Background
Major surgery presents an important threat to internal homeostasis of fluid and electrolytes, partly due to the volume depleting effects of haemorrhage, evaporative loss and pre-operative dehydration, or by excessive fluid administration causing oedema and organ dysfunction. Intravenous fluid solutions used for resuscitation and maintenance purposes should support the circulation adequately to replace missing plasma, whilst avoiding metabolic disturbance or other adverse effects. Modern perioperative fluid management is based on the principle that, as an intervention with risks and benefits, fluids should only be provided to affect a meaningful clinical variable. This principle influences decisions made for monitoring requirements, timing of administration, volume dosing of fluids and the type of fluids provided to patients.
Intravenous fluids, whether crystalloid or colloid, can be categorised as buffered or non-buffered. Hartmann’s fluid formulation more closely matches the constituents of human plasma than 0.9% saline, containing a physiological buffer that helps to maintain acid-base balance. The composition of Hartmann’s fluid also includes additional electrolytes found in plasma, including potassium, magnesium and calcium. Provision of buffered crystalloid fluids may have benefits over 0.9% saline, in which the electrolyte composition is significantly different to the plasma that it is intended to replace.
The primary objective of this systematic review is to investigate the clinical effects of perioperative administration of buffered fluids, such as Hartmann’s solution, when compared with non-buffered fluids administered during all types of surgery.
Discussion
The effects of intravenous fluid on clinical outcomes is a topic of major interest, which has been thoroughly explored in critical care patients but remains controversial in the peri-operative setting. This systematic review provides a comprehensive analysis of current data, demonstrating a paucity of high-quality trials with relevant patient-centred outcomes. It is surprising that the randomised controlled trial data available for meta-analysis is so small, relative to the millions of patients that receiving intravenous fluids during surgery each year. Our data shows that for three studies including 267 patients, the choice of perioperative fluid, either buffered or unbuffered did not result in a significant difference in mortality. The GRADE evidence for this outcome was rated as low. The overall combined mortality from these studies was low at 2%.
The analysis of secondary outcome measures from 18 different RCTs of 1096 participants suggests that intravenous fluids containing a physiological buffer are a safe alternative to saline-based fluids for adult patients undergoing surgery. We found limited evidence on the effects of fluid therapies on postoperative organ dysfunction, particularly on renal failure. For patients not undergoing renal transplantation, there were no differences in terms of renal insufficiency or surrogate markers of renal dysfunction (urine output and serum creatinine). However, there were differences in metabolic variables in post-operative pH, chloride concentration, base-deficits and serum bicarbonate, without significant changes in other electrolytes such as serum potassium and sodium concentrations. High serum chloride is a cause of metabolic acidosis and may explain our findings of both lower pH and lower partial pressure of arterial carbon dioxide (PaCO2) (secondary to respiratory compensation for metabolic acidosis) when non-buffered fluids were used. We rated GRADE evidence for these secondary outcomes as low-moderate quality.
This review focused on the type of perioperative fluid administration. Evidence from studies investigating the volume of fluid and haemodynamic monitoring suggest that decisions regarding perioperative fluid strategy can influence outcome after surgery. Hence, it is not just the type of fluid that is important, but exactly how the fluid is administered, in terms of volume and timing. Protocols for fluid administration in the included studies in this review were seldom available. Studies of goal-directed fluid therapy offer supportive evidence for reduced morbidity and length of hospital stay (Pearse et al.
2014), but poor evidence for reductions in mortality (Calvo-Vecino et al.
2018). Excessive volumes of fluid administration have been associated with harm, such as pulmonary complications and tissue oedema. However, the current trend for conservative fluid administration, as advocated in many perioperative enhanced recovery pathways, has also been recently disputed a major trial measuring an increased proportion of acute kidney injury in patients who received a zero fluid balance regimen in the perioperative period (Myles et al.
2018). In the face of conflicting evidence, getting the fluid strategy right is not easy. However, it is becoming clear that an inflexible, “one size fits all” approach when planning perioperative fluid management may not be the best approach, and a strategy that has been individualised to each patient may be more appropriate with many variable factors taken into consideration. This is reflected in fluid management consensus statements such as the recent American Society of Enhanced Recovery and Perioperative Quality Initiative (POQI) joint statement that advocates an individualised approach to fluid management, taking into account patient-specific variables (Thiele et al.
2016).
In addition to haemodynamic optimisation and total volume dosing, fluid electrolyte composition is also important to consider. Perceived advantages of balanced crystalloid solutions over non-buffered solutions are reflected in the British Consensus Guidelines on Intravenous Fluid Therapy for Adult Surgical Patients (GIFTASUP) (Powell-Tuck et al.
2011) that recommend the use of balanced solutions for crystalloid fluid resuscitation or replacement.
Our findings are consistent with a recent systematic review and meta-analysis, which included studies from ICU patients and demonstrated no difference in the outcomes of hospital mortality, the occurrence of acute kidney injury or need for renal replacement therapy with balanced intravenous fluid resuscitation (Neto et al.
2017). A large single centre, pragmatic, crossover trial comparing lactated Ringer’s solution or Plasma-Lyte A with saline in emergency admissions of non-critically ill adults was published recently. This study, whilst not exclusively conducted in peri-operative patients, included about 20% of general surgical patients and concluded that there was no significant between-group difference in mortality or hospital-free days at day 28. However, the incidence of major adverse kidney events, within 30 days, was lower with balanced fluids (4.7%), compared with saline (5.6%) (Self et al.
2018). A similar trial design was adopted by a multi-centre study of > 15,000 critically ill patients comparing saline with buffered crystalloids (lactated Ringer’s solution or Plasma-Lyte A) that reported a reduction of 1.1% in the composite primary outcome of major adverse kidney events within 30 days (Semler et al.
2018). In both of these studies, the primary outcome of major adverse kidney event within 30 days was defined as a composite of death, new-renal replacement therapy or persistent renal dysfunction (final serum creatinine concentration of > 200% of the baseline). Whilst these large pragmatic studies are highly informative, they were open-label trials reporting a composite outcome, which can be associated with potential caveats of multiple sources of bias and are not specific to surgical patients.
A further, recent study was published subsequent to the search strategy for this review and is therefore not included in the meta-analysis. This double-blind randomised trial of saline versus balanced crystalloid for goal-directed perioperative fluid therapy in major abdominal surgery patients was terminated for safety reasons after recruiting 60 patients of a planned sample size of 240 (Pfortmueller et al.
2018). Patients in the saline group developed hyperchloraemic metabolic acidosis, but also a dose-dependent increase in vasopressor requirements, despite no difference in total in total perioperative fluid volumes. This study signals a serious measure of harm, albeit in an underpowered study format, for perioperative saline administration.
Whilst we used an inclusive search strategy and eligibility criteria to maximise identification of relevant studies, this meant that there was considerable clinical heterogeneity in participant characteristics, types of surgery and protocols for administering fluids in the trials. Some RCTs involved minor surgery in otherwise healthy patients (Chin et al.
2006), whilst others analysed outcomes after very major surgery in high-risk patient groups (Wilkes et al.
2001; Waters et al.
2001). This is important because both the baseline values and tolerance of the magnitude of homeostatic derangement will vary with patient organ function, meaning that a single recommendation cannot be generalised to the whole patient population. For example, an observation that fluid choice influences renal failure in patients with pre-existing severe renal dysfunction is unlikely to be applicable to patients with normal glomerular filtration rates. Subgroup analysis and reporting of multiple secondary outcomes was conducted in order to clarify the results from pooled data. Only trials included adult perioperative patients were included, hence conclusions cannot be directly drawn for paediatric or medically unwell patients from this meta-analysis. Whilst statistical heterogeneity for our primary outcome of mortality was very low (
I2 = 0), many of our secondary outcomes displayed substantially greater statistical heterogeneity.
Some trial data did not contribute to our analyses because they were reported in weight-based units rather than in absolute amounts. We attempted to contact trial authors to obtain individual participant data, but we were not always successful in these attempts.
This review identified small numbers of patients and low numbers of events across outcomes of interest, including the primary outcome of mortality. Alongside this several of the studies were poorly reported and at high or unclear risk of bias. Where relevant, the consequent downgrading of the quality of evidence reduces the confidence in reported effects in pooled data.
Although there are a substantial number of studies in this systematic review, no single, large pragmatic and appropriately blinded randomised controlled trial was identified with sufficient power to detect important differences in clinical outcomes arising from the choice of perioperative fluid. In particular, acute kidney injury should be considered as an important and patient-relevant outcome measure. The SOLAR fluid trial, a large study of saline versus Ringer’s lactate that is assessing major postoperative complications as its primary outcome measure, is currently ongoing and expected to be completed in 2022 (SOLAR trial
2017).
Buffered and non-buffered fluids have predictable effects on post-operative biochemical parameters in surgical patients, are appropriate for fluid replacement and should be considered especially for patients with, or at risk of, metabolic derangement. No complications or adverse effects specific to buffered fluids were identified in surgical patients with a range of co-morbidities and organ dysfunction.
Additional studies are needed, including well designed and adequately powered randomised controlled trials to detect differences in clinical outcomes arising from the physician’s choice of perioperative fluid. Such studies should include meaningful patient-centred outcomes such as mortality, quality of recovery, length of hospital stay, and organ dysfunction (including acute kidney injury) and quality of life measures such as postoperative pain.
Acknowledgements
This review is an abridged version of a Cochrane Review previously published in the Cochrane Database of Systematic Reviews 2017, Issue 09, Art. No. CD004089, DOI: 10oO.1002/14651858.CD004089.pub3. (see
www.thecochranelibrary.com for information). Cochrane Reviews are regularly updated as new evidence emerge and in response to feedback, and Cochrane Database of Systematic Reviews should be consulted for the most recent version of the review.
We would like to thank the Cochrane Review group—Anaesthesia, Critical, and Emergency Care (ACE)—for their support in publishing the Cochrane review. In particular, we would like to thank Jane Cracknell (Managing Editor) for her help and editorial advice during the preparation of the protocol and review.
Sohail Bampoe is supported by an award from the National Institute for Health Research University College London Hospitals Biomedical Research Centre.