Korean J Crit Care Med 증 례2012 August 27(3)182-186 httpdxdoiorg104266kjccm2012273182

182

Skin Necrosis after High Dose Vasopressor Infusion in Septic Shock

985103 Two Case Reports 985103Ah-Reum Cho MD Jeung-Il Kim MD

dagger

Eun-Jung Kim MD and Seung-Min Son MD

Departments of Anesthesia and Pain Medicine Orthopedic Surgery Pusan National University Hospital

daggerDepartment of Orthopedic Surgery School of Medicine Pusan National University Busan Korea

Survival sepsis campaign recommends that vasopressor therapy is required to maintain mean arterial pressure

(MAP) ge 65 mmHg However the absolute maximum dose of vasopressor is difficult to determine Herein we re-

port 2 cases of severe skin necrosis after high dose vasopressor infusion to maintain the recommended MAP in sep-

tic shock In our first case norepinephrine 10－20 μgkgmin and vasopressin 003－01 Umin were infused for 5

days in the second case dopamine 10－20 μgkgmin and norepinephrine 025－25 μgkgmin were infused for 7

days Severe ischemic skin lesions which required amputations developed in both cases The clinical appearance of

the skin lesions in the 2 cases was different because of the unique distribution of target receptors for different

vasopressors Thus when high dose vasopressors are required to achieve recommended MAP extra vigilance is

required Further studies for dose adjustment are needed

Key Words gangrene septic shock vasoconstrictor agents

Received on March 16 2012 Revised on April 25 2012 (1st) May 22

2012 (2nd) Accepted on May 23 2012

Correspondence to Jeung-Il Kim Department of Orthopedic Surgery

Pusan National University Hospital 179 Gudeok-ro Seo-gu

Busan 602-739 Korea

Tel 051-240-7248 Fax 051-247-8395

E-mail osteokimyahoocokr

This work was supported by a clinical research grant of Pusan National

University Hospital 2012

An international effort to improve the conditions that arise

from severe sepsis and a septic shock resulted in the publish-

ing of ldquoSurvival Sepsis Campaign International guidelines for

management of severe sepsis and septic shockrdquo[1] They rec-

ommend that vasopressor therapy is required to maintain mean

arterial pressure (MAP) ge 65 mmHg Dopamine and norepine-

phrine are recommended as the first choice vasopressors for

the management of hypotension in septic shock and epine-

phrine as the second line agent whereas vasopressin may be

effective in patient refractory to other vasopressors However

they did not mention the maximum dose of vasopressors for

the maintenance of MAP ge 65 mmHg Because of the wide

variability in vasopressor usage nationally and internationally

and in individual vasopressor requirement the absolute max-

imum dose of vasopressor is difficult to determine In general

when starting vasopressors their doses should be titrated to the

desired effect by closely monitoring the adverse effects We

report here 2 cases of severe skin necrosis after high dose

vasopressor infusion for the maintenance of MAP ge 65

mmHg in patients with septic shock which showed very dif-

ferent results This report discusses how high dose vasopressor

infusion affects the progress of septic shock and patientrsquos qual-

ity of life after the recovery

CASE REPORT

1) Case 1

A 39 year old man with diagnosed testicular cancer was ad-

mitted for scrotal pain and the aggravation of general condi-

tion On the day of admission diuretics were administrated be-

cause the patient presented with oliguria On the third day in

the hospital he developed hypotension (6040 mmHg) tachy-

cardia (125 beatsmin) tachypnea (40 breatsmin) and hypo-

xemia (SpO2 88) In accordance with the Surviving Sepsis

Campaign guidelines he was treated with fluid resuscitation

Ah-Reum Cho et alSkin Necrosis after High Dose Vasopressor Infusion 183

Fig 1 There are vasopressin-induced

ecchymosis and bullous skin

lesions on the left hand and

both thighs and calves (A B)

whereas dry gangrene induced

by norepinephrine appear on

the fingertips and toes (C D)

Afterward his central venous pressure (CVP) was 15 mmHg

but hypotension persisted Norepinephrine infusion was started

at a dose of 10μgkgmin through the central venous catheter

in the subclavian vein Mechanical ventilation and continuous

veno-venous hemodialysis were initiated

Although norepinephrine was infused for 17 hours and the

dose having been increased up to 20μgkgmin his MAP lev-

el still remained indicative of hypotension We began an in-

fusion of vasopressin 003 Umin through the central venous

catheter and increased the dose up to 01 Umin on the same

day After a 9-hour infusion of vasopressin and 26-hour in-

fusion of norepinephrine he developed multiple ecchymosis

and bullous lesions on the chest and scrotum and peripheral

cyanosis Laboratory examinations revealed disseminated intra-

vascular coagulation (DIC) The ecchymosis and bullous skin

lesion on the chest and scrotal area expanded to both thighs

and calves for two days (Fig 1A B) and ischemic change of

both fingers and toes became aggravated (Fig 1C D) After

72 hours vasopressin and norpeinephrine infusions were ceased

since his septic condition improved Despite the cessation of

vasopressors the development of extensive skin gangrene and

gross fluid exudation on the fingers and the lower limbs of

the patient worsened The orchiectomy and amputation of all

fingertips and feet was planned but was refused by his guar-

dian One week later from orchiectomy he died of cancer pro-

gression and the recurrence of septic shock

2) Case 2

A 40 year old man without medical history who had a

right hand crushing injury and undergone reimplantation 2

weeks previously was admitted to our hospital and prelimi-

narily diagnosed with septic shock After endotracheal intuba-

tion he was transferred to the intensive care unit (ICU) On

the first day in the ICU arterial blood pressure was 8050

mmHg heart rate 100－130 beatsmin and CVP 14－16 mmHg

despite fluid resuscitation Norepinephrine (025－25μgkg

min) and dopamine (10－20μgkgmin) infusions were started

through the central venous catheter in the subclavian vein

Continuous veno-venous hemodialysis was also applied due to

acute kidney insufficiency (AKI)

72 hours after the infusion of vaspressors he began to show

cyanosis at distal areas of both fingers and toes On the sixth

184 한 환자의학회지제 27 권 제 3 호 2012

Fig 2 Norepnephrine and dopamine-

induced dry gangrene only

appear on the fingertips and

toes (A－C) They were all

amputated (D－F)

day dopamine and norepinephrine infusions were discontinued

since his septic condition improved However ischemic lesion

at the distal areas of both fingers and toes were aggravated

eventually leading to the necrosis of the lesions (Fig 2A－C)

Laboratory examinations for vasculitis and autoimmune disease

were all negative DIC was confirmed by laboratory examina-

tions but CT angiography of the upper and lower extremities

showed no evidence of vascular occlusion

Laboratory abnormalities and renal function recovered 1

month after his admission He underwent an amputation of the

right arm below elbow as required for the removal of septic

sources After the formation of a line of demarcation left 2nd

3rd 4th 5th fingers and all toes were amputated (Fig 2D－F)

Nine months later from his hospital admission he was dis-

charged Amputation of all toes caused him a great disturbance

in rapid gait spring squatting and tiptoeing Therefore he had

to wear shoe fillers on both feet for the enhancement of resil-

ience and received rehabilitation training afterward

DISCUSSION

Ischemic skin necrosis is a serious complication in critically

ill patients with a high mortality rate (up to 40) and half of

survivors require amputation of affected limbs[2] One of path-

ophysiologic treatments of ischemic skin necrosis in critically

ill patients is known as vasopressors such as dopamine nor-

epinephrine and vasopressin[3-6] Presumptive mechanisms

leading to ischemic skin necrosis following the use of vaso-

pressors include extravasation peripheral administration and

high dose infusion It is more likely to occur even with low

dose infusion through a central venous catheter[7] in the pres-

ence of risk factors such as sepsis AKI obesity DIC and pe-

Ah-Reum Cho et alSkin Necrosis after High Dose Vasopressor Infusion 185

ripheral arterial occlusive disease[2-6]

Vasopressors must be used following the Surviving Sepsis

Campaign guidelines and its high dose infusion is frequently

required in septic shock Most of septic shock patients have

co-morbidities which are risk factors of ischemic skin necrosis

Standard dose ranges of dopamine norepinephrine and vaso-

pressin infusion are generally known to be 20－20μgkgmin

001－30μgkgmin and 001－01 Umin respectively and

low dose ranges are known to be safer[8] In our cases there

was no extravasation and vasopressors were infused centrally

through subcalvian vein However both cases required high

dose vasopressors for several days to maintain adequate MAP

levels In the first case norepinephrine 10－20μgkgmin and

vasopressin 003－01 Umin were infused for 5 days whereas

in the second case dopamine 10－20μgkgmin and nor-

epinephrine 025－25μgkgmin were infused for 7 days Both

patients had septic shock AKI and DIC Interestingly clinical

appearances of ischemic skin necrosis in two cases were dif-

ferent The first case was caused by norepinephrine and vaso-

pressin Ischemic skin necrosis occurred not only of the fingers

and toes but also on the thighs and calves Fingers and toes

developed dry gangrene whereas thigh and calves were cov-

ered with extensive bruises and large exudative blisters On the

contrary the second case was caused by dopamine and nore-

pinephrine Only the fingertips and tiptoes became dry gangre-

nous This case was consistent with previous reports that skin

necroses due to norepinephrine and vasopressin appear in dif-

ferent areas[5-79] Norepinephrin-induced skin necrosis typi-

cally occurs on the fingers and toes while vasopressin spares

them This is related to the unique distribution of the target

receptor of vasopressin vasopressin receptor type 1 (V1 re-

ceptor) which is located in smooth muscles of the blood ves-

sels mainly in the territory of the splanchnic circulation kid-

ney myometrium bladder adipocytes hepatocytes platelets

spleen testis and skin circulation[10] It might be explained by

wider areas of skin such as thighs and calves which have

more V1 receptors and more likely to be affected by vaso-

pressin[11]

Kingston and Mackey[12] suggested five possible patho-

mechanisms of skin lesion in septic shock DIC direct vas-

cular invasion and occlusion by bacteria and fungi immune

vasculitis and immune complex formation emboli from endo-

carditis and vascular effects of toxins In the second case lab-

oratory tests revealed DIC but CT angiographic results of the

upper and lower extremities for vascular occlusion were nega-

tive Laboratory examinations for autoimmune disease also

showed negative results However in the first case we could

not perform imaging tests wound biopsy nor laboratory exams

to rule out other causes of skin necrosis because of the pa-

tientrsquos financial problem Only DIC was confirmed Although

thorough investigations to rule out other possible causes could

not be performed on the patients of the second case either his

septic condition improved without healing of the skin lesions

This meant that skin lesions were not caused by infection

Clinical manifestations of skin necrosis in the second case

were consistent with previous reports[5-79] It will be reason-

able to assume that skin necrosis was an adverse effect of

norepinephrine and vasopressin

Several studies have reported that the implementation of the

Surviving Sepsis Campaign guidelines was associated with a

significant decrease in mortality[1314] In Spain a three-year

follow-up quasi-experimental study with a historical comparison

group found that achieving ScvO2 ge 70 within 6 hours was

the only single intervention that maintained the predictive value

of survival independently of the other interventions[13] In an-

other study there was a statistically significant decrease of

odds ratio for mortality in patients who had received cortico-

steroids and in mechanically ventilated patients whose inspira-

tory plateau pressure becomes ＜ 30 cmH2O within 24 hours[14]

Treatment of hypotension with fluids and vasopressors were

not the interventions independent of lower mortality in the

both studies Their impact on mortality in severe sepsis and

septic shock has rarely been studied which is also classified

as a low quality evidence (grade C) in Surviving Sepsis Cam-

paign guideline[1] It is obvious that hypotension must be cor-

rected for adequate tissue perfusion in septic shock However

when high dose vasopressors are required to achieve the rec-

ommended MAP especially in patients with ischemic skin ne-

crosis risk factors extra vigilance is also required We should

closely monitor the signs of inadequate skin perfusion and if

needed may assess the skin microcirculation using non-in-

vasive techniques such as capillaroscopy laser Doppler flow-

meter and transcutaneous measurement of oxygen tension[15]

Furthermore prospective studies are needed to suggest guide-

lines for dose adjustment of vasopressors in patients with sep-

tic shock

REFERENCES

1) Dellinger RP Levy MM Carlet JM Bion J Parker MM

Jaeschke R et al Surviving Sepsis Campaign international

guidelines for management of severe sepsis and septic shock

186 한 환자의학회지제 27 권 제 3 호 2012

2008 Intensive Care Med 2008 34 17-60

2) Molos MA Hall JC Symmetrical peripheral gangrene and dis-

seminated intravascular coagulation Arch Dermatol 1985

121 1057-61

3) Duumlnser MW Mayr AJ Tuumlr A Pajk W Barbara F Knotzer

H et al Ischemic skin lesions as a complication of continuous

vasopressin infusion in catecholamine-resistant vasodilatory

shock incidence and risk factors Crit Care Med 2003 31

1394-8

4) Kahn JM Kress JP Hall JB Skin necrosis after extravasation

of low-dose vasopressin administered for septic shock Crit

Care Med 2002 30 1899-901

5) Hayes MA Yau EH Hinds CJ Watson JD Symmetrical pe-

ripheral gangrene association with noradrenaline administra-

tion Intensive Care Med 1992 18 433-6

6) Bonamigo RR Razera F Cartell A Extensive skin necrosis

following use of noradrenaline and dopamine J Eur Acad

Dermatol Venereol 2007 21 565-6

7) Kim EH Lee SH Byun SW Kang HS Koo DH Park HG

et al Skin necrosis after a low-dose vasopressin infusion

through a central venous catheter for treating septic shock

Korean J Intern Med 2006 21 287-90

8) Overgaard CB Dzaviacutek V Inotropes and vasopressors review

of physiology and clinical use in cardiovascular disease

Circulation 2008 118 1047-56

9) Donnellan F Cullen G Hegarty JE McCormick PA

Ischaemic complications of Glypressin in liver disease a case

series Br J Clin Pharmacol 2007 64 550-2

10) Holmes CL Patel BM Russell JA Walley KR Physiology

of vasopressin relevant to management of septic shock Chest

2001 120 989-1002

11) Yefet E Gershovich M Farber E Soboh S Extensive epi-

dermal necrosis due to terlipressin Isr Med Assoc J 2011 13

180-1

12) Kingston ME Mackey D Skin clues in the diagnosis of

life-threatening infections Rev Infect Dis 1986 8 1-11

13) Castellanos-Ortega A Suberviola B Garciacutea-Astudillo LA

Holanda MS Ortiz F Llorca J et al Impact of the Surviving

Sepsis Campaign protocols on hospital length of stay and mor-

tality in septic shock patients results of a three-year follow-up

quasi-experimental study Crit Care Med 2010 38 1036-43

14) Shiramizo SC Marra AR Duratildeo MS Paes AcircT Edmond MB

Pavatildeo dos Santos OF Decreasing mortality in severe sepsis

and septic shock patients by implementing a sepsis bundle in

a hospital setting PLoS One 2011 6 e26790 Available from

httpwwwplosoneorgarticleinfo3Adoi2F1013712

Fjournalpone0026790

15) Rossi M Carpi A Skin microcirculation in peripheral arterial

obliterative disease Biomed Pharmacother 2004 58 427-31

Ah-Reum Cho et alSkin Necrosis after High Dose Vasopressor Infusion 183

Fig 1 There are vasopressin-induced

ecchymosis and bullous skin

lesions on the left hand and

both thighs and calves (A B)

whereas dry gangrene induced

by norepinephrine appear on

the fingertips and toes (C D)

Afterward his central venous pressure (CVP) was 15 mmHg

but hypotension persisted Norepinephrine infusion was started

at a dose of 10μgkgmin through the central venous catheter

in the subclavian vein Mechanical ventilation and continuous

veno-venous hemodialysis were initiated

Although norepinephrine was infused for 17 hours and the

dose having been increased up to 20μgkgmin his MAP lev-

el still remained indicative of hypotension We began an in-

fusion of vasopressin 003 Umin through the central venous

catheter and increased the dose up to 01 Umin on the same

day After a 9-hour infusion of vasopressin and 26-hour in-

fusion of norepinephrine he developed multiple ecchymosis

and bullous lesions on the chest and scrotum and peripheral

cyanosis Laboratory examinations revealed disseminated intra-

vascular coagulation (DIC) The ecchymosis and bullous skin

lesion on the chest and scrotal area expanded to both thighs

and calves for two days (Fig 1A B) and ischemic change of

both fingers and toes became aggravated (Fig 1C D) After

72 hours vasopressin and norpeinephrine infusions were ceased

since his septic condition improved Despite the cessation of

vasopressors the development of extensive skin gangrene and

gross fluid exudation on the fingers and the lower limbs of

the patient worsened The orchiectomy and amputation of all

fingertips and feet was planned but was refused by his guar-

dian One week later from orchiectomy he died of cancer pro-

gression and the recurrence of septic shock

2) Case 2

A 40 year old man without medical history who had a

right hand crushing injury and undergone reimplantation 2

weeks previously was admitted to our hospital and prelimi-

narily diagnosed with septic shock After endotracheal intuba-

tion he was transferred to the intensive care unit (ICU) On

the first day in the ICU arterial blood pressure was 8050

mmHg heart rate 100－130 beatsmin and CVP 14－16 mmHg

despite fluid resuscitation Norepinephrine (025－25μgkg

min) and dopamine (10－20μgkgmin) infusions were started

through the central venous catheter in the subclavian vein

Continuous veno-venous hemodialysis was also applied due to

acute kidney insufficiency (AKI)

72 hours after the infusion of vaspressors he began to show

cyanosis at distal areas of both fingers and toes On the sixth

184 한 환자의학회지제 27 권 제 3 호 2012

Fig 2 Norepnephrine and dopamine-

induced dry gangrene only

appear on the fingertips and

toes (A－C) They were all

amputated (D－F)

day dopamine and norepinephrine infusions were discontinued

since his septic condition improved However ischemic lesion

at the distal areas of both fingers and toes were aggravated

eventually leading to the necrosis of the lesions (Fig 2A－C)

Laboratory examinations for vasculitis and autoimmune disease

were all negative DIC was confirmed by laboratory examina-

tions but CT angiography of the upper and lower extremities

showed no evidence of vascular occlusion

Laboratory abnormalities and renal function recovered 1

month after his admission He underwent an amputation of the

right arm below elbow as required for the removal of septic

sources After the formation of a line of demarcation left 2nd

3rd 4th 5th fingers and all toes were amputated (Fig 2D－F)

Nine months later from his hospital admission he was dis-

charged Amputation of all toes caused him a great disturbance

in rapid gait spring squatting and tiptoeing Therefore he had

to wear shoe fillers on both feet for the enhancement of resil-

ience and received rehabilitation training afterward

DISCUSSION

Ischemic skin necrosis is a serious complication in critically

ill patients with a high mortality rate (up to 40) and half of

survivors require amputation of affected limbs[2] One of path-

ophysiologic treatments of ischemic skin necrosis in critically

ill patients is known as vasopressors such as dopamine nor-

epinephrine and vasopressin[3-6] Presumptive mechanisms

leading to ischemic skin necrosis following the use of vaso-

pressors include extravasation peripheral administration and

high dose infusion It is more likely to occur even with low

dose infusion through a central venous catheter[7] in the pres-

ence of risk factors such as sepsis AKI obesity DIC and pe-

Ah-Reum Cho et alSkin Necrosis after High Dose Vasopressor Infusion 185

ripheral arterial occlusive disease[2-6]

Vasopressors must be used following the Surviving Sepsis

Campaign guidelines and its high dose infusion is frequently

required in septic shock Most of septic shock patients have

co-morbidities which are risk factors of ischemic skin necrosis

Standard dose ranges of dopamine norepinephrine and vaso-

pressin infusion are generally known to be 20－20μgkgmin

001－30μgkgmin and 001－01 Umin respectively and

low dose ranges are known to be safer[8] In our cases there

was no extravasation and vasopressors were infused centrally

through subcalvian vein However both cases required high

dose vasopressors for several days to maintain adequate MAP

levels In the first case norepinephrine 10－20μgkgmin and

vasopressin 003－01 Umin were infused for 5 days whereas

in the second case dopamine 10－20μgkgmin and nor-

epinephrine 025－25μgkgmin were infused for 7 days Both

patients had septic shock AKI and DIC Interestingly clinical

appearances of ischemic skin necrosis in two cases were dif-

ferent The first case was caused by norepinephrine and vaso-

pressin Ischemic skin necrosis occurred not only of the fingers

and toes but also on the thighs and calves Fingers and toes

developed dry gangrene whereas thigh and calves were cov-

ered with extensive bruises and large exudative blisters On the

contrary the second case was caused by dopamine and nore-

pinephrine Only the fingertips and tiptoes became dry gangre-

nous This case was consistent with previous reports that skin

necroses due to norepinephrine and vasopressin appear in dif-

ferent areas[5-79] Norepinephrin-induced skin necrosis typi-

cally occurs on the fingers and toes while vasopressin spares

them This is related to the unique distribution of the target

receptor of vasopressin vasopressin receptor type 1 (V1 re-

ceptor) which is located in smooth muscles of the blood ves-

sels mainly in the territory of the splanchnic circulation kid-

ney myometrium bladder adipocytes hepatocytes platelets

spleen testis and skin circulation[10] It might be explained by

wider areas of skin such as thighs and calves which have

more V1 receptors and more likely to be affected by vaso-

pressin[11]

Kingston and Mackey[12] suggested five possible patho-

mechanisms of skin lesion in septic shock DIC direct vas-

cular invasion and occlusion by bacteria and fungi immune

vasculitis and immune complex formation emboli from endo-

carditis and vascular effects of toxins In the second case lab-

oratory tests revealed DIC but CT angiographic results of the

upper and lower extremities for vascular occlusion were nega-

tive Laboratory examinations for autoimmune disease also

showed negative results However in the first case we could

not perform imaging tests wound biopsy nor laboratory exams

to rule out other causes of skin necrosis because of the pa-

tientrsquos financial problem Only DIC was confirmed Although

thorough investigations to rule out other possible causes could

not be performed on the patients of the second case either his

septic condition improved without healing of the skin lesions

This meant that skin lesions were not caused by infection

Clinical manifestations of skin necrosis in the second case

were consistent with previous reports[5-79] It will be reason-

able to assume that skin necrosis was an adverse effect of

norepinephrine and vasopressin

Several studies have reported that the implementation of the

Surviving Sepsis Campaign guidelines was associated with a

significant decrease in mortality[1314] In Spain a three-year

follow-up quasi-experimental study with a historical comparison

group found that achieving ScvO2 ge 70 within 6 hours was

the only single intervention that maintained the predictive value

of survival independently of the other interventions[13] In an-

other study there was a statistically significant decrease of

odds ratio for mortality in patients who had received cortico-

steroids and in mechanically ventilated patients whose inspira-

tory plateau pressure becomes ＜ 30 cmH2O within 24 hours[14]

Treatment of hypotension with fluids and vasopressors were

not the interventions independent of lower mortality in the

both studies Their impact on mortality in severe sepsis and

septic shock has rarely been studied which is also classified

as a low quality evidence (grade C) in Surviving Sepsis Cam-

paign guideline[1] It is obvious that hypotension must be cor-

rected for adequate tissue perfusion in septic shock However

when high dose vasopressors are required to achieve the rec-

ommended MAP especially in patients with ischemic skin ne-

crosis risk factors extra vigilance is also required We should

closely monitor the signs of inadequate skin perfusion and if

needed may assess the skin microcirculation using non-in-

vasive techniques such as capillaroscopy laser Doppler flow-

meter and transcutaneous measurement of oxygen tension[15]

Furthermore prospective studies are needed to suggest guide-

lines for dose adjustment of vasopressors in patients with sep-

tic shock

REFERENCES

1) Dellinger RP Levy MM Carlet JM Bion J Parker MM

Jaeschke R et al Surviving Sepsis Campaign international

guidelines for management of severe sepsis and septic shock

186 한 환자의학회지제 27 권 제 3 호 2012

2008 Intensive Care Med 2008 34 17-60

2) Molos MA Hall JC Symmetrical peripheral gangrene and dis-

seminated intravascular coagulation Arch Dermatol 1985

121 1057-61

3) Duumlnser MW Mayr AJ Tuumlr A Pajk W Barbara F Knotzer

H et al Ischemic skin lesions as a complication of continuous

vasopressin infusion in catecholamine-resistant vasodilatory

shock incidence and risk factors Crit Care Med 2003 31

1394-8

4) Kahn JM Kress JP Hall JB Skin necrosis after extravasation

of low-dose vasopressin administered for septic shock Crit

Care Med 2002 30 1899-901

5) Hayes MA Yau EH Hinds CJ Watson JD Symmetrical pe-

ripheral gangrene association with noradrenaline administra-

tion Intensive Care Med 1992 18 433-6

6) Bonamigo RR Razera F Cartell A Extensive skin necrosis

following use of noradrenaline and dopamine J Eur Acad

Dermatol Venereol 2007 21 565-6

7) Kim EH Lee SH Byun SW Kang HS Koo DH Park HG

et al Skin necrosis after a low-dose vasopressin infusion

through a central venous catheter for treating septic shock

Korean J Intern Med 2006 21 287-90

8) Overgaard CB Dzaviacutek V Inotropes and vasopressors review

of physiology and clinical use in cardiovascular disease

Circulation 2008 118 1047-56

9) Donnellan F Cullen G Hegarty JE McCormick PA

Ischaemic complications of Glypressin in liver disease a case

series Br J Clin Pharmacol 2007 64 550-2

10) Holmes CL Patel BM Russell JA Walley KR Physiology

of vasopressin relevant to management of septic shock Chest

2001 120 989-1002

11) Yefet E Gershovich M Farber E Soboh S Extensive epi-

dermal necrosis due to terlipressin Isr Med Assoc J 2011 13

180-1

12) Kingston ME Mackey D Skin clues in the diagnosis of

life-threatening infections Rev Infect Dis 1986 8 1-11

13) Castellanos-Ortega A Suberviola B Garciacutea-Astudillo LA

Holanda MS Ortiz F Llorca J et al Impact of the Surviving

Sepsis Campaign protocols on hospital length of stay and mor-

tality in septic shock patients results of a three-year follow-up

quasi-experimental study Crit Care Med 2010 38 1036-43

14) Shiramizo SC Marra AR Duratildeo MS Paes AcircT Edmond MB

Pavatildeo dos Santos OF Decreasing mortality in severe sepsis

and septic shock patients by implementing a sepsis bundle in

a hospital setting PLoS One 2011 6 e26790 Available from

httpwwwplosoneorgarticleinfo3Adoi2F1013712

Fjournalpone0026790

15) Rossi M Carpi A Skin microcirculation in peripheral arterial

obliterative disease Biomed Pharmacother 2004 58 427-31

184 한 환자의학회지제 27 권 제 3 호 2012

Fig 2 Norepnephrine and dopamine-

induced dry gangrene only

appear on the fingertips and

toes (A－C) They were all

amputated (D－F)

day dopamine and norepinephrine infusions were discontinued

since his septic condition improved However ischemic lesion

at the distal areas of both fingers and toes were aggravated

eventually leading to the necrosis of the lesions (Fig 2A－C)

Laboratory examinations for vasculitis and autoimmune disease

were all negative DIC was confirmed by laboratory examina-

tions but CT angiography of the upper and lower extremities

showed no evidence of vascular occlusion

Laboratory abnormalities and renal function recovered 1

month after his admission He underwent an amputation of the

right arm below elbow as required for the removal of septic

sources After the formation of a line of demarcation left 2nd

3rd 4th 5th fingers and all toes were amputated (Fig 2D－F)

Nine months later from his hospital admission he was dis-

charged Amputation of all toes caused him a great disturbance

in rapid gait spring squatting and tiptoeing Therefore he had

to wear shoe fillers on both feet for the enhancement of resil-

ience and received rehabilitation training afterward

DISCUSSION

Ischemic skin necrosis is a serious complication in critically

ill patients with a high mortality rate (up to 40) and half of

survivors require amputation of affected limbs[2] One of path-

ophysiologic treatments of ischemic skin necrosis in critically

ill patients is known as vasopressors such as dopamine nor-

epinephrine and vasopressin[3-6] Presumptive mechanisms

leading to ischemic skin necrosis following the use of vaso-

pressors include extravasation peripheral administration and

high dose infusion It is more likely to occur even with low

dose infusion through a central venous catheter[7] in the pres-

ence of risk factors such as sepsis AKI obesity DIC and pe-

Ah-Reum Cho et alSkin Necrosis after High Dose Vasopressor Infusion 185

ripheral arterial occlusive disease[2-6]

Vasopressors must be used following the Surviving Sepsis

Campaign guidelines and its high dose infusion is frequently

required in septic shock Most of septic shock patients have

co-morbidities which are risk factors of ischemic skin necrosis

Standard dose ranges of dopamine norepinephrine and vaso-

pressin infusion are generally known to be 20－20μgkgmin

001－30μgkgmin and 001－01 Umin respectively and

low dose ranges are known to be safer[8] In our cases there

was no extravasation and vasopressors were infused centrally

through subcalvian vein However both cases required high

dose vasopressors for several days to maintain adequate MAP

levels In the first case norepinephrine 10－20μgkgmin and

vasopressin 003－01 Umin were infused for 5 days whereas

in the second case dopamine 10－20μgkgmin and nor-

epinephrine 025－25μgkgmin were infused for 7 days Both

patients had septic shock AKI and DIC Interestingly clinical

appearances of ischemic skin necrosis in two cases were dif-

ferent The first case was caused by norepinephrine and vaso-

pressin Ischemic skin necrosis occurred not only of the fingers

and toes but also on the thighs and calves Fingers and toes

developed dry gangrene whereas thigh and calves were cov-

ered with extensive bruises and large exudative blisters On the

contrary the second case was caused by dopamine and nore-

pinephrine Only the fingertips and tiptoes became dry gangre-

nous This case was consistent with previous reports that skin

necroses due to norepinephrine and vasopressin appear in dif-

ferent areas[5-79] Norepinephrin-induced skin necrosis typi-

cally occurs on the fingers and toes while vasopressin spares

them This is related to the unique distribution of the target

receptor of vasopressin vasopressin receptor type 1 (V1 re-

ceptor) which is located in smooth muscles of the blood ves-

sels mainly in the territory of the splanchnic circulation kid-

ney myometrium bladder adipocytes hepatocytes platelets

spleen testis and skin circulation[10] It might be explained by

wider areas of skin such as thighs and calves which have

more V1 receptors and more likely to be affected by vaso-

pressin[11]

Kingston and Mackey[12] suggested five possible patho-

mechanisms of skin lesion in septic shock DIC direct vas-

cular invasion and occlusion by bacteria and fungi immune

vasculitis and immune complex formation emboli from endo-

carditis and vascular effects of toxins In the second case lab-

oratory tests revealed DIC but CT angiographic results of the

upper and lower extremities for vascular occlusion were nega-

tive Laboratory examinations for autoimmune disease also

showed negative results However in the first case we could

not perform imaging tests wound biopsy nor laboratory exams

to rule out other causes of skin necrosis because of the pa-

tientrsquos financial problem Only DIC was confirmed Although

thorough investigations to rule out other possible causes could

not be performed on the patients of the second case either his

septic condition improved without healing of the skin lesions

This meant that skin lesions were not caused by infection

Clinical manifestations of skin necrosis in the second case

were consistent with previous reports[5-79] It will be reason-

able to assume that skin necrosis was an adverse effect of

norepinephrine and vasopressin

Several studies have reported that the implementation of the

Surviving Sepsis Campaign guidelines was associated with a

significant decrease in mortality[1314] In Spain a three-year

follow-up quasi-experimental study with a historical comparison

group found that achieving ScvO2 ge 70 within 6 hours was

the only single intervention that maintained the predictive value

of survival independently of the other interventions[13] In an-

other study there was a statistically significant decrease of

odds ratio for mortality in patients who had received cortico-

steroids and in mechanically ventilated patients whose inspira-

tory plateau pressure becomes ＜ 30 cmH2O within 24 hours[14]

Treatment of hypotension with fluids and vasopressors were

not the interventions independent of lower mortality in the

both studies Their impact on mortality in severe sepsis and

septic shock has rarely been studied which is also classified

as a low quality evidence (grade C) in Surviving Sepsis Cam-

paign guideline[1] It is obvious that hypotension must be cor-

rected for adequate tissue perfusion in septic shock However

when high dose vasopressors are required to achieve the rec-

ommended MAP especially in patients with ischemic skin ne-

crosis risk factors extra vigilance is also required We should

closely monitor the signs of inadequate skin perfusion and if

needed may assess the skin microcirculation using non-in-

vasive techniques such as capillaroscopy laser Doppler flow-

meter and transcutaneous measurement of oxygen tension[15]

Furthermore prospective studies are needed to suggest guide-

lines for dose adjustment of vasopressors in patients with sep-

tic shock

REFERENCES

1) Dellinger RP Levy MM Carlet JM Bion J Parker MM

Jaeschke R et al Surviving Sepsis Campaign international

guidelines for management of severe sepsis and septic shock

186 한 환자의학회지제 27 권 제 3 호 2012

2008 Intensive Care Med 2008 34 17-60

2) Molos MA Hall JC Symmetrical peripheral gangrene and dis-

seminated intravascular coagulation Arch Dermatol 1985

121 1057-61

3) Duumlnser MW Mayr AJ Tuumlr A Pajk W Barbara F Knotzer

H et al Ischemic skin lesions as a complication of continuous

vasopressin infusion in catecholamine-resistant vasodilatory

shock incidence and risk factors Crit Care Med 2003 31

1394-8

4) Kahn JM Kress JP Hall JB Skin necrosis after extravasation

of low-dose vasopressin administered for septic shock Crit

Care Med 2002 30 1899-901

5) Hayes MA Yau EH Hinds CJ Watson JD Symmetrical pe-

ripheral gangrene association with noradrenaline administra-

tion Intensive Care Med 1992 18 433-6

6) Bonamigo RR Razera F Cartell A Extensive skin necrosis

following use of noradrenaline and dopamine J Eur Acad

Dermatol Venereol 2007 21 565-6

7) Kim EH Lee SH Byun SW Kang HS Koo DH Park HG

et al Skin necrosis after a low-dose vasopressin infusion

through a central venous catheter for treating septic shock

Korean J Intern Med 2006 21 287-90

8) Overgaard CB Dzaviacutek V Inotropes and vasopressors review

of physiology and clinical use in cardiovascular disease

Circulation 2008 118 1047-56

9) Donnellan F Cullen G Hegarty JE McCormick PA

Ischaemic complications of Glypressin in liver disease a case

series Br J Clin Pharmacol 2007 64 550-2

10) Holmes CL Patel BM Russell JA Walley KR Physiology

of vasopressin relevant to management of septic shock Chest

2001 120 989-1002

11) Yefet E Gershovich M Farber E Soboh S Extensive epi-

dermal necrosis due to terlipressin Isr Med Assoc J 2011 13

180-1

12) Kingston ME Mackey D Skin clues in the diagnosis of

life-threatening infections Rev Infect Dis 1986 8 1-11

13) Castellanos-Ortega A Suberviola B Garciacutea-Astudillo LA

Holanda MS Ortiz F Llorca J et al Impact of the Surviving

Sepsis Campaign protocols on hospital length of stay and mor-

tality in septic shock patients results of a three-year follow-up

quasi-experimental study Crit Care Med 2010 38 1036-43

14) Shiramizo SC Marra AR Duratildeo MS Paes AcircT Edmond MB

Pavatildeo dos Santos OF Decreasing mortality in severe sepsis

and septic shock patients by implementing a sepsis bundle in

a hospital setting PLoS One 2011 6 e26790 Available from

httpwwwplosoneorgarticleinfo3Adoi2F1013712

Fjournalpone0026790

15) Rossi M Carpi A Skin microcirculation in peripheral arterial

obliterative disease Biomed Pharmacother 2004 58 427-31

Ah-Reum Cho et alSkin Necrosis after High Dose Vasopressor Infusion 185

ripheral arterial occlusive disease[2-6]

Vasopressors must be used following the Surviving Sepsis

Campaign guidelines and its high dose infusion is frequently

required in septic shock Most of septic shock patients have

co-morbidities which are risk factors of ischemic skin necrosis

Standard dose ranges of dopamine norepinephrine and vaso-

pressin infusion are generally known to be 20－20μgkgmin

001－30μgkgmin and 001－01 Umin respectively and

low dose ranges are known to be safer[8] In our cases there

was no extravasation and vasopressors were infused centrally

through subcalvian vein However both cases required high

dose vasopressors for several days to maintain adequate MAP

levels In the first case norepinephrine 10－20μgkgmin and

vasopressin 003－01 Umin were infused for 5 days whereas

in the second case dopamine 10－20μgkgmin and nor-

epinephrine 025－25μgkgmin were infused for 7 days Both

patients had septic shock AKI and DIC Interestingly clinical

appearances of ischemic skin necrosis in two cases were dif-

ferent The first case was caused by norepinephrine and vaso-

pressin Ischemic skin necrosis occurred not only of the fingers

and toes but also on the thighs and calves Fingers and toes

developed dry gangrene whereas thigh and calves were cov-

ered with extensive bruises and large exudative blisters On the

contrary the second case was caused by dopamine and nore-

pinephrine Only the fingertips and tiptoes became dry gangre-

nous This case was consistent with previous reports that skin

necroses due to norepinephrine and vasopressin appear in dif-

ferent areas[5-79] Norepinephrin-induced skin necrosis typi-

cally occurs on the fingers and toes while vasopressin spares

them This is related to the unique distribution of the target

receptor of vasopressin vasopressin receptor type 1 (V1 re-

ceptor) which is located in smooth muscles of the blood ves-

sels mainly in the territory of the splanchnic circulation kid-

ney myometrium bladder adipocytes hepatocytes platelets

spleen testis and skin circulation[10] It might be explained by

wider areas of skin such as thighs and calves which have

more V1 receptors and more likely to be affected by vaso-

pressin[11]

Kingston and Mackey[12] suggested five possible patho-

mechanisms of skin lesion in septic shock DIC direct vas-

cular invasion and occlusion by bacteria and fungi immune

vasculitis and immune complex formation emboli from endo-

carditis and vascular effects of toxins In the second case lab-

oratory tests revealed DIC but CT angiographic results of the

upper and lower extremities for vascular occlusion were nega-

tive Laboratory examinations for autoimmune disease also

showed negative results However in the first case we could

not perform imaging tests wound biopsy nor laboratory exams

to rule out other causes of skin necrosis because of the pa-

tientrsquos financial problem Only DIC was confirmed Although

thorough investigations to rule out other possible causes could

not be performed on the patients of the second case either his

septic condition improved without healing of the skin lesions

This meant that skin lesions were not caused by infection

Clinical manifestations of skin necrosis in the second case

were consistent with previous reports[5-79] It will be reason-

able to assume that skin necrosis was an adverse effect of

norepinephrine and vasopressin

Several studies have reported that the implementation of the

Surviving Sepsis Campaign guidelines was associated with a

significant decrease in mortality[1314] In Spain a three-year

follow-up quasi-experimental study with a historical comparison

group found that achieving ScvO2 ge 70 within 6 hours was

the only single intervention that maintained the predictive value

of survival independently of the other interventions[13] In an-

other study there was a statistically significant decrease of

odds ratio for mortality in patients who had received cortico-

steroids and in mechanically ventilated patients whose inspira-

tory plateau pressure becomes ＜ 30 cmH2O within 24 hours[14]

Treatment of hypotension with fluids and vasopressors were

not the interventions independent of lower mortality in the

both studies Their impact on mortality in severe sepsis and

septic shock has rarely been studied which is also classified

as a low quality evidence (grade C) in Surviving Sepsis Cam-

paign guideline[1] It is obvious that hypotension must be cor-

rected for adequate tissue perfusion in septic shock However

when high dose vasopressors are required to achieve the rec-

ommended MAP especially in patients with ischemic skin ne-

crosis risk factors extra vigilance is also required We should

closely monitor the signs of inadequate skin perfusion and if

needed may assess the skin microcirculation using non-in-

vasive techniques such as capillaroscopy laser Doppler flow-

meter and transcutaneous measurement of oxygen tension[15]

Furthermore prospective studies are needed to suggest guide-

lines for dose adjustment of vasopressors in patients with sep-

tic shock

REFERENCES

1) Dellinger RP Levy MM Carlet JM Bion J Parker MM

Jaeschke R et al Surviving Sepsis Campaign international

guidelines for management of severe sepsis and septic shock

186 한 환자의학회지제 27 권 제 3 호 2012

2008 Intensive Care Med 2008 34 17-60

2) Molos MA Hall JC Symmetrical peripheral gangrene and dis-

seminated intravascular coagulation Arch Dermatol 1985

121 1057-61

3) Duumlnser MW Mayr AJ Tuumlr A Pajk W Barbara F Knotzer

H et al Ischemic skin lesions as a complication of continuous

vasopressin infusion in catecholamine-resistant vasodilatory

shock incidence and risk factors Crit Care Med 2003 31

1394-8

4) Kahn JM Kress JP Hall JB Skin necrosis after extravasation

of low-dose vasopressin administered for septic shock Crit

Care Med 2002 30 1899-901

5) Hayes MA Yau EH Hinds CJ Watson JD Symmetrical pe-

ripheral gangrene association with noradrenaline administra-

tion Intensive Care Med 1992 18 433-6

6) Bonamigo RR Razera F Cartell A Extensive skin necrosis

following use of noradrenaline and dopamine J Eur Acad

Dermatol Venereol 2007 21 565-6

7) Kim EH Lee SH Byun SW Kang HS Koo DH Park HG

et al Skin necrosis after a low-dose vasopressin infusion

through a central venous catheter for treating septic shock

Korean J Intern Med 2006 21 287-90

8) Overgaard CB Dzaviacutek V Inotropes and vasopressors review

of physiology and clinical use in cardiovascular disease

Circulation 2008 118 1047-56

9) Donnellan F Cullen G Hegarty JE McCormick PA

Ischaemic complications of Glypressin in liver disease a case

series Br J Clin Pharmacol 2007 64 550-2

10) Holmes CL Patel BM Russell JA Walley KR Physiology

of vasopressin relevant to management of septic shock Chest

2001 120 989-1002

11) Yefet E Gershovich M Farber E Soboh S Extensive epi-

dermal necrosis due to terlipressin Isr Med Assoc J 2011 13

180-1

12) Kingston ME Mackey D Skin clues in the diagnosis of

life-threatening infections Rev Infect Dis 1986 8 1-11

13) Castellanos-Ortega A Suberviola B Garciacutea-Astudillo LA

Holanda MS Ortiz F Llorca J et al Impact of the Surviving

Sepsis Campaign protocols on hospital length of stay and mor-

tality in septic shock patients results of a three-year follow-up

quasi-experimental study Crit Care Med 2010 38 1036-43

14) Shiramizo SC Marra AR Duratildeo MS Paes AcircT Edmond MB

Pavatildeo dos Santos OF Decreasing mortality in severe sepsis

and septic shock patients by implementing a sepsis bundle in

a hospital setting PLoS One 2011 6 e26790 Available from

httpwwwplosoneorgarticleinfo3Adoi2F1013712

Fjournalpone0026790

15) Rossi M Carpi A Skin microcirculation in peripheral arterial

obliterative disease Biomed Pharmacother 2004 58 427-31

186 한 환자의학회지제 27 권 제 3 호 2012

2008 Intensive Care Med 2008 34 17-60

2) Molos MA Hall JC Symmetrical peripheral gangrene and dis-

seminated intravascular coagulation Arch Dermatol 1985

121 1057-61

3) Duumlnser MW Mayr AJ Tuumlr A Pajk W Barbara F Knotzer

H et al Ischemic skin lesions as a complication of continuous

vasopressin infusion in catecholamine-resistant vasodilatory

shock incidence and risk factors Crit Care Med 2003 31

1394-8

4) Kahn JM Kress JP Hall JB Skin necrosis after extravasation

of low-dose vasopressin administered for septic shock Crit

Care Med 2002 30 1899-901

5) Hayes MA Yau EH Hinds CJ Watson JD Symmetrical pe-

ripheral gangrene association with noradrenaline administra-

tion Intensive Care Med 1992 18 433-6

6) Bonamigo RR Razera F Cartell A Extensive skin necrosis

following use of noradrenaline and dopamine J Eur Acad

Dermatol Venereol 2007 21 565-6

7) Kim EH Lee SH Byun SW Kang HS Koo DH Park HG

et al Skin necrosis after a low-dose vasopressin infusion

through a central venous catheter for treating septic shock

Korean J Intern Med 2006 21 287-90

8) Overgaard CB Dzaviacutek V Inotropes and vasopressors review

of physiology and clinical use in cardiovascular disease

Circulation 2008 118 1047-56

9) Donnellan F Cullen G Hegarty JE McCormick PA

Ischaemic complications of Glypressin in liver disease a case

series Br J Clin Pharmacol 2007 64 550-2

10) Holmes CL Patel BM Russell JA Walley KR Physiology

of vasopressin relevant to management of septic shock Chest

2001 120 989-1002

11) Yefet E Gershovich M Farber E Soboh S Extensive epi-

dermal necrosis due to terlipressin Isr Med Assoc J 2011 13

180-1

12) Kingston ME Mackey D Skin clues in the diagnosis of

life-threatening infections Rev Infect Dis 1986 8 1-11

13) Castellanos-Ortega A Suberviola B Garciacutea-Astudillo LA

Holanda MS Ortiz F Llorca J et al Impact of the Surviving

Sepsis Campaign protocols on hospital length of stay and mor-

tality in septic shock patients results of a three-year follow-up

quasi-experimental study Crit Care Med 2010 38 1036-43

14) Shiramizo SC Marra AR Duratildeo MS Paes AcircT Edmond MB

Pavatildeo dos Santos OF Decreasing mortality in severe sepsis

and septic shock patients by implementing a sepsis bundle in

a hospital setting PLoS One 2011 6 e26790 Available from

httpwwwplosoneorgarticleinfo3Adoi2F1013712

Fjournalpone0026790

15) Rossi M Carpi A Skin microcirculation in peripheral arterial

obliterative disease Biomed Pharmacother 2004 58 427-31