By Drayton Hammond, PharmD, MBA, BCPS, BCCCP

Clinical Pharmacy Specialist, Adult Critical Care, Rush University Medical Center, Chicago

Dr. Hammond reports no financial relationships relevant to this field of study.

Septic shock is associated with significant costs and sequelae, as well as mortality rates of 20-50%.1 Current management of septic shock includes early administration of intravenous fluids, antimicrobial agents, and vasopressor support. While norepinephrine is recommended as the first-line vasopressor for septic shock in the 2016 Surviving Sepsis Campaign guidelines, vasopressin is a second-line vasopressor option that may be added to norepinephrine to reduce catecholamine requirements and achieve a target mean arterial pressure (MAP).2,3

Patients with catecholamine-refractory septic shock often are sensitive to exogenous vasopressin administration.4 Plasma vasopressin concentrations initially increase in response to relative hypotension and decreased vascular resistance but decline within six to 36 hours to sub-physiological concentrations because endogenous vasopressin stores have been depleted. The synthesis and release of vasopressin may be impaired for up to seven days after septic shock onset.5 Despite the potential benefits to resolving this relative vasopressin-deficient state, many controversies still exist regarding vasopressin use in septic shock.

Timing Of Vasopressin Initiation

The timing of vasopressin initiation may play a crucial role in septic shock management. The Vasopressin in Septic Shock Trial (VASST) found that administering vasopressin within 12 hours following norepinephrine initiation compared to remaining on norepinephrine monotherapy had a similar rate of 28-day mortality in the full trial cohort (35.4% vs. 39.3%; P = 0.26). However, in a subgroup of patients with less severe septic shock (norepinephrine infusion rate ≤ 14 mcg/min), patients in the vasopressin group had a lower mortality at 28 days (27% vs. 36%; P = 0.05).5 Because this benefit was found in a subgroup analysis of VASST, and vasopressin initiation could have been provided earlier in clinical care, additional studies have investigated the effects of earlier vs. later vasopressin addition to catecholamine vasopressors.6-9

In a retrospective, single-center study (n = 72), researchers investigated the effects of vasopressin that was administered earlier (within six hours of catecholamine vasopressor initiation) vs. later (between six and 48 hours of catecholamine vasopressor initiation).6 Shock duration and catecholamine vasopressor requirements were similar between groups, although patients receiving earlier initiation of vasopressin experienced a new-onset arrhythmia less frequently (37% vs. 64%; P = 0.001). In another retrospective study (n = 96), researchers observed that earlier vasopressin initiation (within four hours of septic shock recognition) was associated with reduced time to achieve and maintain a MAP of 65 mmHg for at least four hours (six vs. 10 hours; P = 0.02) and greater reductions in Sequential Organ Failure Assessment (SOFA) scores at 72 hours (-4 vs. -1; P = 0.01).7 The incidence of new-onset arrhythmia was similar between groups, although only arrhythmias requiring clinical intervention were compared. The reduced time to achieve and maintain target MAP was confirmed in a trial at the same institution.8 Conversely, in a pre-post study that evaluated the effects of a restriction on vasopressin use to patients receiving greater than 50 mcg/min of norepinephrine as opposed to greater than 10 mcg/min of norepinephrine, researchers did not observe a difference in time to achieve a MAP of 65 mmHg for one hour, new-onset arrhythmia, or ICU and hospital mortality rates.9 Finally, the Vasopressin vs. Norepinephrine as Initial therapy in Septic Shock (VANISH) trial also showed no mortality benefit from earlier vasopressin therapy (within six hours of shock recognition), although the primary outcome was focused on kidney failure-free days within a 28-day period after randomization.10 Most patients in the vasopressin group were receiving concomitant norepinephrine.

Although earlier use of vasopressin does not appear to confer a mortality benefit compared to later use, the optimal time to initiate vasopressin remains unknown. This is especially relevant in the era of personalized medicine. Plasma vasopressin levels could guide vasopressin therapy by targeting physiologic levels while avoiding higher concentrations that could lead to adverse effects. However, measurement of plasma vasopressin levels is challenging because vasopressin has a short half-life, is unstable ex-vivo, and requires a cumbersome analytical process for measurement.11 Although copeptin, the C-terminal of a vasopressin precursor, is stable in plasma, easier to measure than vasopressin, and correlates well with vasopressin plasma concentration, its use may be inadequate in select clinical scenarios, such as in patients receiving veno-venous hemofiltration.12,13 The clinical utility of measuring vasopressin or copeptin levels in septic shock requires further investigation.14

Range for Vasopressin Dosing

The optimal vasopressin dosage that facilitates adequate hemodynamic response while limiting adverse effects remains controversial. The 2016 Surviving Sepsis Campaign guidelines recommend a maximum vasopressin rate of 0.03 units/minute because higher rates may increase the risk of limb, digital, and mesenteric ischemia.3,15 Ischemic skin lesions with vasopressin have been reported with doses approaching 0.06 to 0.09 units/min in 70-100 kg patients.16 A prospective, randomized, controlled trial compared lower (0.033 units/minute) and higher (0.067 units/minute) vasopressin dosages (n = 50) in septic shock requiring norepinephrine rates greater than 0.6 mcg/kg/minute.17 Patients in the higher-dose vasopressin group had lower norepinephrine requirements at 48 hours (0.22 ± 0.16 vs. 0.4 ± 0.31 mcg/kg/minute, P = 0.006). Vasopressin serum concentrations were higher in the high-dose group, but were elevated in both groups. Despite this, adverse events were similar between groups, although digital ischemia was not evaluated.17 Patients who received vasopressin in the VANISH trial were exposed to 0.01 to 0.06 units/minute of vasopressin, which was up to twice the rate used in VASST.5,10 The VANISH trial did not detect a mortality benefit from the higher vasopressin dosage and reported a numerically greater incidence of digital ischemia in the vasopressin group (5% vs. 1.5%, 97.5% confidence interval [CI], for risk difference -0.1 to 7.9).

As a general practice, lower-dose vasopressin (e.g., 0.03 units/minute) should be initiated in septic shock and may be titrated to the lowest dosage at which an adequate hemodynamic response is observed.5,18-21 Vasopressin has an apparent half-life of less than 10 minutes, which necessitates a slower titration strategy (i.e., every 30-50 minutes) than catecholamine vasopressors that have half-lives of less than two minutes. The optimal target plasma vasopressin concentration in septic shock remains controversial, with physiologic and supraphysiologic targets being considered at this time.22,23 Vasopressin provided as a continuous infusion at 0.03 units/minute has been proposed to achieve adequate serum vasopressin concentrations and decrease catecholamine vasopressor requirements without an increase in adverse events.5 Finally, vasopressin dosages up to 0.06 units/minute should be reserved for consideration in patients with septic shock refractory to conventional vasopressor dosing.10 Close monitoring for adverse events, particularly reduced liver function, bradycardia, and digital ischemia, should be performed.

Fixed Vs. Weight-Based Vasopressin Dosing

Catecholamine vasopressors are titrated to a specific MAP goal and commonly are dosed based on a patient’s body weight. In contrast, vasopressin is conventionally administered as a fixed, non-weight-based dose continuous infusion. Dosing that is provided irrespective of body weight may predispose patients at each end of the weight spectrum to disparate vasopressin exposure, which may increase the odds for toxicity or decrease the odds for efficacy. Several retrospective evaluations have investigated the interaction between fixed-dose vasopressin and body weight.24-28

In a retrospective analysis of VASST comparing patients based on their body mass index (BMI) using actual body weight, researchers observed that overweight (25 < BMI < 30 kg/m2) and obese (BMI ≥ 30 kg/m2) patients had numerically lower vasopressin serum concentrations at 72 hours after vasopressin infusion initiation (overweight 51.5 ± 16.5 pmol/L and obese 28.9 ± 7.9 pmol/L) compared with under- or usual-weight (BMI < 25 kg/m2) patients (69.9 ± 17.5 pmol/L; P = 0.08).30 The authors also discovered that obese patients had the lowest 28-day mortality, followed by overweight patients, then under- and usual-patients (P = 0.02).24 In another retrospective analysis of 64 patients receiving vasopressin, primarily at a rate of 0.04 units/minute, investigators observed a significant positive correlation between catecholamine vasopressor requirements at two and four hours and vasopressin dosage adjusted for body weight (correlation coefficient -0.36; P = 0.03 and -0.46; P < 0.01, respectively).25 In this analysis, the dosage of vasopressin adjusted for body weight ranged from 0.229 to 0.871 micro-units/kg/minute. However, in a retrospective, single-center study of 40 medical ICU patients with septic shock receiving fixed-dose vasopressin, researchers found no correlation between body weight and change in MAP one hour after vasopressin initiation.26 Although a significant correlation between BMI and change in MAP at six hours was seen in patients with a BMI ≥ 30 kg/m2 (correlation coefficient r = −0.951; P =0.0009); this was not seen at one or 12 hours (r = −0.487, P = 0.24 and r = −0.243, P = 0.53, respectively).

In the largest retrospective cohort study (n = 938) evaluating this correlation to date, researchers showed that adjusting vasopressin dosing based on weight and BMI did not affect vasopressor requirements or change in MAP.27 Weight-based vasopressin dosing did not affect mechanical ventilation duration, ICU-free days, or mortality. This confirmed the results of a previous analysis performed by the same authors.28 Data are conflicting regarding vasopressin weight-based dosing, particularly in overweight and obese patients. Currently, it may be most appropriate not to exceed studied vasopressin dosages in these patients.

Vasopressin Discontinuation in Resolving Septic Shock

Patients in early septic shock who have been resuscitated and stabilized adequately transition to the maintenance phase.29 In the maintenance phase, appropriate vascular tone is maintained with sufficient intravascular volume and vasoactive support. Eventually, an inflection point is reached when endogenous restoration of vascular tone and cardiac function begin to return close to baseline, signaling transition into the recovery phase of septic shock.30 However, this transition occurs at different time points for patients and often is dependent on patient- and treatment-specific factors, including time to achieve and maintain adequate end-organ perfusion, appropriateness of source control, and antimicrobial therapy.8,31-33 Intravenous vasopressors are titrated down and, as able, discontinued during the recovery phase, which often necessitates a decision of whether norepinephrine or vasopressin is most appropriate as the final vasopressor for hemodynamic support.7,34-38

The authors of a recent systematic review and meta-analysis evaluated the effects of penultimate discontinuation of vasopressin or norepinephrine in critically ill adults with resolving septic shock.39 Penultimate discontinuation of norepinephrine compared to vasopressin resulted in a lower incidence and odds of clinically significant hypotension in the meta-analyses at the patient and study level. The difference in hypotension did not translate into differences in the short-term mortality or length of stay in the ICU and hospital from vasopressor discontinuation. In the largest study included in the meta-analysis (n = 585), researchers actually observed a similar incidence of hypotension within 24 hours of penultimate vasopressor discontinuation (vasopressin 55% vs. norepinephrine 50%, P = 0.28).37 However, the four other retrospective, cohort studies supported the hypothesis that penultimate discontinuation of vasopressin resulted in a greater incidence of clinically significant hypotension.7,34-36 There were no standard practices for vasoactive agent discontinuation in the studies. Additionally, a high degree of heterogeneity existed between studies, although this was mitigated in the meta-analysis through the use of random effects modeling.39 The only other outcomes that appeared to be different between groups were the durations of vasopressin and norepinephrine infusions, with the penultimately discontinued agent having a shorter infusion duration.

The duration of septic shock and restoration of the vasopressinergic system appear to be two factors that affect the likelihood of hypotension development following vasopressin discontinuation. In the largest study, researchers observed that penultimate discontinuation of vasopressin was independently associated with an increased hypotension risk with a time-varying effect that decreased over time, suggesting earlier vasopressin discontinuation was more likely to result in hypotension.37 This phenomenon also was observed when data from two other observational cohort studies were combined and stratified by vasopressin duration of less than or greater than 48 hours.33,35,40,41 The hypothesis that hypotension resulted because the vasopressinergic system was not restored adequately this early in septic shock was tested in a randomized, controlled trial of vasoactive agent discontinuation practices.38 Copeptin was measured in patients who discontinued vasopressin or norepinephrine in the maintenance or resolving phase of septic shock. Patients who had an elevated serum copeptin concentration were less likely to develop hypotension, suggesting restoration of the vasopressinergic system activity could be used to predict the likelihood of hypotension development. Additionally, vasopressin was weaned off rather than discontinued from the treatment dose (e.g., 0.03 or 0.04 units/minute) in the two studies in which researchers did not observe greater hypotension with penultimate vasopressin discontinuation.38,39 This practice may be an indirect method for stress-testing restoration of the vasopressinergic system and tolerance for vasopressin discontinuation. In the absence of clinical benefit beyond possibly reduced hypotension development with penultimate norepinephrine discontinuation and the rising cost of vasopressin, weaning off vasopressin before discontinuing norepinephrine during the resolving phase of septic shock may be prudent.42

Conclusion

Norepinephrine remains the first-line vasopressor in septic shock, although vasopressin may be initiated with potential benefits associated with earlier initiation. Vasopressin dosages may exceed 0.03 units in refractory septic shock, although benefits may not outweigh risks in some patients. Additionally, vasopressin may be titrated to an effect in many patients and weaned off in patients who do not respond to it or in the resolving phase of septic shock. Weight-based vasopressin dosing does not appear to confer benefits in most weight classifications. Further studies are needed to identify the patient populations that would benefit most from vasopressin use.

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