Diagnostics , Emergency Medicine/Critical Care

Systemic Inflammatory Response Syndrome and Sepsis, Part 1: Recognition and Diagnosis

Systemic Inflammatory Response Syndrome and Sepsis, Part 1: Recognition and Diagnosis
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Deborah Silverstein, DVM, Diplomate ACVECC

Small animals frequently present to veterinarians with vague signs of illness. The decision whether to treat dogs or cats symptomatically as outpatients or immediately perform diagnostics and recommend hospitalization requires an astute clinician and logical approach to:

  • Patient history
  • Physical examination
  • Preliminary diagnostic findings.

Animals with evidence of a widespread systemic inflammatory condition should never be ignored; the deleterious consequences of excessive inflammation may include organ injury and death.

Recognition and diagnosis of these emergent patients is the focus of Part 1 of this article series; Part 2 will review stabilization and treatment.

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Learn More

Read the ACCP/SCCM Consensus Conference Committee’s Definitions for Sepsis and Organ Failure and Guidelines for the Use of Innovative Therapies in Sepsis at journal.publications.chestnet.org/data/journals/chest/21647/1644.pdf.

PROFILE

Definition

Systemic inflammatory response syndrome (SIRS) describes a clinical condition characterized by widespread activation of the inflammatory system, secondary to a sterile inflammatory disease or infectious insult (Table 1).

The term SIRS was first introduced by the American College of Chest Physicians and Society of Critical Care Medicine (ACCP/SCCM) Consensus Conference in 1991, in an attempt to emphasize the importance of the inflammatory process as a systemic contributor to organ failure in patients with sepsis.1

Inflammatory Response

In sites of localized tissue damage or infection, it is well known that the localized inflammatory response is characterized by 5 cardinal signs—heat, pain, redness, swelling, and loss of function—which are caused by local capillary dilation and an increase in permeability, and occur in order to protect the host and eliminate noxious agents and injured cells.

However, in patients with SIRS, severe local or regional inflammation leads to an “overflow” of inflammatory mediators into the systemic circulation that results in a variety of global derangements that are characterized by vasodilation and increased vascular permeability.

SIRS versus Sepsis

The distinction between SIRS and sepsis is based upon the presence or absence of underlying infection (Table 2).

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DIAGNOSIS

Clinical Manifestations

Clinical manifestations of SIRS and sepsis are often nonspecific and vary depending on the underlying disease process; historical findings also differ and may be nonspecific (Table 3).

It is important to note that clinical signs of SIRS differ in dogs and cats. Cats frequently do not develop a hyperdynamic response (ie, no red mucous membranes nor bounding pulses) and are more likely to have relative bradycardia and hypothermia.2,3 In 1 study, bradycardia was identified in 66% of cats, highlighting the difference between dogs and cats with regard to their physiologic responses to sepsis.2

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Fig 1

FIGURE 1. Brick red mucous membranes of a dog in the hyperdynamic phase of SIRS.

 

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Diagnostic Criteria

Criteria proposed for the diagnosis of SIRS have been extrapolated from the human medical literature for use in dogs and cats.

Table 4 outlines the clinical criteria that provide the best sensitivity and specificity in diagnosing SIRS in septic and nonseptic dogs and cats.2,4

  • In cats, proposed criteria for SIRS were derived from a retrospective study of clinical findings in cats with severe sepsis confirmed at necropsy.2
  • In order for a diagnosis of SIRS to be made, dogs must have at least 2 of the 5 criteria present and cats, 3 of the 5 criteria. Sensitivity is increased with the use of stricter inclusion criteria; therefore, the presence of more SIRS criteria in a given patient increases the likelihood of a true systemic inflammatory process.
  • However, depending on the criteria and reference values used, sensitivity and specificity range from 77% to 97% in dogs and 64% to 77% in cats.
  • The clinician should use the SIRS criteria in the context of the clinical picture and the underlying inflammatory disease process to enhance the specificity of the diagnosis.

Diagnostic Approach

Patients with SIRS and/or sepsis should have a complete blood count, serum biochemical profile, urinalysis, and coagulation testing performed. Animals with SIRS frequently have concomitant organ injury or dysfunction that must be detected early in order to determine appropriate therapy, monitor for changes, and assist with prognosis.

Hematologic and biochemical changes in small animals with sepsis typically reflect the underlying disease process and secondary indices of organ dysfunction, as outlined in Table 5.

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SIRS fig 2aSIRS fig 2b

FIGURE 2. Lateral (A) and ventrodorsal (B) abdominal radiographs from a dog with partial mesenteric torsion and ileocolic intussusception. This dog presented with vomiting and clinical signs consistent with septic shock.

SIRS fig 3

FIGURE 3. Blood smear from a dog. The central band neutrophil is toxic, with foamy basophilic cytoplasm indicating premature release from the bone marrow due to increased demand. (Wright’s stain; original magnification, x100)

FIGURE 4. A toxic band neutrophil containing several distinct Dohle bodies, which indicate presence of systemic toxins (often bacterial) that are interfering with development of neutrophils in the bone marrow or accelerated neutrophil production. (Wright's stain; original magnification, x100)

FIGURE 4. A toxic band neutrophil containing several distinct Dohle bodies, which indicate presence of systemic toxins (often bacterial) that are interfering with development of neutrophils in the bone marrow or accelerated neutrophil production. (Wright’s stain; original magnification, x100)

Specifically, hypoalbuminemia is likely due to 1 or more of the following:5

  1. Loss of albumin from the body via the gastrointestinal tract or wounds, effusion into a third body space, or vascular permeability into interstitial space
  2. Hepatic dysfunction
  3. Preferential synthesis of acute phase proteins by the liver.

Hyperbilirubinemia may be secondary to cholestasis in dogs and, possibly, hemolysis in cats. Ionized hypocalcemia is associated with a longer length of hospitalization in both dogs and cats.6,7

Coagulation testing may reveal abnormalities associated with disseminated intravascular coagulation (DIC) due to:8

  • Cytokine-mediated endothelial cell activation
  • Platelet stimulation
  • Increased tissue factor expression
  • Circulating microparticles
  • Fibrin deposition in the microvasculature
  • Decreased endogenous anticoagulants
  • Perturbations in fibrinolysis.

Animals with SIRS or sepsis are initially hypercoagulable (this can be difficult to diagnose), but often develop hypocoagulability due to consumption of clotting factors. Changes consistent with later stages of DIC are outlined in Table 5.9

In patients with suspected SIRS/sepsis, additional diagnostic tests should include mixed venous or arterial blood gas measurements and measurement of serum lactate. Many patients have a metabolic acidosis that reflects poor tissue perfusion and hyperlactatemia.
Thyroid function tests are frequently deranged in dogs with sepsis or SIRS, but these tests are usually not part of the initial evaluation of these patients.10

Urinalysis abnormalities may include isosthenuria due to loss of concentrating ability, proteinuria due to glomerular and/or tubular damage, glucosuria due to tubular damage and/or hyperglycemia, bacteria (if a urinary tract infection is present), pyuria, hematuria, and casts secondary to acute kidney injury.

Thoracic and abdominal imaging (radiographs and ultrasonography) should be performed in all patients with suspected SIRS or sepsis. Diagnostic imaging should focus on detecting the underlying infectious or sterile inflammatory disease process (eg, pancreatitis), as well as any coexisting secondary organ damage (eg, acute respiratory distress syndrome) (Figure 2).

Identifying Source of Infection

A diagnosis of sepsis can be made once infection is documented and the patient fulfills the species specific criteria for SIRS (Table 4). Patient history and physical examination may initially help guide the search for the source of infection.

Appropriate samples (Table 6) should be collected for culture and susceptibility testing to identify the cause of sepsis and best direct antimicrobial therapy. Aerobic and anaerobic gram-negative and gram-positive bacteria are both frequently cultured from septic dogs and cats, depending on the source of the infection.3

In addition to culture and sensitivity testing, fecal testing should be considered in animals with hemorrhagic diarrhea (eg, parvovirus, salmonellosis). Cats should be tested for retroviral diseases, and dogs tested for rickettsial diseases, fungal diseases, and other infectious agents based on regional epidemiology or travel history.

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Cardiopulmonary Function

Baseline cardiopulmonary function should be established since the underlying disease, cytokine-mediated effects, and secondary organ derangements may lead to abnormalities in any or all of the following:

  • Arterial blood pressure
  • Electrocardiography
  • Pulse oximetry.

PATHOGENESIS OF SIRS

The pathophysiologic mechanisms responsible for generation of SIRS are complex and incompletely understood. The initial insult that stimulates SIRS can come from a variety of sterile sources or infectious agents (Table 1).

Spread of Inflammation

The inflammatory response may initially start locally (eg, abscess on a limb, trauma) (Figure 5) but, if severe, can progress to cause systemic signs when mediators of inflammation enter the circulatory system and instigate global activation of the inflammatory system.

Fig 5

FIGURE 5. A dog with trauma resulting in global activation of the inflammatory system.

Although certain cells, such as platelets, polymorphonuclear leukocytes, and the endothelium, also play a role, it appears that the stimulation of macrophages (Table 7) and their release of inflammatory cytokines are pivotal in the generation of SIRS.

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Production of Cytokines

During gram-negative sepsis, the lipid A portion of lipopolysaccharide (LPS)—the glycolipid component of the cell wall—binds to LPS binding protein (LBP). This LPS—LBP complex binds to membrane-bound CD14 on macrophages, and this binding leads to:

  • Activation of macrophages
  • Initiation of intracellular signaling that begins transcription of inflammatory cytokines (Table 8).

In addition to proinflammatory mediators, the response also generates anti-inflammatory cytokines (Table 8), soluble receptors, and receptor antagonists for cytokines. This compensatory response is often referred to as compensatory anti-inflammatory response syndrome (CARS).

Although CARS beneficially balances out the proinflammatory state often seen with SIRS, excessive CARS stimulation may contribute to immunodeficiency and increased susceptibility to infection in the later stages of sepsis.11,12

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Immune Response

When the immune system is fighting pathogens or repairing damaged tissue, proinflammatory cytokines signal immune cells, such as T-cells and macrophages, to travel to the site of infection. In addition, cytokines activate these recruited immune cells to produce more cytokines.

While cytokines trigger a beneficial inflammatory response that promotes local coagulation to confine tissue damage, excessive production of proinflammatory cytokines can be more dangerous than the original stimulus because they:

  • Overcome the normal regulation of the immune response
  • Produce the clinical signs classically seen in patients with SIRS.

This production of a “cytokine storm” and global activation of white blood cells (WBCs) ultimately overwhelms the CARS, becoming the key component in the pathogenesis of SIRS. The diagnostic and prognostic utility of serum cytokine levels in animals with sepsis and SIRS is the subject of recent and continued investigation.5,13-20

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SIRS fig 6a

SIRS fig 6b

FIGURE 6. A dog with acute respiratory distress syndrome secondary to SIRS; following intubation for unsuccessful cardiopulmonary cerebral resuscitation, a large volume of bloody fluid poured out of the endotracheal tube (A). Thoracic radiograph of a dog with acute respiratory distress syndrome showing diffuse severe bilateral alveolar infiltrates (B).

Development of Organ Dysfunction

In addition to systemic activation of WBCs, other pathologic effects of inflammatory mediators include:

  • Increased capillary permeability
  • Vasodilation
  • Activation of coagulation
  • Myocardial dysfunction
  • Mitochondrial dysfunction.

Mitochondrial dysfunction, which leads to a reduction in cellular adenosine triphosphate, is thought to play an important role in development of organ dysfunction and/or failure. This mitochondrial failure likely occurs secondary to tissue ischemia, resulting from:

  • Circulatory collapse
  • Hypoxemia
  • Poor microcirculatory blood flow (see Videos 1 and 2, available at tvpjournal.com)
  • Mitochondria may also be damaged (or inhibited) by reactive nitrogen and oxygen species.

In the lungs, however, acute respiratory distress syndrome results directly from inflammation rather than mitochondrial dysfunction.

Multiple Organ Dysfunction

These deleterious sequelae of systemic inflammation can lead to the syndrome of multiple organ dysfunction (MODS) (Table 9). MODS—characterized by abnormalities in organs that were not affected by the original insult—is associated with a high morbidity and mortality rate; there is a 20% increase in mortality for each failing system.21 The resulting organ damage may resolve partially or completely once the underlying cause of inflammation has been successfully treated.

 

Changes in Microcirculatory Blood Flow

Animals with septic or nonseptic SIRS frequently develop microcirculatory dysfunction in which there is a decrease in density of capillary vessels and decrease in flow of red blood cells within the functional microcirculatory vessels (arterioles, venules, and capillaries). In addition, heterogeneous distribution of blood frequently occurs and the normal mechanisms to increase or decrease blood flow to a particular tissue bed are deranged secondary to the effects of cytokines. The end result is cellular hypoxia and organ dysfunction.

BOX (A) MC normal dog for Box

Normal microcirculation. Note the large number of capillaries that allow movement of only one red blood cell at a time.

BOX (B) MC septic dog for Box

Microcirculation of a dog with septic peritonitis. There are few capillaries visible, indicating microvascular shunting and decreased perfusion of the associated tissue.

IN SUMMARY

Once a patient has been identified as having clinical evidence of SIRS—with or without sepsis—it is paramount that rapid treatment is initiated to:
Correct the underlying disease process(es)
Restore oxygen delivery to the tissues, using goal-directed therapy to maximize the chance for a successful outcome.

These treatment modalities will be discussed in-depth in Part 2 of this article series, which will be published in an upcoming issue of Today’s Veterinary Practice.

CARS = compensatory anti-inflammatory response syndrome; DIC = disseminated intravascular coagulation; LBP = lipopolysaccharide binding protein; LPS = lipopolysaccharide; MODS = multiple organ dysfunction syndrome; SIRS = systemic inflammatory response syndrome; WBC = white blood cell

Deborah SilversteinDeborah Silverstein, DVM, Diplomate ACVECC, is an associate professor of critical care at University of Pennsylvania Ryan Veterinary Hospital. Her primary research interests include diagnosis and treatment of circulatory shock, microcirculatory imaging in small animals, vasopressor therapy, and fluid therapy. Dr. Silverstein is the co-editor of the Small Animal Critical Care Textbook, speaks both nationally and internationally about numerous topics relating to critical care medicine in small animals, and has published numerous articles based on her research interests. For questions or comments, she can be reached by email at [email protected]

References

  1. Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 1992; 101(6):1644-1655.
  2. Brady CA, Otto CM, Van Winkle TJ, King LG. Severe sepsis in cats: 29 cases (1986—1998). JAVMA 2000; 217(4):531-535.
  3. Hauptman JG, Walshaw R, Olivier NB. Evaluation of the sensitivity and specificity of diagnostic criteria for sepsis in dogs. Vet Surg 1997; 26(5):393-397.
  4. Greiner M, Wolf G, Hartmann K. A retrospective study of the clinical presentation of 140 dogs and 39 cats with bacteraemia. J Small Anim Pract 2008; 49(8):378-383.
  5. DeClue AE, Delgado C, Chang C-H, Sharp CR. Clinical and immunologic assessment of sepsis and the systemic inflammatory response syndrome in cats. JAVMA 2011; 238(7):890-897.
  6. Luschini MA, Fletcher DJ, Schoeffler GL. Incidence of ionized hypocalcemia in septic dogs and its association with morbidity and mortality: 58 cases (2006—2007). J Vet Emerg Crit Care 2010; 20(4):406-412.
  7. Kellett-Gregory LM, Mittleman BE, Brown DC, Silverstein DC. Ionized calcium concentrations in cats with septic peritonitis: 55 cases (1990—2008). J Vet Emerg Crit Care 2010; 20(4):398-405.
  8. Ralph AG, Brainard BM. Hypercoagulable states. In Silverstein DC, Hopper K (eds): Small Animal Critical Care Medicine, 2nd ed. St. Louis: Elsevier Saunders, 2015, pp 541-554.
  9. Bauer N, Moritz A. Coagulation response in dogs with and without systemic inflammatory response syndrome—Preliminary results. Res Vet Sci 2013; 94:122-131.
  10. Pashmakova MB, Bishop MA, Steiner JM, et al. Evaluation of serum thyroid hormones in dogs with systemic inflammatory response syndrome or sepsis. J Vet Emerg Crit Care 2014; 24(3):264-271.
  11. van der Poll T, van Deventer SJH. Cytokines and anticytokines in the pathogenesis of sepsis. Infect Dis Clin North Am 1999; 13(2):413-426.
  12. Frazier WJ, Hall MW. Immunoparalysis and adverse outcomes from critical illness. Pediatr Clin North Am 2008; 55(3):647-668.
  13. Osterbur K, Whitehead Z, Sharp CR, DeClue AE. Plasma nitrate/nitrite concentrations in dogs with naturally developing sepsis and non-infectious forms of the systemic inflammatory response syndrome. Vet Rec 2011; 169(21):554.
  14. Yu DH, Nho DH, Song RH, et al. High-mobility group box 1 as a surrogate prognostic marker in dogs with systemic inflammatory response syndrome. J Vet Emerg Crit Care 2010; 20(3):298-302.
  15. Gebhardt C, Hirschberger J, Rau S, et al. Use of C-reactive protein to predict outcome in dogs with systemic inflammatory response syndrome or sepsis. J Vet Emerg Crit Care 2009; 19(5):450-458.
  16. Fransson BA, Bergstrom A, Hagman R, et al. C-reactive protein, tumor necrosis factor alpha, and interleukin-6 in dogs with pyometra and SIRS. J Vet Emerg Crit Care 2007; 17(4):373-381.
  17. Rau S, Kohn B, Richter C, et al. Plasma interleukin-6 response is predictive for severity and mortality in canine systemic inflammatory response syndrome and sepsis. Vet Clin Pathol 2007; 36(3):253-260.
  18. DeClue AE, Sharp CR, Harmon M. Plasma inflammatory mediator concentrations at ICU admission in dogs with naturally developing sepsis. J Vet Intern Med 2012; 26(3):624-630.
  19. DeClue AE, Williams KJ, Sharp C, et al. Systemic response to low-dose endotoxin infusion in cats. Vet Immunol Immunopathol 2009; 132(2—4):167-174.
  20. Karlsson I, Hagman R, Johannisson A, et al. Cytokines as immunological markers for systemic inflammation in dogs with pyometra. Reprod Domest Anim 2012; 47(S6):337-341.
  21. Kenney EM, Rozanski EA, Rush JE, et al. Association between outcome and organ system dysfunction in dogs with sepsis: 114 cases (2003—2007). JAVMA 2010; 236(1):83-87.

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>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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