TRAVEL MEDICINE/SEPSIS
From Clinical Pharmacology 2007: Drug Therapy Management, sponsored by the University of California, Davis, School
of Medicine, Sacramento
Educational Objectives
| The goal of this program is to review precautions for traveling and to improve the management of sepsis. After hearing
and assimilating this program, the clinician will be better able to:
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 | 1. List drugs and supplies needed for travel emergencies such as abrasions, gastrointestinal illness, and allergies.
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| 2. Counsel traveling patients about high-altitude illness and mosquitoes in tropical areas.
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| 3. Review risk factors and presentation of severe sepsis.
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| 4. Explain the importance of early recognition and resuscitation in patients with sepsis.
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| 5. Discuss the role of adequate antibiotic therapy, activated protein C, and steroids in the management of sepsis.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning
committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest.
Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a
proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Albertson has received research
support from Eli Lilly and Company and Chiron. Dr. Derlet and the planning committee reported nothing to disclose.
Acknowledgements
Drs. Derlet and Albertson spoke in Napa, CA, at Clinical Pharmacology 2007: Drug Therapy Management, presented
April 27-29, 2007, by the UC Davis Health System. The Audio-Digest Foundation thanks the speakers and the UC
Davis Health System for their cooperation in the production of this program.
| HAVE DRUGS, WILL TRAVEL —Robert W. Derlet, MD, Professor, Department of Emergency Medicine, University of
California, Davis, School of Medicine, Sacramento
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| Introduction: no immediate access to pharmacy or health care facility when traveling to mountain areas (eg, Himalayas);
before traveling, update immunizations (eg, tetanus, polio, yellow fever, influenza)
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| Items for small emergency bag: epinephrine (eg, EpiPen); syringe; albuterol for acute allergic reactions; povidone
iodine (eg, Betadine) for wounds; adhesive bandages
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| In-flight emergencies: due to noise, difficult to measure blood pressure (BP); types of emergencies—vasovagal (common);
cardiac (eg, mild arrhythmia); respiratory; neurologic; agitation; trauma (from, eg, items falling from compartments
or hot liquid burns); environment—relative cabin altitude, 5000 to 9000 ft; baseline Pao2 55 to 80 mm Hg;
emergency masks provide 4 L of O2 ; low humidity exacerbates some conditions; cramped seating (increased incidence of
deep venous thrombosis [DVT] on long flights); emergency kit—BP cuff; stethoscope; dextrose; needles; epinephrine;
lidocaine; aspirin; nitroglycerin; defibrillator; albuterol; gloves; bandages
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| Abrasions: common; can cause staphylococcal or streptococcal infection or methicillin-resistant Staphylococcus aureus
(MRSA) bursitis; MRSA seen on wilderness expeditions; Panton-Valentine leukocidin (PVL) gene—increases aggressiveness
and invasiveness of MRSA (can lead to necrotizing pneumonia); kills leukocytes; transferred to methicillin-sensitive
Staphylococcus
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| Wound care: cephalexin (Keflex) effective against Streptococcus, but not against certain strains of Staphylococcus; dicloxacillin;
trimethoprim-sulfamethoxazole; clindamycin; minocycline more concentrated in cutaneous tissue than doxycycline;
expedition kit—ceftriaxone; piperacillin and tazobactam (Zosyn) or ampicillin and sulbactam (Unasyn);
daptomycin; tweezers (to remove tick, place tweezers around head of tick and slowly withdraw); soap; hot water better
for wounds than cold water (caution, hot water in Italy contains Legionella); Betadine; adhesive bandages; Xeroform petrolatum
wound dressing for ongoing wound infections; antibiotic ointment or mupirocin (pseudomonic acid A; Bactroban);
scissors; supplies for laceration repair
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| Gastrointestinal (GI) drugs: constipation—bisacodyl (eg, Dulcolax); nausea and vomiting—prochlorperazine (eg,
Compazine); ondansetron (Zofran); diarrhea—loperamide (eg, Imodium); ciprofloxacin; azithromycin effective for
traveler’s diarrhea
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| Additional drugs to consider: cardiac—nitroglycerin; aspirin for ischemic symptoms; allergy—diphenhydramine (eg,
Benadryl); triamcinolone ointment for rashes and sunburns; albuterol for bronchospasm; epinephrine; prednisone or dexamethasone
(eg, Decadron) for severe allergy, asthma, poison oak or ivy, and angioedema; pain—ibuprofen (eg, Motrin);
anxiety—diazepam
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| Mosquitoes: in tropical regions; precautions—20% diethyltoluamide (DEET); full-coverage clothing; face net; bed net;
mefloquine or atovaquone and proguanil (A-P; Malarone); check Centers for Disease Control and Prevention (CDC)
Web site for drug recommendations; artusenate (newer compound) unavailable in United States, but can be purchased
over-the-counter (OTC) in many parts of southeast Asia
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| Doxycycline: uses—skin infections; rickettsioses; malaria prophylaxis (if taken daily); pneumonia; Lyme disease and
other spirochetes; unusual bacterial infections; characteristics—side effect profile reasonably good; advise patients to
take with full glass of water to prevent esophagitis and esophageal perforation
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| Insects and parasites: consider lice and bed bugs; in Africa and Asia, medications for hookworm may be available
OTC
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| High-altitude illness: occurs with travel to, eg, Bolivia, Nepal; phases include acute mountain sickness, high-altitude
pulmonary edema, and high-altitude cerebral edema; Decadron effective temporarily; patient should be brought to lower
elevation as quickly as possible; acetazolamide (eg, Diamox) can be taken prophylactically; albuterol metered-dose inhalers
shown effective for pulmonary manifestations; nifedipine (“has mixed reviews”); sildenafil for pulmonary manifestations
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| Exposure to sexually transmitted diseases (STDs): ceftriaxone; cefixime (eg, Suprax)—available in Canada;
third-generation cephalosporin used for pneumonia and infections; azithromycin; acyclovir
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| Expedition travel: consider geography (eg, Iceland vs tropical Africa); rescue drugs—furosemide (Lasix); pain medications
(traveling with morphine may be problematic, due to customs policies); supplies for laceration repair—
instruments; lidocaine; irrigate wound thoroughly to prevent infection
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| Drugs or substances not to take while traveling: cocaine; amphetamines; drugs for, eg, attention deficit disorder
(ADD), should be in bottle with appropriate prescription and label; heroin; powder in plastic bags
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| Staying well while traveling: wash hands; rest and sleep; use sunscreen; stay well-hydrated; drink carbonated beverages,
and boil water for tea and coffee; risks—water taps in hotel rooms in underdeveloped countries; bottled water (may
be recycled water); ice; food from street vendors; lukewarm coffee and tea; walking barefoot
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| MANAGEMENT OF SEPSIS —Timothy E. Albertson, MD, PhD, MPH, Gordon A. Wong Professor in Pulmonary and
Critical Care Medicine; Professor of Medicine, Pharmacology and Toxicology, Anesthesia, and Emergency Medicine; Vice
Chair, Department of Internal Medicine; Chief, Division of Pulmonary and Critical Care Medicine, University of California,
Davis, School of Medicine; Medical Director of Clinical Care, UC Davis Health System, Sacramento
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| Continuum of sepsis: systemic inflammatory response syndrome (SIRS)—nonspecific clinical presentations; sepsis—
SIRS with infection; severe sepsis—persistent hypotension; septic shock—refractory hypotension; multiorgan dysfunction
syndrome (MODS)—effects on various organs
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| Epidemiology: >650,000 cases/yr in United States; >100,000 deaths; accounts for ≈2% of all hospital admissions, ≈50%
of admissions into intensive care unit (ICU; septic shock accounts for 6%-8%); mortality rate—high (15%-20%; higher
in severe sepsis and multiorgan failure); increases by 10% with respiratory failure and with each additional organ system
failure
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| Risk factors: increasing age; male sex; nonwhite ethnicity; comorbidities (eg, diabetes, immunosuppression, transplantation,
liver disease); risk increases during neonatal period (eg, neonate with congenital disease at high risk); risk decreases
between ages 1 and 5 yr, then increases
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| Length of stay in hospital: for severe sepsis, average length of stay in ICU, 9.8 days (vs 4.4 days with other admissions);
total hospital days, 16 (vs 8 for general population)
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| Pathophysiology and presentation: infection leads to release of mediators; process of increased coagulation and decreased
fibrinolysis; small clots form on vessel wall distal in organ; presentation of severe sepsis—increased or severely
decreased heart rate (HR); increased or decreased body temperature; 80% of patients present with shock (may respond to
fluid); 75% to 80% present with acute lung injury (requires ventilator or supplemental O2 ); elevated interleukin (IL)-6 or
other inflammatory markers; elevated tumor necrosis factor (TNF) seen in ≈50% of patients; circulating volume decreases
as capillaries leak; available volume shunted to wrong parts of body, resulting in imbalance between O2 supply
and demand, alterations in cellular metabolism, hypoperfusion, organ failure, and MODS
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| Organ dysfunction: altered mental status; lung failure; liver failure; HR increases, but contractility lost (results in reduction
in blood flow); renal problems; decreased platelet count; decreased protein C; increased D-dimer suggests active
coagulation process; alterations in prothrombin time (PT) and partial thromboplastin time (PTT); risk for death increases
as number of failing organs increases
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| Management approach: team approach required; necessitates input from many specialists (eg, clinical pharmacists,
intensivists, nurses, respiratory therapists, nephrologists)
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| Early recognition and resuscitation: prompt recognition and initiation of resuscitation important (“if you miss the
opportunity to resuscitate, you’re going to miss the golden hour; sensitivity over specificity”); 37% of patients present in
emergency department (ED); maintain high index of suspicion; early goal-directed therapy—in study, patients with septic
shock randomized to traditional therapy (ie, fluids to maintain central venous pressure [CVP], pressors, and maintenance
of urine output) or early goal-directed therapy (ie, high nursing ratio and aggressive therapy, including
maintenance of central venous O2 saturation >70% [if <70%, blood given to maintain hematocrit >30%], empiric dobutamine,
and fluids); in first 6 hr, early goal-directed therapy group received more fluids (eg, packed red blood cells),
fewer pressors, and more dobutamine, and showed significant improvement in in-hospital mortality (40% vs 60%) than
traditional therapy group; appears to alter course of disease process; saline vs albumin resuscitation—trial of all patients
in ICU for shock and hypotension suggests no advantage to using albumin; however, in patients with hypotension due to
severe sepsis, relative risk appeared better with albumin
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| Antibiotics: no randomized trial data available in which antibiotics compared to placebo; speaker unaware of any antibiotic
approved by Food and Drug Administration (FDA) for sepsis; choice of antibiotic highly important (“if you pick
wrong, it’s going to be difficult to turn things around; do it right and do it quick”); consider obtaining cultures first to narrow
in on organisms; retrospective data—1) trial showed 25.8% of patients received inadequate antibiotics; use of inadequate
antibiotics seen in 45% of patients with community-acquired infections and nosocomial infections, 34% with
nosocomial infections alone, and 17% with community-acquired infections alone; all-cause hospital mortality significantly
different between those who received inadequate antibiotics and those who received adequate antibiotics (>50% vs
≈22%); infection-related deaths similarly statistically significantly different; inadequate initial antibiotics (at least within
first 24 hr) appeared to increase mortality rate; 2) study of ≈2700 patients in Canada looked at duration of hypotension
before initiation of effective antimicrobial therapy in septic shock patients; 78.9% received effective antibiotics after onset
of recurrent or persistent hypotension; odds ratio 1.119 per hour of delay for increasing in-hospital mortality; when effective
antibiotics given within 1 hr, survival ≈80%; during first 6 hr, each hour of delay decreased survival by ≈7.6%
(odds ratio 1.67); multivariate analysis found timing of initiation of adequate antibiotics strongest predictor of outcome;
median time for effective antibiotics, 6 hr; conclusions—adequate antibiotic use requires aggressiveness, early recognition,
obtaining cultures promptly, and “shooting a broad shotgun”; although restricting spectrum of antibiotics important,
patients with complicated and potentially life-threatening infections warrant broad-spectrum antibiotics until antibiotic
susceptibilities known
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| Source control: “drain it, debride it, or take it out”; if patient has, eg, fasciitis, dead organs must be addressed; infected
catheters must be removed
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| Activated protein C (APC): anticoagulant; inactivates factors Va and VIIIa; prevents generation of thrombin; feedback
loop turns off neutrophil recruitment; first anti-inflammatory anticoagulant approved specifically for sepsis; biologic
agent; prevents clot formation; stabilizes white blood cells; promotes fibrinolysis; survivability higher than with
placebo; Extended Evaluation of Recombinant Human Activated Protein C (ENHANCE) trial—open-label multicenter
trial; use of APC, 24 µg/kg per hour for 96 hr showed mortality rate similar to that seen in placebo-controlled trial; another
trial looked at patients with severe sepsis and low-risk death (patients had lower Acute Physiology and Chronic
Health Evaluation [APACHE] scores); mortality rate 18.5% vs 17%; bleeding ratio higher in those treated with APC;
small meta-analysis found if APACHE score >25, APC effectively improved mortality; if APACHE score <25, patients
did worse; data lack homogeneity; retrospective study of diagnosis-related groups similar to sepsis showed that patients
who received APC had shorter in-hospital stays if APC given on first day patient met criteria for sepsis (length of stay increased
to 19 days if APC given on second day, 30 days if given after 2 days); conclusions and considerations—APC
should be used early; expensive; increases risk for bleeding (including cerebral bleeding); should be confined to patients
with APACHE scores >25 and 2-organ failure; significant exclusion factors; may be acceptable to use with low-dose heparin;
use in children unclear; considered for removal from European market; placebo-controlled trials raise ethical issues;
current study looking at protein C levels and outcomes
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| Supportive care: appropriate mechanical ventilation; small tidal volumes important for maintenance of patients and better
outcome; daily interruption of sedation (usually in morning) results in earlier discontinuation of mechanical ventilation;
in long term, transfusion restriction shown better than liberal use of transfusion; stress ulcer prevention; DVT
prophylaxis with, eg, low-molecular-weight heparin; steroids; glucose control—costly (eg, nursing care time); potential
morbidity with hypoglycemia; surgical patients in ICU shown to have better outcomes with tight glucose control (80-110
mg/dL) than with loose glucose control (180-215 mg/dL); study looked at 1200 medical patients in ICU with expected
length of stays >3 days; no mortality benefit seen with tight glucose control (37% vs 40%); decreased morbidity in terms
of renal injury, ventilator time, and length of stay in ICU with tight glucose control; if patient stayed in ICU >3 days,
mortality rate 43% (vs 53%; suggests if patient’s length of stay can be predicted to be longer, mortality benefit may be
likely); controversial
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| Steroids: controversial; trials using industrial doses of steroids, eg, methylprednisolone, failed to show advantage (higher
mortality seen in patients with renal failure); compared to placebo, hydrocortisone (50 mg qid) and oral fludrocortisone
advantageous, regardless of results of corticotropin (ACTH) stimulation test; shown that low-dose steroids advantageous
in septic shock; meta-analyses showed low-dose steroids advantageous, but did not show ACTH stimulation test able to
separate group; low pharmacologic doses may be indicated in septic shock; acute respiratory distress syndrome
(ARDS)—steroids ineffective for acute ARDS; according to study, patients who had ARDS for 7 to 14 days improved
with steroid; patients who had ARDS for >14 days did not improve
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| Summary: infections complicated and heterogeneous; be aggressive with early resuscitation; give appropriate antibiotics
early; source control crucial (“drain it, pull it out, whatever you have to do”); more data about APC emerging; supportive
care important; parameters of glycemic control unclear
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Suggested Reading
No authors listed: American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference:
definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 20:864,
1992; Angus DC et al: Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated
costs of care. Crit Care Med 29:1303, 2001; Balk RA: Pathogenesis and management of multiple organ dysfunction
or failure in severe sepsis and septic shock. Crit Care Clin 16:337, 2000; Dellinger RP et al: Surviving Sepsis Campaign
guidelines for management of severe sepsis and septic shock. Crit Care Med 32:858, 2004; Finfer S et al: A comparison
of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med 350:2247, 2004; Freedman
DO et al: Spectrum of disease and relation to place of exposure among ill returned travelers. N Engl J Med 354:119, 2006;
Hasegawa N et al: Role of the coagulation system in ARDS. Chest 105:268, 1994; Kollef MH et al: Inadequate antimicrobial
treatment of infections: a risk factor for hospital mortality among critically ill patients. Chest 115:462, 1999;
Kumar A et al: Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of
survival in human septic shock. Crit Care Med 34:1589, 2006; Luks AM et al: Medication and dosage considerations in
the prophylaxis and treatment of high-altitude illness. Chest 133:744, 2008; Mathews DS et al: Prevention and treatment
of travel-related illness. Am Fam Physician 44:1343, 1991; Rivers E et al: Early goal-directed therapy in the treatment
of severe sepsis and septic shock. N Engl J Med 345:1368, 2001; Steinberg KP et al: Efficacy and safety of
corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med 354:1671, 2006; Townes DA: Wilderness
medicine. Prim Care 29:1027, 2002; Trzeciak S et al: Translating research to clinical practice: a 1-year experience
with implementing early goal-directed therapy for septic shock in the emergency department. Chest 129:225, 2006; Vincent
JL et al: Drotrecogin alfa (activated) treatment in severe sepsis from the global open-label trial ENHANCE: further
evidence for survival and safety and implications for early treatment. Crit Care Med 33:2266, 2005; Weber SJ et al:
Health advice for the international traveler. Am Fam Physician 32:165, 1985.
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