journal of

Review Article

Critical Care Volume 6, No 3, July-September 2010

Contents

Published, Printed and Edited by Dr KK Aggarwal, on behalf of IJCP Publications Pvt. Ltd. and Published at Daryacha, 39, Hauz Khas Village, New Delhi - 110 016. E-mail: editorial@ijcp.com

for the clinician

Pain Not Minimized after Minimally Invasive Cardiac Surgery

Michael Vlessides

Printed at Entire Printers Nampally, Hyderabad

Still Asleep at the (Ventilator) Switch?

ÂŠ Copyright 2010 IJCP Publications Pvt. Ltd. All rights reserved. The copyright for all the editorial material contained in this journal, in the form of layout, content including images and design, is held by IJCP Publications Pvt. Ltd. No part of this publication may be published in any form whatsoever without the prior written permission of the publisher.

Ted Agres

Timing of Tracheotomy Linked to Length of Stay: Study Finds no Effect on Mortality from Early Procedure 30 Adam Marcus

Editorial Policies The purpose of IJCP Academy of CME is to serve the medical profession and provide print continuing medical education as a part of their social commitment. The information and opinions presented in IJCP group publications reflect the views of the authors, not those of the journal, unless so stated. Advertising is accepted only if judged to be in harmony with the purpose of the journal; however, IJCP group reserves the right to reject any advertising at its sole discretion. Neither acceptance nor rejection constitutes an endorsement by IJCP group of a particular policy, product or procedure. We believe that readers need to be aware of any affiliation or financial relationship (employment, consultancies, stock ownership, honoraria, etc.) between an author and any organization or entity that has a direct financial interest in the subject matter or materials the author is writing about. We inform the reader of any pertinent relationships disclosed. A disclosure statement, where appropriate, is published at the end of the relevant article.

photo quiz

Acute Chest Pain in an Adolescent

emedinews section

Note: Asian Journal of Critical Care does not guarantee, directly or indirectly, the quality or efficacy of any product or service described in the advertisements or other material which is commercial in nature in this issue.

From eMedinewS

Editorial & Business Offices

Delhi

Mumbai

Kolkata

Bangalore

Chennai

Hyderabad

Dr Veena Aggarwal 9811036687 Daryacha, 39 Hauz Khas Village N.D. - 110 016 Cont.: 26965874/75 editorial@ijcp.com drveena@ijcp.com drveenaijcp@gmail.com Subscription Dinesh: 9891272006 subscribe@ijcp.com Ritu: 09831363901 ritu@ijcp.com

Dr Veena Aggarwal 9811036687

Sr. BM Ritu Saigal 9831363901 Flat 5E Merlin Estate Geetanjali 25/8 Diamond Harbour Road Kolkata - 700 008 Cont.: 24452066 ritu@ijcp.com

Sr. BM H Chandrashekar 9845232974 Arora Business Centre, 111/1 & 111/2 Dickenson Road (Near Manipal Centre) Bangalore - 560 042 Cont.: 25586337 chandra@ijcp.com

Sr. BM Chitra Mohan 9841213823 40A, Ganapathypuram Main Road Radhanagar Chromepet Chennai - 600 044 Cont.: 22650144 chitra@ijcp.com

Sr. BM Venugopal 9849083558 H. No. 16-2-751/A/70 First Floor Karan Bagh Gaddiannaram Dil Sukh Nagar Hyderabad - 500 059 Cont.: 65454254 venu@ijcp.com

Building No. D-10 Flat No 43, 4th Floor Amita Co-operative Housing Society Marvey Road Near Charkop Naka Malad (W) Mumbai - 400 095 drveenaijcp@gmail.com

Sr.: Senior; BM: Business Manager

Asian Journal of Critical Care Vol. 6, No. 3, July-September 2010

From the desk of Group editor-in-chief

Critical Care Update

trial that randomly assigned 300 patients with severe sepsis to undergo resuscitation targeting either a lactate clearance ≥10% or an ScvO2 ≥70% found no differences in hospital mortality, length of stay, ventilator-free days, or the incidence of multiorgan failure.1 A meta-analysis that included 1,892 patients with acute respiratory distress syndrome (ARDS, defined as a PaO2/FiO2 ≤200 mmHg) found that those who were mechanically ventilated using a high positive end-expiratory pressure (PEEP) strategy had lower ICU mortality than those who were mechanically ventilated using a low PEEP strategy.2 A multicenter trial that randomly assigned 1,679 patients with shock to receive either dopamine or norepinephrine as the initial vasopressor found that the patients who received dopamine were more likely to have arrhythmias.3

Dr KK Aggarwal Padma Shri and Dr BC Roy National Awardee Sr Physician and Cardiologist, Moolchand Medcity President, Heart Care Foundation of India Group Editor-in-Chief, IJCP Group Chief Editor, eMedinewS Chairman Ethical Committee, Delhi Medical Council Director, IMA AKN Sinha Institute (08-09) Hony. Finance Secretary, IMA (07-08) Chairman, IMA AMS (06-07) President, Delhi Medical Association (05-06) emedinews@gmail.com https//twitter.com/DrKKAggarwal Krishan Kumar Aggarwal (Facebook)

A meta-analysis of 12 randomized trials (2,236 patients) found no difference in the incidence of ventilator-associated pneumonia, while a meta-analysis of 12 randomized trials (1,951 patients) found no difference in mortality when they used passive or active humidification.4 A meta-analysis included 13 trials (1,369 patients) and found that patients who received continuous positive airway pressure (CPAP) plus standard care had a lower hospital mortality than those who received standard care alone.5 A metaanalysis of subgroups from seven randomized trials (555 patients with a PaO2/FiO2 <100 mmHg) found that prone ventilation reduced hospital mortality.6 A meta-analysis of seven randomized trials (936 patients) compared stress ulcer prophylaxis with a proton pump inhibitors (PPI) to prophylaxis with an H2 blocker.7 It found a trend toward less GI bleeding among those who received a PPI, although the effect was smaller when an outlying trial was excluded. This suggests that PPIs might be more effective than H2 blockers. References 1. Jones AE, Shapiro NI, Trzeciak S, et al. Emergency Medicine Shock Research Network (Emshocknet investigators) Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA 2010;303(8):739-46. 2. Briel M, Meade M, Mercat A, et al. Higher vs lower positive end-expiratory pressure in patients with acute lung injury and acute respiratory distress syndrome: systematic review and meta-analysis. JAMA 2010;303(3):865-73. 3. De Backer D, Biston P, Devriendt J, et al. Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med 2010;362(9):779-89. 4. Kelly M, Gillies D, Todd DA, Lockwood C. Heated humidification versus heat and moisture exchangers for ventilated adults and children. Cochrane Database Syst Rev 2010;4:CD004711. 5. Weng CL, Zhao YT, Liu QH, et al. Meta-analysis: noninvasive ventilation in acute cardiogenic pulmonary edema. Ann Intern Med 2010;152(9):590-600. 6. Sud S, Friedrich JO, Taccone P, et al. Prone ventilation reduces mortality in patients with acute respiratory failure and severe hypoxemia: systematic review and meta-analysis. Intensive Care Med 2010;36(4):585-99. 7. Lin PC, Chang CH, Hsu PI, et al. The efficacy and safety of proton pump inhibitors vs histamine-2 receptor antagonists for stress ulcer bleeding prophylaxis among critical care patients: a meta-analysis. Crit Care Med 2010;38(4):1197-205. Asian Journal of Critical Care Vol. 6, No. 3, July-September 2010

clinical practice clinical practice

Sedation Practices for the Patient in the ICU Peter J Papadakos*, Jack Haitsma**, Stephen Eskaros†

Abstract Over the past decade, intensive care units (ICUs) worldwide have adopted the goal of maintaining an optimal level of comfort and safety for critical care patients.1,2 Guidelines and protocols for the sedation of ICU patients are now also mandated by accreditation agencies. As a result, sedation and pain management are being tracked as vital signs in the care of patients throughout their hospital stay, which has led to widespread efforts to address sedation and pain control in this patient population. Key words: ICU, sedation, pain control

may influence morbidity and mortality, and specific compounds may modulate the release of cytokines and vasoactive compounds.1,2

As the customized care of patients continues to evolve, a common language is mandated for the titration and use of sedative agents. With this language also comes the development of protocols and guidelines to better use these drugs, and to maximize the unique pharmacodynamic profile of each drug for individual patients.

Agitation and anxiety are common in ICU patients of all ages, occurring at least once in 71% of patients admitted to a medical-surgical ICU.3 Agitation can be caused by multiple factors, such as extreme anxiety, delirium, adverse drug effects, and pain. Inadequate pain control is a significant factor in the development of agitation in critically ill patients, predominantly in the postoperative period. Insufficient pain management often results from suboptimal dosing of opioids because of concerns about respiratory depression and the development of dependence. Normally, these side effects are unlikely to develop over the short term if the medication is properly titrated to patient comfort.

he large number of modern sedatives and analgesics has given critical care practitioners the ability to titrate specific agents for specific patient types, allowing patients to be comfortable throughout their stay in the ICU. This wide selection of drugs also has reduced the length of hospital stays and permitted patients to participate in drug weaning and physical and occupational therapy.

No longer is it necessary to be trapped by the all-ornone effect of very long-acting compounds that depress respiration and prolong the ICU stay. Titratable sedation also may modulate the immune system. Evidence now shows that high levels of anxiety and pain *Director, Division of Critical Care Medicine Professor, Anesthesiology, Surgery and Neurosurgery Associate Director, Kessler Regional Trauma Center University of Rochester School of Medicine and Dentistry Rochester, New York **Division of Critical Care Medicine St. Michael’s Hospital, University of Toronto Toronto, Ontario, Canada † Dept. of Anesthesiology and Critical Care Medicine University of California-Los Angeles Ronald Reagan Medical Center Los Angeles, California Source: Adapted from Anesthesiology News Special edition, October 2009, McMahon Publishing.

Evaluation for Agitation and Anxiety

Hypoxemia has long been associated with agitation. It is crucial for ICU staff to monitor the oxygen levels of all patients. A partial pressure of oxygen of 60 mm Hg or lower (or oxygen saturation <90%) can contribute to agitation secondary to hypoxemia. Hypotension also can lead to agitation due to hypoperfusion of the brain. Common metabolic problems such as hyperglycemia and, especially, hypoglycemia can promote severe agitation. Uremia and elevated levels of heavy metals (e.g., lead, mercury) have been identified as causes of significant agitation. Sepsis also is a common cause of agitation and must be immediately ruled out. Asian Journal of Critical Care Vol. 6, No. 3, July-September 2010

clinical practice The trauma patient with a closed head injury may have minor to severe agitation. Patients without traumatic head injury, including those with subarachnoid bleeds, also may present with agitation. Thrombotic stroke may cause agitation, and patients with brain neoplasms, brain seizures, infections such as meningitis, or air embolism also may have associated persistent and severe agitation. One of the most common problems confronting providers of critical care is a patient’s withdrawal from alcohol or other agents, including cocaine, opioids, and sedatives such as benzodiazepines; all these substances contribute to brain injury and agitation.4 Withdrawal in cigarette smokers, who can suffer agitation from the lack of nicotine, should be ruled out. Another common cause of agitation in the ICU patient is significant ventilator desynchronization in patients on mechanical ventilation. This is frequently the result of poorly set ventilators that delay response to the patient’s efforts at spontaneous breathing. The problem is becoming less common because of the availability of advanced computer-controlled ventilators and the use of graphic displays to titrate ventilation. Patients who undergo short- or long-term intubation also become agitated because of the stimulus of the endotracheal tube itself. Patients who are alert and intubated may become frustrated by their inability to communicate with staff and family and descend into a cycle of continued agitation. The ICU itself, with its high levels of technology, lights, and noise and continuous stimuli, can significantly contribute to further agitation. Numerous drug interventions, drug reactions, and drugdrug interactions, as well as drug withdrawal, all increase the incidence of patient agitation in the modern ICU. The occurrence of undesirable drug-drug interactions always should be considered when multiple drugs are being used for pain, anxiety, infection, and cardiac arrhythmias (a brief list of medications associated with agitation appears in Table 1). Even after the withdrawal of a pharmacologic compound suspected of increasing agitation, it may take several days for the drug and its metabolites to clear from the patient’s system before a positive response can be seen. A differential diagnosis of agitation begins with a review of the patient’s disease process, mechanism of injury, laboratory values, treatments, baseline medications, Asian Journal of Critical Care Vol. 6, No. 3, July-September 2010

Table 1. Medications Associated with Agitation in ICU Patients Antibiotics Acyclovir Amphotericin B Cephalosporins Ciprofloxacin Imipenem-cilastatin Ketoconazole Metronidazole Penicillin Rifampin Trimethoprim-sulfamethoxazole Anticonvulsants Phenobarbital Phenytoin Cardiac drugs Captopril Clonidine Digoxin Dopamine Labetalol Lidocaine Nifedipine Nitroprusside Procainamide Propranolol Quinidine sulfate Corticosteroids Dexamethasone Methylprednisolone Opioid analgesics Codeine Meperidine Morphine sulfate Miscellaneous drugs Anticholinergics Benzodiazepines Hydroxyzine Ketamine Metoclopramide Nonsteroidal anti-inflammatory drugs Theophylline

clinical practice and history of chronic diseases (e.g., hepatic or renal). Only after this type of rapid evaluation can the process move toward proper treatment for agitation. Evaluation and Titration of Sedative Agents The complex disease state of ICU patients typically demonstrates a rapidly changing spectrum of hemodynamic parameters, so the requirements to treat agitation fluctuate over time. Bedside clinicians must frequently reassess and redefine the goals of therapy, so that ICU patients and their levels of sedation must be evaluated in real time. Tools and scales to monitor agitation in the ICU should be simple to apply yet describe clearly graded changes between levels of sedation to allow the titration of both pharmacologic and nonpharmacologic interventions, depending on the patientâ&#x20AC;&#x2122;s condition.

Table 2. Ramsay Scale for Assessing Level of Sedation Level

Response

Patient awake and anxious, agitated, and/ or restless

Patient awake, cooperative, accepting ventilation, oriented, and tranquil

Patient awake; responds to commands only

Patient asleep; brisk response to light glabellar tap or loud auditory stimulus

Patient asleep; sluggish response to light glabellar tap or loud auditory stimulus but responds to painful stimulus

Patient asleep; no response to light glabellar tap or loud auditory stimulus

Based on reference 5.

Table 3. Riker Sedation-agitation Scale Score

Diagnosis

Description

Large numbers of scales and tools for the evaluation of ICU patients are described in the literature. Many of these assess the level of consciousness with descriptive responses to interventions; for example, if the level of a drug is raised, the patientâ&#x20AC;&#x2122;s condition will change. No scale is a gold standard, but most ICUs use modifications of those described in the literature. The development of customized unit-based scales, protocols, and guidelines is highly important for promoting their acceptance by all members of the health care team.

Dangerously agitated

Pulls at endotracheal tube; tries to remove catheters; climbs over bed rail; strikes at staff; thrashes from side to side

Very agitated

Does not calm down despite frequent verbal reminding of limits; requires physical restraints; bites endotracheal tube

Agitated

Sedation Scales

Calm and cooperative

Anxious or mildly agitated; attempts to sit up; calms down in response to verbal instructions Calm; awakens easily; follows commands

The most commonly used sedation scale is the Ramsay Sedation Scale,5 which identifies 6 levels of sedation ranging from severe agitation to deep coma (Table 2). Despite its frequent use, the Ramsay Scale has some shortcomings when applied at the bedside of patients with complex problems. For example, a patient who appears to be asleep with a sluggish response to glabellar tap (Ramsay 5) also may be restless and anxious (Ramsay 1). The Ramsay Scale is simple, however, and is widely used throughout the world.

Sedated

Difficult to arouse; awakens to verbal stimuli or gentle shaking but drifts off again; follows simple commands

Very sedated

Arouses to physical stimuli but does not communicate or follow commands; may move spontaneously

Unable to be aroused

The Riker Sedation-Agitation Scale (SAS) was the first scale formally tested and developed for reliability in the ICU (Table 3). The SAS identifies 7 symmetric levels, ranging from dangerous agitation to deep sedation. This scale provides descriptions of patient behavior that can assist the bedside practitioner in distinguishing between levels.6

Minimal or no response to noxious stimuli; does not communicate or follow commands

Based on references 2 and 6.

The Motor Activity Assessment Scale (MAAS), which is similar in structure to the SAS, uses patient behaviors to describe the different levels of agitation.7 The MAAS identifies 7 levels, ranging from unresponsive to dangerously agitated (Table 4). Asian Journal of Critical Care Vol. 6, No. 3, July-September 2010

clinical practice Table 4. Motor Activity Assessment Scale Score

Description

Definition

Unresponsive

Does not move with noxious stimulus

Responsive only Opens eyes or raises eyebrows to noxious stimuli or turns head toward stimulus or moves limbs with noxious stimulus Responsive to Opens eyes or raises eyebrows touch or name or turns head toward stimulus or moves limbs when touched or name is loudly spoken Calm and Does not require external cooperative stimulus to elicit movement; adjusts sheets or clothes purposefully; follows commands Restless but Does not require external cooperative stimulus to elicit movement; picks at sheets or clothes or uncovers self; follows commands Agitated Does not require external stimulus to elicit movement; attempts to sit up or moves limbs out of bed; does not consistently follow commands Dangerously Does not require external agitated, stimulus to elicit movement; pulls uncooperative at tubes or catheters or thrashes from side to side or strikes at staff or tries to climb out of bed; does not calm down when asked

Based on references 7 and 16.

A newer assessment tool for the ICU was described by Ely and colleagues as the Confusion Assessment Method for the ICU (CAM-ICU).8 This tool is being validated in critically ill patients with delirium. It is used in combination with the Glasgow Coma Scale to evaluate highly complex, agitated patients. The CAMICU is simple to apply at the bedside and has been found to have a high level of reliability, sensitivity, and specificity. There is hope that real-time, computer-based monitors of brain function may remove human variability from the evaluation of patients with agitation. One such monitor that is popular in the operating room is the Bispectral Index (BIS, Aspect Medical). This objective monitor is especially helpful for the deeply sedated patient receiving neuromuscular blockade. The BIS monitor provides discrete values from 100 (completely Asian Journal of Critical Care Vol. 6, No. 3, July-September 2010

awake), to <60 (deep sedation), to 40 or below (deep hypnotic state or barbiturate coma) by incorporating several electroencephalographic components.9 Although the technique has been shown to be valid in the operating room, it has not been studied to any great extent in the ICU. This device should be carefully evaluated against the wide spectrum of critically ill patients in all types of ICUs. Establishing and Implementing Sedation Guidelines and Protocols One of the most important goals for any ICU is the development of protocols and guidelines for the use of pain medications and sedative drugs. The development of such protocols requires multidisciplinary input and should be unit-specific. All staff, including physicians, nurses, and pharmacists, need to agree on which monitoring scales and tools to use and then ensure that they are applied reliably across disciplines. It is key for staff to agree on documentation, frequency of assessment, predefined end points of therapy, and evaluation of patient outcomes. Tools to evaluate sedation and pain should be added to flow sheets placed at the bedside. The use of these types of protocols with documentation in daily practice can foster communication between disciplines and shifts. Each hospital should develop guidelines based on current pharmacologic and pharmacokinetic recommendations and supported by national standards.1,2 Several studies have shown that when ICUs institute protocol-driven sedative use, patients spend less time on mechanical ventilation and have shorter stays in the ICU and the hospital.10 Another easy bedside strategy for optimizing outcome in patients receiving therapy for agitation is to institute a daily schedule for the reassessment and interruption of sedation infusions.11 This practice is common in the trauma-burn ICU at the University of Rochester in Rochester, NY, where daily interruptions of sedative infusions are found to decrease the duration of mechanical ventilation and decrease time in the ICU. This practice allows the maximal use of bed resources in a busy hospital. A â&#x20AC;&#x153;sedation holidayâ&#x20AC;? also improves cliniciansâ&#x20AC;&#x2122; ability to perform daily neurologic examinations, thereby reducing the need for diagnostic studies to evaluate unexplained alterations in mental status.12

Analgesic sedative

Remifentanil

Midazolam

Propofol

10 mg

Morphine

Lorazepam

75-100 mg

Meperidine

Ketorolac

Diazepam

1.5 mg NA

Hydromorphone Ibuprofen

200 mcg

Fentanyl

Dexmedetomidine

120 mg

Codeine

2-3 min

6-15 min

3-20 min

30-66 min

~6 min

3-10 min

3-7 h

3-4 h

2.4-8.6 h

2-3 h 1.8-2.5 h

1.5-6 h

Glucuronidation

Hydroxylation

Glucuronidation

Glucuronidation, hydroxylation, and methylation Hepatic microsomal enzymes

Plasma esterase

Glucuronidation

Demethylation and hydroxylation

Renal

Glucuronidation Oxidation

Demethylation and glucuronidation Oxidation

Conjugation

Acetaminophen

Equianalgesic Distribution Metabolic Dose (IV) Half life Pathway

Agent

None

Yes

None

None (glucuronidation); undetermined for P-450mediated pathways Yes

None

Yes (neuroexcitation, especially with renal insufficiency or high doses) Yes (sedation, especially with renal insufficiency)

None

No metabolite, parent accumulates None None

Yes (analgesia, sedation)

Active Metabolites (Effect)

CNS, central nervous system; D5W, 5% dextrose in water; GI, gastrointestinal; MAOIs, monoamine oxidase inhibitors; NA, not applicable; SSRIs, selective serotonin reuptake inhibitors a More frequent doses may be needed for acute pain management in mechanically ventilated patients. c Strict aseptic technique required.

Sedatives

Analgesics

Table 5. Pharmacology of Selected Analgesics and Sedatives Intermittent Dosea

0.01-0.15 mg/kg IV q1-2h

Apnea, hypotensionc

Respiratory depression, respiratory arrest, hypotension

Respiratory depression

CNS depressant, â&#x20AC;&#x153;paradoxicalâ&#x20AC;? reactions

Increments of 20-50 mg as needed

25% of induction dose

5 mg as needed q2-5 min; maximum dose 0.25 mg/kg 2 mg as needed q2-5 min; maximum dose 1 mg/kg

Hypotension, transient Intermittent dosing not hypertension, bradycardia FDA-approved

Histamine release

Risk for bleeding, GI and 15-30 mg IV q6h; renal adverse effects decrease if age >65 y or weight <50 kg or renal impairment; avoid use >5 d Avoid with MAOIs and Not recommended SSRIs

325-650 mg PO q4-6h; avoid >4 g/d Lacks potency, histamine Not recommended release Rigidity with high doses 0.35-1.5 mcg/kg IV q0.5-1h NA 10-30 mcg/kg IV q1-2h Risk for bleeding, GI and 400 mg PO q4-6h renal adverse effects

Adverse Effects

100-200 mcg/kg/min

0.02-0.10 mg/kg/h (1-7 mg/h)

2-4 mg (0.044-0.05 mg/kg)

2 mg/kg/d

0.6-15 mcg/kg/h (0.1 mcg/kg/min) 0.2-0.7 mcg/kg/h

0.07-0.5 mg/kg/h

Not recommended

Infusion not FDA-approved

7-15 mcg/kg/h NA

0.7-10 mcg/kg/h

Not recommended

Infusion Dose Range (Usual, Continuous)

clinical practice

Asian Journal of Critical Care Vol. 6, No. 3, July-September 2010

clinical practice It is important that pharmacologic colleagueshospital pharmacists and PharmDs-be involved in the development of sedation guidelines. Pharmacists can provide guidance and educational input regarding specific pharmacodynamic profiles of individual agents. The participation of pharmacists on rounds and as members of the ICU team can only improve care in complex cases. The institution of guidelines and protocols has the added benefit of decreasing the use of sedative drugs, thereby enhancing hospital finances. Sedatives and narcotic agents are the most commonly prescribed drugs in the ICU and may account for a major percentage of the patientsâ&#x20AC;&#x2122; pharmacy charges. Review of Agents Commonly Used in Sedation Analgesics and sedatives are the mainstays of supportive patient care in the ICU, where they are the most commonly used drugs. Over the past few years, several novel, highly titratable agents have been introduced that have greatly altered patient care. The pharmacology of several of these widely used agents, along with that of classic drugs with long-use profiles, is reviewed in Table 5. Opioids

Opioids are the primary agents used for analgesia in the ICU. Analgesia greatly affects the need for sedation and other therapies. Unrelieved pain evokes a powerful stress response characterized by tachycardia, increased myocardial oxygen consumption, hypercoagulability, immunosuppression, and persistent catabolism.13 Effective analgesia also can diminish pulmonary complications in post operative patients. Opioids are lipid-soluble and bind to opiate receptors in the central nervous system (CNS) and peripheral nervous system. At low doses, opioids provide analgesia but not anxiolysis, whereas at higher doses, they act as sedatives. All the opioids share therapeutic properties but vary in potency and pharmacokinetics. Although opioids can be given via several routes, the IV method is the most common in the ICU. It is important to consult with anesthesiologists when developing pathways for novel uses of these agents, such as epidural placement. When given intravenously in therapeutic doses, opioids cause sedation by clouding Asian Journal of Critical Care Vol. 6, No. 3, July-September 2010

the sensorium, but they do not possess amnestic properties.14 Comparative trials of opioids have not been performed in critically ill patients. The selection of a specific agent depends on its pharmacology and potential for causing adverse effects. For opioids, desirable attributes include a rapid onset of effect, ease of titration, lack of accumulation of the parent drug or its metabolites, and low cost. Morphine sulfate, the prototypic opioid, is the preferred opioid analgesic in patients with stable hemodynamics. Its relatively low lipid solubility may result in a delayed onset of action. Morphine also induces the release of histamine, increasing the likelihood of hypotension secondary to vasodilation. Morphine-6-glucuronide, a metabolite of morphine, is excreted in the urine and may accumulate in patients with renal failure. The opiate activity of this metabolite is several times greater than that of morphine, and its accumulation in patients with renal failure has been reported to prolong narcosis. Fentanyl has the most rapid onset and shortest duration of action of the opioids, but repeated dosing may cause accumulation and prolonged effects. Fentanyl citrate, a synthetic narcotic analgesic, is up to 100 times more potent than morphine, is highly lipid-soluble, and has a rapid onset of action because it quickly crosses the blood-brain barrier. Fentanyl has no active metabolites and is not associated with histamine release or veno dilating effects. Because of these characteristics, fentanyl has become a widely used agent in the ICU. It is ideal for use in patients with unstable hemodynamics. Fentanyl should be administered by continuous infusion for sustained effect because of its short duration of action.15 Remifentanil, a newer agent, has not been widely studied in ICU patients. The drug has a very short half-life and may be best used in patients requiring serial examinations or neurologic evaluations. Because of its short duration of action, continuous infusion is necessary for pain management.16 Hydromorphone is a highly potent opioid with no active metabolites. It can be used in the ICU but has not found broad-based application in this setting. 11

clinical practice Meperidine is not recommended for repetitive use; it has an active metabolite that causes neuroexcitation (apprehension, tremors, delirium, and seizures) and may interact with antidepressants (contraindicated with monoamine oxidase inhibitors, and best avoided with selective serotonin reuptake inhibitors). Because of risks from multiple interactions with other medications, meperidine should not be used in the ICU. Certain adverse effects of opioid analgesics occur frequently in ICU patients. Of greatest concern are respiratory, hemodynamic, CNS, and gastrointestinal effects. Respiratory depression is a concern in spontaneously breathing patients or in those receiving partial ventilatory support. Opioids may also increase intracranial pressure in patients with traumatic brain injury, although the data are inconsistent and the clinical significance is unknown.17 Nonopioids

Nonsteroidal Anti-inflammatory Drugs. The use of nonopioid agents is increasing in ICU patients. Nonsteroidal anti-inflammatory drugs (NSAIDs) provide analgesia via the nonselective, competitive inhibition of cyclooxygenase (COX), a critical enzyme in the inflammatory cascade. The use of COX-2 inhibitors has been reevaluated as the result of reports of cardiovascular complications, and several have been withdrawn from the market by the manufacturers. Therefore, COX-2 agents should not be recommended for critically ill patients. NSAIDs have many positive attributes, including the ability to reduce opioid requirements, but they also have many adverse effects and must be used with caution. A more complete discussion of the use of NSAIDs is not within the scope of this review. Benzodiazepines. Benzodiazepines are the most widely used sedative drugs in medicine.18 They are sedative and hypnotic-but not analgesic-agents that block the acquisition and encoding of new information and potentially unpleasant experiences (anterograde amnesia), but they do not induce retrograde amnesia. They have an opioid-sparing effect by moderating the anticipatory pain response.19 Benzodiazepines vary in potency, onset and duration of action, uptake, and number of active metabolites. The 2 predominant mechanisms of action of benzodiazepines 12

in the nervous system involve activity at the Îł-aminobutyric acid (GABA) receptors. Potentiation of GABA-mediated transmission by benzodiazepines is apparently responsible for somnolent, anxiolytic, and anticonvulsant actions, whereas the amnestic property appears to correlate with GABA agonist activity in the limbic cortex.2,15 Benzodiazepines are metabolized in the liver, where they are extensively cleared. The effects of these drugs may be prolonged in critically ill patients (because of decreased metabolism) or in patients with liver disease. A prolonged and continuous infusion of benzodiazepines should proceed with caution; an accumulation of the parent drug or active metabolites may produce inadvertent and prolonged oversedation, as is seen in elderly patients. It is therefore paramount that these drugs be titrated carefully and used in low doses, or the patients will be somnolent for several days after the infusion has been stopped. Benzodiazepines should be titrated to a pre defined end point, often by using a series of loading bolus doses. Hypotension may develop in hemodynamically unstable patients with the initiation of sedation. Intermittent or â&#x20AC;&#x2DC;as-neededâ&#x20AC;&#x2122; doses of diazepam, lorazepam, or midazolam may be adequate to maintain sedation because of the relatively long half-life of these drugs.18,20 The clinical practice guidelines of the Society of Critical Care Medicine (SCCM) recommend lorazepam for the sedation of most patients, administered by either intermittent IV dosing or continuous infusion.1,2 Lorazepam, an intermediate-acting benzodiazepine, is less lipophilic than diazepam and thus has less potential for accumulation. Lorazepam is associated with a stable hemodynamic profile, even when opioids are concurrently administered. It has no active metabolites, and its metabolism is less affected by advanced age or liver dysfunction than that of midazolam.21 Lorazepam, however, should be used with caution; propylene glycol toxicity, marked by acidosis and renal failure, has occurred with high doses or prolonged infusions of the drug.22 The other commonly prescribed benzodiazepine is midazolam, more widely used in the operating room than in the ICU. Midazolam is a short-acting, water-soluble benzodiazepine that is transformed to a lipophilic compound in the blood. Midazolam Asian Journal of Critical Care Vol. 6, No. 3, July-September 2010

clinical practice exhibits dose related hypnotic, anxiolytic, amnestic, and anticonvulsant actions. The drug produces doserelated respiratory depression, and larger doses may cause hypotension and vasodilation. Midazolam is metabolized in the liver to an active compound that is less potent and more transient than the parent compound. The SCCM guidelines recommend midazolam for the rapid sedation of actively agitated patients,1 but with short-term use only; it is associated with unpredictable awakening and prolonged time to extubation when infusions continue for longer than 48 to 72 hours. Paradoxical agitation has been observed with the use of benzodiazepines during light sedation and in the elderly and may be the result of drug-induced amnesia or disorientation. The effects of these drugs can be reversed with the benzodiazepine-receptor antagonist flumazenil. However, the routine use of flumazenil is not recommended after prolonged benzodiazepine therapy; there is a risk for inducing withdrawal symptoms and increasing myocardial oxygen consumption with as little as 0.5 mg of flumazenil.23 A starting dose of 0.15 mg of flumazenil is recommended and is associated with fewer withdrawal symptoms. Propofol. Propofol has a rapid onset of action, within 1 to 2 minutes after a single IV dose, and a short duration of action, only 10 to 15 minutes, when discontinued.12,24 This is a result of its rapid penetration of the CNS and subsequent redistribution. Therefore, in the ICU, propofol is used by continuous infusion for sedation. Long-term infusions result in accumulation within lipid stores, a prolonged elimination phase, and a half-life of 300 to 700 minutes. Note, however, that subtherapeutic plasma concentrations of the drug are maintained after discontinuation because of rapid clearance; this limits the clinical significance of the drugâ&#x20AC;&#x2122;s half-life value. Although the mechanism of action of propofol is still not completely understood, the drug appears to activate the GABA receptor within the CNS. Propofol alters the sensorium in an extremely rapid dose-dependent manner, from light sedation to general anesthesia, making it a highly useful drug. It is also a potent respiratory depressant, causing a reduction in systemic vascular resistance and possible hypotension, especially when given as a bolus. Propofol should be Asian Journal of Critical Care Vol. 6, No. 3, July-September 2010

administered with caution in hypovolemic patients. It has highly interesting effects on neurophysiology, parallel with the patientâ&#x20AC;&#x2122;s level of arousal. Propofol decreases cerebral metabolism, resulting in a coupled decline in cerebral blood flow and decrease in intracranial pressure. One of the most important benefits associated with propofol is a decrease in weaning time from mechanical ventilation. A large Spanish study,25 using a cost-ofcare approach, compared propofol and midazolam in regard to the ICU costs for prolonged sedation of critically ill patients and weaning time from mechanical ventilation. Although the 2 drugs provided equivalent sedation, propofol was associated with a shorter weaning time than midazolam, resulting in a more favorable economic profile. Because of its rapid wake-up time, propofol is considered the fundamental drug in many fast-track surgical programs, including cardiovascular surgery.12 Within 1 year of its introduction in the United States in 1990, reports appeared of clusters of infections in surgical patients treated with propofol.26 The majority of cases were due to contamination of the drug resulting from poor aseptic techniques. To prevent contamination, the additive ethylenediamine tetraacetic acid (EDTA) was included to help retard the growth of microorganisms. EDTA, at a concentration of 0.005%, has no effect on the physical or chemical stability of the emulsion compound. In the years following the introduction of the EDTA-containing formulation, the incidence of fevers and infections was reduced to zero. EDTA is a chelator of various ions, including calcium. In a randomized multicenter trial,27 patients were treated with either the original propofol formulation or the formulation with EDTA. The EDTA-containing formulation had no effect on calcium or magnesium homeostasis, renal function, or sedative efficacy compared with the original formulation. One of the interesting aspects of propofol with EDTA is its ability to modulate the systemic inflammatory response. In a study of surgical ICU patients,28 those receiving propofol with EDTA had significantly lower mortality rates at 7 and 28 days than those of patients receiving the original formulation. This potential positive effect of propofol with EDTA may 13

clinical practice be related to the ability of EDTA to bind cations. The EDTA-containing formulation of propofol increases the excretion of zinc; this, in turn, can diminish the inflammatory response to stress by decreasing the release of cytokines involved in inflammation (e.g., tumor necrosis factor) and the generation of free radicals and other oxidants. The authors of this review are part of a group in Rotterdam that has investigated the release of cytokines and the transmigration of bacteria in an animal model, as modulated by various sedative agents. The full scope of the use of sedative agents to modulate the systemic inflammatory response is a highly interesting avenue of research for the future. In the United States, 3 generic formulations of propofol are now available. The distinguishing feature of the first generic product is the presence of sodium metabisulfite (0.025%); it carries an FDA warning about use in patients sensitive to sulfite compounds and should not be used in this group of patients. This generic formulation also has a lower pH (4.5-6.4) than that of the formulation with EDTA. It is highly important for clinical staff to know which propofol formulation is being used in their facility. The other 2 generic formulations of propofol contain benzyl alcohol as a preservative. These formulations should not be used in neonates because of previous problems with benzyl alcohol in that patient population. Further studies are needed to evaluate the long-term administration of benzyl alcohol-containing formulations by continuous infusion in critically ill patients. Also, several 2% formulations are in development for use in both the operating room and the ICU. Propofol is not recommended for pediatric patients in the ICU because of reports of metabolic acidosis with accompanying lipemic serum, bradyarrhythmias, and fatal myocardial failure with excessively high doses.29 In adults with massive head trauma, prolonged use of propofol at very high doses may have contributed to cardiac failure;30 however, these were highly complex cases with a high mortality index. The SCCM guidelines recommend propofol as the agent of choice for rapid awakening and early extubation.1 Because propofol is formulated as a lipid emulsion, triglyceride concentrations should be monitored after 2 days of propofol infusion. The total caloric intake 14

from the lipids should be included in the nutritional support prescription and may decrease hospital costs for added nutritional support. Haloperidol. Haloperidol, a butyrophenone neuroleptic drug, is the agent of choice for the treatment of delirium in critically ill patients. Patients treated with haloperidol generally seem calmer and are better able to respond appropriately to commands.12 Haloperidol does not cause major respiratory depression. The drug, however, cannot be used alone in intubated critically ill patients. The adverse effects associated with haloperidol include occasional hypotension resulting from the α-adrenergic-blocking properties of the drug. Although it is rare with IV use, haloperidol may cause extrapyramidal effects such as drowsiness, lethargy, a fixed stare, rigidity, and akathisia. A highly dangerous side effect is neuroleptic malignant syndrome (NMS), with a mortality rate of 20% to 30%. NMS develops slowly over 24 to 72 hours and can last up to 10 days after discontinuation of the drug.31 The incidence of NMS may be higher when haloperidol is given by continuous infusion, which is not recommended. Dexmedetomidine. Dexmedetomidine is a newer selective α2-adrenergic receptor agonist. It exhibits sympatholytic, sedative, and analgesic effects and is 8 times more potent for the α2-adrenergic receptor than clonidine. Dexmedetomidine has been approved for short-term sedation and analgesia in the ICU. Its combined sedative and analgesic effects make it a highly promising therapy. The use of this agent is being actively investigated to determine its final place among sedation-analgesia guidelines. Dexmedetomidine acts at 2 adrenergic sites. It works by presynaptic activation of the α2-adrenoceptor, thereby inhibiting the release of norepinephrine and terminating the propagation of pain signals; it also affects postsynaptic activation of these receptors in the CNS. Dexmedetomidine inhibits sympathetic activity, resulting in a decrease in blood pressure and heart rate. Together, these 2 effects can produce sedation, anxiolysis, sympatholysis, and analgesia.32 Dexmedetomidine has several advantages as a sedative in the ICU. Because the drug does not cause respiratory depression, a patient can be extubated without prior Asian Journal of Critical Care Vol. 6, No. 3, July-September 2010

clinical practice discontinuation. This property also makes it ideal for use in extubated patients. The drug provides great flexibility. It also may be ideal for use during weaning from mechanical ventilation. Another advantage of dexmedetomidine is the easy awakening of treated patients, making it useful for those with head injury.33 Because dexmedetomidine also lowers the requirement for opioids, it can decrease opioid side effects. At the University of Rochester, the drug is widely used in burn patients, allowing complex wound care without the need for intubation. One of the greatest challenges in administering sedatives to patients who have a history of alcohol or drug abuse is to maintain the correct balance-avoiding both excessive sedation and agitation/withdrawal syndromes. The Îą2adrenergic receptor properties of dexmedetomidine may be highly useful in this patient population. We have had great success in weaning patients in the ICUespecially those with heavy alcohol or cocaine use. Further studies in this large population are necessary to map out the physiologic effects of sedation. Dexmedetomidine in the neurologic ICU offers a unique quality of sedation described as similar to normal sleep. Several investigators have noted that their patients were in a tranquil state but were able to understand and communicate their needs upon verbal stimulation by the medical staff (including the use of pen and paper).34 This particular profile of sedation may allow a more accurate evaluation of the neurophysiologic status of mechanically ventilated patients, which is difficult to accomplish with any other available sedative agents. Thus, dexmedetomidine may be the preferred sedative for neurosurgical patients who require a real-time assessment of their neurologic status. Another interesting population for further investigation are patients with head injuries, many of whom are highly agitated and expressing sympathetic outflow. With dexmedetomidine, we have been able to blunt the response of these patients and increase their rate of successful extubation. Dexmedetomidine has decreased the length of ICU stay and the rate of tracheotomies in patients with closed head injuries.35 Because elimination is primarily hepatic, dexmedetomidine dosing should be lowered in patients with Asian Journal of Critical Care Vol. 6, No. 3, July-September 2010

hepatic dysfunction. Also, the inappropriate use of dexmedetomidine may induce or aggravate cardiac conduction defects. Dexmedetomidine should not be used in hypovolemic or bradycardic patients, or in patients with low cardiac output or heart conduction blocks. The administration of this compound for more than 24 hours to critically ill patients has been found to be safe and effective in the ICU.36 Dexmedetomidine is a promising agent with multiple actions that reduce analgesic and other sedative requirements, and it produces a cooperatively sedated patient. It may open a whole new arena in the sedation of extubated patients who have high levels of anxiety. The compound may also enhance our ability to evaluate lung function and perform bronchoscopy in nonintubated patients, critically ill patients, and patients with moderate to severe chronic obstructive pulmonary disease or emphysema.37 Dexmedetomidine needs to be further studied and its place in the ICU identified by well-designed research to evaluate both its short- and long-term effects. Conclusion The most important aspect of ICU sedation is understanding the drugs given and their specific advantages and disadvantages. Each drug is ideal for a specific use. It is crucial for the clinician to develop guidelines and pathways for the administration of these drugs within a specific environment. Each unit should develop protocols that grade effect based on the type of patient population in the unit. Newer drugs like dexmedetomidine should be introduced and studied in controlled trials in specific populations. In this way, protocols can be developed that enable patients to be comfortable and anxiety-free in the ICU. Poor levels of sedation should be a thing of the past. The immunomodulation properties of sedative drugs must also be explored, as these properties may greatly affect outcome. With an increased understanding of sedative drugs will come a better ability to use multiple drugs at specific times during the hospital stay. References 1. Jacobi J, Fraser GL, Coursin DB, et al. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit Care Med. 2002;30(1):119â&#x20AC;&#x2018;41.

clinical practice 2. Cohen IL, Abraham E, Dasta JF, Gallagher TJ, Papadakos PJ, Pohlman AS. Management of the agitated intensive care unit patient. Crit Care Med. 2002;30(suppl):S97‑S123. 3. Fraser GL, Prato BS, Riker RR, Berthiaume D, Wilkins ML. Frequency, severity, and treatment of agitation in young versus elderly patients in the ICU. Pharmacotherapy. 2000;20(1):75-82. 4. Hassan E, Fontaine DK, Nearman HS. Therapeutic considerations in the management of agitated or delirious critically ill patients. Pharmacotherapy. 1998;18(1):113‑29. 5. Hansen-Flaschen J, Cowen J, Polomano RC. Beyond the Ramsay scale: need for a validated measure of sedating drug efficacy in the intensive care unit. Crit Care Med. 1994;22(5):732-3. 6. Riker RR, Picard JT, Fraser GL. Prospective evaluation of the Sedation-Agitation Scale for adult critically ill patients. Crit Care Med. 1999;27(7):1325-29. 7. Devlin JW, Boleski G, Mlynarek M, et al. Motor Activity Assessment Scale: a valid and reliable sedation scale for use with mechanically ventilated patients in an adult surgical intensive care unit. Crit Care Med. 1999;27(7):1271-5. 8. Ely EW, Margolin R, Francis J, et al. Evaluation of delirium in critically ill patients: validation of the confusion assessment method for the Intensive Care Unit (CAM-ICU). Crit Care Med. 2001;29(7):1370-9. 9. Riker RR, Fraser GL. Monitoring sedation, agitation, analgesia, neuromuscular blockade, and delirium in adult ICU patients. Semin Respir Crit Care Med. 2001;22(2):189-98. 10. Brook AD, Ahrens TS, Schaiff R, et al. Effect of a nursing-implemented sedation protocol on the duration of mechanical ventilation. Crit Care Med. 1999;27(12):2609-15. 11. Kress JP, Pohlman AS, O’Connor MF, Hall JB. Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med. 2000;342(20):1471-7. 12. Lund N, Papadakos PJ. Barbiturates, neuroleptics, and propofol for sedation. Crit Care Clin 1995;11 (4):875‑86. 13. Lewis KS, Whipple JK, Michael KA, Quebbeman EJ. Effect of analgesic treatment on the physiological consequences of acute pain. Am J Hosp Pharm. 1994;51 (12):1539-54.

in the intensive care unit: an executive summary. Society of Critical Care Medicine. Crit Care Med. 1995;23(9):1596-600. 16. Tipps LB, Coplin WM, Murry KR, Rhoney DH. Safety and feasibility of continuous infusion of remifentanil in the neurosurgical intensive care unit. Neurosurgery. 2000;46(3):596-602. 17. Albanese J, Viviand X, Potie F, Rey M, Alliez B, Martin C. Sufentanil, fentanyl, and alfentanil in head trauma patients: a study on cerebral hemodynamics. Crit Care Med. 1999;27(2):407-11. 18. Watling SM, Dasta JF, Seidl EC. Sedatives, analgesics, and paralytics in the ICU. Ann Pharmacother. 1997;31 (2):148-53. 19. Gilliland HE, Prasad BK, Mirakhur RK, Fee JP. An investigation of the potential morphine-sparing effect of midazolam. Anaesthesia. 1996;51(9):808-11. 20. Watling SM, Johnson M, Yanos J. A method to produce sedation in critically ill patients. Ann Pharmacother. 1996;30(11):1227-31. 21. Shafer A. Complications of sedation with midazolam in the intensive care unit and a comparison with other sedative regimens. Crit Care Med. 1998;26(5): 947-56. 22. Young C, Knudsen N, Hilton A, Reves JG. Sedation in the intensive care unit. Crit Care Med. 2000;28(3):854‑66. 23. Kamijo Y, Masuda T, Nishikawa T, Tsuruta H, Ohwada T. Cardiovascular response and stress reaction to flumazenil injection in patients under infusion with midazolam. Crit Care Med. 2000;28(2):318-23. 24. Bailie GR, Cockshott ID, Douglas EJ, Bowles BJ. Pharmacokinetics of propofol during and after longterm continuous infusion for maintenance of sedation in ICU patients. Br J Anaesth. 1992;68(5):486-91. 25. Barrientos-Vega R, Mar Sánchez-Soria M, MoralesGarcía C, Robas- Gómez A, Cuena-Boy R, AyensaRincón A. Prolonged sedation of critically ill patients with midazolam or propofol: impact on weaning and costs. Crit Care Med. 1997;25(1):33-40. 26. Bennett SN, McNeil MM, Bland LA, et al. Postoperative infections traced to contamination of an intravenous anesthetic, propofol. N Engl J Med. 1995; 333(3):147‑54.

14. Levine RL. Pharmacology of intravenous sedatives and opioids in critically ill patients. Crit Care Clin. 1994;10(4):709-31.

27. Abraham E, Papadakos PJ, Tharratt RS, Hall JB, Williams GJ. Effects of propofol containing EDTA on mineral metabolism in medical ICU patients with pulmonary dysfunction. Intensive Care Med. 2000;26(suppl 4): S422-S432.

15. Shapiro BA, Warren J, Egol AB, et al. Practice parameters for intravenous analgesia and sedation for adult patients

28. Herr DL, Kelly K, Hall JB, et al. Safety and efficacy of propofol with EDTA when used for sedation of Asian Journal of Critical Care Vol. 6, No. 3, July-September 2010

clinical practice surgical intensive care unit patients. Intensive Care Med. 2000;26(suppl 4):S452-S462.

for sedation in patients with traumatic brain injury. Anesthesiology. 2002;97(ASCCA suppl):B20.

29. Mirenda J, Broyles G. Propofol as used for sedation in the ICU. Chest. 1995;108(2):539-48.

34. Bekker A, Sturaitis MK. Dexmedetomidine for neurological surgery. Neurosurgery 2005;57(1suppl): 1â&#x20AC;&#x2018;10.

30. Cremer OL, Moons KG, Bouman EA, Kruijswijk JE, deSmet AM, Kalkman CJ. Long-term propofol infusion and cardiac failure in adult head-injured patients. Lancet 2001;357(9250):117-8. 31. Padegal V, Venkata B, Papadakos PJ. Neuroleptic malignant syndrome and malignant hyperthermia. In: Kruse JA, Fink MP, Carlson RW, eds. Saunders Manual of Critical Care. Philadelphia, PA: WB Saunders; 2002:301-3. 32. Gertler R, Brown HC, Mitchell DH, Silvius EN. Dexmedetomidine: a novel sedative-analgesic agent. Proc (Bayl Univ Med Cent). 2001;14(1):13-21. 33. Chhangani SV, Papadakos PJ. The use of dexmedetomidine

35. Barreiro TJ, Papadakos PJ. Current practices in intensive care unit sedation. In: Papadakos PJ, Szalados JE, eds. Critical Care, the Requisites in Anesthesiology. Philadelphia, PA: Elsevier Mosby; 2005. 36. Rodrigues MG, Salgado DR, Paiva RNA, Chindamo G, Martins LC, Verdeal JCR. Use of dexmedetomidine beyond 24 hours in the intensive care unit. Crit Care 2003;7(suppl 2):95. 37. Abouzgheib W, Littman J, Pratter M, Bartter T. Efficacy and safety of dexmedetomidine during bronchoscopy in patients with moderate to severe COPD or emphysema. J Bronchol. 2007;14(4):233-6.

Asian Journal of Critical Care Vol. 6, No. 3, July-September 2010

research article clinical practice

Should C-reactive Protein Concentration at ICU Discharge be Used as a Prognostic Marker? Joana Silvestre, Lu铆s Coelho, Pedro P贸voa

Abstract Background: About one third of hospital mortality in critically ill patients occurs after Intensive Care Unit (ICU) discharge. Some authors have recently hypothesized that unresolved or latent inflammation and sepsis may be an important factor that contributes to death following successful discharge from the ICU. Aim: The aim of our study was to determine the ability of the clinical and inflammatory markers at ICU discharge to predict post-ICU mortality. Methods: A prospective observational cohort study was conducted during a 14-month period in an 8 bed polyvalent ICU. Acute Physiology and Chronic Health Evaluation (APACHE) II score, Simplified Acute Physiology Score (SAPS) II, Sequential Organ Failure Assessment (SOFA) score, Therapeutic Intervention Scoring System-28 (TISS-28), C-reactive protein (CRP), white cell count (WCC) and body temperature of the day of ICU discharge were collected from patients who survived their first ICU admission. Results: During this period 156 patients were discharged alive from the ICU. A total of 29 patients (18.6%) died after ICU discharge. There were no differences in clinical and demographic characteristics between survivors and nonsurvivors. C-reactive protein levels at ICU discharge were not significantly different between survivors and nonsurvivors. The area under receiver operating characteristics curves of APACHE II, SAPS II, SOFA, TISS-28, CRP, WCC and body temperature at ICU discharge as prognostic markers of hospital death were 0.76 (95% confidence interval (CI) 0.67-0.86); 0.75 (95% CI 0.66-0.85); 0.72 (95% CI 0.62-0.83); 0.64 (95% CI 0.52-0.77); 0.55 (95% CI 0.43-0.67); 0.55 (95% CI 0.42-0.66) and 0.54 (95% CI 0.44-0.67) respectively. The hospital mortality rate of the patients with CRP <5, 5-10, >10 mg/dL was 15.1%, 16.1% and 33.3% respectively (p = NS). Conclusions: At ICU discharge serum CRP concentration was a poor marker of post-ICU prognosis. Post-ICU death appears to be unrelated to the persistent inflammatory response. Key words: APACHE II, SAPS II, SOFA, TISS-28, marker, post-ICU prognosis

ritically ill patients are responsible for 10-25% global hospital costs.1 The ability to identify critically ill patients who will not survive until hospital discharge may allow identification of high risk patients leading to more conservative strategies of ICU discharge. About one third of hospital mortality of critically ill patients occurs after Intensive Care Unit (ICU) discharge.2 Smith et al. observed in 283 patients discharged from the ICU to hospital wards that patients with higher Therapeutic Intervention Scoring System (TISS)-28 had higher post-ICU mortality (TISS-28 >20 = 21.4% vs. TISS-28 <10 = 3.7%, p < 0,0001).3 Several other risk prediction models have been used to predict inhospital mortality after patient discharge from the ICU.4,5 However risk estimated by these models showed considerable variation across the disease spectrum of ICU patients. Citation: Silvestre et al.: Should C-reactive protein concentration at ICU discharge be used as a prognostic marker?. BMC Anesthesiology 2010;10:17.

Post ICU deaths arise mainly as a result of incomplete resolution of the primary condition or from the development of new complications.6-8 Some authors have recently hypothesized that unresolved or latent inflammation and sepsis may be an important factor that contributes to death following successful discharge from the ICU.6 In two recent studies with critically ill patients, a high C-reactive protein (CRP) concentration at ICU discharge was associated with a subsequent increase in in-hospital mortality.6,9 The aim of our study was to determine the ability of the clinical and inflammatory markers at ICU discharge to predict post ICU mortality. Methods This study was a prospective, single center, observational study conducted during a 14-month period in the ICU of Garcia de Orta Hospital, an 8-bed multidisciplinary ICU. Asian Journal of Critical Care Vol. 6, No. 3, July-September 2010

research article The Hospital Ethics Committee approved the study design, and informed consent was waived because this was an observational study without any deviation from the current medical practice. Patients were included in the study if they were discharged alive from the ICU and if they were more than 17 years old. Discharged criteria were clinical improvement without need of further organ support and/or intensive monitoring. Patients were followed until hospital death or hospital discharge. Only the first ICU admission was included. The clinical predictors analyzed included Acute Physiology and Chronic Health Evaluation (APACHE) II10, Simplified Acute Physiology Score (SAPS) II11, Sequential Organ Failure Assessment scores (SOFA)12 and Therapeutic Intervention Scoring System-28 (TISS-28).13 CRP body temperature and white cells count (WCC) were measured at admission and then daily until discharge. Measurement of CRP was performed by an immunoturbidimetric method (Tina-quant CRP; Roche Diagnostics, Mannheim, Germany). We compared the clinical and laboratory data of survivors and nonsurvivors after ICU discharge. A subgroup analysis between infected and noninfected patients was performed. Surgical and medical patients were also analyzed. We considered that the patient belong to the surgical group if the main reason of ICU admission was surgical, obstetric or trauma. Statistical Analyses

The outcome measure was post-ICU mortality. Continuous variables are presented as mean ± standard deviation (SD), unless stated otherwise. Differences in continuous variables were performed with the parametric unpaired Student’s t test and one-way ANOVA or with the nonparametric Mann-Whitney U-test or KruskalWallis H-test according to data distribution. The Chisquare test was used to carry out comparisons between categorical variables. CRP levels were categorized in three groups (CRP <5, 5-10, >10 mg/dL) and compared with mortality rate. Linear regression analysis was used to compare SOFA with CRP levels. Discrimination of APACHE II, SAPS II, SOFA, TISS-28, CRP, body temperature Asian Journal of Critical Care Vol. 6, No. 3, July-September 2010

and WCC was tested to produce receiver-operating characteristic (ROC) curves. Areas under curves (AUC), with 95% confidence intervals (CI) were calculated in prediction of ICU mortality. A p value below 0.05 was considered statistically significant. Statistical analyses were performed using SPSS 16.0 software. Results During a 14-month period a total of 262 patients were admitted in the ICU. The overall ICU mortality was 40%. One hundred and fifty six patients were discharged alive from ICU to ward with a mean age of 55 ± 18 and 93 (60%) were males (Table 1). A total of 29 patients (18.6%) died in hospital after ICU discharge. Clinical and demographic characteristics of post-ICU survivors and nonsurvivors are presented in table 1. The mean duration of follow-up post-ICU discharge was 34.8 days, with no difference between survivors and nonsurvivors (34.3 ± 26.8 versus 37.6 ± 24.9 days; p = NS). Nonsurvivors were sicker with higher levels of APACHE II, SAPS II, SOFA and TISS-28. (Table 1). CRP protein was determined in all patients at ICU discharge. CRP values varied from 0.15 to 43.5 mg/dl. Although 25% higher in nonsurvivors, CRP levels at ICU discharge was not significantly difference in relation to survivors (survivors - 8.1 ± 8.0 vs nonsurvivors - 10.2 ± 12.0 mg/dl; p = NS). In addition, no correlation could be found between higher CRP levels and mortality. Post-ICU mortality rate of the patients with CRP <5, between 5-10, >10 mg/dl was 15.1% (n = 9), 16.1% (n = 9) and 33.3% (n = 11) respectively (p = NS). The area under the ROC curves of APACHE II, SAPS II, TISS-28, SOFA, CRP, WCC and body temperature and at ICU discharge as prognostic markers of post-ICU death were 0.76 (95% CI 0.67-0.86), 0.75 (95% CI 0.67-0.86), 0.72 (95% CI 0.62-0.83), 0.64 (95% CI 0.52-0.77), 0.55 (95% CI 0.43-0.68), 0.56 (95% CI 0.44-0.67) and 0.54 (95% CI 0.44-0.67) respectively (Fig. 1). CRP as a Prognostic Marker in Patients with Previous Documented Infection

One hundred and thirty six out of 262 of the patients discharged from ICU presented at least one documented 19

research article Table 1. Baseline Characteristics of the Patients Discharged from the Intensive Care Unit All (n = 156)

Survivors (n = 127)

Nonsurvivors (n = 29)

p values

Age, years

55 ± 18

53 ± 19

62 ± 12

Sex (M/F)

93/63

79/48

14/15

APACHE II

14.6 ± 6.2

13.4 ± 5.3

20.0 ± 7.1

<0.001

SAPS II

28.6 ± 12.7

25.9 ± 9.6

40.5 ± 17.5

<0.001

TISS-28

25.1 ± 5.3

24.2 ± 4.3

28.8 ± 7.1

<0.001

SOFA

3.5 ± 2.7

3.0 ± 1.8

5.6 ± 4.7

<0.001

CRP (mg/dL)

8.5 ± 8.3

8.1 ± 8.0

10.1 ± 9.5

Temperature (ºC)

36.9 ± 2.7

36.8 ± 3.0

37.2 ± 0.8

WCC (x1000)/mL

11.3 ± 7.4

10.6 ± 6.0

14.4 ± 11.4

Respiratory Trauma Surgical

47 24 21

35 21 17

12 3 4

Cardiovascular Neurological

21 14

17 13

4 1

Obstetrics Gastroenterological Others

6 6 17

6 5 13

0 1 4

Admission diagnosis (N)

Values expressed as mean ± standard deviation

ROC Curve

1.0

Source of the Curve SAPS I APACHE II SOFA TISS WCC CRP Body temperature

Sensitivity

0.8 0.6 0.4 0.2 0.0

0.0

0.2

0.4 0.6 1-Specificity

0.8

1.0

Table 2. Baseline Characteristics of the Patients with Documented Infection Survivors (n = 127)

Nonsurvivors (n = 29)

p values

Age, years

54 ± 18

62 ± 12

p = NS

Sex (M/F)

69/39

14/14

p = NS

APACHE II

13.7 ± 4.9

20.3 ± 10.0

p < 0.001

SAPS II

26.2 ± 8.8

41.3 ± 17.2

p < 0.001

TISS-28

24.1 ± 3.6

29.1 ± 7.1

p < 0.001

SOFA

3.0 ± 1.7

5.7 ± 4.7

p < 0.001

CRP (mg/dL)

8.4 ± 8.2

10.3 ± 9.6

p = NS

Values expressed as mean ± standard deviation

Figure 1. Receiver operating characteristics (ROC) curves of Simplified Acute Physiology Score (SAPS) II, Acute Physiology and Chronic Health Evaluation (APACHE) II, Therapeutic Intervention Scoring System-28 (TISS-28), Sequential Organ Failure Assessment (SOFA) scores, serum C- reactive protein (CRP), body temperature and white cell count (WCC).

were observed between survivors and nonsurvivors (8.4 ± 8.2 vs 10.3 ± 9.6 mg/dL, p = NS, respectively) after discharge. However, the SAPS II, APACHE II, TISS-28 and SOFA score were significantly higher in nonsurvivors (Table 2).

infection during their ICU stay. The mean age was 55 ± 17 years and 83 (61%) were males. The primary reason for ICU admission was respiratory failure due to pneumonia. The in-hospital mortality rate from the patients with documented infection was 21%. At ICU discharge, CRP values varied from 0.15 to 43.5 mg/ dL (median 5.7 mg/dL). No differences in CRP levels

The AUC showed a good discriminative power of post-ICU mortality for TISS-28 (AUC 0.75;95% CI 0.665-0.86), SAPS II (AUC 0. 77;95% CI 0.68-0.87) and APACHE II score (AUC 0.78; 95% CI 0.680.87). For CRP levels the AUC did not demonstrate a good discriminative power of post-ICU mortality (AUC 0.55; 95% CI 0.42-0.67). Asian Journal of Critical Care Vol. 6, No. 3, July-September 2010

research article CRP as a Prognostic Marker in Surgical and Medical Patients

In 51 patients the main admission diagnosis was surgical. The mean age was 49 ± 19 years and 33 (65%) were male. The post-ICU mortality rate was 14% and no differences were observed between surgical and medical patients. CRP levels at ICU discharge were significantly higher than in medical patients (6.5 ± 7.0 vs 12.5 ± 9.2; p < 0.001). However no differences in CRP levels at ICU discharge could be found between survivors and nonsurvivors in both surgical and medical patients (5.9 ± 6.7 mg/dl vs 8.7 ± 8.9 mg/dl; p = NS and 12.2 ± 8.6 mg/dl vs 14.6 ± 13.0; p = NS, respectively). CRP also did not demonstrate a good discriminative power of post-ICU mortality (Medical Group: AUC 0. 51; 95% CI 0.19-0.82 and Surgical Group: AUC 0.38; 95% CI 0.24-0.52). Discussion In this prospective observational study with 156 patients discharged alive from ICU, we evaluated the relation between CRP levels at ICU discharge and postICU mortality. Our data demonstrate that CRP at ICU discharge was not correlated with in-hospital mortality. Even in patients with higher levels of CRP (>10 mg/dl) there was no significant increase in post-ICU mortality. In the subgroup analysis these data were similar and no association could be found between CRP levels and postICU mortality in patients with previous documented infection and in medical and surgical patients. In a heterogeneous ICU patient population, Lobo et al. showed that admission CRP levels correlated with an increased risk of organ failure and death.14 In addition, our group showed that persistently elevated CRP concentrations in infected critically ill patients were associated with poor outcome.15,16 Recently, it has been described that in survivors of an acute infection could present a state of persistent inflammation that may lead to deterioration of other diseases, such as cardiovascular disease, and an increased long-term mortality.7 Long-term mortality has been assessed in a recent multicenter study conducted by Yende et al.8 Authors included 1799 patients discharged from emergency department with a primary diagnosis of community pneumonia. Interleukin-6 (IL-6) concentrations at hospital discharge were higher among subjects who did not survive at 100 days compared with those who survived (12.9 vs 6.6 pg/ml, p < 0.001). This difference Asian Journal of Critical Care Vol. 6, No. 3, July-September 2010

was not obtained among those who did and did not survive between 101 days and 1 year (7.7 vs. 6.5 pg/mL, p = NS). However, nonsurvivors compared with survivors at one year, nonsurvivors were older, had more co-morbid conditions, as evidenced by higher Charlson scores, and had more severe CAP on presentation, as evidenced by higher Pneumonia Severity Index and APACHE III scores. In a recently published study by Ho et al.,6 that analyzed short-term mortality among ICU patients, a significant association between CRP concentrations at ICU discharge and subsequent inhospital mortality was identified. In this prospective cohort study of 603 consecutive patients who survived their first ICU admission, CRP concentrations at ICU discharge were associated with subsequent in-hospital mortality in the univariate analysis (non-survivors-17.4 vs. survivors - 8.56 mg/l, p = 0.001). In our study we were unable to reproduce these findings, since CRP was a poor prognostic marker of post- ICU mortality (AUC 0.55; 95% CI 0.42-0.67). However, in Ho et al study6, CRP concentrations were available only in 73% of the nonsurvivors and the number of unexpected post-ICU deaths was small (4.3%). Hence the results could be imprecise and may not be extrapolated to ICUs with higher post-ICU mortality rates. In opposition, our data does not support the use of CRP in outcome prediction in critically ill patients, however, in comparison with Ho et al. data, our population had higher APACHE II, SOFA scores and TISS-28 as well as a larger subgroup of patients with documented infection. In a recently published study, we also could not found a relation between CRP levels of the day of sepsis diagnosis and ICU survival.17 Both these results demonstrate that, despite CRP has been repeatedly shown to be a sensitive marker of infection; it predicts poorly the patient outcome. Our study has some limitations. First, this was a cohort single centre study with only 8 beds of intensive care. Second a mixed group of medical and surgical patients were included; whether CRP will have a better performance in a particular subgroup of patients, for example in patients with lower respiratory tract infection remains uncertain, but deserves further investigation. Finally severity scores were used at ICU discharge, however these scores were only developed and validated to be used in the first 24 hours after ICU admission. Our study design had some distinctions: we analyzed separately the patients with previous 21

research article documented infection as well as medical and surgical patient, and patients with end-life limitations were not excluded. Conclusions Some studies suggest that persistent inflammation may precipitate deterioration in other diseases, such as cardiovascular disease, and increase long-term mortality.7 In our data no correlation between CRP concentrations at ICU discharge and post-ICU hospital mortality could be found, with post-ICU survival appearing to be unrelated to higher levels of inflammatory biomarkers. Reasons for increased long and short-term mortality among ICU survivors are not fully understood. As a result, future studies are needed to explore the relationship between biomarkers on subsequent health-related outcomes. Key Messages 



In the present study CRP concentrations at ICU discharge were not related to post-ICU hospital outcome. CRP despite being a sensitive marker of infection, it predicts poorly the patient outcome. Similar results were observed in the subgroup of ICU survivors with documented infection. CRP also did not demonstrate a good discriminative power of post-ICU mortality between medical and surgical patients.

List of abbreviations APACHE: Acute Physiology and Chronic Health Evaluation; AUC: Areas under curves; CI: Confidence intervals; CRP: C-reactive protein; ICU: Intensive Care Unit; ROC: Receiveroperating characteristic; SAPS: Simplified Acute Physiology Score; SD: Standard deviation; SOFA: Sequential Organ Failure Assessment; TISS-28: Therapeutic Intervention Scoring System-28; WCC: White cell count.

References 1. Barrera R, Nygard S, Sogoloff H, Groeger J, Wilson R. Accuracy of predictions of survival at admission to the intensive care unit. J Crit Care 2001;16(1):32-5. 2. Moreno R, Agthe D: ICU discharge decision-making: are we able to decrease post-ICU mortality? Intensive Care Med 1999;25(10):1035-6. 3. Smith L, Orts CM, O’Neil I, Batchelor AM, Gascoigne AD, Baudouin SV: TISS and mortality after discharge from intensive care. Intensive Care Med 1999; 25(10):1061-5. 4. Moreno R, Morais P: Outcome prediction in intensive care: results of a prospective, multicentre, Portuguese study. Intensive Care Med 1997;23(2):177-86.

5. Beck DH, Taylor BL, Millar B, Smith GB: Prediction of outcome from intensive care: a prospective cohort study comparing Acute Physiology and Chronic Health Evaluation II and III prognostic systems in a United Kingdom intensive care unit. Crit Care Med 1997; 25(1):9-15. 6. Ho KM, Lee KY, Dobb GJ, Webb SA. C-reactive protein concentration as a predictor of in-hospital mortality after ICU discharge: a prospective cohort study. Intensive Care Med 2008;34(3):481-7. 7. Smeeth L, Thomas SL, Hall AJ, Hubbard R, Farrington P, Vallance P. Risk of myocardial infarction and stroke after acute infection or vaccination. N Engl J Med 2004;351(25):2611-8. 8. Yende S, D’Angelo G, Kellum JA, Weissfeld L, Fine J, Welch RD, Kong L, Carter M, Angus DL:. Inflammatory markers at hospital discharge predict subsequent mortality after pneumonia and sepsis. Am J Respir Crit Care Med 2008;177(11):1242-7. 9. Litton E, Ho KM, Chamberlain J, Dobb GJ, Webb SA: C-reactive protein concentration as a predictor of in-hospital mortality after ICU discharge: a nested case-control study. Crit Care Resusc 2007;9(1):19-25. 10. Knaus WA, Draper EA, Wagner DP, Zimmerman JE: APACHE II: a severity of disease classification system. Crit Care Med 1985;13(10):818-29. 11. Le Gall JR, Lemeshow S, Saulnier F: A new Simplified Acute Physiology Score (SAPS II) based on a European/North American multicenter study. Jama 1993;270(24):2957-63. 12. Vincent JL, Moreno R, Takala J, Willatts S, De Mendonca A, Bruining H, Reinhartck, Suter PM, Thijs LG:. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med 1996;22(7):707-10. 13. Miranda DR, de Rijk A, Schaufeli W: Simplified Therapeutic Intervention Scoring System: the TISS-28 items-results from a multicenter study. Crit Care Med 1996;24(1):64‑73. 14. Lobo SM, Lobo FR, Bota DP, Lopes-Ferreira F, Soliman HM, Melot C,Vincent SL: C-reactive protein levels correlate with mortality and organ failure in critically ill patients. Chest 2003;123(6):2043-9. 15. Povoa P, Coelho L, Almeida E, Fernandes A, Mealha R, Moreira P, Sabino H: Pilot study evaluating C-reactive protein levels in the assessment of response to treatment of severe bloodstream infection. Clin Infect Dis 2005; 40(12):1855‑7. 16. Povoa P, Coelho L, Almeida E, Fernandes A, Mealha R, Moreira P, Sabino H: C-reactive protein as a marker of infection in critically ill patients. Clin Microbiol Infect 2005;11(2):101‑8. 17. Silvestre J, Povoa P, Coelho L, Almeida E, Moreira P, Fernandes A, Mealha R, Sabino H: Is C-reactive protein a good prognostic marker in septic patients? 2009, 35(5):909-913. Asian Journal of Critical Care Vol. 6, No. 3, July-September 2010

for the clinician clinical practice

Clostridium Difficile: Moving Beyond Antimicrobial Therapy Amesh A Adalja, John A Kellum

Abstract Infection with Clostridium difficile places a significant burden on healthcare facilities. One of the major factors hindering successful treatment of C. difficile-associated disease is the high rate of recurrence. monoclonal antibodies will reduce the recurrence of disease and should be routinely administered to those at highest risk for recurrence. Key words: Clostridium difficile infection, monoclonal antibodies

ew therapies are needed to manage the increasing incidence, severity and high rate of recurrence of Clostridium difficile infection.

Methods Objective: To assess the ability of monoclonal antibodies directed against two toxins of C. difficile to prevent recurrence of disease. Design: Randomized, double-blind, placebo-controlled study. Setting: 30 medical centers in the United States and Canada Subjects: 200 subjects with diarrhea and a positive stool toxin assay for C. difficile being treating with metronidazole or vancomycin. Intervention: Antibodies administered together as a single infusion, each at a dose of 10 mg per kilogram of body weight. Outcomes: The primary outcome was laboratory documented recurrence of infection during the 84 days after the administration of monoclonal antibodies or placebo. Results Among the 200 patients who were enrolled (101 in the antibody group and 99 in the placebo group), the rate of recurrence of C. difficile infection was lower among patients treated with monoclonal antibodies (7% vs. 25%; 95% confidence interval, 7 to 29; P < 0.001). The absolute risk reduction (ARR) was 16%, yielded a number needed to treat (NNT) of 5.5. The recurrence rates among patients with the epidemic BI/NAP1/027 strain were 8% for the antibody group and 32% for the placebo group (P = 0.06); among patients Citation: Adalja AA, Kellum JA: Clostridium difficile: moving beyond antimicrobial therapy. Critical Care 2010;14:320.

Asian Journal of Critical Care Vol. 6, No. 3, July-September 2010

with more than one previous episode of C. difficile infection, recurrence rates were 7% and 38%, respectively (P = 0.006). The mean duration of the initial hospitalization for inpatients did not differ significantly between the antibody and placebo groups (9.5 and 9.4 days, respectively). At least one serious adverse event was reported by 18 patients in the antibody group and by 28 patients in the placebo group (P = 0.09). Conclusions The addition of monoclonal antibodies against C. difficile toxins to antibiotic agents significantly reduced the recurrence of C. difficile infection. (Clinical Trials.gov number, NCT00350298 [Clinical Trials.gov]). Commentary

Infection with C. difficile places a significant burden on healthcare facilities. C. difficile has been shown to substantially increase hospital costs, hospital length of stay, and contribute to mortality.1,2 One of the major factors hindering successful treatment of C. difficileassociated disease is the high rate of recurrence. Risk factors for recurrence include continued antibiotic use, antacid use, and older age.3 Anecdotal evidence supports the use of several different modalities, such as tapering doses of vancomycin, rifaxamin, and fecal transplant. Yet, to date none of these therapies have been shown to be effective. Myriad risk factors for C. difficile infection coalesce in intensive care units, making it a highly relevant condition for intensivists. 23

for the clinician The present study sought to evaluate the efficacy of an infusion of monoclonal antibodies directed towards the two principle toxins that emanate from C. difficile at preventing relapse of infection.4 The study was a double blind, phase II, randomized, controlled trial at 30 medical centers in the US and Canada. This study enrolled 200 subjects between 2006 and 2008 with C. difficile infection in both inpatient and outpatient settings. All subjects were followed up for 84 days. Both study groups received antibiotic treatment with either metronidazole or vancomycin. The proportion of the hypervirulent BI/NAPI strain of C. difficile was similar in both the treatment and placebo arms. The study results revealed a significant decrease in the relapse rate of C. difficile in the treatment arm. The absolute risk reduction (ARR) was 18% and the number needed to treat (NNT) is 5.5. In those with more than one recurrence, the ARR of a recurrence was even greater (ARR = 31% and NNT = 3.2). There was no difference in the rates of serious adverse events between the placebo and treatment groups. However, the infusion failed to impact the severity of the initial episode of C. difficile infection or length of stay. All recurrences occurred in hospitalized subjects. The study was well conducted and had few limitations. One limitation was that the study defined severity of C. difficile infection solely in terms of stool counts and may have unduly dismissed the benefit of the antibodies against the initial infection. Utilizing other parameters, such as quality of life and ability to tolerate meals, may have provided more information concerning the impact on the initial episode. Additionally, the exclusion of the sickest patients with C. difficile may have limited the generalizability of the study to acute care settings. Recurrent C. difficile-associated disease is an important problem that not only affects the patient, but places others at risk from environmental contamination with the bacteria. The monoclonal antibodies studied in

this paper provide hope that those plagued with recurrent infections can be treated effectively and safely. The utilization of monoclonal antibodies against infectious diseases is a crucial advance in developing specific therapies that are targeted at the organism of interest and not likely to inflict collateral damage to the patient’s microbiome, an important point made in the editorial accompanying the study.5 Recommendation

In conclusion, the addition of monoclonal antibodies did not alter the severity of C. difficile-associated disease. However, monoclonal antibodies will reduce the recurrence of disease and should be routinely administered to those at highest risk for recurrence. Determining the cost-effectiveness of this approach remains to be seen. References 1. Dubberke ER, Butler AM, Reske KA, Agniel D, Olsen MA, D’Angelo G, McDonald LC, Fraser VJ: Attributable outcomes of endemic Clostridium difficile-associated disease in nonsurgical patients. Emerg Infect Dis 2008; 14:1031‑38. 2. Dubberke ER, Reske KA, Olsen MA, McDonald LC, Fraser VJ: Short- and longterm attributable costs of Clostridium difficile-associated disease in nonsurgical inpatients. Clin Infect Dis 2008;46:497-504. 3. Garey KW, Sethi S, Yadav Y, DuPont HL: Meta-analysis to assess risk factors for recurrent Clostridium difficile infection. J Hosp Infect 2008;70:298-304. 4. Lowy I, Molrine DC, Leav BA, Blair BM, Baxter R, Gerding DN, Michol G, Thomas WD, Leney M, Sloan S, Hay CA, Ambrosino DM: Treatment with monoclonal antibodies against Clostridium difficile toxins. N Engl J Med 2010;362:197-205. 5. Kyne L: Clostridium difficile-beyond N Engl J Med 2010;362:264-265.

antibiotics.

Asian Journal of Critical Care Vol. 6, No. 3, July-September 2010

for the clinician clinical practice

ICU Intubation Success Hampered by Non-ideal Conditions: Based on Small Cohort Study... Lynne Peeples

Abstract One out of every five endotracheal intubations attempted in the intensive care unit is problematic, and alternative tools needed to secure these difficult airways are often several life-threatening minutes away, researchers in Germany have found. Key words: Endotracheal intubation, difficult airway

ne out of every five endotracheal intubations attempted in the intensive care unit is problematic, and alternative tools needed to secure these difficult airways are often several lifethreatening minutes away, researchers in Germany have found.

the Society of Critical Care Medicine (abstract 396). “These were all highly experienced residents with at least three years of anesthesia experience.”

“We had a feeling that there’s a high incidence of difficult airway in the ICU, just based on experiences of physicians,” said lead author Rüdiger Noppens, MD, an anesthesiologist at University Medical Center of the Johannes Gutenberg University in Mainz. “But we weren’t prepared for this finding.”

William Rosenblatt, MD, professor of anesthesiology at Yale University School of Medicine in New Haven, Conn., said he was not surprised by the findings.

During the nine-month prospective cohort study, Dr. Noppens and colleagues examined all endotracheal intubations by physicians in an anesthesia-led surgical ICU. Of the 106 adult patients intubated–most commonly for respiratory or oxygenation failure– airways were secured on the first attempt 80% of the time. “This is a very, very high number [of failures],” Dr. Noppens said of the remaining 20%. On the second try, 14% of the intubations were successful; more than three attempts were needed in the remaining 6%. Previous studies have found that only about 5% of endotracheal intubations in the operating room (OR) run into problems. “I don’t think it’s a lack of training of the doctors [in the ICU],” said Dr. Noppens, who presented his findings at the 2010 annual meeting of Source: Adapted from Anesthesiology News, March 2010, McMahon Publishing.

Asian Journal of Critical Care Vol. 6, No. 3, July-September 2010

Rather, he said conditions in the ICU can be far worse than in the OR—both in terms of the working environment and the health of the patient.

“While [ORs] are controlled environments idealized for the management of the airway, the ICU is designed for so much else,” he said. For example, rather than lying on a table free on all sides with adjustable height and lighting, critically ill patients may be found on a gurney or in a hospital bed under less ideal and crowded conditions. Patients in critical care also are typically sicker than those in the OR and perhaps more likely to present with a condition—such as edema—that obstructs the glottic view. With a wider array of devices available, such as video laryngoscopes and supraglottic airway devices, the clinician has more tools for working around intubation difficulties and minimizing complications. (Dr. Noppens found that in 10% of study patients, problems were encountered after the airway was secured, including soft tissue injuries and glottic swelling.) However, whereas such tools may be standard equipment in the OR, access to them in the ICU may take five or 10 minutes, Dr. Rosenblatt said. Given the high-risk patients and the potential for dire outcomes—including cardiac arrest and asphyxia— Cont’d on page 27... 25

for the clinician clinical practice

Pain Not Minimized after Minimally Invasive Cardiac Surgery Michael Vlessides

Abstract Although minimally invasive cardiac surgery may offer several benefits over cardiac surgery with open sternotomy, less pain during the first week postoperatively does not appear to be one of them, a Montreal research team has concluded. Key words: Pain scores, postoperative pain

lthough minimally invasive cardiac surgery may offer several benefits over cardiac surgery with open sternotomy, less pain during the first week postoperatively does not appear to be one of them, a Montreal research team has concluded. Jennifer Cogan, MD, assistant professor of anesthesiology at the University of Montreal, and her colleagues found that average pain scores–on a numerical rating scale–following movement among patients undergoing minimally invasive cardiac surgery (MICS) were 5.3 at 24 hours, 5.2 at 48 hours and 3.9 seven days after surgery. In comparison, a group of patients who had open sternotomy reported pain scores of 5.5 at 24 hours, 5.5 at 48 hours and 4.3 on the fifth postoperative day. “We’ve been interested in pain after surgery for some time,” Dr. Cogan said. “Minimally invasive cardiac surgery is relatively new here, and we were interested in determining if it was less painful than the traditional route of open sternotomy. Certainly the surgeons feel that minimally invasive surgery is less painful, but the nurses who look after the patients were telling us something different.” The investigators collected pain-related information from 101 consecutive MICS patients presenting at the Montreal Heart Institute since 2007 (mean age, 56.8 years; 59% male). Measures included the location and intensity of pain, barriers to taking pain medication and patient satisfaction with treatment.

Source: Adapted from Anesthesiology News, July 2010, McMahon Publishing.

In addition to average pain scores, a large majority of patients reported pain scores on movement of ≥4 throughout the postoperative period: 74%, 77.5% and 56.5% at 24 hours, 48 hours and seven days, respectively, according to Dr. Cogan, who reported the findings at the 2010 annual meeting of the Society of Cardiovascular Anesthesiologists (abstract SCA89). Most patients (89%) were satisfied with their care, although only five reported that a nurse had provided instructions regarding the importance of good pain management. Three patients reported that a nurse explained the importance of informing medical staff if he or she was in pain. While the researchers may have been surprised to find close similarities between pain scores reported by patients undergoing MICS and open sternotomy, Dr. Cogan offered several possible explanations. “Although it’s considered minimally invasive surgery, some patients receive much larger incisions than others, so the surgeon can actually look inside the incision,” she told Anesthesiology News. “That would certainly account for some of the lack of differences we noted between patients.” “It’s also an area that is known to be particularly painful,” she continued. “So the patient may feel pain irrespective of the incision size, simply because of intercostal insertion of scopes, instruments and drains.” It is also possible that MICS patients have never been given the opportunity to rate their pain, Dr. Cogan said. “Patients only tell us that things hurt when we ask them,” she continued. “So, if you go out of your way to ask patients about their pain, there is usually more than you expected.” Asian Journal of Critical Care Vol. 6, No. 3, July-September 2010

for the clinician With this in mind, she suggested that clinicians be more cognizant of the potential for significant postoperative pain in MICS patients. “I think we need to take a closer look at what we’re doing with these patients, and see if smaller incisions would help, too,” she said.

“The average age of the study population is less than 60,” Dr. Bainbridge said. “Most young people tend to have more pain for a given surgery than their elderly counterparts. We have 80-year-olds who fracture hips and don’t notice much. But if you’re a 20-year-old and you fracture a hip, you’re in severe pain.”

Daniel T. Bainbridge, MD, associate professor of anesthesia at The University of Western Ontario in London, Canada, offered another possible explanation for the relatively high pain levels found among MICS patients.

“People think minimally invasive means minimally painful,” Dr. Bainbridge continued. “So we try to be a bit more aggressive in treating pain in these patients than in sternotomy patients, to try to meet those expectations.” n

...Cont’d from page 25 how has the difficult airway remained below the critical care radar? A partial explanation may be the relative rarity of intubations in the ICU compared with the OR. According to Dr. Noppens, in one year an ICU physician may see fewer than 10 patients who require intubation; so, encountering roughly two difficult airways may not be striking. On the other hand, a clinician may perform more than 200 intubations over the course of a year in the OR and see fewer than

10 difficult intubations. “For a doctor, this feels very similar,” Dr. Noppens said-even if the actual rate of difficult airways encountered is significantly different between the two settings. “What it says to us,” Dr. Rosenblatt told Anesthesiology News, “is that when it comes to managing airways outside the [OR], we need to have a higher level of vigilance as to the conditions that we’re working in and what equipment is immediately available for us.” n

Asian Journal of Critical Care Vol. 6, No. 3, July-September 2010

for the clinician clinical practice

Still Asleep at the (Ventilator) Switch? Ted Agres

Abstract Despite growing recognition that daily interruption of sedation saves lives, reduces coma as well as the duration of mechanical ventilation and time spent in the intensive care unit, the adoption of the “wake up and breathe” protocol at hospitals remains slow and inconsistent. Key words: Mechanical ventilation, sedation-weaning regimen, spontaneous awakening trial

espite growing recognition that daily interruption of sedation saves lives, reduces coma as well as the duration of mechanical ventilation and time spent in the intensive care unit, the adoption of the “wake up and breathe” protocol at hospitals remains slow and inconsistent. The latest indication of lethargy? A new study showing that less than half of eligible patients are being placed on the sedation-weaning regimen. The results dovetail with a 2008 survey sent to Society of Critical Care Medicine (SCCM) members showing a similar hesitancy. Simon Lam, PharmD, co-investigator of the new study and a clinical pharmacist at the Cleveland Clinic, in Ohio, said he was not surprised by the results. Because of individual patient and prescriber variation, ‘we certainly didn’t expect 100% adherence,’ he said. The study was based on a retrospective chart study of patients admitted to the Cleveland Clinic’s intensive care unit (ICU) during a two-month period in 2008. All of the patients were mechanically ventilated and given a continuous infusion of sedative and/or analgesic. Patients were not considered eligible for the weaning protocol if they were given a fraction of inspired oxygen of 0.7 or greater, positive end expiratory pressure of 12 cm H2O or greater, neuromuscular blocking agents or specialized mechanical ventilation (e.g., oscillation). Source: Adapted from Anesthesiology News, March 2010, McMahon Publishing.

Forty-one patients were evaluated, resulting in 154 individual patient-day episodes. Although 70.1% of the patient episodes were eligible for a spontaneous awakening trial (SAT), the awakening trial was performed only 40.7% of the time, the researchers found. Fear of hypoxia was the most common reason cited by nurses for not performing a SAT, Dr. Lam said. He added, however, that the Cleveland Clinic results were not outside the norm. “Upon discussion with other institutions and evaluation of existing data, it appears that our rate of SAT performed was similar to other centers.” Lack of a Follow-up Study

Timothy Girard, MD, lead researcher of the randomized, multicenter Awakening and Breathing Controlled (ABC) trial that demonstrated striking benefits from use of the protocol (Lancet 2008;371:126-134), said that he is not surprised at the slow rate of adoption documented in the Cleveland Clinic study. Part of the problem, Dr. Girard said, is the lack of additional studies confirming his results. “I am not aware of any new trials published in the last year examining our wake up and breathe protocol,” said Dr. Girard, a critical care physician at the Vanderbilt University School of Medicine, in Nashville, Tenn. Nevertheless, “anecdotally, we frequently hear from clinicians in ICUs across the country who are using the protocol that they are having great success with it.” In Dr. Girard’s ABC trial, eligible patients underwent daily interruption of sedatives coupled with spontaneous Asian Journal of Critical Care Vol. 6, No. 3, July-September 2010

for the clinician breathing trials to determine if patients were ready to be weaned from mechanical ventilation. Compared with a control group, ICU patients who received the protocol at four community and university hospitals experienced three more ventilator-free days in the ICU, were discharged four days earlier and had significantly fewer days in coma. Mortality benefits were also striking: Patients who underwent the sedation-weaning protocol were 32% less likely to die than were patients in the control group, Dr. Girard reported. The benefits of the protocol were first reported 10 years ago (N Engl J Med 2000;342:1471-1477) and a daily interruption of sedation strategy has been part of SCCM’s practice guidelines since 2002. Despite this, only 40% of SCCM members reported having such a strategy in place in 2008 (J Crit Care 2009;24:66-73). Reasons for lack of use included no physician order (35%), lack of nursing support (11%) and fear of oversedation (7%). Resistance to use included a lack of nursing acceptance (22%), concern about risk for patient-initiated device removal (19%) and inducement of either respiratory compromise (26%) or patient discomfort (13%). One of the major concerns about turning off patient sedation in the ICU is that it might lead to adverse

psychological outcomes. But according to Dr. Girard, those concerns are largely unfounded. “We found no difference between [awakened and nonawakened patients] with regard to post-traumatic stress disorder symptoms, depression symptoms, functional status or cognitive outcomes,” Dr. Girard said. ‘So, the short-term improvements in time spent off the ventilator and time to ICU and hospital discharge, as well as the long-term survival benefit, did not come at the cost of long-term psychological problems.’ That the protocol is being performed in less than half of all eligible patients is ‘unfortunate but not unexpected,’ Dr. Girard said, noting that it often takes years from the time a clinical trial is published before its findings are put into practice. “I certainly hope this won’t be the case for the ABC trial results, but it’s now been 10 years since Kress and colleagues published their trial of daily interruption of sedation, and [only] 40% to 50% of ICUs say they are doing daily interruption of sedatives,” he said. Dr. Girard said there is a reason to hope that the protocol will soon gain new traction: The longterm results of the ABC trial are under review, and publication is expected by mid-year. n

Asian Journal of Critical Care Vol. 6, No. 3, July-September 2010

for the clinician clinical practice

Timing of Tracheotomy Linked to Length of Stay: Study Finds no Effect on Mortality from Early Procedure Adam Marcus

Abstract Early tracheotomy can significantly shorten a patient’s length of stay in the intensive care unit and hospital in general, although the procedure does not appear to reduce mortality, new research has found. Key words: Bedside tracheotomy, mechanical ventilation, wean screen

arly tracheotomy can significantly shorten a patient’s length of stay in the intensive care unit and hospital in general, although the procedure does not appear to reduce mortality, new research has found. The retrospective study, by investigators at Northwestern University’s Feinberg School of Medicine, in Chicago, compared outcomes in 147 patients who had undergone a bedside tracheotomy while on mechanical ventilation. In 20 cases, the procedure was performed less than seven days after intubation. The rest (127) received the tracheotomy seven or more days later. Early tracheotomy was clearly linked to shorter stays in the ICU-11 versus 26 days (P = 0.0001)— and hospital—25 versus 32 (P = 0.004), according to the researchers. Patients receiving early tracheotomy also were less likely to die in the hospital (5% vs. 14.2%) than were those in the later group, but the difference was not statistically significant (P = 0.473; Table).

Table. Comparison of Early and Late Tracheotomy Tracheotomy Tracheotomy <7 days ≥7 days

p value

Length of ICU stay, median days

0.0001

Length of hospital stay, median days

0.004

Survival rate, %

14.2

0.473

Dr. Morris’ group presented its findings at the 2010 annual meeting of the International Anesthesia Research Society, in Honolulu (abstract S-129). “Wean Screen” Recent recommendations advise daily “wean screen” assessments of patients on mechanical ventilation to determine when weaning from the machines is

“There have been a lot of studies on when is the optimal time to trach patients,” said Linda Morris, PhD, a respiratory care nurse and assistant professor of clinical anesthesiology at Northwestern Memorial Hospital, also in Chicago. “But part of the problem with these different studies is that they used different time frames” to define early and late tracheotomy, she said. “So of course, there are going to be great differences” in outcomes.

Source: Adapted from Anesthesiology News, May 2010, McMahon Publishing.

Asian Journal of Critical Care Vol. 6, No. 3, July-September 2010

for the clinician appropriate. Spontaneous breathing trials have been shown to markedly reduce the time to extubation compared with patients on pressure-support ventilation (N Engl J Med 1995;332:345-350). Performing a tracheotomy soon in the course of treatment can permit earlier weaning from mechanical ventilation, although why that’s the case is unclear, Dr. Morris said. ‘The reason that patients wean better after tracheotomy is multifactorial. Numerous theories have been proposed, including improved aerodynamics through a shorter, rigid tracheostomy tube compared with the longer endotracheal tube. No one is really certain how it happens, but there is definitely a trend toward improved ability to wean patients after tracheotomy. It happens so frequently that I have referred to this phenomenon as ‘surgical weaning,’ she explained. In the ICU, giving every patient an early tracheotomy does not make sense because many patients have conditions from which they will recover rapidly. ‘But it might be more likely in patients who we know are going to require a long-term trach–such as those with spinal cord injuries or other kinds of neurologic issues,’ she said. The Northwestern researchers did not have a large enough study population to perform a subgroup analysis, she noted, although they are planning a prospective trial. As with most clinical controversies, which side of the tracheotomy debate one supports largely depends on the complications one has seen in practice, said Charles

Watson, MD, chair of anesthesia and deputy surgeonin-chief at Bridgeport Hospital in Connecticut. “The operative risk of tracheotomy is not quite low,” Dr. Watson said. “These are often high-risk patients and have an unpleasant tendency to have respiratory and hemodynamic events during the procedure, even though it’s often performed at the bedside, using percutaneous techniques.” Data first suggested the newer techniques were more benign than surgical tracheotomy, but the follow-up research has not confirmed the lack of complications, he added. “One has to see the entire risk-benefit relationship, not just that those who needed a longterm airway did better if they avoided the long-term airway injury from a tracheal tube cuff as well as that from a trach tube and cuff,” said Dr. Watson, a member of the editorial board of Anesthesiology News. Meanwhile, the Northwestern findings have prompted the hospital to more closely scrutinize its tracheotomy patients and to add a dedicated tracheotomy service that Dr. Morris directs. Under the new system, she personally examines all tracheotomy patients on a regular, if not daily, basis, following up on potential problems and trying, whenever appropriate, to hasten the removal of the tracheotomy. “What we want to do is try to use this new service to prevent complications,’ she said, ‘such as inadvertent decannulation, excessive cuff inflation, tracheal stenosis, mucus plugs and airway emergencies.” n

Asian Journal of Critical Care Vol. 6, No. 3, July-September 2010

photo quiz clinical practice

Acute Chest Pain in an Adolescent

16-year-old patient presented to the emergency department with sudden onset of chest pain and shortness of breath while playing basketball. There was no history of trauma. Physical examination revealed an otherwise healthy male in no acute distress with a blood pressure of 129/66 mmHg, heart rate of 71 beats per minute, respiratory rate of 20 breaths per minute, and a pulse oximetry reading of 97 percent. Swelling and crepitus were noted in the neck. On auscultation, a crunching sound was noted over the precordium with each heartbeat. Pulmonary examination was unremarkable, and results of electrocardiography were normal. Chest radiography was performed (see accompanying figure). Question Based on the patient’s history and physical examination, which one of the following is the most likely diagnosis? A. Aortic dissection. B. Pneumomediastinum. C. Atypical chest pain. D. Reactive airways disease. E. Esophageal rupture. Discussion The answer is B: pneumomediastinum. Physical examination demonstrated subcutaneous emphysema and Hamman’s sign, the audible crunching accompanying each heartbeat. These findings are characteristic of pneumomediastinum. Chest pain and dyspnea are the most common symptoms. The chest radiograph shows a radiolucent outline of the mediastinum as well as the continuous diaphragm sign.1 Pneumomediastinum is extra-alveolar air within the mediastinum. Numerous etiologies have been identified, Source: Adapted from Am Fam Physician August 1, 2006.

including penetrating or crushing chest trauma, rapid shearing of the fixed carina, and increased intrabronchial pressure.2 Other causes include esophageal rupture in Boerhaave’s syndrome, repeated Valsalva maneuver during inhalation drug use, or colonic perforation during colonoscopy.3-5 Spontaneous pneumomediastinum is rare, especially episodes not related to chest trauma, tracheobronchial or esophageal procedures, mechanical ventilation, cardiac catheterization, or chest surgery. Pneumomediastinum mainly affects previously healthy young men.6 Pulmonary alveolar rupture is the most common etiology. Potential precipitating conditions include asthma, vomiting, Valsalva maneuver, esophageal rupture, and intense exercise or sports participation.7 Rapid recovery is common, and interventions such as needle decompression and ventilatory assistance rarely are needed. An important associated or causative condition to rule out is spontaneous pneumothorax. Asian Journal of Critical Care Vol. 6, No. 3, July-September 2010

photo quiz Selected Differential Diagnosis of Acute Chest Pain in an Adolescent Condition

Characteristics

Aortic dissection

Sudden tearing pain with widened mediastinum; possible history of collagen-vascular disorders or trauma

Pneumomediastinum

Air within the mediastinum; subcutaneous emphysema, Hamman’s sign, chest pain, dyspnea

Atypical chest pain

Exclusionary diagnosis once cardiopulmonary etiologies have been ruled out; may be musculoskeletal, gastrointestinal, or psychological

Reactive airways disease Inflammatory response to allergens, infection, climate, exercise; dyspnea with or without wheezing Esophageal rupture

Often seen as air within the mediastinum; usually history of trauma or forceful vomiting; chest pain, especially worsened by swallowing

In this patient, a small left pneumothorax was visible on computed tomography. Etiologies include alveolar rupture secondary to straining against a closed glottis or rupture of subpleural blebs.8

and chest pain, especially worsened by swallowing, are common. However, the patient’s history usually includes trauma or forceful vomiting.

Aortic dissection is a rare but potentially fatal occurrence. Prevalence increases with age and is higher in men. Risk factors include hypertension, trauma, and collagen-vascular disorders (e.g., Marfan syndrome). Patients may present with sudden, severe, tearing abdominal or back pain. Radiographic findings may include mediastinal widening.

1. Murray JF, Nadel JA (eds). Textbook of Respiratory Medicine. 3rd edition, Philadelphia, Pa.: Saunders, 2000.

Atypical chest pain is a diagnosis of exclusion. In this case, there is a clear diagnosis based on chest radiography. Reactive airways disease, in particular exercise-induced asthma, could present with chest pain and shortness of breath after exercise. Wheezing does not have to be present. This patient had no history of reactive airways disease, and chest radiography provided the diagnosis. However, some cases of spontaneous pneumomediastinum are associated with asthma or other pulmonary disease, leading some experts to recommend pulmonary function testing after recovery.7 The presentation of esophageal rupture is similar to that of pneumomediastinum. Subcutaneous emphysema

References

2. Ullman EA, Donley LP, Brady WJ. Pulmonary trauma emergency department evaluation and management. Emerg Med Clin North Am 2003;21:291-313. 3. Howton JC. Boerhaave’s syndrome in a healthy adolescent male presenting with pneumomediastinum. Ann Emerg Med 2004;43:785. 4. Hazouard E, Koninck JC, Attucci S, FauchierRolland F, Brunereau L, Diot P. Pneumorachis and pneumomediastinum caused by repeated Muller’s maneuvers: complications of marijuana smoking. Ann Emerg Med 2001;38:694-7. 5. Chao D. Air, air everywhere. Am Fam Physician 2003;68:1381-3. 6. Mihos P, Potaris K, Gakidis I, Mazaris E, Sarras E, Kontos Z. Sports-related spontaneous pneumomediastinum. Ann Thorac Surg 2004;78:983-6. 7. Chalumeau M, Le Clainche L, Sayeg N, Sannier N, Michel JL, Marianowski R, et al. Spontaneous pneumomediastinum in children. Pediatr Pulmonol 2001;31:67-75. 8. Kirchner JT. Diagnosis and management of spontaneous pneumothorax. Am Fam Physician 2000;62:1398-400.

Asian Journal of Critical Care Vol. 6, No. 3, July-September 2010

emedinews section clinical practice

From eMedinewS

Intervention Improves Outlook in Type 2 Diabetes

Emergency Appendectomy not a must for All with Acute Appendicitis

A program designed to help people with type 2 diabetes lose and keep off extra weight led to improved diabetes control and cardiovascular disease risk factors. The finding suggests that lifestyle changes can have long-term benefits for overweight and obese people with diabetes. Type 2 diabetes, which accounts for up to 95% of all diabetes cases, is strongly linked with excess weight and inactivity. Past studies have shown the short-term benefits of lifestyle interventions to help people with diabetes control their weight. The Look AHEAD (Action for Health in Diabetes) trial, chaired by Dr. Rena Wing of the Miriam Hospital/Brown Medical School aims to look at the long-term effects. The ongoing study is sponsored by NIH’s National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), along with NIH’s National Heart, Lung and Blood Institute (NHLBI) and the Centers for Disease Control and Prevention.

Appendectomy is the most common emergency surgery worldwide. However, a study from the Oregon Health and Science University says that it doesn’t have to be the most common surgery. The patients were grouped into three depending on how soon they underwent the surgery after being hospitalized. There was no significant difference among the groups in the patients’ condition 30 days after surgery or in the length of their operation or hospital stay. Data from more than 30,000 patients were assessed in the study published in the Archives of Surgery.

Elevated Chloride Levels Predict 30-day Mortality in C. difficile Infections A study presented at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy reports that hyperchloremia in patients with Clostridium difficile infections is an indicator of disease severity and a risk factor for death within 30 days. According to the study author, Dr. Anilrudh A. Venugopal, hyperchloremia was the only electrolyte abnormality associated with severe C. difficile infection as determined by using two C. difficile infection scoring systems. International Medical Science Academy (IMSA) Update Conventional versus Compression-only CPR

Compression-only cardiopulmonary resuscitation for bystanders is suggested in limited situations in adults with cardiac arrest. However, this recommendation does not apply to children, because cardiac arrest is more commonly due to respiratory causes. 34

Recurrent Aphthous Ulcers Recurrent aphthous ulcers (RAUs) are one of the most common oral lesions. This condition seems to be a T-cell mediated immunologic reaction triggered by a variety of agents, such as an allergy, genetic factors, infections, hormonal changes, and systemic diseases. There are three types: minor, major, and herpetiform. All of them behave differently and are treated differently. Some diseases present with aphthous-like lesions e.g. Behcet’s syndrome, celiac disease and nutritional deficiencies. Minor ulcers are recurrent, extremely painful and multifocal and they heal without scarring. Duration is one to two weeks. The treatment for minor RAUs is usually palliative. The ulcer lasts 1 or 2 weeks and heals by itself. Vertebroplasty More Effective than Medical Therapy for Spine Fractures Caroline Klazen, MD, of St. Elisabeth Hospital in Tilburg, the Netherlands, and coauthors report that vertebroplasty reduced pain more than medical therapy in patients with acute osteoporotic vertebral compression fractures. The study showed that patients who underwent vertebroplasty had considerably greater decrease in the 10-point visual analog scale score at both one month and 12 months than those under conservative management. The decline in pain in the vertebroplasty group from baseline were 5.2 and Asian Journal of Critical Care Vol. 6, No. 3, July-September 2010

emedinews section 5.7 points at both time points, which exceeded the 3-point reduction required to be considered clinically significant. In the control group, these values were 2.7 and 3.7 at both time points. The study findings are reported online in The Lancet.

Dr. Good and Dr. Bad Situation:

A 25-year-old patient was brought to the emergency room after kerosene ingestion.

Hepatitis E Vaccine Shows 700 Efficacy Rate in Study

FDA Releases List of Harmful Tobacco Components The FDA has identified more than 100 compounds that it plans to list as harmful or potentially harmful, making way for a more stringent regulation of commercial tobacco products. A list has been released in advance by the agency’s Center for Tobacco Products. The advisory committee will review recommended criteria for classifying tobacco and smoke components as harmful. The 2009 legislation empowering the FDA to regulate tobacco products requires that, by 2012, tobacco companies produce lists of harmful or potentially harmful compounds in their products. It also gives the agency authority to order the reduction or removal of any such constituent and to restrict advertising, but it bars the FDA from completely banning tobacco products. Tobacco and its smoke contain a range of organic compounds as well as elemental heavy metals including lead, cobalt, cadmium, and even uranium (including the weapons-grade isotope, U-235). Asian Journal of Critical Care Vol. 6, No. 3, July-September 2010

Refrain from a Ryle’s tube lavage. Get CXR done to see for lipid pneumonia

Put in a Ryle’s tube and do gastric lavage

Lesson: Never attempt Ryle’s tube insertion and lavage in kerosene poisoning as it can cause perforation. Instead, chemical pneumonitis should be suspected and an X-ray chest should be ordered for confirmation. Dr. K.K. Aggarwal

Make Sure A 7-month-old infant presented with grunting respiration, fever, anorexia and irritability. On chest X-ray, pneumatoceles was present. Oh my God! Why did you not start erythromycin immediately?

Make sure: To remember that erythromycin is an effective drug for Staphylococcal acquired pneumonia.

©I JCP Group

An investigational vaccine against hepatitis E had an efficacy rate of 700, as per a study from China that involved >100,000 patients. No patient reportedly developed hepatitis E over a 12-month follow-up after receiving the full three doses of the investigational vaccine (HEV 239 or Hecolin). But, there were 15 cases of hepatitis E in the placebo group (who received a licensed hepatitis B vaccine). The study findings are reported online by Ning-Shao Xia, MD, of Xiamen University in Xiamen, China and colleagues in The Lancet. The vaccine had equivalent high efficacy when the analysis was expanded to include participants who had received only 2 doses and reached 95.5% among those who got at least one dose, the researchers reported.

KK Aggarwal

Asian Journal of

Critical Care Information for Authors Manuscripts should be prepared in accordance with the ‘Uniform requirements for manuscripts submitted to biomedical journals’ compiled by the International Committee of Medical Journal Editors (Ann. Intern. Med. 1992;96: 766-767). Asian Journal of Critical Care strongly disapproves of the submission of the same articles simultaneously to different journals for consideration as well as duplicate publication and will decline to accept fresh manuscripts submitted by authors who have done so. The boxed checklist will help authors in preparing their manuscript according to our requirements. Improperly prepared manuscripts may be returned to the author without review. The checklist should accompany each manuscript. Authors may provide on the checklist, the names and addresses of experts from Asia and from other parts of the World who, in the authors’ opinion, are best qualified to review the paper. Covering letter –

The covering letter should explain if there is any deviation from the standard IMRAD format (Introduction, Methods, Results and Discussion) and should outline the importance of the paper.

–

Principal/Senior author must sign the covering letter indicating full responsibility for the paper submitted, preferably with signatures of all the authors.

–

Articles must be accompanied by a declaration by all authors stating that the article has not been published in any other Journal/Book. Authors should mentioned complete designation and departments, etc. on the manuscript.

Manuscript –

Three complete sets of the manuscript should be submitted and preferably with a CD; typed double spaced throughout (including references, tables and legends to figures).

–

The manuscript should be arranged as follow: Covering letter, Checklist, Title page, Abstract, Keywords (for indexing, if required), Introduction, Methods, Results, Discussion, References, Tables, Legends to Figures and Figures.

–

All pages should be numbered consecutively beginning with the title page. Note: Please keep a copy of your manuscript as we are not responsible for its loss in the mail. Manuscripts will not be returned to authors. Title page Should contain the title, short title, names of all the authors (without degrees or diplomas), names and full location of the

Asian Journal of Critical Care Vol. 6, No. 3, July-September 2010

departments and institutions where the work was performed, name of the corresponding authors, acknowledgment of financial support and abbreviations used. – The title should be of no more than 80 characters and should represent the major theme of the manuscript. A subtitle can be added if necessary. – A short title of not more than 50 characters (including inter-word spaces) for use as a running head should be included. – The name, telephone and fax numbers, e-mail and postal addresses of the author to whom communications are to be sent should be typed in the lower right corner of the title page. – A list of abbreviations used in the paper should be included. In general, the use of abbreviations is discouraged unless they are essential for improving the readability of the text. Summary – The summary of not more than 200 words. It must convey the essential features of the paper. – It should not contain abbreviations, footnotes or references. Introduction – The introduction should state why the study was carried out and what were its specific aims/objectives. Methods – These should be described in sufficient detail to permit evaluation and duplication of the work by others. – Ethical guidelines followed by the investigations should be described. Statistics The following information should be given: – The statistical universe i.e., the population from which the sample for the study is selected. – Method of selecting the sample (cases, subjects, etc. from the statistical universe). – Method of allocating the subjects into different groups. – Statistical methods used for presentation and analysis of data i.e., in terms of mean and standard deviation values or percentages and statistical tests such as Student’s ‘t’ test, Chi-square test and analysis of variance or non-parametric tests and multivariate techniques. –

Confidence intervals for the measurements should be provided wherever appropriate.

Results –

These should be concise and include only the tables and figures necessary to enhance the understanding of the text.

Discussion

Figures

–

Two complete sets of glossy prints of high quality should be submitted. The labelling must be clear and neat.

–

All photomicrographs should indicate the magnification of the print.

–

Special features should be indicated by arrows or letters which contrast with the background.

–

The back of each illustration should bear the first author’s last name, figure number and an arrow indicating the top. This should be written lightly in pencil only. Please do not use a hard pencil, ball point or felt pen.

–

Color illustrations will be accepted if they make a contribution to the understanding of the article.

–

Do not use clips/staples on photographs and artwork.

–

Illustrations must be drawn neatly by an artist and photographs must be sent on glossy paper. No captions should be written directly on the photographs or illustration. Legends to all photographs and illustrations should be typed on a separate sheet of paper. All illustrations and figures must be referred to in the text and abbreviated as “Fig.”.

This should consist of a review of the literature and relate the major findings of the article to other publications on the subject. The particular relevance of the results to healthcare in India should be stressed, e.g., practicality and cost.

References These should conform to the Vancouver style. References should be numbered in the order in which they appear in the texts and these numbers should be inserted above the lines on each occasion the author is cited (Sinha12 confirmed other reports13,14...). References cited only in tables or in legends to figures should be numbered in the text of the particular table or illustration. Include among the references papers accepted but not yet published; designate the journal and add ‘in press’ (in parentheses). Information from manuscripts submitted but not yet accepted should be cited in the text as ‘unpublished observations’ (in parentheses). At the end of the article the full list of references should include the names of all authors if there are fewer than seven or if there are more, the first six followed by et al., the full title of the journal article or book chapters; the title of journals abbreviated according to the style of the Index Medicus and the first and final page numbers of the article or chapter. The authors should check that the references are accurate. If they are not this may result in the rejection of an otherwise adequate contribution. Examples of common forms of references are: Articles Paintal AS. Impulses in vagal afferent fibres from specific pulmonary deflation receptors. The response of those receptors to phenylguanide, potato S-hydroxytryptamine and their role in respiratory and cardiovascular reflexes. Q. J. Expt. Physiol. 1955;40:89-111. Books Stansfield AG. Lymph Node Biopsy Interpretation Churchill Livingstone, New York 1985. Articles in Books Strong MS. Recurrent respiratory papillomatosis. In: Scott Brown’s Otolaryngology. Paediatric Otolaryngology Evans JNG (Ed.), Butterworths, London 1987;6:466-470. Tables –

These should be typed double spaced on separate sheets with the table number (in Roman Arabic numerals) and title above the table and explanatory notes below the table.

Legends –

–

These should be typed double spaces on a separate sheet and figure numbers (in Arabic numerals) corresponding with the order in which the figures are presented in the text. The legend must include enough information to permit interpretation of the figure without reference to the text.

Please complete the following checklist and attach to the manuscript: 1. Classification (e.g. original article, review, selected summary, etc.)_______________________________ 2. Total number of pages ________________________ 3. Number of tables ____________________________ 4. Number of figures ___________________________ 5. Special requests _____________________________ 6. Suggestions for reviewers (name and postal address) Indian 1.____________Foreign 1._ _______________

2.____________

2._ _______________

3.____________

3._ _______________

4.____________

4._ _______________

7. All authors’ signatures________________________ 8. Corresponding author’s name, current postal and e-mail address and telephone and fax numbers __________________________________________

Online Submission For Editorial Correspondence

Dr K.K. Aggarwal Group Editor-in-Chief

Asian Journal of Critical Care Daryacha, 39, Hauz Khas Village, New Delhi - 110 016 Tele/Fax: 26965874/75, 26865644 E-mail: editorial@ijcp.com Website: www.ijcpgroup.com

Asian Journal of Critical Care Vol. 6, No. 3, July-September 2010