a old diabetic woman with septic shock and symmetric

A old diabetic woman with septic shock and Symmetric Peripheral Gangrene

—case report and journal reading 2007-8-10

新樓基督教醫院內分泌暨新陳代謝科徐維信醫師

Case presentation

• 陳女士 , 70 years old female• She was a case of DM and CAD. She fol

lowed up at OPD regularly. • One week ago, diarrhea was noted. She

came to LMD for help. It improved gradually.

• The night before admission, she watched TV at home as usual. In the midnight(3:30-5AM), fever and chillness and diarrhea occurred.

Case presentation

• She was sent to ER for help around 8:00am. • At ER, BP: 101/54, PR:112/min, BT: 36.4C, RR:

20/min, conscious: clear, Heart: RHB, no murmur, BS: clear, Abdomen: soft, Extremity: NO edema, no ecchymosis.

• Laboratory data: WBC:3800, D/C: band 30%, segament: 53%, Hb: 11.2, PLT:164k, CRP:15,

• Glu: 501mg/dl, BUN/Cr: 25/1.3, Na/K:133/3.8, GOT/GPT: 744/228, r-GT: 104, ALK-p:96, PH: 7.44, PCO2: 32, PaO2:59, HCO3: 21.3,

• Abdominal sonogram: mild left hydronephrosis, cause ?

1st hospital day• After blood culture and urine culture, Mexipim

e (3:00Pm) was used.• Residual urine: 500cc.• 19:00pm. Blood pressure dropped to 68/40 mm

Hg. N/S 300 cc challenge. • Low blood pressure was still noted after N/S 1

000 cc challenge and Inotropic agent (Dopamine 10.3 ug/kg/min) was used.

• She was transferred to ICU. IV Fluid challenge and Add Cravit.

• At 10:16 pm. IVF 200cc/hour for 4 hours, then 120cc/hour. D-dimer test:1:8x(+) Platelet :102k

2nd hospital day

• Fu CXR: mild engorgemnt of right hilum. Suspect pulmonary edema.

• ON CVP

• Dopamine was tapered within 20 hours.

• Monitor Vital sign and SaO2 and urine output, electrolyte and blood sugar.

• Keep antibiotics mexpime and cravit.

3rd hospital day

• UGI bleeding from NG tube, PPI was used.

• Blood test showed platelet: 12k, Platelet was transfused.

• Apnea and blood pressure undetectable with conscious loss occurred. ETT was inserted.

• Dopamine was used again.

4th hospital day

• Cyanosis of digits were noted. Despite intensive treatment, gangrene of digits of left feet and digits of bilateral hands occurred.

• Blood culture and urine culture: E.coli .

General survey-NCKUH • After admission, screening cardiac echo for r/o IE s

howed adequate LV performance and no evidence of vegetation.

• Antibiotics were shifted to Unasyn and fluconazole for susp A.B. and fungus UTI.

• Abdominal CT-angiography was arranged and showed multiple stenosis and artherosclerosis of her artery of lower limbs.

• CVS was consulted and they favor medical treatment, and plasty surgeon consultation if progressive in gangrene changes or progression of infection.

After ETT weaning-NCKUH

• IVF was given for dry skin turgor and tachycarida.

• Af with RVR was noted on EKG monitor and amiodarone loading then orally were given.

• Insulin infusioin was transient used due to hyperglycemia, susp steroid related.

• Her stridor and wheezing were better. • Due to stable condition, she was transferred to wa

rd for further care.

GU problem -NCKUH

• Antegrade pyelography was done and urologist was consulted for her left hydronephrosis.

• But high fever up to 39.1C was noted after antegrade pyelography, empirical antibiotics with Tienam and Fluconazole were used immediately according to previous culture result.

• Left PCN wound culture was done due to pus was noted and the result showed ORSA. Antibiotics with Vancomycin was added since. No more fever was noted after that.

GU problem -NCKUH

• The result of antegrade pyelography showed obstruction on the UPJ and retrograde pyelography was suggested after condition stable.

• The urine culture showed pseudomonas putida and antibiotics was changed to Cefepime and no more fever up to 38C was noted.

• PCN revision was done and removed due to no more urine from PCN two days alter.

Symmetric Peripheral Gangrene

N Engl J Med. 2001;344:1593May 24, 2001

M. MICHELLE BERREY , M.D., M.P.H.JO-ANNE VAN BURIK, M.D.University of Washington

Seattle, WA 98109


• Fevers, chills, hypotension, and a generalized seizure occurred in a 57-year-old man who had undergone splenectomy for stage IV non-Hodgkin's lymphoma three years earlier.

• He was treated initially with ceftriaxone, vancomycin, and rifampin.

• A Gram's stain of the cerebrospinal fluid showed gram-positive organisms in pairs and short chains, but cultures of cerebrospinal fluid were negative. A latex-agglutination test was positive for Streptococcus pneumoniae.

BERREY M.M. & BURIK JA,

N Engl J Med. 2001;344:1593

• During the next several days, disseminated intravascular coagulation and symmetric areas of pallor developed on the back of both hands and the soles of the feet, with overlying bullae.

• Cultures of the bullous fluid were sterile. The lesions progressed to dry gangrene (Panels A and B).

• All blood cultures remained negative. The patient was treated with antibiotics for four weeks.

• The arterial supply to each of the arms and legs remained patent.



N Engl J Med. 2001;344:1593



N Engl J Med. 2001;344:1593

• Although the patient had been vaccinated against S. pneumoniae at the time of his splenectomy, he showed a protective antibody response to only 8 of 12 serotypes tested. He was revaccinated.

• The images are typical of symmetric peripheral gangrene associated with S. pneumoniae bacteremia in a patient whose spleen has been removed.



N Engl J Med. 2001;344:1593

Peripheral Symmetrical Gangrene

Mayo Clin Proc. 2004;79:914

MARK DENIS P. DAVIS MD

Department of Dermatology,

Mayo Clinic College of Medicine, Rochester, Minn

Introduction

• Peripheral symmetrical gangrene describes the clinical manifestation of sudden onset of peripheral (acral), frequently symmetrical gangrene in the absence of major vascular occlusive disease.

• The broader term purpura fulminans has been used, but it does not adequately describe this specific scenario.

• Any condition that critically diminishes the blood, nutrient, or oxygen supply to acral areas for a prolonged period can lead to peripheral symmetrical gangrene.

MARK DENIS P. DAVIS


Introduction

• The commonest cause is disseminated intravascular coagulation (DIC), most often secondary to infection. Another documented cause is use of vasopressors.

• The gangrene may be a manifestation of multiple organ system failure.

• Gangrene of the distal extremities is common. Other acral areas may be involved, such as the nose, ears, or vertex of the scalp.

• In the setting of DIC, hemorrhagic patches may coexist with the peripheral gangrene.

MARK DENIS P. DAVIS


Management

• Although peripheral symmetrical gangrene has been described for decades, information dealing with its management is scant.

• Therapeutic alternatives are largely anecdotal and are not based on controlled clinical trials.

• No specific treatment has been shown to consistently prevent progression or to reverse the gangrene.

MARK DENIS P. DAVIS


Management• Management of underlying causes is crucial.

• Disseminated intravascular coagulation should be corrected as appropriate; its cause should be delineated and treated aggressively.

• Precipitating or exacerbating factors, such as vasopressor therapy (eg, dopamine infusion), should be eliminated if possible.

MARK DENIS P. DAVIS


Management

• Amputation of the gangrenous areas may be inevitable, but initially a nonsurgical approach to management is preferred to allow time for the patient’s condition to stabilize and to allow the gangrene to become demarcated. The degree of gangrene may be less extensive than expected initially.2

• Meticulous, supportive management is essential.• A mortality rate of 35% has been reported in associati

on with DIC.

MARK DENIS P. DAVIS


Purpura Fulminans in Sepsis

The american journal of the medical science 2006;332(6):339-345

Betrosian, Alex P. MD; Berlet, Tom DEAA, EDIC; Agarwal, Banwari MBBS, MD, MRCP, FRCA, ED

IC

Introduction• Purpura fulminans is an uncommon disorder fi

rst described by Guelliot in 1884.

• Initially noted in children in association with bacterial or viral infection, it was later seen in neonates with a family history of homozygous protein C or protein S deficiency without infection.1

Introduction• Purpura fulminans secondary to sepsis is a life-threat

ening condition characterized by hemorrhagic infarction of the skin caused by disseminated intravascular coagulation and dermal vascular thrombosis.1,2

• It is associated with high mortality rate (>50%) owing to multiple organ dysfunction and is also accompanied by considerable long-term morbidity.

• Meningococcal sepsis is the most common form, followed by pneumococcal sepsis in adults.

• Necrotic lesions usually progress to distal ischemia, often necessitating skin grafting or limb amputation.

Introduction• Early antibiotic administration and intensive c

are management according to the recommendations of severe sepsis and shock is crucial for patients’ survival.

• Adjuvant therapies against inflammatory and coagulation cascades and augmenting fibrinolysis are controversial and need further assessment.

Etiology• Purpura fulminans can be identified in three clinical c

onditions: 1) preexistent inherited or acquired abnormality of the pro

tein C or protein S anticoagulant pathway; 2) with acute severe infection, predominantly gram-negati

ve bacterial infections, called acute infectious purpura fulminans;

3) without known abnormalities of the protein C pathway or acute infections, termed idiopathic purpura fulminans.

• The last subtype occurs primarily in children, usually after benign infections.

Etiology• A multitude of infections can cause this syndrome, Neisse

ria meningitidis being the foremost among the microorganisms, followed by streptococcal infections.

• Pneumococcal purpura fulminans (Streptococcus pneumoniae) is reported with increased frequency (>60%) in the setting of asplenia or functional hyposplenia. Other encapsulated bacteria such as Haemophilus influenzae and group A and B streptococci have been implicated in infants and adults.

• Staphylococcus aureus as a cause of purpura fulminans is considered rare, probably because these cases are reported as toxic shock syndrome., but may be as common as other nonmeningococcal organisms.

Time Course of Cutaneous Manifestations of Skin Necrosis

• The cutaneous lesions of sepsis-induced purpura fulminans are similar regardless of the causative microorganism.

• Clinically cutaneous necrosis begins with a region of dermal discomfort that quickly progresses within hours to petechiae, which coalesce to form purple ecchymoses.

• At this stage, the cutaneous lesions can be completely reversible without progressing to skin necrosis.


• The hallmark of hemorrhagic infarction is the development of hemorrhagic bullae, which can progress to frank skin necrosis and gangrene (Fig 1).

• The stage of necrosis is associated with considerable morbidity and mortality (>50%).

• The pathologic feature of skin necrosis in purpura fulminans is characterized by occlusion of dermal venules and capillaries by microthrombi (Figure 2), resulting in hemorrhagic infarction.1,3


• Soon after the vascular occlusion, the endothelial cells become edematous, resulting in capillary dilation with congestion of the vessels by erythrocytes. Clinically, this stage is manifested as erythema and some edema at the site of skin injury.14

• Progression of ischemia and capillary dilatation results in extravasation of blood elements into dermis. Clinically this stage is characterized by petechiae.

• A minimal to mild inflammatory neutrophil infiltrate may be found in the perivascular region.

• As ischemia and vascular damage progresses, there is further hemorrhage into dermis and ecchymoses develop.

• Ecchymoses formation is followed by the development of hemorrhagic bullae in the subepidermal area.15


• Affected areas are painful and indurated. • The end result is coagulative necrosis of the dermal and subcuta

neous tissues with extensive dermal hemorrhage manifested as gangrenous necrosis.

• Although initially sterile, secondary infection of gangrenous tissue may occur with time, contributing to late morbidity and mortality.

• Occasionally gram-stained microorganisms are present within the microthrombi, the vessel walls, and the perivascular region.

• In cases of sepsis-induced purpura fulminans, these vascular changes are not limited to the skin but are widespread, involving multiple organs such as lungs, kidneys, and adrenal glands (Waterhouse-Friderichsen syndrome when associated with adrenal hemorrhage), leading to multiple systems organ failure.16

Pathogenesis• The pathogenesis of petechiae in sepsis-induced

purpura fulminans is strongly suggestive of the localized Shwartzman phenomenon.

• Shwartzman reaction is initiated by a local, priming intradermal injection of endotoxin, which elicits a transient perivascular inflammatory reaction and increased vascular permeability.

• Intravenous challenge with the same endotoxin 12 to 24 hours later results in vascular thrombosis and necrotizing vasculitis.

Pathogenesis• Sepsis-induced purpura fulminans and the Shwart

zman reaction share a pathogenesis involving a disturbance in the balance of anticoagulant and procoagulant activities of endothelial cells.

• This disturbance, which is triggered by endotoxin in gram-negative and exotoxin in gram-positive sepsis, appears to be mediated by cytokines, particularly tumor necrosis factor-alpha (TNF-[alpha]), and interleukin-1 (IL-1), leading to the consumption of the natural anticoagulants, proteins C and S and antithrombin III.

Pathogenesis

• Virtually all patients with sepsis have coagulation abnormalities that may range from a mild drop in platelet count and subclinical prolongation of the clotting parameters without clinical signs of bleeding or thrombosis (nonovert disseminated intravascular coagulation [DIC]) to fulminant DIC, characterized by widespread microvascular thrombosis and bleeding from various sites.18

Pathogenesis• DIC has been shown to be present in more than 90

% of these cases, supporting the notion that purpura fulminans is a cutaneous marker of DIC.

• The development of DIC is mediated by several simultaneously occurring mechanisms initiated by the proinflammatory cytokines TNF-[alpha], IL-1, and IL-6.

• The mechanisms include ongoing generation of thrombin, the inhibition of the natural anticoagulant mechanisms, and the impairment of fibrinolysis caused by the plasminogen activator inhibitor-1.

Pathogenesis

1. Thrombin Generation

2. Inhibition of the Natural Anticoagulant Mechanisms

3. Inhibition of Fibrinolysis

Clinical Features

• Along with purpuric rash, the clinical features of sepsis-induced purpura fulminans are mainly those of the underlying sepsis and its complications.

• It is usually preceded by a flu-like illness, with fever or chills, sore throat, malaise, and occasionally gastroenteric symptoms occurring 12 to 24 hours before the development of the spreading petechial rash.

• The majority of affected patients develop septic shock and DIC.

Clinical Features• In one study among 70 patients with purpura fulmina

ns of various origins, 67% appeared with septic shock and 78% were associated with DIC.

• Nearly all patients experienced deterioration of their condition…

• Of interest is the absence of shock in 21 of 43 cases (51%) of pneumococcal sepsis—induced purpura fulminans, suggesting a difference in the rate and severity of activation of the cytokine cascade between gram-negative and gram-positive strains (endotoxin versus exotoxins). However, DIC was present in the majority of the reported cases.

Differential Diagnosis

• Other causes of purpura such as

1. Henoch-Schönlein purpura,

2. postinfectious thrombocytopenic purpura,

3. thrombotic thrombocytopenic purpura

4. idiopathic purpura fulminans.


1. The skin lesions of Henoch-Schönlein purpura are typically small and rarely lead to extensive necrosis.

2. Thrombotic thrombocytopenic purpura is associated with hemolysis, thrombocytopenia, and hyaline thrombosis of small vessels but never cause massive skin necrosis. However, thrombotic thrombocytopenic pupura occasionally is associated with DIC.


• Sepsis-induced purpura fulminans differs from acute infectious or idiopathic purpura fulminans in that it is associated with an overwhelming acute infection and shock. The idiopathic variety is commonly associated with normal blood pressure and a well-preserved peripheral pulse. The skin involvement also differs in these two conditions.


• In cases of sepsis-induced purpura fulminans, skin necrosis often begins in the distal extremities affecting feet, toes, tip of the nose, earlobes, hands, and fingertips, while progressing gradually to the entire body in a patchy distribution.

• In contrast, idiopathic purpura fulminans skin necrosis usually involves the skin of the thighs, the buttocks, and the lower trunk and less commonly the extremities.1,31

Management• Purpura fulminans is a syndrome, not a specific disea

se; therefore, treatment must be aimed toward the underlying infection along with on-going supportive management.

• The majority of the reported cases are due to Neisseria meningitidis, empiric antibiotic treatment should consist of a third-generation cephalosporin, which also provides good cover against streptococcus.

• Vancomycin or teicoplanin should be added if MRSA is suspected.

• The mortality rate remains high and is reported to average 40% (range, 20–70%).

Surgical Treatment

• Purpura fulminans almost invariably leads to some full-thickness skin loss.

• The similarity between skin necrosis secondary to DIC and full-thickness cutaneous burns forms the rationale for treating them as if they were full-thickness burns.

• Surgical treatment includes aggressive debridement of necrotic tissues to decrease the risk of secondary contamination and sepsis.

• Areas of dry gangrene of the digits should be left to demarcate, since early surgery might be unnecessarily extensive.

Surgical Treatment• Monitoring of compartment pressure and early fascio

tomy before the development of demarcation may improve the prognosis of limb preservation.

• The majority of cases would need skin grafting. • Limb amputations are performed for severe cases. • In a retrospective analysis of patients with purpura fu

lminans in a burn center, 87% of them required skin grafting and 90% limb amputations. In one-fourth of them, amputation was performed in all extremities.

• Streptococcal-induced purpura fulminans resulted in more extensive amputations when compared with other infections with a mean of three amputations per person.

Therapies Against Inflammatory Cascade

• Corticosteroids inhibit many components of inflammatory cascade, including complement activation, cytokine production, and neutrophil function and migration.

• The use of steroids in treating sepsis and purpura fulminans remains controversial.

• Although there is a survival benefit with low-dose, short-term hydrocortisone in septic patients with relative adrenal insufficiency, evidence does not conclusively support routine use of corticosteroids in sepsis-induced purpura fulminans of any cause.

• Other anti-inflammatory treatment strategies that had been used for meningococcal sepsis include the use of recombinant bactericidal permeability-increasing protein and human monoclonal antibody-binding endotoxin, which have failed to show a survival benefit for this disease.37–39

Therapies Against Inflammatory Cascade

• Several case reports and a few small randomized trials used plasmapheresis and hemofiltration as methods to remove proinflammatory cytokines in meningococcal purpura fulminans. No effect on survival has been reported.

• These techniques in theory could remove cytokines from circulation, but whether they can remove cytokines from tissues remains questionable.39

• Plasma exchange has been used in pediatric patients with sepsis-induced purpura fulminans and was reported to improve prognosis by virtue of a significant increase in the level of coagulation factors II, V, VII, and VIII.

Therapies Against Coagulation Cascade

• Since microvascular thrombosis appears to be the predominant pathophysiologic feature of purpura fulminans, the majority of therapeutic approaches have focused on reduction of coagulation activation and improvement of fibrinolysis.

1. Heparin2. Antithrombin III3. Protein C/Activated Protein C4. Therapies Augmenting Fibrinolysis--Recombinant

Tissue Plasminogen Activator

1.Heparin

• The use of heparin in cases of sepsis-induced purpura fulminans may appear counterintuitive given the hemorrhagic nature of the disease.

• There is some evidence that heparin could be of benefit in reducing the severity of distal necrosis by inhibiting thrombus formation and consumption of coagulation factors in sepsis-induced purpura fulminans.

• Arbitrary schemes of unfractionated or low molecular weight heparin have been used, but until now, no effect on survival has been demonstrated in animal models or small clinical trials.41

2.Antithrombin III• Sepsis-induced purpura fulminans is often associated

with markedly reduced levels of antithrombin III due to consumptive coagulopathy.

• Antithrombin III is not only an important physiologic inhibitor of coagulation but also possesses anti-inflammatory properties through release of prostaglandin I2 from endothelial cells.

• Several authors have shown that antithrombin III supplementation therapy in patients with severe sepsis and shock is beneficial in restoring organ function and reversing DIC.

Antithrombin III• In adults with purpura fulminans, a loading dose of 1

00 IU/kg followed by 100 IU/kg/day was able to correct the levels of antithrombin activity, which was subsequently maintained by continuous infusion.

• In contrast to the initial positive results, a large-scale multicenter randomized controlled trial investigating the use of antithrombin III in more than 2300 patients with severe sepsis and shock failed to demonstrate any significant reduction in mortality. However, the trial did not investigate DIC, but rather severe sepsis in general.

3.Protein C/Activated Protein C

• Dysfunction of the protein C pathway during sepsis is one of the major factors contributing to the development of purpura fulminans.

• Severe depletion of protein C leads to uncontrolled hemorrhage and thrombosis and is associated with poor outcome.

• Treatment with protein C concentrate or recombinant activated protein C (drotrecogin alfa, activated) has been shown to be beneficial in cases of sepsis-induced purpura fulminans.

• Several case reports and open-label studies on protein C (unactivated) substitution therapy have shown encouraging results.

Protein C/Activated Protein C• However, a phase II dose-finding study in children with menin

gococcal sepsis and purpura fulminans showed that a dose of 150 IU/kg or more is required to increase the levels of activated protein C and a cumulative dose of 600 IU/kg/day is necessary for sustained protein C activation.

• Drotrecogin alpha activated has been approved for the treatment of severe sepsis and organ dysfunction (APACHE II >24).

• Patients with sepsis-induced purpura fulminans fulfill the criteria for adjuvant therapy with this drug at the dose of 24 µg/kg per hour for 96 hours.

• A few case reports with encouraging results have been published on the use of this drug in patients with purpura fulminans.7,49

• However, no randomized trial is yet available.50

4.Therapies Augmenting FibrinolysisRecombinant Tissue Plasminogen Activator

• Administration of a fibrinolytic agent such as recombinant tissue plasminogen activator (t-PA) is an alternative for limiting ongoing thrombin generation.

• Concentrations of PAI-1 are increased in purpura fulminans and correlate with risk for mortality.

• Although a few case reports have shown promising results, a retrospective analysis on the use of recombinant t-PA in children with meningococcal purpura fulminans showed a high incidence of intracerebral hemorrhage.

• Since there has not been a randomized trial, no definite answers on the use of recombinant t-PA in sepsis-induced purpura fulminans could be drawn.

Other Strategies• Fresh frozen plasma infusions containing anticoagula

nt factors have been suggested as an adjuvant therapy in purpura fulminans, providing both fluid resuscitation and immunomodulation.

• Cryoprecipitate, fibrinogen concentrate, or recombinant factor VIIa can be used in patients with severe bleeding not responding in other treatment options.36,37,53

• Plasma exchange using fresh frozen plasma has been used successfully in patients with sepsis-induced purpura fulminans by restoring low levels of protein C and antithrombin III.

Other Strategies• A few anecdotal reports have suggested impr

oved distal perfusion and pain relief with the use of vasodilating agents such as

1. prostacyclin or epoprostenol,

2. sodium nitroprusside,

3. topical nitroglycerin.

Other Strategies

• Hyperbaric oxygenation has been used, and one study demonstrated improvement of limb perfusion in 12 of 14 patients with sepsis-induced purpura fulminans caused by various pathogens. Because this treatment needs to be instituted early in the course of the disease, its usefulness is limited for logistical reasons.

• Extracorporeal membrane oxygenation has been used to support patients with intractable meningococcal sepsis and purpura fulminans. However, there is no exact answer to whether this technique offers any advantage over conventional therapy.

ABSTRACT• Sepsis-induced purpura fulminans is a rare but life-threaten

ing disorder, characterized by hemorrhagic infarction of the skin caused by disseminated intravascular coagulation and dermal vascular thrombosis.

• The pathogenesis is linked to enhanced expression of the natural procoagulants and depletion of the natural anticoagulant proteins particularly protein C.

• Meningococcal sepsis is the most common cause, followed by pneumococcal sepsis in adults.

• The syndrome is associated with more than 50% mortality secondary to multiple organ dysfunction syndrome and is accompanied by long-term morbidity.

ABSTRACT

• Necrotic lesions usually progress to distal ischemia, and skin grafting and extremities or limb amputation are often required.

• Early antibiotic administration and intensive care management according to the recommendations of severe sepsis and shock is crucial for patients’ survival.

• Adjuvant therapies against inflammatory and coagulation cascades and augmenting fibrinolysis are still controversial and need further assessment.

• Among them activated protein C and supplementation therapy have given promising results.

Thank you for your attention

How to manage of septic shock with DIC and acryl ischemia ?

1. If possible, discontinuation or reduction, if possible, of vasopressor therapy.

2. vigorous therapy of sepsis and DIC with intravenous antibiotic therapy

3. Heparinization

4. sympathetic blockade (ganglion block or intravenous trimethaphan therapy),

5. intravenous nitropruside therapy,

6. topical nitroglycerine ointment,

7. local or intravenous infusion of an α-blocker (phentolamine, chlorpromazine)

8. intravenous infusion of prostaglandin (epoprostenol)

Parmar, M. S. CMAJ 2002;167:1037-1038

Diagnosis of peripheral artery occlusion disease

• Four limb arterial blood pressure.

• Angiogram

• MRA

a old diabetic woman with septic shock and symmetric

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