Korean J Crit Care Med

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

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.

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-
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.
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.

182
 Ah-Reum Cho, et al：Skin Necrosis after High Dose Vasopressor Infusion
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
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).
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
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
Fig. 2. Norepnephrine and dopamine-
induced dry gangrene only
appear on the fingertips and
toes (A－C). They were all
amputated (D－F).
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
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
185
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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