Because the severity of hypotension is associated with adverse outcomes in critically ill patients (1), physicians prescribe vasopressors under the assumption that increasing arterial blood pressure improves tissue perfusion (2, 3). In septic shock, hypotension is largely attributable to pathological vasodilation (4), and vasopressors constitute a mainstay of therapy (2). Animal studies suggest that coronary, renal, and cerebral blood flow autoregulation is lost with mean arterial pressures (MAPs) below 60 mmHg (5, 6). Although ensuring that MAP remains above this threshold seems to prevent intestinal injury in previously healthy children undergoing surgery (7), experts have highlighted the somewhat arbitrary nature of these targets and point out that systolic blood pressure values or MAPs between 50 and 60 mmHg are also used to guide vasopressor use (8). Guidelines recommend titrating vasopressors to a target MAP of 65 mmHg or more (9, 10), acknowledging that the quality of the evidence supporting this recommendation is weak (GRADE 1C) (10).
The risks of vasopressor-associated adverse effects, such as visceral ischemia (11, 12), must be weighed carefully against the danger of under-resuscitating hypotensive patients. Correcting hypotension with vasopressors while tissue dysoxia persists may worsen outcomes (13). A recent survey of Canadian intensivists suggests that “usual care” regarding vasopressor use in sepsis is highly variable, especially when treating patients with comorbidities (14). Faced with similar clinical scenarios, intensivists adopt different strategies regarding vasopressor dosing.
Systematic reviews integrate existing information for rational decision making (15). Even when available data do not provide clear guidance, explicit methods improve the reliability of their conclusions. Although expert opinions may also guide clinical decisions, they may be discordant with best evidence (16). We undertook a systematic review of clinical studies evaluating different blood pressure targets for the dosing of vasopressors in septic shock. The research question was “Do higher blood pressure targets for vasopressor therapy impact mortality in patients with septic shock?”
The design and reporting of this systematic review followed the PRISMA guidelines (see Supplemental Digital Content 1 at http://links.lww.com/SHK/A281).
Search strategy and study selection
With the assistance of a medical librarian, we developed a search strategy for the electronic databases MEDLINE, EMBASE, and CENTRAL from each database’s inception to November 2013 without any language restriction. Database-specific subject headings and corresponding key words for sepsis and septic shock were entered and combined with subject headings and key words for vasopressors (see Supplemental Digital Content 2 at http://links.lww.com/SHK/A282). Adequate sensitivity of the search strategy was demonstrated by verifying that it captured studies previously identified as relevant from a broad scoping review. In addition to clinical trials, we sought observational studies reporting associations between blood pressure targets (as opposed to blood pressure values) and clinical outcomes but excluded other noninterventional studies (care reports, case series). Two reviewers independently screened abstracts for potentially relevant studies; the full text publication of any citation considered relevant by either reviewer was retrieved. The two reviewers read all potentially relevant publications and selected randomized controlled trials (RCTs), crossover intervention studies, and observational studies evaluating the impact of blood pressure targets on patients with septic shock. Blood pressure targets, as opposed to observed blood pressure values or vasopressor doses, reflect intentional therapeutic strategies. Accordingly, we excluded observational studies reporting associations between clinical outcomes and either observed vasopressor doses or blood pressure because these associations are prone to residual confounding. We also excluded comparisons between different agents titrated to the same resuscitation end points, comparisons among different baseline preresuscitation clinical states, and comparisons between fixed doses of the same drug. We considered studies enrolling patients of any age and used the authors’ definitions of septic shock. In addition, reviewers scanned the references of included studies for additional eligible studies and searched www.clinicaltrials.gov for unpublished studies. Disagreements on article selection were resolved in consultation with a third reviewer.
Data extraction and analysis
Using pretested standardized forms, two reviewers independently abstracted data from each included study. Forms captured information related to study design, risk of bias, and results. We contacted the investigators of one RCT because the original study report did not include parallel arm comparisons (17). For the purpose of this systematic review, this study was treated as a crossover trial. When studies examined more than two blood pressure targets, we used the lowest and highest blood pressure targets for the meta-analytical comparison. When pooling crossover trials, we did not account for the pairing of data (correlation coefficient between comparisons equals zero). In the absence of studies reporting the SD of mean differences in relevant crossovers studies, this is the most conservative statistical assumption. We also did not consider possible interactions between treatment effect and treatment order.
We assessed the risk of bias in RCTs using the Cochrane Collaboration toolkit (18). Specifically, we determined whether the investigators randomized and concealed treatment allocation, blinded study personnel, obtained complete outcome data, and avoided selective reporting. For risk of bias assessment in crossover trials, we derived explicit criteria from the recommendations of the EPOC (Effective Practice and Organisation of Care) Cochrane Group (19). Specifically, we assessed randomization and concealment of the treatment allocation sequence, blinding of study personnel, likelihood that the medical condition would remain stable during the experiment, incomplete outcome data, selective reporting, prespecification of the primary outcome, and expected effect. We assessed the risk of bias across studies following the previously cited GRADE approach (20) for 28-day mortality, atrial fibrillation, initiation of renal replacement therapy, cardiac index, heart rate, and blood lactate levels. We used funnel plots of standard error of treatment effect vs. treatment effect to assess the risk of publication bias.
Mortality and other clinical outcomes were reported in only one RCT. For secondary physiological outcomes reported in crossover trials, we pooled results for outcomes selected based on their clinical relevance under standard care conditions. Thus, we summarized mean differences (MDs) in cardiac index, heart rate, and blood lactate levels between patients treated with higher versus lower blood pressure targets.
Statistical pooling using a random-effects model (inverse variance method) was conducted with Review Manager (version 5.2). We describe statistical heterogeneity with the I2 statistic. We did not plan subgroup analyses a priori. Post hoc, we explored whether certain study characteristics could explain statistical heterogeneity observed in the meta-analysis for cardiac index. Available candidate explanatory variables were admission APACHE II (Acute Physiology And Chronic Health Evaluation II) scores of more than 25, difference in target mean arterial blood pressure of more than 20 mmHg, total duration of the experiment of more than 120 min, propofol-based sedation, and full publication of study versus abstract only.
The initial literature search yielded 4,418 citations. After title and abstract review, we screened the full text of 67 publications and ultimately included two RCTs (21, 22) and 10 crossover trials (Fig. 1). Among the studies that we excluded because they did not compare resuscitation end points were observational and crossover studies that measured associations between dose of vasopressor therapy or severity of hypotension with clinical outcomes (23–25) or that compared different agents titrated to the same resuscitation end points (26–29). We also excluded studies that compared the effects of fixed doses of vasopressors (30–37) or of vasopressor therapy versus baseline status before resuscitation was initiated (38, 39). One observational study described prescribed blood pressure targets, but clinical outcomes were not reported (40); one study measured the immediate effects of vasopressors titrated to end points unrelated to blood pressure (41) and, another, to variable pre-illness blood pressure values (42). We identified only one additional ongoing trial comparing different blood pressure targets in shock (OVATION [Optimal Vasopressor Titration], NCT01800877) the study is not reported.
Important differences separate the two RCTs (Table 1). Suk et al. (21) enrolled 16 patients with septic shock within the first 6 h of diagnosis. The investigators adjusted norepinephrine infusions to achieve a MAP target of 65 mmHg in one group and 85 mmHg in the other for 8 h. However, the interpretation of this trial is challenged by the fact that neither achieved blood pressure nor norepinephrine dose differed between the two arms, suggesting poor protocol adherence or between-arm differences in illness severity. The other larger more recent trial enrolled 776 patients with septic shock within 6 h of vasopressor initiation (22). Patients received vasopressors to achieve a MAP of 65 to 70 mmHg or 80 to 85 mmHg. Although the choice of vasopressor was left to the treating team, norepinephrine was the most common agent. The primary outcome was 28-day mortality, but patients were followed until day 90. In this study, measured blood pressure and vasopressor doses were higher in the higher MAP.
One study enrolled 28 patients with septic shock and dysfunction of two or more organs and randomized them to receive norepinephrine to attain a MAP of 65 mmHg for 8 h (n = 14) or 65 mmHg for 4 h followed by 85 mmHg for 4 h (n = 14) (17). The publication of this parallel-arm clinical trial reports only before-after observations of physiological variables in the experimental arm. After contacting the investigators, we conducted parallel-arm comparisons and found no statistically significant differences at the end of this 8-h experiment. We therefore classified this study as a crossover trial.
All crossover trials were small. Sample sizes ranged from 8 to 32. In every experiment, adjustments in vasopressor doses hinged on MAP targets (Table 2). The median initial target was 65 mmHg, and the median maximal target was 85 mmHg. The duration of the study ranged between 10 and 405 min, and norepinephrine was uniformly used across all studies. Heart rate, cardiac index, and serum lactate were the most consistently reported outcomes. A number of studies also measured microcirculatory blood flow.
Risk of bias was high in the smallest RCT (21) because of the lack of allocation concealment and blinding of outcome assessors (Table 1). Although the larger RCT (22) was also unblinded, the primary outcome could not be biased by subjective assessments. For outcome assessments potentially influenced by knowledge of treatment allocation, like the need for renal replacement therapy, risk of bias is high (Table 3).
Overall, risk of bias was high in crossover trials because of lack of randomization of the treatment sequence and unblinded outcome assessments (Table 4). Few studies prespecified a primary outcome and the expected effect. Also, confidence in the stability of the illness during the entire course of the experiment was low and observations could be attributable to changes in patients’ status across time rather than the intervention.
Randomized controlled trial results do not suggest that one blood pressure target is superior (Table 1). Suk et al. (21) reported no difference in cardiac index, diuresis, mixed venous oxygen saturation, lactate production, creatinine clearance, pH/base excess, hepatic blood flow, and gastric PCO2 gap. Asfar et al. (22) found no difference in mortality (hazard ratio 1.07 [0.89 – 1.29] at 28 days and hazard ratio 1.03 [0.88 – 1.22] at 90 days). However, the investigators reported a greater risk of atrial fibrillation in the higher MAP arm (6.7% vs. 2.8%, P = 0.02). Although the proportion of patients requiring renal replacement therapy was not different overall (33.5% vs. 35.8%, P = 0.5), the subgroup of patients with a history of hypertension required less renal replacement therapy during the first week of the trial (32% vs. 42%, P = 0.046).
The results of the crossover trials are summarized in Table 5. Pooled results suggest that achieving higher MAPs is associated with higher cardiac indices (MD, 0.65 L min−1 m−2; 95% CI, 0.2 – 1.1) and heart rates (MD, 5 beats min−1; 95% CI, 2 – 8) but not with significant changes in lactate levels, which were in the normal range or only mildly elevated (Fig. 2). The I2 statistic for cardiac index was 80%. Post hoc subgroup analyses based on experiment duration, propofol-based sedation, and publication status reduced statistical heterogeneity (see Supplemental Digital Contents 3, 4, and 5 at http://links.lww.com/SHK/A283, http://links.lww.com/SHK/A284, and http://links.lww.com/SHK/A285). Funnel plots suggest that the positive association between higher MAP targets and heart rate but not cardiac indices could be the result of publication bias (Fig. 3).
A summary of the available evidence for risk of death, atrial fibrillation, and requirement for renal replacement therapy appears in Table 6. Only one trial provides data for these clinical end points (22). In absolute terms, this trial shows that a MAP target of 80 to 85 mmHg could be associated with a large survival benefit (number needed to treat of 26) or significant harm (number needed to harm of 10). A summary of effects table for heart rate, cardiac index, and blood lactate level presents mean changes with higher blood pressure targets in crossover trials (Table 7).
The findings from this systematic review of clinical studies comparing the effects of different blood pressure targets for patients in septic shock neither support nor reject the current recommendation of the Surviving Sepsis Campaign (10). Out of three published clinical trials, only one addressed the effect of different blood pressure targets sustained during a course of many days and reported on clinical outcomes including mortality (22). However, this trial was underpowered to rule out a clinically important improvement in survival. Statistically significant differences in secondary outcomes suggest that benefit (lower risk of renal replacement therapy in chronically hypertensive patients) and harm (higher risk of atrial fibrillation) may result from setting higher blood pressure targets for vasopressors. Crossover experiments suggest that higher blood pressure targets are associated with faster heart rates and higher cardiac indices without short-term differences in lactate levels. These results apply to norepinephrine.
This review underscores the paucity of published clinical data to inform practice regarding vasopressor dosing. The strength of this work lies in the application of rigorous systematic review methodology to a clinically important but overlooked research question. Systematic reviews finding insufficient data to guide clinical practice underscore the uncertain effects of variation in usual practices. Nevertheless, our study has limitations. First, we focused on comparisons between blood pressure targets. Although some clinicians may titrate vasopressors to other physiologic end points, these alternative practices are less common and not incorporated in clinical practice guidelines. Second, the association between higher blood pressure targets and cardiac index varies considerably across crossover trials, suggesting that it may depend on specific study characteristics. Unfortunately, many potential explanatory variables were not measured in included studies. Post hoc subgroup analyses should be considered hypothesis generating. At this time, we cannot identify with certainty under what conditions this association exists. Third, although our search strategy for published studies was comprehensive, we cannot rule out publication bias. Funnel plots analysis suggests that the risk of publication bias is more likely to affect the positive association between blood pressure targets and heart rate. Fourth, we found no observational study directly addressing our research question, which highlights the paucity of the evidence informing vasopressor use. Cohort studies reporting associations between vasopressor doses or observed blood pressure values and clinical outcomes are subject to residual confounding and are not suitable to provide guidance for titration of vasopressors. Finally, given the limited experimental evidence in humans, a summary of preclinical data may be of interest. We opted to focus on clinical studies because the limited clinical relevance of animal experiments precludes any inference to clinical practice even when the results are compelling (43, 44).
Increasing research activity in this field reflects a growing interest in the question of optimal vasopressor dosing and provides context to our work. Our findings point to a paradox of contemporary critical care: fewer than 850 patients have been enrolled in clinical trials of blood pressure targets for septic shock, yet administration of vasopressors to the sickest patients in our hospitals occurs daily. Because strong recommendations for clinical care require concordant results from a number of clinical trials (10, 20), further research comparing the target recommended by the Surviving Sepsis Campaign with alternative dosing regimens is needed.
In addition to the data incorporated in this systematic review, our work highlights important questions that remain unaddressed. First, certain patient subgroups may require different blood pressure targets. Although the SEPSISPAM Trial addressed the potential effect modifier role of chronic hypertension (22), other preliminary data suggest that race could influence response to vasopressors (45). Second, as mentioned, the studies included herein used norepinephrine. Whether different blood pressure targets achieved with other vasopressors would have different effects may prove important. The different effects of dopamine and norepinephrine on mortality (46) could be specific to the dose that was necessary to achieve the blood pressure that was targeted. Using different blood pressure targets, the splanchnic preservation of dopamine (47, 48) may be achieved without the adverse cardiac effects. The effects of vasopressin analogs may also hinge on the blood pressure targets used in previous clinical trials. If these agents were used to target a higher blood pressure without increasing catecholamines, improvements in renal function may occur without an increased risk of cardiac arrhythmias. Terlipressin has been used safely in both adults and children (49–51). Third, specific practical methodological aspects of existing trials may influence study results. For example, radial arterial lines frequently underestimate central arterial pressure, which could lead to unnecessary upward titration of vasopressor doses (52). Fourth, what are the long-term effects (e.g., cognitive and physical function) of higher blood pressure targets and what outcomes (e.g., renal function versus atrial fibrillation) are most important to patients? And finally, considering that physicians frequently prescribe blood pressure targets but adjust these end points to other physiological variables, clinical trials comparing vasopressor dosing with different end points are lacking. Many studies report the prognostic value of lactate clearance and the feasibility of using real-time variations as markers of therapeutic success, even within normal range (9, 53, 54). Echocardiography (55) and near-infrared spectroscopy (56) may provide acceptable resuscitation end points. However, despite the limitations of gross resuscitation end points such as MAP (57), the superiority of these alternatives should be proven in rigorous clinical trials powered to show meaningful differences in important outcomes.
This systematic review underscores the paucity of clinical evidence to guide the common administration of vasopressors in critically ill patients with septic shock. Further rigorous research is needed to establish an evidence base for vasopressor administration in this population.
The authors thank Neera Bhatnagar, Claudio Martin, Lauralyn McIntyre, and Robert Green for their critical review of the manuscript and Nicolay Ferrari for his administrative support. This work was conducted without designated funding.
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