Cardiology , Emergency Medicine/Critical Care

Systemic Inflammatory Response Syndrome & Sepsis, Part 2: Stabilization & Treatment

Systemic Inflammatory Response Syndrome & Sepsis, Part 2: Stabilization & Treatment
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Erin McGowan, VMD, and Deborah Silverstein, DVM, Diplomate ACVECC
University of Pennsylvania

Early recognition of patients with systemic inflammatory response syndrome (SIRS) and sepsis is imperative in order to optimize the chance of patient survival. Early intervention is then necessary to minimize further tissue ischemia, cellular damage, and organ injury.

Part 1 of this series—Systemic Inflammatory Response Syndrome & Sepsis: Recognition & Diagnosis (January/February 2015)—addressed early recognition. This article will discuss stabilization and treatment, focusing on:

  • Rapid circulatory support
  • Appropriate antimicrobial choices
  • Goal-directed supportive measures.

STABILIZATION WITH FLUID THERAPY

Patients with SIRS or sepsis commonly have decreased systemic oxygen delivery. Optimizing cardiovascular function helps support tissue perfusion and minimizes further ischemic damage.

While early aggressive fluid therapy is essential to help increase cardiac output, tailoring fluid requirements to individual patient needs is important to avoid the detrimental effects of fluid overload. Patients with SIRS/sepsis may be resuscitated and supported with one or more of the following fluids:

  • Isotonic crystalloids
  • Hypertonic crystalloids
  • Synthetic colloids
  • Blood component therapy.

Isotonic Crystalloids

Isotonic crystalloids are the cornerstone for resuscitation and treatment of patients with SIRS/sepsis.

In patients with severe cardiovascular shock (noncardiogenic), the safest way to administer these fluids, and tailor fluid resuscitation to the patient, is to:

  1. Administer and repeat small 10 to 20 mL/kg boluses
  2. Then closely monitor patient response to each bolus.

In normal animals, approximately 30% of the volume administered remains in the vasculature 30 minutes after isotonic crystalloid administration, with the remainder lost into the interstitium and via the kidneys. However, patients with SIRS/sepsis often have vascular leak syndrome, which can lead to even more fluid loss from the intravascular space. Therefore, judicious fluid therapy is especially important in these patients.1

In addition, excessive isotonic crystalloid administration may quickly lead to intravascular fluid overload and subsequent cardiogenic pulmonary edema.2 Thus, these patients require close monitoring of physical examination parameters and their response to fluid therapy.

The practice of delivering a “shock dose” of fluids—90 mL/kg (dogs) and 50 mL/kg (cats)—as a single bolus is no longer recommended due to predisposition to volume overload.

Signs of Positive Patient Response to Isotonic Crystalloids

  • Improved pulse quality
  • Decreased lactate level
  • Decreased heart rate
  • Improved mentation

 Hypertonic Crystalloids

Administration of hypertonic (7%–7.5%) sodium chloride, also known as hypertonic saline (HTS), causes a transient osmotic shift of water from the extravascular to the intravascular compartment in interstitially hydrated animals.

Evidence suggests that HTS may also aid in:3–5

  • Increasing cardiac contractility
  • Reducing endothelial swelling
  • Mildly vasodilating the peripheral vasculature
  • Modulating the inflammatory response.

A 3 to 5 mL/kg IV bolus of HTS may be administered at a rate not to exceed 1 mL/kg per minute, which avoids dangerous adverse effects, such as vagally mediated hypotension, bradycardia, and bronchoconstriction.6,7 The volume-expanding effects of HTS are greatest 30 minutes after infusion; then gradually decline over the following 2 to 4 hours.1

Because osmotic diuresis results after HTS administration, additional therapy with isotonic crystalloids or colloids is indicated to prevent interstitial dehydration and maintain volume expansion. However, HTS therapy should not be repeated due to risk for hypernatremia.

Synthetic Colloids

Colloids are large molecules (molecular weight > 10,000–20,000 Da) that, theoretically:

  • Do not leave the vascular space
  • Are hyperoncotic to normal animals
  • Help pull fluid to, and keep it within, the vascular space.

Synthetic colloids may be useful in patients with SIRS/sepsis, especially if they are hypoproteinemic.

Hydroxyethyl starch solutions, such as hetastarch (Hextend, hospira.com), are commonly used and are suspended in an isotonic crystalloid solution. Tetrastarch solutions, such as VetStarch (abbottanimalhealth.com), have been more recently studied, and at standard doses may have less of a tendency to cause coagulopathies than hetastarch.

  • The recommended dose for hydroxyethyl starch solutions is up to 20 mL/kg Q 24 H in dogs and cats. However, this dose is frequently exceeded when deemed clinically necessary; close monitoring for adverse effects is recommended.
  • Bolus therapy for hydroxyethyl starch solutions in dogs should be delivered in 5-mL/kg increments up to 20 mL/kg; in cats, 3- to 5-mL/kg increments up to 10 mL/kg should be used.
  • Constant rate infusions (CRIs) of hydroxyethyl starch solutions of 1 to 2 mL/kg/H can be administered to increase oncotic pressure in stable, hypoproteinemic patients.

Adverse effects of excessive synthetic colloid use may include volume overload, hemodilution, coagulopathy, platelet dysfunction, and acute kidney injury.8,9

Even though evidence is lacking in veterinary patients, there is serious concern in human medicine that colloid solutions may be associated with an increased need for renal replacement therapy. As a result, use of synthetic colloids in humans has been dramatically reduced in recent years.9

Blood Products

The need for blood products in patients with SIRS/sepsis depends on the disease process and individual characteristics of the patient.

Red blood cell (RBC) transfusion may benefit patients with:

  • Recent blood loss (or RBC lysis)
  • Requirement for general anesthesia and surgery
  • Packed cell volume (PCV) below 25% to 30%.

Fresh frozen plasma therapy may benefit patients with:

  • Evidence of bleeding
  • Prolonged clotting times.

Other important parameters that help determine a patient’s transfusion needs are increasing lactate level, changes in respiratory rate, and increasing heart rate; all of these are possible indicators of poor oxygen delivery to the tissues.

Suggested doses for transfusion therapy are:

  • Packed RBCs: 10 to 15 mL/kg
  • Fresh whole blood: 20 to 25 mL/kg
  • Fresh frozen plasma: 15 mL/kg.

Therapy should be guided by the individual patient’s response and improvement of tissue perfusion parameters.

Management Goals for Patients with SIRS/Sepsis

  1. Use transfusion therapy to help maintain PCV > 25% in animals with acute anemia secondary to loss or lysis of RBCs.
  2. Use colloids and/or plasma therapy in animals with acute hypoproteinemia to maintain colloid osmotic pressure > 16 mm Hg or total solids > 4.5 g/dL. Note: Synthetic colloid therapy makes refractometer readings inaccurate.
  3. Consider plasma therapy to maintain coagulation times within reference ranges.
  4. Monitor and maintain serum glucose within the normal range with insulin therapy or dextrose supplementation, as needed.
  5. Monitor and supplement electrolytes, as needed.
  6. Ensure a mean arterial pressure of at least 65 to 70 mm Hg (not > 130 mm Hg).
  7. Maintain heart rate between 70 and 120 beats/min (may be breed dependent); administer antiarrhythmic agents, as needed.
  8. Monitor for increased respiratory rate and effort as an early indicator for volume overload/pulmonary edema/acute lung injury.
  9. Monitor and ensure urine output of at least 1 to 2 mL/kg/H.
  10. Use supplemental oxygen, as needed, to maintain a pulse oximeter reading > 93% or PaO2 > 80 mm Hg. To prevent oxygen toxicity, do not use inspired oxygen concentrations of > 60% for > 24 hours.

Albumin Therapy

Albumin is critical for the transport of drugs, chemicals, toxins, bilirubin and enzymes, and for wound healing.

Animals with SIRS/sepsis and severe hypoalbuminemia (ie, albumin level < 2 g/dL) may benefit from concentrated albumin (human or canine) therapy. Studies in dogs showed that administration of human albumin increased circulating albumin concentrations, total solids, and colloid osmotic pressure.10 However, sensitization, acute and delayed reactions, and potentially lethal complications from administration of human albumin to dogs have been reported.10–14 Therefore, this treatment should be reserved for patients that are:

  • Severely hypoalbuminemic
  • At high risk for complications secondary to hypoalbuminemia (ie, severely ill perioperative patients)
  • Likely to benefit from hyperoncotic infusion, such as hypoalbuminemic patients with concurrent hypovolemia and hypotension.

When administering 25% human albumin (250 mg/mL), use the following approach:

  • Calculate the albumin deficit (in g) as:

10 × (serum albumin goal [g/dL] − patient’s serum albumin [g/dL]) × body weight (kg) × 0.3
or approximately 2 to 3 g/kg

  • Administer the first part of the calculated dose at up to 2 mL/kg over 1 to 2 H
  • Monitor closely for a reaction; then reduce the rate to 0.3 mL/kg/H as a CRI for the remaining dose.

Canine albumin—which is sold as a lyophilized product that has had intermittent availability in recent years—may offer a safer alternative, but further research will prove useful.

VASOPRESSOR & INOTROPE THERAPY

Patients with SIRS/sepsis can develop hypotension—as a result of excessive vasodilation—despite adequate intravascular volume replacement. This vascular relaxation may necessitate use of adjunct vasoactive agents.

Treatment for persistently hypotensive patients includes:

  • Maximizing cardiac function with fluid therapy and inotropic drugs and/or
  • Modifying vascular tone with vasopressor agents, including catecholamines (ie, epinephrine, norepinephrine, phenylephrine, dopamine), and vasopressin.

When to Use a Vasopressor Drug

This decision is generally made when:

  • Estimated volume deficits have been replaced
  • Vasodilation is still present (dark pink/red mucous membranes and warm extremities)
  • Echocardiography confirms adequate intraventricular volumes
  • Central venous pressures have normalized.

Most vasopressor drugs are given as a CRI. Initially, the lowest recommended dose is typically used, with upward titration every 15 to 30 minutes based on the patient’s cardiovascular response. Table 1 provides dosages of commonly administered vasopressors.

The general aim of treatment—an attempt to support vital organ perfusion—is a mean arterial pressure of 65 to 70 mm Hg or Doppler blood pressure of > 100 mm Hg.

2015_0506_Sepsis SIRS Part2_Table1

Dopamine

Dopamine has dopaminergic, beta-adrenergic, and alpha-adrenergic effects at varying doses. In a given patient, the actual dose response is unpredictable, but the range typically varies between 5 to 12 mcg/kg/min in hypotensive patients.15

Norepinephrine

Norepinephrine has preferentially alpha-adrenergic effects, acting as a pressor in animals with normal or increased cardiac output states. Recent human studies have shown that, in septic patients, more renal protective effects and successful outcomes are seen when norepinephrine is used as the first-line pressor of choice rather than dopamine.16 This is most likely because norepinephrine is associated with fewer tachyarrhythmias and a more predictable dose-response curve. In addition, in some patients, dopamine can adversely affect renal blood flow at relatively low doses.17–19

Epinephrine

Epinephrine is a potent pressor with mixed alpha- and beta-agonist activity. Compared to other vasopressor drugs, it may have increased proarrhythmogenic effects and a greater tendency to impair splanchnic blood flow.20 Epinephrine is rarely used as a first-line vasopressor agent due to its high rate of adverse effects, but it may be indicated in critically ill animals.

Phenylephrine

Phenylephrine acts as a pure alpha-agonist drug, resulting in profound vasoconstriction. It is typically used in patients unresponsive to other sympathomimetics, but may be considered a sole first-line agent in vasodilated, hypotensive animals. Due to its lack of beta-agonist activity, it is the least arrhythmogenic of the sympathomimetic pressors and may be desirable in patients already displaying tachyarrhythmias. However, adequate cardiac contractility should be confirmed before administering phenylephrine as a sole vasoactive agent because of risks for increased afterload due to this drug’s strong alpha effects.

Dobutamine

Dobutamine is a pure beta-agonist that results in increased cardiac output and oxygen delivery and mild peripheral vasodilation. It is useful in patients with decreased systolic function, but may worsen tachyarrhythmias and increase cardiac oxygen consumption.

Vasopressin

Vasopressin is a nonadrenergic vasoconstrictor agent with both direct and indirect effects on the vascular smooth muscle via V1 receptors. During the early stages of shock, endogenous vasopressin is released to help stabilize arterial pressure and organ perfusion, but this results in depleted hypothalamic stores during prolonged states of shock. Use of low-dose vasopressin in the later stages of catecholamine-refractory vasodilatory shock may be beneficial. Vasopressin is also more effective in severely acidemic patients because, in states of low pH, the catecholamine response is blunted.

ANTIBIOTIC THERAPY

In recent human guidelines for treatment of sepsis, one of the only treatments that significantly decreased the risk for death was initiation of appropriate antimicrobials as soon as possible. The risk for death secondary to sepsis increased by 7.6% every hour that appropriate antimicrobial use was delayed.21

In septic dogs, early empiric antimicrobial therapy has proven beneficial. When an early antibiotic protocol was used to treat intra-abdominal sepsis, survival increased from 60% to 70%.22

Before antimicrobial administration, obtain samples from any suspected sources of sepsis for culture and susceptibility testing, if possible. Common fluid samples submitted for culture include urine, respiratory secretions (endotracheal or transtracheal wash), pleural or peritoneal fluid, wound exudates, and blood (if endocarditis highly suspected).

Once samples have been obtained for culture, or if high suspicion for a septic process exists but samples cannot be obtained immediately, initiate broad-spectrum antimicrobial therapy as soon as possible (Table 2).

  • Empirical antimicrobial choices should be effective against gram-positive, gram-negative, and anaerobic bacteria.
  • If the patient has recently received antibiotic therapy, a higher-tier antimicrobial combination may be indicated to combat potential inherent antimicrobial resistance.

2015_0506_Sepsis SIRS Part2_Table2

 

GASTROINTESTINAL THERAPY

Gastrointestinal (GI) bleeding and dysfunction secondary to SIRS/sepsis is common:

  • Decreased perfusion to the GI mucosa may lead to excessive gastric acid secretion, impaired protective mucus secretion, and subsequent ulceration.
  • GI transit time may be significantly decreased by cardiovascular instability, the SIRS/sepsis inflammatory cascade, and opioids used for analgesia.

Strategies to minimize and treat GI upset include use of antiemetics, antacids, promotility agents, and early enteral nutrition (Table 3).

2015_0506_Sepsis SIRS Part2_Table3

 

CARE AFTER STABILIZATION

Enteral Feeding

Once a patient has been stabilized, nutritional needs should be addressed. If tolerated by the patient, enteral feeding is preferred to maintain GI villi health, decrease bacterial translocation, and encourage gastric motility.

Options for Enteral Feeding Assistance

  • Nasoesophageal tubes
  • Nasogastric tubes (also helpful for regurgitating patients and to monitor gastric residuals)
  • Esophagostomy tubes (provide benefit of long-term use but require anesthesia for placement)
  • Gastrostomy tubes
  • Jejunostomy tubes

Parenteral Nutrition

Pursue parenteral nutrition if enteral feeding results in vomiting, nausea, or abdominal pain, and does not appear to be well tolerated.

Parenteral nutrition is typically administered through a centrally placed IV catheter due to its high osmolality, which may cause thrombophlebitis if given peripherally (Figure 1). However, isotonic parenteral nutrition solutions can be delivered through a peripheral catheter if central venous access is not possible.

Patients should be monitored every 12 to 24 hours for:

  • Electrolyte derangements (phosphorus, magnesium, potassium, and sodium fluctuations)
  • Hyperglycemia
  • Lipemic serum.

Electrolytes should be supplemented as indicated, and hyperglycemia should be avoided because, in humans, it has been associated with a higher risk for infection and morbidity.23

Microsoft Word - 1 May_Jun15 Sepsis & SIRS Stabilization Figure

FIGURE 1. A critically ill postoperative patient receiving total parenteral nutrition, multiple vasopressor agents, oxygen therapy with nasal cannula, and intensive fluid therapy.

In-Hospital Monitoring
Patients with SIRS/sepsis can be very dynamic and require frequent adjustment and changes in treatment; thus, close monitoring of patient parameters is important (Table 4). Intensively manage these animals in a hospital with 24-hour care. Figure 2 demonstrates a critically ill patient receiving intensive monitoring, including continuous electrocardiography and direct measurement of arterial blood pressure.

2015_0506_Sepsis SIRS Part2_Table4

Microsoft Word - 1 May_Jun15 Sepsis & SIRS Stabilization Figure

FIGURE 2. A critically ill patient receiving total parenteral nutrition through a jugular catheter, multiple fluids and drug infusions, oxygen therapy with a mask, and close monitoring via continuous electrocardiography and direct arterial blood pressure measurement.

PROGNOSIS

Prognosis for patients with SIRS/sepsis depends on the type of underlying disease, ability to correct the underlying disease process, and patient’s response to aggressive treatment and supportive care.
Due to the typical prolonged length of hospitalization, intensive monitoring, and necessity for 24-hour care, these patients require a substantial financial commitment from their owners, and regardless of cause, SIRS/sepsis has a high mortality rate in both humans and animals. The most common causes of a declining condition, even with aggressive treatment, include cardiovascular collapse, persistent coagulation abnormalities, multiorgan dysfunction syndrome, and acute lung injury.

A patient’s chance of survival depends on:

  • Early recognition of SIRS/sepsis process
  • Aggressive early fluid resuscitation
  • Early appropriate antimicrobial use
  • Identification and treatment of underlying disease process
  • Close monitoring and treatment of anemia and coagulation disorders.

CRI = constant rate infusion; GI = gastrointestinal; HTS = hypertonic saline; PCV = packed cell volume; RBC = red blood cell; SIRS = systemic inflammatory response syndrome

References

  1. Silverstein DC, Aldrich J, Haskins SC, et al. Assessment of changes in blood volume in response to resuscitative fluid administration in dogs. J Vet Emerg Crit Care 2005; 15(3):185-192.
  2. Cotton BA, Guy JS, Morris JA, et al. The cellular, metabolic and systemic consequences of aggressive fluid resuscitation strategies. Shock 2006; 26(2):115-121.
  3. Rizoli SB, Rhind SG, Shek PN, et al. The immunomodulatory effects of hypertonic saline resuscitation in patients sustaining traumatic hemorrhagic shock. Ann Surg 2006; 243(1):47-57.
  4. Bulger EM, Jurkovich GJ, Nathens AB, et al. Hypertonic resuscitation of hypovolemic shock after blunt trauma: A randomized controlled trial. Arch Surg 2008; 143(2):139-148.
  5. Mouren S, Delayance S, Mion G, et al. Mechanisms of increased myocardial contractility with hypertonic saline solutions in isolated blood perfused rabbit hearts. Anesth Analg 1995; 81:777-782.
  6. O’Hickey S, Belcher N, Rees P, et al. Role of histamine release in hypertonic saline induced bronchoconstriction. Thorax 1989; 44(8):650-653.
  7. Kien ND, Kramer GC, White DA. Acute hypotension caused by rapid hypertonic saline infusion in anesthetized dogs. Anesth Analg 1991; 73:597-602.
  8. Mortier E, Ongenae M, De Baerdemaeker L, et al. In vitro evaluation of the effect of profound hemodilution with hydroxyethyl starch 6%, modified fluid gelatin 4%, and dextran 40 10% on coagulation profile measured by thromboelastography. Anaesthesia 2005; 52(11):1061-1064
  9. Ekseth K, Abildgaard L, Vegfors M, et al. The in vitro effects of crystalloids and colloids on coagulation. Anaesthesia 2002; 57(11):1102-1108.
  10. Trow AV, Rozanski EA, deLaforcade AM, et al. Evaluation of use of human albumin in critically ill dogs: 73 cases (2003-2006). JAVMA 2008; 233(4):607-612.
  11. Cohn LA, Kerl ME, Lenox CE, et al. Response of healthy dogs to infusions of human serum albumin. Am J Vet Res 2007; 68:657-663.
  12. Martin LG, Luther TY, Alperin DC, et al. Serum antibodies against human albumin in critically ill and healthy dogs. JAMVA 2008; 232:1004-1009.
  13. Matthews KA, Barry M. The use of 25% human serum albumin: Outcome and efficacy in raising serum albumin and blood pressure in critically ill dogs and cats. J Vet Emerg Crit Care 2005; 5(2):110-118.
  14. Vigano F, Perissinotto L, Bosco VRF. Administration of 5% human serum albumin in critically ill small animal patients with hypoalbuminemia: 418 dogs and 170 cats (1994-2008). J Vet Emerg Crit Care 2012; 20:237-243.
  15. Westfall TC, Westfall DP. Adrenergic agonists and antagonists. In Brunton LL, Chabner BA, Knollman BC (eds): Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 12th ed. New York: McGraw-Hill Professional; 2011, pp 277-333.
  16. Vasu TS, Cavallazzi R, Hirani A, et al. Norepinephrine or dopamine for septic shock: systematic review of randomized clinical trials. J Intensive Care Med 2012; 27:172-178.
  17. Bellomo R, Chapman M, Finfer S, et al. Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled randomised trial. Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group. Lancet 2000; 356:2139-2143.
  18. Kellum JA, Decker JM. Use of dopamine in acute renal failure: a meta-analysis. Crit Care Med 2001; 29:1526-1531.
  19. Lauschke A, Teichgraber UK, Frei U, et al. ‘Low-dose’ dopamine worsens renal perfusion in patients with acute renal failure. Kidney Int 2006; 69:1669-1674.
  20. Levy B, Perez P, Perny J, et al. Comparison of norepinephrine-dobutamine to epinephrine for hemodynamics, lactate metabolism, and organ function variables in cardiogenic shock. A prospective, randomized pilot study. Crit Care Med 2011; 39(3):450-455.
  21. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 2006; 34(6):1589-1596.
  22. Abelson A, Buckley G, Rozanski E. Positive impact of an emergency department protocol on time to antimicrobial administration in dogs with septic peritonitis. J Vet Emerg Crit Care 2013; 23(5):551-556.
  23. Noordzji PG, Boersma E, Schreiner F, et al. Increased preoperative glucose levels are associated with perioperative mortality in patients undergoing noncardiac nonvascular surgery. Eur J Endocrinol 2007; 156(1):137-142

 

Erin McGowanErin McGowan, VMD, is a second-year emergency and critical care resident at University of Pennsylvania Ryan Veterinary Hospital. She received her VMD from University of Pennsylvania and completed her small animal rotating internship at Red Bank Veterinary Hospital in Tinton Falls, New Jersey.

 

 

Deborah SilversteinDeborah Silverstein, DVM, Diplomate ACVECC, is an associate professor of critical care at University of Pennsylvania Ryan Veterinary Hospital. She is the co-editor of the Small Animal Critical Care Textbook, speaks both nationally and internationally on topics relating to critical care medicine in small animals, and has published numerous articles. For questions or comments, she can be reached by email at [email protected]

 

 

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id='input_6_10_5_label' >ZIP / Postal Code</label> </span><span class='ginput_right address_country' id='input_6_10_6_container' > <select name='input_10.6' id='input_6_10_6' aria-required="true"><option value='' selected='selected'></option><option value='Afghanistan' >Afghanistan</option><option value='Åland Islands' >Åland Islands</option><option value='Albania' >Albania</option><option value='Algeria' >Algeria</option><option value='American Samoa' >American Samoa</option><option value='Andorra' >Andorra</option><option value='Angola' >Angola</option><option value='Anguilla' >Anguilla</option><option value='Antarctica' >Antarctica</option><option value='Antigua and Barbuda' >Antigua and Barbuda</option><option value='Argentina' >Argentina</option><option value='Armenia' >Armenia</option><option value='Aruba' >Aruba</option><option value='Australia' >Australia</option><option value='Austria' >Austria</option><option value='Azerbaijan' >Azerbaijan</option><option value='Bahamas' >Bahamas</option><option value='Bahrain' >Bahrain</option><option value='Bangladesh' >Bangladesh</option><option value='Barbados' >Barbados</option><option value='Belarus' >Belarus</option><option value='Belgium' >Belgium</option><option value='Belize' >Belize</option><option value='Benin' >Benin</option><option value='Bermuda' >Bermuda</option><option value='Bhutan' >Bhutan</option><option value='Bolivia' >Bolivia</option><option value='Bonaire, Sint Eustatius and Saba' >Bonaire, Sint Eustatius and Saba</option><option value='Bosnia and Herzegovina' >Bosnia and Herzegovina</option><option value='Botswana' >Botswana</option><option value='Bouvet Island' >Bouvet Island</option><option value='Brazil' >Brazil</option><option value='British Indian Ocean Territory' >British Indian Ocean Territory</option><option value='Brunei Darussalam' >Brunei Darussalam</option><option value='Bulgaria' >Bulgaria</option><option value='Burkina Faso' >Burkina Faso</option><option value='Burundi' >Burundi</option><option value='Cambodia' >Cambodia</option><option value='Cameroon' >Cameroon</option><option value='Canada' >Canada</option><option value='Cape Verde' >Cape Verde</option><option value='Cayman Islands' >Cayman Islands</option><option value='Central African Republic' >Central African Republic</option><option value='Chad' >Chad</option><option value='Chile' >Chile</option><option value='China' >China</option><option value='Christmas Island' >Christmas Island</option><option value='Cocos Islands' >Cocos Islands</option><option value='Colombia' >Colombia</option><option value='Comoros' >Comoros</option><option value='Congo, Democratic Republic of the' >Congo, Democratic Republic of the</option><option value='Congo, Republic of the' >Congo, Republic of the</option><option value='Cook Islands' >Cook Islands</option><option value='Costa Rica' >Costa Rica</option><option value='Côte d&#039;Ivoire' >Côte d&#039;Ivoire</option><option value='Croatia' >Croatia</option><option value='Cuba' >Cuba</option><option value='Curaçao' >Curaçao</option><option value='Cyprus' >Cyprus</option><option value='Czech Republic' >Czech Republic</option><option value='Denmark' >Denmark</option><option value='Djibouti' >Djibouti</option><option value='Dominica' >Dominica</option><option value='Dominican Republic' >Dominican Republic</option><option value='Ecuador' >Ecuador</option><option value='Egypt' >Egypt</option><option value='El Salvador' >El Salvador</option><option value='Equatorial Guinea' >Equatorial Guinea</option><option value='Eritrea' >Eritrea</option><option value='Estonia' >Estonia</option><option value='Eswatini (Swaziland)' >Eswatini (Swaziland)</option><option value='Ethiopia' >Ethiopia</option><option value='Falkland Islands' >Falkland Islands</option><option value='Faroe Islands' >Faroe Islands</option><option value='Fiji' >Fiji</option><option value='Finland' >Finland</option><option value='France' >France</option><option value='French Guiana' >French Guiana</option><option value='French Polynesia' >French Polynesia</option><option value='French Southern Territories' >French Southern Territories</option><option value='Gabon' >Gabon</option><option value='Gambia' >Gambia</option><option value='Georgia' >Georgia</option><option value='Germany' >Germany</option><option value='Ghana' >Ghana</option><option value='Gibraltar' >Gibraltar</option><option value='Greece' >Greece</option><option value='Greenland' >Greenland</option><option value='Grenada' >Grenada</option><option value='Guadeloupe' >Guadeloupe</option><option value='Guam' >Guam</option><option value='Guatemala' >Guatemala</option><option value='Guernsey' >Guernsey</option><option value='Guinea' >Guinea</option><option value='Guinea-Bissau' >Guinea-Bissau</option><option value='Guyana' >Guyana</option><option value='Haiti' >Haiti</option><option value='Heard and McDonald Islands' >Heard and McDonald Islands</option><option value='Holy See' >Holy See</option><option value='Honduras' >Honduras</option><option value='Hong Kong' >Hong Kong</option><option value='Hungary' >Hungary</option><option value='Iceland' >Iceland</option><option value='India' >India</option><option value='Indonesia' >Indonesia</option><option value='Iran' >Iran</option><option value='Iraq' >Iraq</option><option value='Ireland' >Ireland</option><option value='Isle of Man' >Isle of Man</option><option value='Israel' >Israel</option><option value='Italy' >Italy</option><option value='Jamaica' >Jamaica</option><option value='Japan' >Japan</option><option value='Jersey' >Jersey</option><option value='Jordan' >Jordan</option><option value='Kazakhstan' >Kazakhstan</option><option value='Kenya' >Kenya</option><option value='Kiribati' >Kiribati</option><option value='Kuwait' >Kuwait</option><option value='Kyrgyzstan' >Kyrgyzstan</option><option value='Lao People&#039;s Democratic Republic' >Lao People&#039;s Democratic Republic</option><option value='Latvia' >Latvia</option><option value='Lebanon' >Lebanon</option><option value='Lesotho' >Lesotho</option><option value='Liberia' >Liberia</option><option value='Libya' >Libya</option><option value='Liechtenstein' >Liechtenstein</option><option value='Lithuania' >Lithuania</option><option value='Luxembourg' >Luxembourg</option><option value='Macau' >Macau</option><option value='Macedonia' >Macedonia</option><option value='Madagascar' >Madagascar</option><option value='Malawi' >Malawi</option><option value='Malaysia' >Malaysia</option><option value='Maldives' >Maldives</option><option value='Mali' >Mali</option><option value='Malta' >Malta</option><option value='Marshall Islands' >Marshall Islands</option><option value='Martinique' >Martinique</option><option value='Mauritania' >Mauritania</option><option value='Mauritius' >Mauritius</option><option value='Mayotte' >Mayotte</option><option value='Mexico' >Mexico</option><option value='Micronesia' >Micronesia</option><option value='Moldova' >Moldova</option><option value='Monaco' >Monaco</option><option value='Mongolia' >Mongolia</option><option value='Montenegro' >Montenegro</option><option value='Montserrat' >Montserrat</option><option value='Morocco' >Morocco</option><option value='Mozambique' >Mozambique</option><option value='Myanmar' >Myanmar</option><option value='Namibia' >Namibia</option><option value='Nauru' >Nauru</option><option value='Nepal' >Nepal</option><option value='Netherlands' >Netherlands</option><option value='New Caledonia' >New Caledonia</option><option value='New Zealand' >New Zealand</option><option value='Nicaragua' >Nicaragua</option><option value='Niger' >Niger</option><option value='Nigeria' >Nigeria</option><option value='Niue' >Niue</option><option value='Norfolk Island' >Norfolk Island</option><option value='North Korea' >North Korea</option><option value='Northern Mariana Islands' >Northern Mariana Islands</option><option value='Norway' >Norway</option><option value='Oman' >Oman</option><option value='Pakistan' >Pakistan</option><option value='Palau' >Palau</option><option value='Palestine, State of' >Palestine, State of</option><option value='Panama' >Panama</option><option value='Papua New Guinea' >Papua New Guinea</option><option value='Paraguay' >Paraguay</option><option value='Peru' >Peru</option><option value='Philippines' >Philippines</option><option value='Pitcairn' >Pitcairn</option><option value='Poland' >Poland</option><option value='Portugal' >Portugal</option><option value='Puerto Rico' >Puerto Rico</option><option value='Qatar' >Qatar</option><option value='Réunion' >Réunion</option><option value='Romania' >Romania</option><option value='Russia' >Russia</option><option value='Rwanda' >Rwanda</option><option value='Saint Barthélemy' >Saint Barthélemy</option><option value='Saint Helena' >Saint Helena</option><option value='Saint Kitts and Nevis' >Saint Kitts and Nevis</option><option value='Saint Lucia' >Saint Lucia</option><option value='Saint Martin' >Saint Martin</option><option value='Saint Pierre and Miquelon' >Saint Pierre and Miquelon</option><option value='Saint Vincent and the Grenadines' >Saint Vincent and the Grenadines</option><option value='Samoa' >Samoa</option><option value='San Marino' >San Marino</option><option value='Sao Tome and Principe' >Sao Tome and Principe</option><option value='Saudi Arabia' >Saudi Arabia</option><option value='Senegal' >Senegal</option><option value='Serbia' >Serbia</option><option value='Seychelles' >Seychelles</option><option value='Sierra Leone' >Sierra Leone</option><option value='Singapore' >Singapore</option><option value='Sint Maarten' >Sint Maarten</option><option value='Slovakia' >Slovakia</option><option value='Slovenia' >Slovenia</option><option value='Solomon Islands' >Solomon Islands</option><option value='Somalia' >Somalia</option><option value='South Africa' >South Africa</option><option value='South Georgia' >South Georgia</option><option value='South Korea' >South Korea</option><option value='South Sudan' >South Sudan</option><option value='Spain' >Spain</option><option value='Sri Lanka' >Sri Lanka</option><option value='Sudan' >Sudan</option><option value='Suriname' >Suriname</option><option value='Svalbard and Jan Mayen Islands' >Svalbard and Jan Mayen Islands</option><option value='Sweden' >Sweden</option><option value='Switzerland' >Switzerland</option><option value='Syria' >Syria</option><option value='Taiwan' >Taiwan</option><option value='Tajikistan' >Tajikistan</option><option value='Tanzania' >Tanzania</option><option value='Thailand' >Thailand</option><option value='Timor-Leste' >Timor-Leste</option><option value='Togo' >Togo</option><option value='Tokelau' >Tokelau</option><option value='Tonga' >Tonga</option><option value='Trinidad and Tobago' >Trinidad and Tobago</option><option value='Tunisia' >Tunisia</option><option value='Turkey' >Turkey</option><option value='Turkmenistan' >Turkmenistan</option><option value='Turks and Caicos Islands' >Turks and Caicos Islands</option><option value='Tuvalu' >Tuvalu</option><option value='Uganda' >Uganda</option><option value='Ukraine' >Ukraine</option><option value='United Arab Emirates' >United Arab Emirates</option><option value='United Kingdom' >United Kingdom</option><option value='United States' >United States</option><option value='Uruguay' >Uruguay</option><option value='US Minor Outlying Islands' >US Minor Outlying Islands</option><option value='Uzbekistan' >Uzbekistan</option><option value='Vanuatu' >Vanuatu</option><option value='Venezuela' >Venezuela</option><option value='Vietnam' >Vietnam</option><option value='Virgin Islands, British' >Virgin Islands, British</option><option value='Virgin Islands, U.S.' >Virgin Islands, U.S.</option><option value='Wallis and Futuna' >Wallis and Futuna</option><option value='Western Sahara' >Western Sahara</option><option value='Yemen' >Yemen</option><option value='Zambia' >Zambia</option><option value='Zimbabwe' 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