Which Types of Fluids Are More Effective in the Management of Sepsis

Sepsis can be defined as a life-threatening organ dysfunction, resulting from a dysregulated host response to infection (American journal of critical care, 2016). Sepsis and septic shock are common, pathophysiological complexes. These clinical conditions that are associated with high morbidity, mortality and cost of care(Mayr et al, 2014).Sepsis arises as an inflammatory response to infection and the results being organ dysfunction in cases of severe sepsis or circulatory shock, which have high morbidity and mortality rates for hospitalized patients (Cohen et al,2015).

Care bundles are a group of best evidence-based interventions which when instituted together gives maximum outcome benefit. The surviving sepsis campaign launched in 2004 and is aimed at improving diagnosis, management and survival of patients with sepsis. The surviving service campaign guidelines, in 2008, incorporated two sepsis care bundles. There are 2 severe sepsis bundles; sepsis resuscitation bundle and sepsis management bundle.

Case study

The following would be a scenario that best illustrates a sepsis occurrence. A 51-year-old female was admitted to the intensive care unit with Type 1 respiratory failure. Suspected sepsis screening tool was done in Accident and Emergency according to local policy and this case was escalated. She suffered from a cardiovascular problem thus very unstable with systolic blood pressure of lesser than 50 mm of Hg with low saturation. She started experiencing breath shortness, cold body temperatures and clammy extremities. An arterial line was inserted thus enabling hospital attendants observe her blood pressure and take arterial blood gas. A central line was also inserted to monitor the central venous pressure and administer drugs. Upon checking ABG, her PH was 7.24, p02-6, PC02-4, BE+/-OF 11.1, lactate of 6.1. Inotropes were started and lots of fluid boluses administered to remedy the situation. The hospital attendants decided to conduct emergency intubation as her condition became very unstable. They first conducted mechanical ventilation. Unfortunately she had cardiac arrest, deteriorated very suddenly and died.

This case is a clear illustration of a patient suffering from severe sepsis which eventually metamorphoses to fluid resistance resulting to a septic shock hence the fatality. Thus it is of essence for a treatment that manages the situation best.

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Sepsis is caused by an inflammatory immune response triggered by an infection (Seskesen et al, 2016). Most commonly, infection is bacterial, but it may also be fungal, viral or protozoan. Common locations for the primary infection include the lungs, brain, urinary tract, skin and abdominal organs.

There are two major ways of dealing with sepsis. First is the use of antibiotics and secondly, and the most popular, is the use of intravenous (IV) fluids Septic.org (accessed on 31st December 2019). Yet the question of which fluid to use and the quantity for every case and like circumstances still puzzles medical workers to date even though most health workers resort to either crystalloid or colloid fluids Semlar and Rice (2016).

Current guidelines for the management of patients with severe sepsis and septic shock recommend crystalloids as the initial fluid solution of choice in the resuscitation of these patients. In recent years there have been numerous studies published on this type of fluid used in the resuscitation of patients with sepsis (Journal of emergency medicine, 2017).Fluid resuscitation is a critical component in cases of emergency resuscitation of patients with severe sepsis and septic shock. IV fluids serve to increase intravascular volume, thereby augmenting cardiac output and improving tissue perfusion. In the early goal-directed therapy by Rivers and colleagues, patients randomized to the early goal-directed therapy group received more IV fluid within the initial 6 hours compared with those randomized to standard care. Although IV fluids are critical in sepsis resuscitation, there are variations in the choice of fluid used for resuscitation of these patients. Resuscitation fluids are commonly classified by their composition and whether they are crystalloid or colloid solution, as earlier highlighted. Thus it could be that for our case study above the clinicians conducted rote feeding of IV fluids without due regard to the specific effects they would have.

Evidence from randomized trials and meta-analysis (Gregory et al, 2019) have found no convincing difference between using albumin solution and crystalloid solution (e.g.: normal saline, ringer lactate) in the treatment of sepsis or septic shock. However, they have identified potential harm from using pentastarch or hydroxyethyl starch. There is no role for hypertonic saline. In our practice, we generally prefer a crystalloid solution over an albumin solution because of the higher cost of albumin. Moreover, there is no major difference in outcomes when either of them is used. However, some experts administer albumin as an additive or maintenance fluid if there is a perceived need to avoid or treat the hyper chloremia that occurs when large volume of crystalloids are administered. Although the data to support this practice is nigh. Among patients with sepsis, several randomized trials and meta-analysis have resulted into difference in mortality when albumin was used. However, one meta-analysis suggested there is a positive result in using albumin over crystalloid in those with septic shock.

In the saline versus albumin fluid evaluation trial performed in critically ill patients there was no benefit in albumin compared with saline. Even in a subgroup of patients with severe sepsis, who comprised 18 % of the total group, the same outcome was recorded. However, among the crystalloids there are no guidelines to suggest that one form is more beneficial than the other.

Randomized controlled trials (RCTS) were conduct to compare colloids to crystalloids in patients requiring volume replacement. Two authors independently extracted data and rated the quality of allocation conceived. We analysed the trials with a double intermission, such as those comparing colloid in hypertonic crystalloids to isotonic crystalloids separately. The statistics of the analysis according to colloid type and quality of allocation conceived were as follows. 74 eligible trials were made of which presented 66% mortality rate. Colloids compared to crystalloids albumin or plasma protein fraction. 24 trials reported data on mortality including a total of 9920 patients. The pooled relative risks (RR) from those trials were 1.01. We excluded the trials with poor quality allocation conceived hence the pooled RR was 1.00. Hydroxyethylstarch 21 trials compared to hydroxyethylstarch with crystalloids in 1385 patients. The pooled RR was 0.91 dextran where 4 trials compared dextran with a crystalloid on 834 patients. The pooled RR was 124 colloids in hypertonic crystalloids compared to isotonic crystalloids. 9 trials compared dextran in hypertonic crystalloids in 1985 randomized patients and the pooled RR was 0.91. There is no evidence from RCTS that resuscitation with colloids reduces the risk of death compared to resuscitation with crystalloids in patients with trauma or burns following surgery. As colloids are not associated with an improvement in survival of patients. Moreover, they are more expensive than crystalloids.

A medical literature review was completed to identify studies that investigate the type of resuscitation fluid in the management of patients with severe sepsis and septic shock. The articles involved were those published in between 2011-2016, enrolled human subjects and limited to the following types: randomized controlled trial, prospective observational trial, retrospective cohort trial and meta analyses. All articles then underwent review by authors. 9062 articles were identified in the search with 17 being selected for review. 11 of these original investigation and 6 were meta analysed and systemically reviewed. Crystalloids are the perfect fluids of emergency patients with severe sepsis and septic shock. Balanced crystalloids may improve patient cantered outcomes and should be considered as an alternate to normal saline if available. There is strong evidence that suggests that semisynthetic colloid decreases survival and should be avoided. The role of albumin in the resuscitation of a patient with sepsis and septic shock is uncertain.

Sharon et al, (2018) highlighted the effect of using crystalloids versus colloids in critically ill people requiring fluid volume replacement on mortality, need for blood transfusion or renal replacement therapy and adverse events. They included randomized controlled trials and quasi randomized controlled trials of critically ill people who required fluid replacement in hospital or emergency out of hospital settings. Participants had trauma, burns or medical conditions such as sepsis. Two review authors assessed studies and included 69 studies with 30,020 patients.28 studied starch solutions, 20 dextran, 7gelatinand 22 Albumin or FFP versus crystalloids. Sharon et al (2018) found moderate –certainty evidence that there is probably little or no difference between using starches or crystalloids in mortality. At the end of follow up in 11,177 participants spanning over 24studies the risk ratio (RR) was 0.97, 95% confidence interval (cl) 0.86 to 1.09. Within 90 days RR was 0.99, 95%cl 0.90-1.09 for 10,135 participants in 11 studies. Studies showed starches probably slightly increased the need for blood transfusion and renal replacement therapy with RR 1.30, 95% cl 1.14 to 1.48 for 852 participate in just 9 studies. There is little or no difference in allergic reaction, fewer incidence of itching with crystalloids and fewer incidences of rashes with crystalloids. Furthermore, studies found moderate –certainty evidence that there is probably little or no difference between using dextran or crystalloids in mortality at the end of follow up (RR 0.99, 95%CL 0.87TO 1.12 for 3,353 participants in 10 studies).It was uncertain whether the dextran/crystalloids reduce the need for blood transfusion and found little or no difference between groups I allergic reactions. Sharon et al (2018) also studied Albumin or FFP versus crystalloids and found moderate quality evidence that there is probably no difference between using Albumin, FFP or using crystalloids in mortality as at the end of follow up, RR 0.98, 95% cl 0.92 to 1.06 for 13,047 participants in 20 studies with 90 days. RR 0.98, 95% cl 0.92 to 1.04 for 12,492 participants in 2 studies with 90 days RR 0.98, 95% cl 0.93 to 1.06 for 12,506 participants in10 studies. It remains uncertain about the use of these fluids in renal replacement therapy or in allergic reaction. This is also the case for blood transfusion for Dextran and Albumin or FFP as well as in adverse circumstances.

For Bram Porcwerg et al (2017) the use of fluids in sepsis and septic shock (FISSH) can only be assessed through randomized, concealed, blinded, parallel group multicentre pilot trial resulted into critically ill patients with septic shock which he defined as on-going hypotension despite using 1 litre of fluid, or a serum lactate >4 mmol/litre, who are within 6hours of hospital presentation or rapid response team activation. The primary outcome of this trial must be based on feasibility assessment by consent then rate the recruitment success and protocol adherence. This pilot trial will measure the feasibility of conducting the main trial which will examine the effect of high versus low chloride fluid in patients with septic shock on patients. This study should include patients around 16 years of age and required fluid resuscitation for refractory hypotension, systolic of 90 mm/hg, mean arterial pressure MAP 65 mm/hg after 1 litre bolus over 1hour or organ perfusion serum Lactate of 4 mmol/l, within 6 hours. Or it could be done by a critical care team consultation and admitted to an eligible patient. The researcher will use the web based system www.randomize.net to randomize patients. Patients will undergo concealed randomization stratified by centre in a 1:1 schedule to either the lower chloride fluids or higher chloride groups .The web based systems will generate email alerts to the local research to pharmacist and the blood bank information regarding patient allocation. The pharmacist and transfusion specialist with then ensure the patient receives the assigned study fluid. Enrolled patients will be allocated to either a high or low chloride fluid strategy. Within the allocation, a clinician may order crystalloids or albumin with chloride content which must be compared to their allocated arm. The allocated fluid will be administered immediately after randomization, continued until discharge from the ICU, death or until 30 days after enrolment, whichever comes first. Patient will receive the fluid type for both resuscitation and maintenance infusions.

As most clinicians use crystalloids as the initial resuscitation fluid in patients with septic shock, saline of 0.9%will be used as crystalloids for those randomized to high chloride (chloride concentrate 154 mmol/l) while Ringers Lactate will be used as crystalloid with low Chlorine (Chlorine concentration of 110mmol/litre).Plasbumin 5%will be used as low chloride albumin and Octabulin 5%used as high chloride albumin. The blood bank at each centre will receive a list of enrolled patients and their allocation and this list is updated when a new patient is enrolled. Analysis of three feasibility outcomes may be done without necessarily paying attention to the groupings. Ap value of 0.05 will be considered statistically significant for all outcomes. The question of whether chloride concentration in saline and balanced crystalloids affects the treatment of sepsis has also been the subject of several studies. Using the Stewart physiochemical approach invented by Stewart (1983) suggests that an increase in chloride increases metabolic acidosis affects patient outcome. However Semler and Rice argue that it has not been established how exactly it affects patients.

The expected outcome should be in line with the current evidence which suggests that albumin and crystalloids but not starches represent reasonable choices for fluid resuscitation in sepsis. FISSH protocol reflects a design that is novel yet practical, overcoming the applicability limitation of prior trials by allowing physicians to prescribe either crystalloids or colloids in the critical care unit, they perceive in clinically indicated.

Crystalloids remain the first in line sepsis resuscitation fluid because they are widely available, inexpensive, and have not been shown to result in worse outcomes. The question of whether balanced crystalloids result in better organ function is still a matter of on-going trials. Despite extensive study, the effect of albumin solution on sepsis outcome remains unclear. Hydroxyethyl starch is the only semisynthetic colloid robustly studied in sepsis and increasing the incidence of acute kidney injury and potentially mortality. On-going research on the endothelial glycocalyx balanced crystalloids and early albumin administration hold the potential to further improve sepsis survival.

However, it is a well-established fact that albumin solutions tend to increase chances of death by close to 10% (Cochrane Injuries Group Albumin Reviewers 1998).Yet it is the most preferred of all colloids as its effects are not as harsh and extreme as, dextran would for example be (Delaney et al 2011).

It is fallacious though to demonize colloids as being entirely grim and dangerous and thus fair to give credit that some colloids at certain concentrations would in fact give a much desired outcome Avila et al (2016). Delaney et al (2011) conducted trials on the use of albumin solution at certain diverse concentrations, his expected outcome, albeit ironical and sarcastic, was to measure whether death would arise a direct result of the use of colloids. His experiment was to be done on 383 patients who were induced with albumin solutions of >20% concentration over eight studies. He further used albumin solutions of a concentration ranging between 4% -5% in nine studies on 1,594 subjects. The result was remarkably fulfilling as he found that whenever concentrated colloids are used over dilute colloids there is a higher chance of survival of patients suffering from severe sepsis or septic shock. However, Delaney’s experiment is in relation to only albumin solutions and not any other colloid hence we cannot conclusively say that all colloids will register a similar result.

Rivers et al (2014) also invented the Albumin Italian Outcome Sepsis (ALBIOS) trial whose intention was to measure the effect of an albumin solution compared to a crystalloid. The ALBIOS trial used an albumin solution of 20% concentration and a crystalloid which was not specified with a goal to observe the level of deaths within 28 days. Remarkably, albumin solutions recorded lesser deaths at 31.8% over 32% of crystalloid deaths. At 90 days the albumin solution recorded 41.1% over 43.6% deaths in the patients administered with crystalloid solutions (RR 0.94; 95% CI, 0.85–1.05; P= 0.29).

Perhaps a very recent research would cement arguments made for colloid solutions. Lewis et al (2018) conducted searches on medical literature available online on the preference and performance measurements between colloids and crystalloids. The research identified 69 studies covering a whopping 30,020 patients in critical conditions administered with all manner of fluids from sides of the isle. The outcomes in deed amplifies the results of the studies done by Delaney et al (2011) and Rivers et al (2014) that colloids are slightly better performers than crystalloids. However, they recognized that when starch is used it may cause, as Sharon et al has illustrated, the need to have renal replacement therapy or additionally cause allergic reactions unlike any other crystalloid. This however does not mean that patients administered with colloids are susceptible to allergic reactions.

These studies tend to illustrate that every form of fluid within the general class of colloids may have different results and impact on patients and different levels of illness. However, there is an alarming lack of individual studies done on the existing types of fluids which would perhaps offer a better and more certain conclusion. The whole issue of cost of colloids has perhaps fuelled the lack of investment in research and studies on colloids. Dellinger et al 20110 as well as Semler and Rice have recommended that albumin solution be used more often in the like manner in which crystalloids have been used.

TYPES OF CRYSTALLOIDS

As the debate of preference is well settled in a superficial level, the debate continues to develop within the crystalloid fluid choices. The investment, as in the previous case is also not remarkable and may offer, slightly different, if not the same level of insight.

Zhou et al (2014) studied using the acute kidney injury method the import of using NS, non-balanced crystalloid, versus PlasmaLyte, balanced crystalloid, on patients but conducted the trials on rats. They found that when NS fluids are used they resulted into accelerated deaths compared to the use in other balanced crystalloids (83% vs. 28%, p <.001). They also discovered that damage to the renal blood vessels were more prevalent and arose when NS fluids are used over PlasmoLyte hence resulting to severe pain and death. Important to note is that even though this test was conducted on animals rather than human beings, the result has not been different from records retrieved from New Zealand ICUs. In deed all patients administered with NS fluids for resuscitation died even though this has been attributed to the incompetence of doctors for failing to sort out the most suitable candidates for the administration of these fluids (Avila et al 2016).

However, Avila et al reports that based on several studies done on 18,916 patients in 14 randomized controlled trials balanced crystalloids recorded low mortality rate in comparison with normal saline. And still reverting to the original debate of colloids versus crystalloids, balanced crystalloids had similar outcomes with albumin colloids. Hence they conclude that based on numerous studies done; there is better performance when balanced crystalloids are used over NS crystalloid.

This literature review by Avila et al is cemented by the study done by Shaw et al (2012) which concluded on better performance when balanced crystalloid is used over non-balanced crystalloid such as NS when used during surgery. Shaw et al recorded acute organ dysfunction such as respiratory and cardiac arrests within a day after surgery with potential cases of re-admission of patients after release from hospital. In the research, approximately 30,994 patients were administered with a non-balanced crystalloid during operation while 926 patients were administered with a balanced crystalloid. This study may be criticized for the lack of proper balance in terms of the scale of the study especially for lack of an even number when using balanced crystalloid. However, it may be argued for that if the opposite were true then near all fatalities would have been experienced when balanced crystalloids are used.

The Best Practice for Use of Fluids after Resuscitation

It is settled and recognized by scientists that fluid management is not standard in all circumstances and levels of treatment on patients with sepsis. However, Semler and Rice (2016) acknowledge lack of any concern to research on the best practice in managing the proper fluids to be used after resuscitation thus preventing a catastrophic failure. It is for that reason that for our 51 year old female example the doctors downed their tools upon resuscitation only for her fluid response to turn catastrophic. Semler and Rice (2016), agreeably submit that most patients are perceived to suffer death eventually even after fluid resuscitation hence the apparent lack of concern.

Dellinger et al (2013) in issuing the Surviving Septic Campaign (SSC) guidelines recommended several things to be done to patients depending on their conditions and reactions after resuscitation. Immediately after resuscitation is achieved Dellinger et al recommended continued fluid bolus challenge so long it was clear that the patient’s haemodynamic improved. For a balanced arterial pressure to be retained at ≥ 65 mm Hg, the initial vasopressor recommended should be norepinephrine. They recommended conservative fluid strategy in general but opined that there should be reduced sedation of patients. However, the patients should be fed with IV glucose within 2 days of resuscitation or oral administration of food but not injections directly into the blood circulatory system.

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Although this conservative approach is largely untested, it appears to be the only hallmark as other methods and trials such as the Sepsis Occurrence in Acutely Ill Patients (SOAP) research suggested that in every fluid balance achieved after resuscitation there was in increased mortality rate for 1,177 patients involved (Vincent et al 2006). However Semler and Rice (2016) report that other methods such as the Fluid and Catheter Treatment Trial (FACTT) have demonstrated controlled fluid management for patients suffering from acute respiratory distress syndrome. In conclusion, the area remains murky and unchartered with need of urgent research to reduce the stigmatisation that resuscitated patients mostly never recover fully.

CONCLUSION

It appears that the confusion that exists with regard to the choice of fluids to be used for resuscitation is caused by the lack of investment in research and studies. As Avila et al (2016) argues, there is need to increase studies and randomized controlled trials in large scale. Moreover, the presumption and preference of crystalloids should be discouraged and instead RCTs conducted on the specific fluids over both classes of colloids and crystalloids. This will enable the appreciation of specific colloid fluids that are actually more beneficial than some crystalloids such as PlasmaLytes. Eventually even if resuscitation is achieved, the management of the aftermath is still grim as there has been no investment in fluid management research after resuscitation; save for the existing SSC guidelines.

REFERENCES

  • Avila, A. A., Kinberg, E. C., Sherwin, N. K., & Taylor, R. D. (2016). The Use of Fluids in Sepsis. Cureus, 8(3), e528. doi:10.7759/cureus.528
  • Cohen, J., Vincent, L., Adhikari, K., Machado, R., Angus, D., Calandra, T., Jaton, K., Giulieri, S., Delaloye, J., Tracey, K., Opal, S., Poll, T., Pelfrene, E. (2015) Sepsis: a roadmap for future research. Lancet Infect Dis
  • Delaney, A.P., Dan, A., McCaffrey, J., & Finfer, S. (2011). The role of albumin as a resuscitation fluid for patients with sepsis: a systematic review and meta-analysis. Crit Care Med. Retrieved December, 31, 2019 from https://www.ncbi.nlm.nih.gov/pubmed/21248514
  • Dellinger, R.P., Levy, M.M., Rhodes, A., Annane, D., Gerlach, H., Opal, S.M., … Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup. (2013). Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. Retrieved January, 1, 2020 from https://www.ncbi.nlm.nih.gov/pubmed/23353941/
  • Lewis, S. R., Pritchard, M. W., Evans, D. J. W., Butler, A. R., Alderson, P., Smith, A. F., Roberts, I. (2018). Colloids or Crystalloids for Fluid Replacement in Critically People, Retrieved from Cochrane Library website: https://www.cochrane.org/CD000567/INJ_colloids-or-crystalloids-fluid-replacement-critically-people
  • Mayr, F., Yende, S., Angus, D. (2014) Epidemiology of Severe sepsis. Virulence
  • Semler, M. W., & Rice, T. W. (2016). Sepsis Resuscitation: Fluid Choice and Dose. Clinics in chest medicine, 37(2), 241–250. doi:10.1016/j.ccm.2016.01.007
  • Sharon, E., Chen, S., Khosla, M., Smith, J., Pritchard, J., Fraser, B (2018) Functional Genetic Varians Revealed by Massively Parallel Precise Genome Editing. Cell
  • Shaw, A.D., Bagshaw, S.M., Goldstein, S.L. Scherer, L.A., Duan, M., Schermer, C.R., & Kellum, J.A. (2012). Major complications, mortality, and resource utilization after open abdominal surgery: 0.9% saline compared to Plasma-Lyte. Ann Surg Retrieved December, 31, 2019 from https://www.ncbi.nlm.nih.gov/pubmed/22470070
  • Vincent, J.L., Sakr, Y., Sprung, C.L., Ranieri, V.M., Reinhart, K., Gerlach, H., … Sepsis Occurrence in Acutely Ill Patients Investigators. (2006).Sepsis in European intensive care units: results of the SOAP study. Crit Care Med. Retrieved January, 1, 2019 from https://www.ncbi.nlm.nih.gov/pubmed/16424713/
  • Zhou, F., Peng, Z.Y., Bishop, J.V., Cove, M.E., Singbartl, K., & Kellum, J.A. (2014). Effects of fluid resuscitation with 0.9% saline versus a balanced electrolyte solution on acute kidney injury in a rat model of sepsis. Crit Care Med. Retrieved December, 31, 2019 from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4143135/

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