Author: Adrianna Long, MD (Senior EM Resident at SAUSHEC, US Army) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital) and Brit Long, MD (EM Chief Resident at SAUSHEC, USAF)

A 74 year-old female is brought in by ambulance from a rehabilitation facility with a chief complaint of confusion and vomiting for the past day. Her husband reports that she is normally alert and oriented but has been more confused over the past day. She is in rehabilitation after a fall three weeks ago when she sustained a fracture to her left hip.

Her initial vital signs include temperature of 100.5°F, pulse of 114, blood pressure 76/34 mmHg (mean arterial pressure 48 mmHg), respiratory rate of 22, and saturating 98% on room air. Exam reveals suprapubic tenderness and right sided costovertebral angle tenderness. Laboratory values reveal leukocytosis with 18,200 WBCs, BUN/sCr of 32/1.6 and all other values within normal limits. The patient has frank pyuria with urinalysis markedly positive for nitrites, WBCs, RBCs, and bacteria.

You recognize that your patient is in septic shock due to a urinary tract infection, so you order an IV fluid bolus and initiate antibiotic therapy. With recognition that this patient already has poor renal function and a decreased MAP, when should you consider starting a vasopressor?

The true goal seems to be targeting the MAP

The current recommendations from the Surviving Sepsis Campaign are to maintain a MAP ≥ 65 mmHg (Level 1C).1 However, the current evidence does not indicate subsets of patients that may need to be treated differently (i.e. patients with chronic hypertension, patients with history of renal disease, etc.). Here are the studies available regarding MAP and septic shock:

A retrospective study of 274 septic shock patients indicated that one or more episodes of MAP decreased less than 60 mmHg was associated with an increased risk of death by 2.96. Further, one or more episode of MAP decreased less than 75 mmHg increased the need for renal replacement therapy. 2

A prospective study on 10 patients with septic shock aimed to titrate norepinephrine to target a MAP of 65, 75 and 85 mmHg. There was no significant difference found in the serum lactate, UOP, skin capillary blood flow, or red blood cell velocity as the MAP increased higher than 65mmHg. 3

Another prospective study of 28 patients with septic shock treated half of the patients with norepinephrine to target a MAP of 65 mmHg and the other half with norepinephrine to target a MAP of 85 mmHg, showing no significant difference in urine output or creatinine clearance. 4

In 2014, a large prospective study of 776 septic shock patients targeted MAPs of 65 to 70 mmHg or 80 to 85 mmHg and found no significant difference in 28- or 90-day mortality. This study did indicate that the patients with targeted MAPs of 80 to 85 mmHg were found to have increased risk of new onset atrial fibrillation, were on vasopressors longer, and required higher doses of norepinephrine. 5

A retrospective study of 111 patients with septic shock found a strong correlation with mortality and duration of time spent below MAP 65 mmHg.6

Should we “fill the tank” first? Or when should we initiate vasopressor therapy?

The current guidelines require that patients be treated with 30cc/kg of IV fluid before being treated with vasoactive medications, but not all patients are responsive to IV fluids and studies indicate the vitality in starting norepinephrine early.

A retrospective study of 2,849 septic shock patients found that mortality was lowest when vasoactive agents were begun 1-6 hours after onset . 7

. A retrospective study of 213 patients found that every hour of delayed treatment with norepinephrine was associated with 5.3% increased mortality . They also found that when norepinephrine was started within 2 hours of diagnosis of septic shock, patients were more likely to have increased MAPs, decreased serial serum lactates, and shorter duration of norepinephrine. 8

. They also found that when norepinephrine was started within 2 hours of diagnosis of septic shock, patients were more likely to have increased MAPs, decreased serial serum lactates, and shorter duration of norepinephrine. A retrospective study in 2004 of 142 patients showed that norepinephrine started early may have some benefit.9

The basic theory behind giving IV fluids prior to vasopressors is that septic patients are often intravascularly volume depleted due to third-space losses, and there is concern that arterial constriction alone could impair perfusion. However, not all patients in septic shock are volume-depleted causing decreased perfusion. There are several factors that may lead to hypoperfusion in a septic patient to include venodilation, arterial dilation, cardiomyopathy, cor pulmonale, renal failure, in addition to dehydration/intravascular depletion. When initiating IV fluids, we are only treating one of these issues. Further, excess volume status is correlated with renal failure and increased mortality in shock patients.10 It is much more reasonable to address the patient’s physiological state especially assessing volume status prior to blindly treating with IV fluids and delaying treatment with vasopressors.

What is the problem in waiting to start vasopressors?

Renal and pulmonary injuries may be the result of delayed initiation of vasopressors, affecting morbidity and mortality. The kidneys are prone to experiencing hypoperfusion as a result of shock status.11 Renal injury is associated with septic shock and hypotension, which may be reduced with the use of norepinephrine and decrease the risk of renal failure.5,10 Also, patients who are resuscitated for septic shock often have resulting pulmonary edema, which may be the result of volume overload or the result of cytokine release with renal injury.12 Patients who suffer renal injury often have long-term sequelae as a result, including increased risk of chronic renal failure and end stage renal disease.13 The RIFLE classification for renal injury shows a clear increase in mortality with worsened renal failure.14

Can vasoactive drugs be given peripherally?

One barrier to starting vasoactive agents early is the concern for a need to have a central line for infusion of these medications. This is another reason that many providers may still prefer the fluid-first approach.

However, it has been shown that norepinephrine may be given peripherally for a limited period of time while stabilizing the patient. There is risk for extravasation, which can be minimized with appropriate protocols, use of a well-functioning proximal intravenous catheter, and a goal to obtain central venous access as quickly as possible. Intraosseous infusion of norepinephrine is also temporarily permissible with verification that the line has been placed appropriately.15

One benefit to starting vasoactive drugs peripherally is that they can be infused simultaneously with intravenous fluids to target an adequate MAP. If a patient is fluid responsive, the norepinephrine may be titrated down and potentially discontinued before central access is obtained.

More evidence is needed to make appropriate recommendations regarding the initiation of early vasopressor therapy and who would benefit.

In a patient who presents with MAPs less than 65 mmHg, it is unknown how quickly those patients should reach that target MAP to avoid renal injury. The data indicates that hypotension should be avoided to prevent hypoperfusion of the kidneys, but are there specific patients that are at higher risk for renal injury? Is there a rate at which we should be increasing MAP or a specific amount of time that the blood pressure must be corrected? The data and recommendations only indicate that we should urgently address a septic shock patient with a MAP less than 65 mmHg.

The studies that have been published regarding delay to vasopressor initiation and outcome are all retrospective and correlate time of onset with outcomes, but are all likely to have confounding variables. Subramanian et al found a trend toward increased mortality with initiation of early vasopressors, which was not significant.16 Beck et al found a correlation between early vasopressors and improved mortality.17 Waechter et al found that it may be detrimental to start vasoactive agents within the first hour after shock onset, but vasopressors started within 1-6 hours had the lowest mortality rates.7 Bai et al found an association between early norepinephrine and survival.8 Interestingly, Beck and Waechter used the same database of patients with the same research group and had differing results. Only one of these studies used norepinephrine only, while the others used a variety of vasoactive medications. This makes some question the clinical significance of these studies with regards to Emergency Department treatment because we are primarily concerned about the early use of norepinephrine.

Currently, the CENSER study is being performed, which is the first prospective randomized controlled trial to evaluate the use of early norepinephrine in septic shock with a control group of 5% dextrose water intravenous infusion. This study is not expected to finish until August 2017.18

Conclusions

Vital signs are vital ! Drops in blood pressure lead to increased mortality, and blood pressure may not respond simply to fluids.

! Drops in blood pressure lead to increased mortality, and blood pressure may not respond simply to fluids. Vasopressors should be started early in septic shock patients, but there is controversy as to how early and what subsets of patients would benefit most due to a lack of evidence currently available.

due to a lack of evidence currently available. Delaying norepinephrine in a septic shock patient with a low MAP while first attempting to fluid resuscitate may increase morbidity and mortality, but further studies must be conducted to confirm this.

A drop in MAP causes renal hypoperfusion and renal injury contributing to further complications and possibly worsening shock.

and possibly worsening shock. It is essential to assess your patient’s fluid status and weigh the risk of renal injury when considering initiation of vasopressor therapy.

References / Further Reading

Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41(2):580-637. Dunser MW, Takala J, Ulmer H, et al. Arterial blood pressure during early sepsis and outcome. Intensive Care Med. 2009;35(7):1225-1233. LeDoux D, Astiz ME, Carpati CM, Rackow EC. Effects of perfusion pressure on tissue perfusion in septic shock. Crit Care Med. 2000;28(8):2729-2732. Bourgoin A, Leone M, Delmas A, Garnier F, Albanese J, Martin C. Increasing mean arterial pressure in patients with septic shock: effects on oxygen variables and renal function. Crit Care Med. 2005;33(4):780-786. Asfar P, Meziani F, Hamel JF, et al. High versus low blood-pressure target in patients with septic shock. N Engl J Med. 2014;370(17):1583-1593. Varpula M, Tallgren M, Saukkonen K, Voipio-Pulkki LM, Pettila V. Hemodynamic variables related to outcome in septic shock. Intensive Care Med. 2005;31(8):1066-1071. Waechter J, Kumar A, Lapinsky SE, et al. Interaction between fluids and vasoactive agents on mortality in septic shock: a multicenter, observational study. Crit Care Med. 2014;42(10):2158-2168. Bai X, Yu W, Ji W, et al. Early versus delayed administration of norepinephrine in patients with septic shock. Crit Care. 2014;18(5):532. Morimatsu H, Singh K, Uchino S, Bellomo R, Hart G. Early and exclusive use of norepinephrine in septic shock. Resuscitation. 2004;62(2):249-254. Bellomo R, Wan L, May C. Vasoactive drugs and acute kidney injury. Crit Care Med. 2008;36(4 Suppl):S179-186. Lehman LW, Saeed M, Moody G, Mark R. Hypotension as a Risk Factor for Acute Kidney Injury in ICU Patients. Comput Cardiol (2010). 2010;37:1095-1098. Basu RK, Wheeler D. Effects of ischemic acute kidney injury on lung water balance: nephrogenic pulmonary edema? Pulm Med. 2011;2011:414253. Chawla LS, Kimmel PL. Acute kidney injury and chronic kidney disease: an integrated clinical syndrome. Kidney Int. 2012;82(5):516-524. Ricci Z, Cruz D, Ronco C. The RIFLE criteria and mortality in acute kidney injury: A systematic review. Kidney Int. 2008;73(5):538-546. Weingart S. Podcast 107 – Peripheral Vasopressor Infusions and Extravasation. Emcrit. 2013.http://emcrit.org/podcasts/peripheral-vasopressors-extravasation/ Subramanian S, Yilmaz M, Rehman A, Hubmayr RD, Afessa B, Gajic O. Liberal vs. conservative vasopressor use to maintain mean arterial blood pressure during resuscitation of septic shock: an observational study. Intensive Care Med. 2008;34(1):157-162. Beck V, Chateau D, Bryson GL, et al. Timing of vasopressor initiation and mortality in septic shock: a cohort study. Crit Care. 2014;18(3):R97. Permpikul C. Early Use of Norepinephrine in Septic Shock Resuscitation (CENSER). https://clinicaltrials.gov/ct2/show/study/NCT01945983#contacts.