Electrolyte and Acid–Base Disturbances in Emergency High-Risk Abdominal Surgery, a Retrospective Study

Patients undergoing emergency high-risk abdominal surgery potentially suffer from both systemic dehydration and hypovolaemia. Data on the prevalence and clinical impact of electrolyte disturbances in this patient group, specifically the differences in patients with intestinal obstruction (IO) versus perforated viscus (PV) are lacking. Adult patients undergoing emergency high-risk abdominal surgery in a standardized perioperative pathway were included in this retrospective single-center cohort study. Electrolytes and arterial blood gas analysis were measured during the early perioperative period. Prevalence and clinical impact of electrolyte disturbances were assessed. A total of 354 patients were included in the study. Preoperative alkalemia dominated preoperatively, significantly more prevalent in IO (45 vs. 32%, p < .001), while acidosis was most pronounced postoperatively in PV (49 vs. 28%, p < .0001). Preoperative hypochloraemia and hypokalemia were more frequent in the IO (34 vs. 20% and 37 vs. 25%, respectively). Hyponatremia was highly prevalent in both IO and PV. Pre- and postoperative hypochloremia were independently associated with 30-day postoperative morbidity and mortality in patients with IO (OR 2.87 (1.35, 6.23) p = 0.006, OR 6.86 (1.71, 32.2) p = 0.009, respectively). Hypochloremic patients presented with reduced long-term survival as compared with the normo- and hyperchloremic patients (p < 0.05). Neither plasma sodium nor potassium showed a significant association with outcome. These observations suggest that acute high-risk abdominal patients have frequent preoperative alkalosis shifting to postoperative acidosis. Both pre- and postoperative hypochloremia were independently associated with both impaired short- and long-term outcome in patients with intestinal obstruction, with potential implications for the choice of resuscitations fluids.


Introduction
Intravenous fluid therapy is one of the most frequent interventions in critically ill patients [1]. All high-risk surgical patients are given intravenous fluid therapy [2] and abnormalities in acid-based homeostasis and electrolytes are common but insufficiently described.
Patients undergoing emergency high-risk abdominal surgery due to e.g. intestinal obstruction (IO) or perforated viscus (PV) potentially suffer from systemic dehydration due to inadequate fluid intake, vomiting, pathological vasodilation with subsequent hypotension and preload dependency, and increased capillary permeability secondary to inflammation [3,4].
Acute intestinal dysfunction resulting in malabsorption of macronutrients and/or water and electrolytes is almost universal in these patients, leading to a requirement for intravenous fluid and electrolyte supplementation [5]. This condition is accompanied by both septic and metabolic complications as well as electrolyte shifts.
Further possible mechanisms for electrolyte disturbances include reduced kidney perfusion due to hypovolemia or hypotension; activation of hormonal systems such as renin-angiotensin-aldosterone system and vasopressin; and tubular dysfunction caused by ischemic or nephrotoxic kidney damage [6].
Sodium and chloride are the main ions of solutions used for volume expansion in critically ill and surgical patients. Due to the administration of large volumes of normal saline and/or a decreased urinary output, iatrogenic electrolyte disorders such as hyperchloremic acidosis or dysnatremia are common abnormalities in the clinical practice [7] and appear to be associated with worse outcome [8][9][10]. This has led to a shift towards hypochloraemic fluids (balanced solutions) in perioperative care, but the impact of these on the outcome is controversial, and their optimal use in the care of emergency abdominal surgery has not been established.
As such, detailed descriptive data on the prevalence and clinical impact of electrolyte disturbances in patients undergoing emergency high-risk abdominal surgery are lacking [11]. This study aimed to assess the prevalence of electrolyte and acid-base disturbances and the associations with postoperative outcome in patients undergoing emergency high-risk abdominal surgery, treated within a standardized pathway, specifically focusing on potential differences in patients with IO versus PV.

Design, settings, patients
This was a planned sub-study of the principal trial [12] approved by the Danish Data Protection Agency (HVH-2013-014/052), though not addressed in the original study. In consensus with Danish law, The Regional Committee on Health Research Ethics waived the requirement for informed patient consent (H-19011165). The manuscript followed the Strengthening The Reporting of Observational Studies in Epidemiology (STROBE) statement.
Primary outcome was the incidence of electrolyte disturbances in patients undergoing emergency high-risk abdominal surgery. Secondary outcomes were postoperative 30-day mortality and postoperative complications, as well as ICU stay. Exposure variables included were age, ASA, functional performance, cardiac, pulmonary, and renal comorbidities, serum electrolyte levels, fluids administered.
Data were obtained from the electronic patient record and documented using a standard report formula. There was a 100% follow-up on mortality through the Danish Civil Registration System. We evaluated patients undergoing emergency surgery due to suspicion of abdominal pathology from 1 June 2013 to 21 February 2015 (Fig. 1).
Adults (aged 18 years and over) undergoing emergency high-risk abdominal surgery for following abdominal pathologies were included in the study: perforated viscus, intestinal obstruction, emergency re-operation after elective surgery including: anastomotic leak, postoperative perforated viscus owing to other than anastomotic leak and postoperative intestinal obstruction.
Intestinal ischemia, abdominal bleeding were excluded. Patients with missing data on fluid administration, vasopressor and inotropes administration, plasma electrolyte levels; as well as patients transferred to another hospital immediately following surgery were also excluded. Patients where the surgical treatment was considered futile upon the incision were also excluded. Disseminated cancer was not an exclusion criteria.

Perioperative management
At this surgical center, a multimodal standardized protocol [12] was applied to patients undergoing emergency highrisk abdominal surgery with focus on fast track surgery. The protocol, described in detail elsewhere [12], included perioperative stroke volume guided fluid-and hemodynamic management for anesthesia and followed present NELA recommendations [3] during surgery and for the first 24 h after surgery, including neuraxial analgesia unless contraindicated and anesthesia.
The electronic medical records of enrolled patients were reviewed, and pre-, intra-, and postoperative data were collected, including demographics; comorbidities; postoperative complications; intraoperative hemodynamics and hemodynamic therapy; surgery characteristics; pre-and postoperative blood analysis, postoperative defined as drawn up to 2 h after the end of surgery. Fluid administration and fluid output were registered through anesthesia charts and postoperative PACU charts. Postoperative complications and death were defined according to Clavien Dindo (CD) Classifications [13], where major complications were defined as CD [ II.

Fluid administration
The preoperative resuscitation fluid amount constitutes a part of the intraoperative fluid balance and fluid administration. Intraoperative fluid balance and fluid balance for up to 24 h postoperatively were calculated as the total fluid input (volume of colloids, crystalloids, transfusions) minus fluid output (urine output, fluid from drains and gastric aspiration). Intra-and postoperative fluid balances were calculated in 6-h intervals, maximal for 24 h after surgery.
Selection of plasma sodium, potassium, chloride and lactate cut-offs Patients were divided into groups based on admission plasma sodium, potassium and chloride concentrations for analysis. The normal range for plasma sodium, potassium and chloride in our laboratory is 137-144 mmol/L and 3, 5-4, 4 mmol/L and 98-106 mmol/L, respectively, and were chosen as the initial cut-off points.
All patients with admission values above the normal range were classified as having hyper-natremia, -kalemia and -chloremia, respectively, while patients under the normal range were classified as having hypo-natremia, -kalemia and -chloremia, respectively. Hyperlactatemia was defined as lactate [ 2.1 mmol/L.

Statistics
Statistical analysis was performed using R Statistical Software. Patients were classified into hypo-normo-and hyper-condition as previously described, based on their baseline levels. Continuous variables were presented as means ± standard deviation or median (interquartile range), categorical variables as numbers and percentages. T-test was applied in comparison of normally distributed data, and Mann-Whitney for non-normally distributed data. For categorical variables, a Chi-square test was used.
Logistic regression was used to test for association of chloride, potassium and sodium parameters with postoperative outcome.
Univariate logistic regression was used to test for unadjusted association between chloride/sodium/potassium and outcome. Multivariate logistic regression was used to test for association between chloride/sodium/potassium and outcome after adjusting for potential confounders. Independent variables from univariate models were incorporated as covariates in the multivariate regression model.

Results
During the inclusion period, 600 patients underwent emergency high-risk abdominal surgery. Three-hundred and fifty-four (354) patients were included in the analysis, 192 patients with intestinal obstruction (IO) and 162 patients with perforated viscus (PV) (Fig. 1).
Patient demographics are presented in Table 1.

Comparison of electrolyte levels and acid-base status in patients with intestinal obstruction and perforated viscus
Patients with PV were significantly more acidotic before and after the surgery (p \ 0.0001), while patients with IO presented with more prevalent alkalemia compared to PV (p = 0.0007) but normalizing postoperatively. Furthermore, there was an increase in proportion of acidemia in both cohorts pre-to postoperatively, most pronounced in patients with PV (Fig. 2). Patients with PV received a significantly larger amount of hypochloremic fluids, both pre-and postoperatively (p = 0.007 and p = 0.037, respectively). Patients with IO had a higher incidence of hypochloraemia and hypokalemia preoperatively, whereas a higher proportion of patients with PV presented with preoperative hyponatremia (Fig. 2). In total, preoperative hypochloremia was observed in 99 patients (28%) of the cohort, while 88 patients (25%) were hyperchloremic. Preoperative hypochloremia was significantly more frequent in those with IO (p = 0.002). Preoperative hyponatremia was prevalent in 57% of the overall cohort, with 52% in the OI, and 64% of those with PV (p = 0.016). A significantly higher number of hypokalemic patients was also seen in the intestinal obstruction cohort, both prior and after surgery (p = 0.013 and p = 0.002, respectively).
Adjusted for age, gender, ASA, physical performance, co-morbid disease, sepsis and fluids administered, pre-as well as postoperative hypochloremia was significantly associated with day-30 postoperative major complications, including death in patients with IO, OR 2.87 (1.35, 6.23) p = 0.006 and OR 6.86 (1.71, 32.2) p = 0.009, respectively (Appendix 1). This was not seen in patients with PV. Neither plasma sodium nor potassium changes were associated with 30-day complications.
Again, after adjusting for confounders, preoperative hypochloremia was associated with postoperative major complications, specifically pulmonary complications (adjusted OR 1.25 95% CI [1.05, 2.60], p = 0.035) in patients with IO. No association was found in patients with PV.
Hypochloremic patients presented with reduced longterm survival as compared with the normo-and hyperchloremic patients, with postoperative hypochloremia having the most pronounced association (Fig. 3).

Discussion
In this retrospective analysis of 354 patients undergoing emergency high-risk abdominal surgery, perioperative electrolyte derangement was frequent, with a high incidence of hyponatremia and hypochloremia. We found significant associations between pre-and postoperative hypochloremia and both overall morbidity and short-and long-term morbidity in patients with intestinal obstruction, which was not found in patients with perforated viscus. Neither sodium nor potassium derangement had a statistically significant impact on postoperative outcome. Data from a recent prospective observational investigation demonstrate that temporary hyperchloremia may occur in 75% of ICU patients during the first 24 h of ICU stay [14]. However, despite a rather high prevalence in critically ill patients, few outcome-related data regarding systemic chloride levels exist. The available data suggest that increased disease severity may be associated with abnormal chloride levels, however, in various cohort studies, discrepant results exist [14][15][16][17]. Our findings seem to coincide with several negative retrospective cohorts assessing the role of hyperchloremia in critically ill patients [18][19][20][21], where no association with outcome was found.
Although chloride is one of the major electrolytes, it is not measured routinely in daily practice and optimal management of hypochloremia is inadequately understood in critically ill surgical patients [22]. Emerging evidence shows that low chloride levels affect the outcome in heart failure patients [23,24]. Furthermore, several studies have found hypochloremia associated with impaired outcome in critically ill patients [22,25].
In patients with IO, we found a higher degree of electrolyte imbalances than in those with PV, specifically hypokalemia and hypochloremia. Almost 35% of patients with IO presented with preoperative hypochloremia versus 24% of the patients with PV (p = 0.002). The manifestations of IO and its degree of severity generally depend on the site of obstruction [26], however, both obstructive and paralytic ileus are associated with profound effects on body fluid balance. Accumulation of fluids and gases drives elevated intraluminal pressure and inflammation, microcirculatory dysfunction of the bowel wall and disruption of the mucosal barrier results leading to fluid sequestration into the intestinal wall lumen, potentially accounting for several liters of fluid and promoting hypovolemia and electrolyte derangement [27,28]. It could be argued that patients with PV all have a degree of IO, either an obstruction as the underlying cause of perforation or paralysis of the intestines as a result of inflammation and stress, partly explaining the preoperative electrolyte Metabolic alkalosis, as was seen to be prevalent in the preoperative phase in patients with IO, could be caused by both hypochloremia and hypokalemia especially in patients who lose high quantities of chloride-rich fluids [29] both via inadequate renal Cl-reabsorption or via dilution following infusion of hypotonic fluids [30,31]. Loss of chloride is further aggravated by surgical stress and adrenal hormone unbalance.
As the current study is a retrospective observational study, the cause of hypochloremia was not ascertained.
Future prospective studies focusing on the preoperative loss of chloride, as well as the postoperative adrenal function and inflammatory response, should be conducted to refute or confirm these considerations. In this context, a recently published retrospective study did find a statistically significant positive correlation between fluid balance and inflammation in patients with OI, as well as an association between high pre-and postoperative C-reactive protein and a high positive fluid balance with worse outcome in patients with IO, but not in patients with PV [32].
Linear regression models found an association between preoperative hypochloremia and the amount of fluid administrated during the observational period in patients with IO. The severity of hypochloremia could be indicative of the severity of the IO and the associated degree of dehydration and potential hypovolaemia, explaining the association between preoperative hypochloremia and postoperative major complications. As such, the potential iatrogenic fluid overload as a result of treatment of hypovolemia with hypochloremic fluids could promote postoperative complications, however we cannot dispute that the initial hypovolemia led to adverse outcomes. Buffered intravenous fluids do indeed reduce the incidence of hyperchloremia and metabolic acidosis [33,34], however, the question remains if normal saline has a more advantageous position when treating patients with IO. This is the first analysis describing electrolyte derangement and the potential role of hypochloremia on the outcome of patients undergoing emergency high-risk abdominal surgery. However, this is a retrospective cohort, thus prone to selection bias but also potentially limiting the study due to the relevance of the data. Nonetheless, the theoretical foundation for and the practice of perioperative management including goal-directed therapy for this patient population is unchanged, as is seen in recent large trials like OPTIMIZE II [35] and ongoing FLO-ELA trial [36], and the protocolized treatment of the patients in this study followed the current NELA criteria [3].
The patients were classified as hypo-, normo-and hyperchloremic according to our hospital laboratory reference. There are no clearly established cutoff values, with hypochloremia defined as levels below 96-101 mmol/L, and hyperchloremia higher than 106-111 mmol/L [37], depending on the laboratory. Some studies showed an independent effect of hypochloremia defined as below 100 mmol/L, on cardiovascular, non-cardiovascular, and all-cause mortality [38][39][40]. Also, we analyzed only change in chloride level pre-to immediate postoperatively and data cannot be extrapolated beyond that.
We should note that this study is a hypothesis-generating, indicating the need for future prospective research, assessing the preoperative cause of hypochloremia and the mechanisms of its association with worse outcome. Our results showed the association (not causality) of hypochloremia and higher mortality.
Perioperative hypochloremia may have clinical importance as an indicator of prognosis in patients undergoing emergency high-risk abdominal surgery, with a significant association with morbidity in patients who have IO. Further studies should examine the pathophysiological similarities and more important, the differences in patients with IO and PV, as well as potential effects of different resuscitation strategies for acute fluid and electrolyte disturbances in emergency abdominal surgery. 0.008 *adjusted for age, gender, ASA, physical performance, co-morbid disease, sepsis, fluid administration (total input and total balance, respectively)

Declarations
Conflict of interest The authors declare that they have no competing interests.
Ethical approval In consensus with Danish law, The Regional Committee on Health Research Ethics waived the requirement for informed patient consent.
Consent for publication Not applicable.