Korean J Crit Care Med ■증 례■2012 August 27(3):182-186 / http://dx.doi.org/10.4266/kjccm.2012.27.3.182

182

Skin Necrosis after High Dose Vasopressor Infusion in Septic Shock

Two Case Reports Ah-Reum Cho, M.D., Jeung-Il Kim, M.D.*

,†,

Eun-Jung Kim, M.D. and Seung-Min Son, M.D.*

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

†Department 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) ≥ 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 1.0－2.0 μg/kg/min and vasopressin 0.03－0.1 U/min were infused for 5

days; in the second case, dopamine 10－20 μg/kg/min and norepinephrine 0.25－2.5 μg/kg/min 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: osteokim@yahoo.co.kr

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 “Survival Sepsis Campaign: International guidelines for

management of severe sepsis and septic shock”.[1] They rec-

ommend that vasopressor therapy is required to maintain mean

arterial pressure (MAP) ≥ 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 ≥ 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 ≥ 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 patient’s 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 (60/40 mmHg), tachy-

cardia (125 beats/min), tachypnea (40 breats/min), and hypo-

xemia (SpO2 88%). In accordance with the Surviving Sepsis

Campaign guidelines, he was treated with fluid resuscitation.

Ah-Reum Cho, et al：Skin 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 1.0μg/kg/min 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 2.0μg/kg/min, his MAP lev-

el still remained indicative of hypotension. We began an in-

fusion of vasopressin 0.03 U/min through the central venous

catheter and increased the dose up to 0.1 U/min 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 80/50

mmHg, heart rate 100－130 beats/min, and CVP 14－16 mmHg

despite fluid resuscitation. Norepinephrine (0.25－2.5μg/kg/

min) and dopamine (10－20μg/kg/min) 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 대한중환자의학회지：제 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 al：Skin 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 2.0－20μg/kg/min,

0.01－3.0μg/kg/min, and 0.01－0.1 U/min, 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 1.0－2.0μg/kg/min and

vasopressin 0.03－0.1 U/min were infused for 5 days, whereas,

in the second case, dopamine 10－20μg/kg/min and nor-

epinephrine 0.25－2.5μg/kg/min 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.[5-7,9] 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-

tient’s 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.[5-7,9] 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.[13,14] In Spain, a three-year

follow-up quasi-experimental study with a historical comparison

group found that achieving ScvO2 ≥ 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.

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

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3) Dünser MW, Mayr AJ, Tür A, Pajk W, Barbara F, Knotzer

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